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Sample records for genome-wide transcriptome analyses

  1. Transcriptome sequencing and genome-wide association analyses reveal lysosomal function and actin cytoskeleton remodeling in schizophrenia and bipolar disorder.

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    Zhao, Z; Xu, J; Chen, J; Kim, S; Reimers, M; Bacanu, S-A; Yu, H; Liu, C; Sun, J; Wang, Q; Jia, P; Xu, F; Zhang, Y; Kendler, K S; Peng, Z; Chen, X

    2015-05-01

    Schizophrenia (SCZ) and bipolar disorder (BPD) are severe mental disorders with high heritability. Clinicians have long noticed the similarities of clinic symptoms between these disorders. In recent years, accumulating evidence indicates some shared genetic liabilities. However, what is shared remains elusive. In this study, we conducted whole transcriptome analysis of post-mortem brain tissues (cingulate cortex) from SCZ, BPD and control subjects, and identified differentially expressed genes in these disorders. We found 105 and 153 genes differentially expressed in SCZ and BPD, respectively. By comparing the t-test scores, we found that many of the genes differentially expressed in SCZ and BPD are concordant in their expression level (q⩽0.01, 53 genes; q⩽0.05, 213 genes; q⩽0.1, 885 genes). Using genome-wide association data from the Psychiatric Genomics Consortium, we found that these differentially and concordantly expressed genes were enriched in association signals for both SCZ (Pgenes show concordant expression and association for both SCZ and BPD. Pathway analyses of these genes indicated that they are involved in the lysosome, Fc gamma receptor-mediated phagocytosis, regulation of actin cytoskeleton pathways, along with several cancer pathways. Functional analyses of these genes revealed an interconnected pathway network centered on lysosomal function and the regulation of actin cytoskeleton. These pathways and their interacting network were principally confirmed by an independent transcriptome sequencing data set of the hippocampus. Dysregulation of lysosomal function and cytoskeleton remodeling has direct impacts on endocytosis, phagocytosis, exocytosis, vesicle trafficking, neuronal maturation and migration, neurite outgrowth and synaptic density and plasticity, and different aspects of these processes have been implicated in SCZ and BPD.

  2. Genome-Wide Association and Transcriptome Analyses Reveal Candidate Genes Underlying Yield-determining Traits in Brassica napus

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    Lu, Kun; Peng, Liu; Zhang, Chao; Lu, Junhua; Yang, Bo; Xiao, Zhongchun; Liang, Ying; Xu, Xingfu; Qu, Cunmin; Zhang, Kai; Liu, Liezhao; Zhu, Qinlong; Fu, Minglian; Yuan, Xiaoyan; Li, Jiana

    2017-01-01

    Yield is one of the most important yet complex crop traits. To improve our understanding of the genetic basis of yield establishment, and to identify candidate genes responsible for yield improvement in Brassica napus, we performed genome-wide association studies (GWAS) for seven yield-determining traits [main inflorescence pod number (MIPN), branch pod number (BPN), pod number per plant (PNP), seed number per pod (SPP), thousand seed weight, main inflorescence yield (MIY), and branch yield], using data from 520 diverse B. napus accessions from two different yield environments. In total, we detected 128 significant single nucleotide polymorphisms (SNPs), 93 of which were revealed as novel by integrative analysis. A combination of GWAS and transcriptome sequencing on 21 haplotype blocks from samples pooled by four extremely high-yielding or low-yielding accessions revealed the differential expression of 14 crucial candiate genes (such as Bna.MYB83, Bna.SPL5, and Bna.ROP3) associated with multiple traits or containing multiple SNPs associated with the same trait. Functional annotation and expression pattern analyses further demonstrated that these 14 candiate genes might be important in developmental processes and biomass accumulation, thus affecting the yield establishment of B. napus. These results provide valuable information for understanding the genetic mechanisms underlying the establishment of high yield in B. napus, and lay the foundation for developing high-yielding B. napus varieties. PMID:28261256

  3. Unraveling Fungal Radiation Resistance Regulatory Networks through the Genome-Wide Transcriptome and Genetic Analyses of Cryptococcus neoformans

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    Kwang-Woo Jung

    2016-11-01

    Full Text Available The basidiomycetous fungus Cryptococcus neoformans has been known to be highly radiation resistant and has been found in fatal radioactive environments such as the damaged nuclear reactor at Chernobyl. To elucidate the mechanisms underlying the radiation resistance phenotype of C. neoformans, we identified genes affected by gamma radiation through genome-wide transcriptome analysis and characterized their functions. We found that genes involved in DNA damage repair systems were upregulated in response to gamma radiation. Particularly, deletion of recombinase RAD51 and two DNA-dependent ATPase genes, RAD54 and RDH54, increased cellular susceptibility to both gamma radiation and DNA-damaging agents. A variety of oxidative stress response genes were also upregulated. Among them, sulfiredoxin contributed to gamma radiation resistance in a peroxiredoxin/thioredoxin-independent manner. Furthermore, we found that genes involved in molecular chaperone expression, ubiquitination systems, and autophagy were induced, whereas genes involved in the biosynthesis of proteins and fatty acids/sterols were downregulated. Most importantly, we discovered a number of novel C. neoformans genes, the expression of which was modulated by gamma radiation exposure, and their deletion rendered cells susceptible to gamma radiation exposure, as well as DNA damage insults. Among these genes, we found that a unique transcription factor containing the basic leucine zipper domain, named Bdr1, served as a regulator of the gamma radiation resistance of C. neoformans by controlling expression of DNA repair genes, and its expression was regulated by the evolutionarily conserved DNA damage response protein kinase Rad53. Taken together, the current transcriptome and functional analyses contribute to the understanding of the unique molecular mechanism of the radiation-resistant fungus C. neoformans.

  4. Genome-wide transcriptome analyses of silicon metabolism in Phaeodactylum tricornutum reveal the multilevel regulation of silicic acid transporters.

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    Guillaume Sapriel

    Full Text Available BACKGROUND: Diatoms are largely responsible for production of biogenic silica in the global ocean. However, in surface seawater, Si(OH(4 can be a major limiting factor for diatom productivity. Analyzing at the global scale the genes networks involved in Si transport and metabolism is critical in order to elucidate Si biomineralization, and to understand diatoms contribution to biogeochemical cycles. METHODOLOGY/PRINCIPAL FINDINGS: Using whole genome expression analyses we evaluated the transcriptional response to Si availability for the model species Phaeodactylum tricornutum. Among the differentially regulated genes we found genes involved in glutamine-nitrogen pathways, encoding putative extracellular matrix components, or involved in iron regulation. Some of these compounds may be good candidates for intracellular intermediates involved in silicic acid storage and/or intracellular transport, which are very important processes that remain mysterious in diatoms. Expression analyses and localization studies gave the first picture of the spatial distribution of a silicic acid transporter in a diatom model species, and support the existence of transcriptional and post-transcriptional regulations. CONCLUSIONS/SIGNIFICANCE: Our global analyses revealed that about one fourth of the differentially expressed genes are organized in clusters, underlying a possible evolution of P. tricornutum genome, and perhaps other pennate diatoms, toward a better optimization of its response to variable environmental stimuli. High fitness and adaptation of diatoms to various Si levels in marine environments might arise in part by global regulations from gene (expression level to genomic (organization in clusters, dosage compensation by gene duplication, and by post-transcriptional regulation and spatial distribution of SIT proteins.

  5. Genome-wide transcriptomic and proteomic analyses of bollworm-infested developing cotton bolls revealed the genes and pathways involved in the insect pest defence mechanism.

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    Kumar, Saravanan; Kanakachari, Mogilicherla; Gurusamy, Dhandapani; Kumar, Krishan; Narayanasamy, Prabhakaran; Kethireddy Venkata, Padmalatha; Solanke, Amolkumar; Gamanagatti, Savita; Hiremath, Vamadevaiah; Katageri, Ishwarappa S; Leelavathi, Sadhu; Kumar, Polumetla Ananda; Reddy, Vanga Siva

    2016-06-01

    Cotton bollworm, Helicoverpa armigera, is a major insect pest that feeds on cotton bolls causing extensive damage leading to crop and productivity loss. In spite of such a major impact, cotton plant response to bollworm infection is yet to be witnessed. In this context, we have studied the genome-wide response of cotton bolls infested with bollworm using transcriptomic and proteomic approaches. Further, we have validated this data using semi-quantitative real-time PCR. Comparative analyses have revealed that 39% of the transcriptome and 35% of the proteome were differentially regulated during bollworm infestation. Around 36% of significantly regulated transcripts and 45% of differentially expressed proteins were found to be involved in signalling followed by redox regulation. Further analysis showed that defence-related stress hormones and their lipid precursors, transcription factors, signalling molecules, etc. were stimulated, whereas the growth-related counterparts were suppressed during bollworm infestation. Around 26% of the significantly up-regulated proteins were defence molecules, while >50% of the significantly down-regulated were related to photosynthesis and growth. Interestingly, the biosynthesis genes for synergistically regulated jasmonate, ethylene and suppressors of the antagonistic factor salicylate were found to be up-regulated, suggesting a choice among stress-responsive phytohormone regulation. Manual curation of the enzymes and TFs highlighted the components of retrograde signalling pathways. Our data suggest that a selective regulatory mechanism directs the reallocation of metabolic resources favouring defence over growth under bollworm infestation and these insights could be exploited to develop bollworm-resistant cotton varieties.

  6. Genome-wide transcriptome analysis of 150 cell samples†

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    Russom, Aman; Xiao, Wenzhong; Wilhelmy, Julie; Wang, Shenglong; Heath, Joe Don; Kurn, Nurith; Tompkins, Ronald G.; Davis, Ronald W.; Toner, Mehmet

    2013-01-01

    A major challenge in molecular biology is interrogating the human transcriptome on a genome wide scale when only a limited amount of biological sample is available for analysis. Current methodologies using microarray technologies for simultaneously monitoring mRNA transcription levels require nanogram amounts of total RNA. To overcome the sample size limitation of current technologies, we have developed a method to probe the global gene expression in biological samples as small as 150 cells, or the equivalent of approximately 300 pg total RNA. The new method employs microfluidic devices for the purification of total RNA from mammalian cells and ultra-sensitive whole transcriptome amplification techniques. We verified that the RNA integrity is preserved through the isolation process, accomplished highly reproducible whole transcriptome analysis, and established high correlation between repeated isolations of 150 cells and the same cell culture sample. We validated the technology by demonstrating that the combined microfluidic and amplification protocol is capable of identifying biological pathways perturbed by stimulation, which are consistent with the information recognized in bulk-isolated samples. PMID:20023796

  7. Genome-wide transcriptome analysis of 150 cell samples.

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    Irimia, Daniel; Mindrinos, Michael; Russom, Aman; Xiao, Wenzhong; Wilhelmy, Julie; Wang, Shenglong; Heath, Joe Don; Kurn, Nurith; Tompkins, Ronald G; Davis, Ronald W; Toner, Mehmet

    2009-01-01

    A major challenge in molecular biology is interrogating the human transcriptome on a genome wide scale when only a limited amount of biological sample is available for analysis. Current methodologies using microarray technologies for simultaneously monitoring mRNA transcription levels require nanogram amounts of total RNA. To overcome the sample size limitation of current technologies, we have developed a method to probe the global gene expression in biological samples as small as 150 cells, or the equivalent of approximately 300 pg total RNA. The new method employs microfluidic devices for the purification of total RNA from mammalian cells and ultra-sensitive whole transcriptome amplification techniques. We verified that the RNA integrity is preserved through the isolation process, accomplished highly reproducible whole transcriptome analysis, and established high correlation between repeated isolations of 150 cells and the same cell culture sample. We validated the technology by demonstrating that the combined microfluidic and amplification protocol is capable of identifying biological pathways perturbed by stimulation, which are consistent with the information recognized in bulk-isolated samples.

  8. Genetic and genome-wide transcriptomic analyses identify co-regulation of oxidative response and hormone transcript abundance with vitamin C content in tomato fruit

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    Lima-Silva Viviana

    2012-05-01

    Full Text Available Abstract Background L-ascorbic acid (AsA; vitamin C is essential for all living plants where it functions as the main hydrosoluble antioxidant. It has diverse roles in the regulation of plant cell growth and expansion, photosynthesis, and hormone-regulated processes. AsA is also an essential component of the human diet, being tomato fruit one of the main sources of this vitamin. To identify genes responsible for AsA content in tomato fruit, transcriptomic studies followed by clustering analysis were applied to two groups of fruits with contrasting AsA content. These fruits were identified after AsA profiling of an F8 Recombinant Inbred Line (RIL population generated from a cross between the domesticated species Solanum lycopersicum and the wild relative Solanum pimpinellifollium. Results We found large variability in AsA content within the RIL population with individual RILs with up to 4-fold difference in AsA content. Transcriptomic analysis identified genes whose expression correlated either positively (PVC genes or negatively (NVC genes with the AsA content of the fruits. Cluster analysis using SOTA allowed the identification of subsets of co-regulated genes mainly involved in hormones signaling, such as ethylene, ABA, gibberellin and auxin, rather than any of the known AsA biosynthetic genes. Data mining of the corresponding PVC and NVC orthologs in Arabidopis databases identified flagellin and other ROS-producing processes as cues resulting in differential regulation of a high percentage of the genes from both groups of co-regulated genes; more specifically, 26.6% of the orthologous PVC genes, and 15.5% of the orthologous NVC genes were induced and repressed, respectively, under flagellin22 treatment in Arabidopsis thaliana. Conclusion Results here reported indicate that the content of AsA in red tomato fruit from our selected RILs are not correlated with the expression of genes involved in its biosynthesis. On the contrary, the data

  9. Genome-wide analyses of small noncoding RNAs in streptococci

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    Nadja ePatenge

    2015-05-01

    Full Text Available Streptococci represent a diverse group of Gram-positive bacteria, which colonize a wide range of hosts among animals and humans. Streptococcal species occur as commensal as well as pathogenic organisms. Many of the pathogenic species can cause severe, invasive infections in their hosts leading to a high morbidity and mortality. The consequence is a tremendous suffering on the part of men and livestock besides the significant financial burden in the agricultural and healthcare sectors. An environmentally stimulated and tightly controlled expression of virulence factor genes is of fundamental importance for streptococcal pathogenicity. Bacterial small noncoding RNAs (sRNAs modulate the expression of genes involved in stress response, sugar metabolism, surface composition, and other properties that are related to bacterial virulence. Even though the regulatory character is shared by this class of RNAs, variation on the molecular level results in a high diversity of functional mechanisms. The knowledge about the role of sRNAs in streptococci is still limited, but in recent years, genome-wide screens for sRNAs have been conducted in an increasing number of species. Bioinformatics prediction approaches have been employed as well as expression analyses by classical array techniques or next generation sequencing. This review will give an overview of whole genome screens for sRNAs in streptococci with a focus on describing the different methods and comparing their outcome considering sRNA conservation among species, functional similarities, and relevance for streptococcal infection.

  10. Genome-wide methylation analyses in glioblastoma multiforme.

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    Rose K Lai

    Full Text Available Few studies had investigated genome-wide methylation in glioblastoma multiforme (GBM. Our goals were to study differential methylation across the genome in gene promoters using an array-based method, as well as repetitive elements using surrogate global methylation markers. The discovery sample set for this study consisted of 54 GBM from Columbia University and Case Western Reserve University, and 24 brain controls from the New York Brain Bank. We assembled a validation dataset using methylation data of 162 TCGA GBM and 140 brain controls from dbGAP. HumanMethylation27 Analysis Bead-Chips (Illumina were used to interrogate 26,486 informative CpG sites in both the discovery and validation datasets. Global methylation levels were assessed by analysis of L1 retrotransposon (LINE1, 5 methyl-deoxycytidine (5m-dC and 5 hydroxylmethyl-deoxycytidine (5hm-dC in the discovery dataset. We validated a total of 1548 CpG sites (1307 genes that were differentially methylated in GBM compared to controls. There were more than twice as many hypomethylated genes as hypermethylated ones. Both the discovery and validation datasets found 5 tumor methylation classes. Pathway analyses showed that the top ten pathways in hypomethylated genes were all related to functions of innate and acquired immunities. Among hypermethylated pathways, transcriptional regulatory network in embryonic stem cells was the most significant. In the study of global methylation markers, 5m-dC level was the best discriminant among methylation classes, whereas in survival analyses, high level of LINE1 methylation was an independent, favorable prognostic factor in the discovery dataset. Based on a pathway approach, hypermethylation in genes that control stem cell differentiation were significant, poor prognostic factors of overall survival in both the discovery and validation datasets. Approaches that targeted these methylated genes may be a future therapeutic goal.

  11. Genome-wide analyses for dissecting gene regulatory networks in the shoot apical meristem.

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    Bustamante, Mariana; Matus, José Tomás; Riechmann, José Luis

    2016-03-01

    Shoot apical meristem activity is controlled by complex regulatory networks in which components such as transcription factors, miRNAs, small peptides, hormones, enzymes and epigenetic marks all participate. Many key genes that determine the inherent characteristics of the shoot apical meristem have been identified through genetic approaches. Recent advances in genome-wide studies generating extensive transcriptomic and DNA-binding datasets have increased our understanding of the interactions within the regulatory networks that control the activity of the meristem, identifying new regulators and uncovering connections between previously unlinked network components. In this review, we focus on recent studies that illustrate the contribution of whole genome analyses to understand meristem function. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  12. Genome-wide binding and transcriptome analysis of human farnesoid X receptor in primary human hepatocytes.

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    Le Zhan

    Full Text Available Farnesoid X receptor (FXR, NR1H4 is a ligand-activated transcription factor, belonging to the nuclear receptor superfamily. FXR is highly expressed in the liver and is essential in regulating bile acid homeostasis. FXR deficiency is implicated in numerous liver diseases and mice with modulation of FXR have been used as animal models to study liver physiology and pathology. We have reported genome-wide binding of FXR in mice by chromatin immunoprecipitation - deep sequencing (ChIP-seq, with results indicating that FXR may be involved in regulating diverse pathways in liver. However, limited information exists for the functions of human FXR and the suitability of using murine models to study human FXR functions.In the current study, we performed ChIP-seq in primary human hepatocytes (PHHs treated with a synthetic FXR agonist, GW4064 or DMSO control. In parallel, RNA deep sequencing (RNA-seq and RNA microarray were performed for GW4064 or control treated PHHs and wild type mouse livers, respectively.ChIP-seq showed similar profiles of genome-wide FXR binding in humans and mice in terms of motif analysis and pathway prediction. However, RNA-seq and microarray showed more different transcriptome profiles between PHHs and mouse livers upon GW4064 treatment.In summary, we have established genome-wide human FXR binding and transcriptome profiles. These results will aid in determining the human FXR functions, as well as judging to what level the mouse models could be used to study human FXR functions.

  13. Quality control and conduct of genome-wide association meta-analyses

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    Winkler, Thomas W; Day, Felix R; Croteau-Chonka, Damien C

    2014-01-01

    Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC...... at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide...

  14. Genome-wide transcriptome and expression profile analysis of Phalaenopsis during explant browning.

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    Chuanjun Xu

    Full Text Available Explant browning presents a major problem for in vitro culture, and can lead to the death of the explant and failure of regeneration. Considerable work has examined the physiological mechanisms underlying Phalaenopsis leaf explant browning, but the molecular mechanisms of browning remain elusive. In this study, we used whole genome RNA sequencing to examine Phalaenopsis leaf explant browning at genome-wide level.We first used Illumina high-throughput technology to sequence the transcriptome of Phalaenopsis and then performed de novo transcriptome assembly. We assembled 79,434,350 clean reads into 31,708 isogenes and generated 26,565 annotated unigenes. We assigned Gene Ontology (GO terms, Kyoto Encyclopedia of Genes and Genomes (KEGG annotations, and potential Pfam domains to each transcript. Using the transcriptome data as a reference, we next analyzed the differential gene expression of explants cultured for 0, 3, and 6 d, respectively. We then identified differentially expressed genes (DEGs before and after Phalaenopsis explant browning. We also performed GO, KEGG functional enrichment and Pfam analysis of all DEGs. Finally, we selected 11 genes for quantitative real-time PCR (qPCR analysis to confirm the expression profile analysis.Here, we report the first comprehensive analysis of transcriptome and expression profiles during Phalaenopsis explant browning. Our results suggest that Phalaenopsis explant browning may be due in part to gene expression changes that affect the secondary metabolism, such as: phenylpropanoid pathway and flavonoid biosynthesis. Genes involved in photosynthesis and ATPase activity have been found to be changed at transcription level; these changes may perturb energy metabolism and thus lead to the decay of plant cells and tissues. This study provides comprehensive gene expression data for Phalaenopsis browning. Our data constitute an important resource for further functional studies to prevent explant browning.

  15. Genome-wide transcriptome and expression profile analysis of Phalaenopsis during explant browning.

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    Xu, Chuanjun; Zeng, Biyu; Huang, Junmei; Huang, Wen; Liu, Yumei

    2015-01-01

    Explant browning presents a major problem for in vitro culture, and can lead to the death of the explant and failure of regeneration. Considerable work has examined the physiological mechanisms underlying Phalaenopsis leaf explant browning, but the molecular mechanisms of browning remain elusive. In this study, we used whole genome RNA sequencing to examine Phalaenopsis leaf explant browning at genome-wide level. We first used Illumina high-throughput technology to sequence the transcriptome of Phalaenopsis and then performed de novo transcriptome assembly. We assembled 79,434,350 clean reads into 31,708 isogenes and generated 26,565 annotated unigenes. We assigned Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations, and potential Pfam domains to each transcript. Using the transcriptome data as a reference, we next analyzed the differential gene expression of explants cultured for 0, 3, and 6 d, respectively. We then identified differentially expressed genes (DEGs) before and after Phalaenopsis explant browning. We also performed GO, KEGG functional enrichment and Pfam analysis of all DEGs. Finally, we selected 11 genes for quantitative real-time PCR (qPCR) analysis to confirm the expression profile analysis. Here, we report the first comprehensive analysis of transcriptome and expression profiles during Phalaenopsis explant browning. Our results suggest that Phalaenopsis explant browning may be due in part to gene expression changes that affect the secondary metabolism, such as: phenylpropanoid pathway and flavonoid biosynthesis. Genes involved in photosynthesis and ATPase activity have been found to be changed at transcription level; these changes may perturb energy metabolism and thus lead to the decay of plant cells and tissues. This study provides comprehensive gene expression data for Phalaenopsis browning. Our data constitute an important resource for further functional studies to prevent explant browning.

  16. Genome-wide analyses of aggressiveness in attention-deficit hyperactivity disorder.

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    Brevik, Erlend J; van Donkelaar, Marjolein M J; Weber, Heike; Sánchez-Mora, Cristina; Jacob, Christian; Rivero, Olga; Kittel-Schneider, Sarah; Garcia-Martínez, Iris; Aebi, Marcel; van Hulzen, Kimm; Cormand, Bru; Ramos-Quiroga, Josep A; Lesch, Klaus-Peter; Reif, Andreas; Ribasés, Marta; Franke, Barbara; Posserud, Maj-Britt; Johansson, Stefan; Lundervold, Astri J; Haavik, Jan; Zayats, Tetyana

    2016-07-01

    Aggressiveness is a behavioral trait that has the potential to be harmful to individuals and society. With an estimated heritability of about 40%, genetics is important in its development. We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyperactivity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggressiveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P aggressiveness and provide targets for further genetic exploration of aggressiveness across psychiatric disorders. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

  17. Genome-wide analyses of the transcriptomes of salicylic acid-deficient versus wild-type plants uncover Pathogen and Circadian Controlled 1 (PCC1) as a regulator of flowering time in Arabidopsis.

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    Segarra, Silvia; Mir, Ricardo; Martínez, Cristina; León, José

    2010-01-01

    Salicylic acid (SA) has been characterized as an activator of pathogen-triggered resistance of plants. SA also regulates developmental processes such as thermogenesis in floral organs and stress-induced flowering. To deepen our knowledge of the mechanism underlying SA regulation of flowering time in Arabidopsis, we compared the transcriptomes of SA-deficient late flowering genotypes with wild-type plants. Down- or up-regulated genes in SA-deficient plants were screened for responsiveness to ultraviolet (UV)-C light, which accelerates flowering in Arabidopsis. Among them, only Pathogen and Circadian Controlled 1 (PCC1) was up-regulated by UV-C light through a SA-dependent process. Moreover, UV-C light-activated expression of PCC1 was also dependent on the flowering activator CONSTANS (CO). PCC1 gene has a circadian-regulated developmental pattern of expression with low transcript levels after germination that increased abruptly by day 10. RNAi plants with very low expression of PCC1 gene were late flowering, defective in UV-C light acceleration of flowering and contained FLOWERING LOCUS T (FT) transcript levels below 5% of that detected in wild-type plants. Although PCC1 seems to function between CO and FT in the photoperiod-dependent flowering pathway, transgenic plants overexpressing a Glucocorticoid Receptor (GR)-fused version of CO strongly activated FT but not PCC1 after dexamethasone treatment.

  18. Genome-wide transcriptome analysis of fluoroquinolone resistance in clinical isolates of Escherichia coli.

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    Yamane, Takashi; Enokida, Hideki; Hayami, Hiroshi; Kawahara, Motoshi; Nakagawa, Masayuki

    2012-04-01

    Coincident with their worldwide use, resistance to fluoroquinolones in Escherichia coli has increased. To identify the gene expression profiles underlying fluoroquinolone resistance, we carried out genome-wide transcriptome analysis of fluoroquinolone-sensitive E. coli. Four fluoroquinolone-sensitive E. coli and five fluoroquinolone-resistant E. coli clinical isolates were subjected to complementary deoxyribonucleic acid microarray analysis. Some upregulated genes' expression was verified by real-time polymerase chain reaction using 104 E. coli clinical isolates, and minimum inhibitory concentration tests were carried out by using their transformants. A total of 40 genes were significantly upregulated in fluoroquinolone-resistant E. coli isolates (P fluoroquinolone-resistant E. coli. One of the phage shock protein operons, pspC, was significantly upregulated in 50 fluoroquinolone-resistant E. coli isolates (P fluoroquinolone-resistant E. coli. Deoxyribonucleic acid adenine methyltransferase (dam), which represses type I fimbriae genes, was significantly upregulated in the clinical fluoroquinolone-resistant E. coli isolates (P = 0.007). We established pspC- and dam-expressing E. coli transformants from fluoroquinolone-sensitive E. coli, and the minimum inhibitory concentration tests showed that the transformants acquired fluoroquinolone resistance, suggesting that upregulation of these genes contributes to acquiring fluoroquinolone resistance. Upregulation of psp operones and dam underlying pilus operons downregulation might be associated with fluoroquinolone resistance in E. coli. © 2011 The Japanese Urological Association.

  19. A genome-wide longitudinal transcriptome analysis of the aging model Podospora anserina.

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    Oliver Philipp

    Full Text Available Aging of biological systems is controlled by various processes which have a potential impact on gene expression. Here we report a genome-wide transcriptome analysis of the fungal aging model Podospora anserina. Total RNA of three individuals of defined age were pooled and analyzed by SuperSAGE (serial analysis of gene expression. A bioinformatics analysis identified different molecular pathways to be affected during aging. While the abundance of transcripts linked to ribosomes and to the proteasome quality control system were found to decrease during aging, those associated with autophagy increase, suggesting that autophagy may act as a compensatory quality control pathway. Transcript profiles associated with the energy metabolism including mitochondrial functions were identified to fluctuate during aging. Comparison of wild-type transcripts, which are continuously down-regulated during aging, with those down-regulated in the long-lived, copper-uptake mutant grisea, validated the relevance of age-related changes in cellular copper metabolism. Overall, we (i present a unique age-related data set of a longitudinal study of the experimental aging model P. anserina which represents a reference resource for future investigations in a variety of organisms, (ii suggest autophagy to be a key quality control pathway that becomes active once other pathways fail, and (iii present testable predictions for subsequent experimental investigations.

  20. Genome-wide survey of ds exonization to enrich transcriptomes and proteomes in plants.

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    Liu, Li-Yu Daisy; Charng, Yuh-Chyang

    2012-01-01

    Insertion of transposable elements (TEs) into introns can lead to their activation as alternatively spliced cassette exons, an event called exonization which can enrich the complexity of transcriptomes and proteomes. Previously, we performed the first experimental assessment of TE exonization by inserting a Ds element into each intron of the rice epsps gene. Exonization of Ds in plants was biased toward providing splice donor sites from the beginning of the inserted Ds sequence. Additionally, Ds inserted in the reverse direction resulted in a continuous splice donor consensus region by offering 4 donor sites in the same intron. The current study involved genome-wide computational analysis of Ds exonization events in the dicot Arabidopsis thaliana and the monocot Oryza sativa (rice). Up to 71% of the exonized transcripts were putative targets for the nonsense-mediated decay (NMD) pathway. The insertion patterns of Ds and the polymorphic splice donor sites increased the transcripts and subsequent protein isoforms. Protein isoforms contain protein sequence due to unspliced intron-TE region and/or a shift of the reading frame. The number of interior protein isoforms would be twice that of C-terminal isoforms, on average. TE exonization provides a promising way for functional expansion of the plant proteome.

  1. A differential genome-wide transcriptome analysis: impact of cellular copper on complex biological processes like aging and development.

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    Jörg Servos

    Full Text Available The regulation of cellular copper homeostasis is crucial in biology. Impairments lead to severe dysfunctions and are known to affect aging and development. Previously, a loss-of-function mutation in the gene encoding the copper-sensing and copper-regulated transcription factor GRISEA of the filamentous fungus Podospora anserina was reported to lead to cellular copper depletion and a pleiotropic phenotype with hypopigmentation of the mycelium and the ascospores, affected fertility and increased lifespan by approximately 60% when compared to the wild type. This phenotype is linked to a switch from a copper-dependent standard to an alternative respiration leading to both a reduced generation of reactive oxygen species (ROS and of adenosine triphosphate (ATP. We performed a genome-wide comparative transcriptome analysis of a wild-type strain and the copper-depleted grisea mutant. We unambiguously assigned 9,700 sequences of the transcriptome in both strains to the more than 10,600 predicted and annotated open reading frames of the P. anserina genome indicating 90% coverage of the transcriptome. 4,752 of the transcripts differed significantly in abundance with 1,156 transcripts differing at least 3-fold. Selected genes were investigated by qRT-PCR analyses. Apart from this general characterization we analyzed the data with special emphasis on molecular pathways related to the grisea mutation taking advantage of the available complete genomic sequence of P. anserina. This analysis verified but also corrected conclusions from earlier data obtained by single gene analysis, identified new candidates of factors as part of the cellular copper homeostasis system including target genes of transcription factor GRISEA, and provides a rich reference source of quantitative data for further in detail investigations. Overall, the present study demonstrates the importance of systems biology approaches also in cases were mutations in single genes are analyzed to

  2. Genome-wide association and linkage analyses localize a progressive retinal atrophy locus in Persian cats.

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    Alhaddad, Hasan; Gandolfi, Barbara; Grahn, Robert A; Rah, Hyung-Chul; Peterson, Carlyn B; Maggs, David J; Good, Kathryn L; Pedersen, Niels C; Lyons, Leslie A

    2014-08-01

    Hereditary eye diseases of animals serve as excellent models of human ocular disorders and assist in the development of gene and drug therapies for inherited forms of blindness. Several primary hereditary eye conditions affecting various ocular tissues and having different rates of progression have been documented in domestic cats. Gene therapy for canine retinopathies has been successful, thus the cat could be a gene therapy candidate for other forms of retinal degenerations. The current study investigates a hereditary, autosomal recessive, retinal degeneration specific to Persian cats. A multi-generational pedigree segregating for this progressive retinal atrophy was genotyped using a 63 K SNP array and analyzed via genome-wide linkage and association methods. A multi-point parametric linkage analysis localized the blindness phenotype to a ~1.75 Mb region with significant LOD scores (Z ≈ 14, θ = 0.00) on cat chromosome E1. Genome-wide TDT, sib-TDT, and case-control analyses also consistently supported significant association within the same region on chromosome E1, which is homologous to human chromosome 17. Using haplotype analysis, a ~1.3 Mb region was identified as highly associated for progressive retinal atrophy in Persian cats. Several candidate genes within the region are reasonable candidates as a potential causative gene and should be considered for molecular analyses.

  3. Understanding PRRSV infection in porcine lung based on genome-wide transcriptome response identified by deep sequencing.

    Directory of Open Access Journals (Sweden)

    Shuqi Xiao

    Full Text Available Porcine reproductive and respiratory syndrome (PRRS has been one of the most economically important diseases affecting swine industry worldwide and causes great economic losses each year. PRRS virus (PRRSV replicates mainly in porcine alveolar macrophages (PAMs and dendritic cells (DCs and develops persistent infections, antibody-dependent enhancement (ADE, interstitial pneumonia and immunosuppression. But the molecular mechanisms of PRRSV infection still are poorly understood. Here we report on the first genome-wide host transcriptional responses to classical North American type PRRSV (N-PRRSV strain CH 1a infection using Solexa/Illumina's digital gene expression (DGE system, a tag-based high-throughput transcriptome sequencing method, and analyse systematically the relationship between pulmonary gene expression profiles after N-PRRSV infection and infection pathology. Our results suggest that N-PRRSV appeared to utilize multiple strategies for its replication and spread in infected pigs, including subverting host innate immune response, inducing an anti-apoptotic and anti-inflammatory state as well as developing ADE. Upregulation expression of virus-induced pro-inflammatory cytokines, chemokines, adhesion molecules and inflammatory enzymes and inflammatory cells, antibodies, complement activation were likely to result in the development of inflammatory responses during N-PRRSV infection processes. N-PRRSV-induced immunosuppression might be mediated by apoptosis of infected cells, which caused depletion of immune cells and induced an anti-inflammatory cytokine response in which they were unable to eradicate the primary infection. Our systems analysis will benefit for better understanding the molecular pathogenesis of N-PRRSV infection, developing novel antiviral therapies and identifying genetic components for swine resistance/susceptibility to PRRS.

  4. Genome-wide meta-analyses identify multiple loci associated with smoking behavior.

    LENUS (Irish Health Repository)

    2010-05-01

    Consistent but indirect evidence has implicated genetic factors in smoking behavior. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], beta = 1.03, standard error (s.e.) = 0.053, P = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], beta = 0.367, s.e. = 0.059, P = 5.7 x 10(-10); and rs1028936[A], beta = 0.446, s.e. = 0.074, P = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], beta = 0.333, s.e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.

  5. Genome-wide analyses reveal a role for peptide hormones in planarian germline development.

    Directory of Open Access Journals (Sweden)

    James J Collins

    Full Text Available Bioactive peptides (i.e., neuropeptides or peptide hormones represent the largest class of cell-cell signaling molecules in metazoans and are potent regulators of neural and physiological function. In vertebrates, peptide hormones play an integral role in endocrine signaling between the brain and the gonads that controls reproductive development, yet few of these molecules have been shown to influence reproductive development in invertebrates. Here, we define a role for peptide hormones in controlling reproductive physiology of the model flatworm, the planarian Schmidtea mediterranea. Based on our observation that defective neuropeptide processing results in defects in reproductive system development, we employed peptidomic and functional genomic approaches to characterize the planarian peptide hormone complement, identifying 51 prohormone genes and validating 142 peptides biochemically. Comprehensive in situ hybridization analyses of prohormone gene expression revealed the unanticipated complexity of the flatworm nervous system and identified a prohormone specifically expressed in the nervous system of sexually reproducing planarians. We show that this member of the neuropeptide Y superfamily is required for the maintenance of mature reproductive organs and differentiated germ cells in the testes. Additionally, comparative analyses of our biochemically validated prohormones with the genomes of the parasitic flatworms Schistosoma mansoni and Schistosoma japonicum identified new schistosome prohormones and validated half of all predicted peptide-encoding genes in these parasites. These studies describe the peptide hormone complement of a flatworm on a genome-wide scale and reveal a previously uncharacterized role for peptide hormones in flatworm reproduction. Furthermore, they suggest new opportunities for using planarians as free-living models for understanding the reproductive biology of flatworm parasites.

  6. Genome-wide comparative transcriptome analysis of CMS-D2 and its maintainer and restorer lines in upland cotton.

    Science.gov (United States)

    Wu, Jianyong; Zhang, Meng; Zhang, Bingbing; Zhang, Xuexian; Guo, Liping; Qi, Tingxiang; Wang, Hailin; Zhang, Jinfa; Xing, Chaozhu

    2017-06-08

    Cytoplasmic male sterility (CMS) conferred by the cytoplasm from Gossypium harknessii (D2) is an important system for hybrid seed production in Upland cotton (G. hirsutum). The male sterility of CMS-D2 (i.e., A line) can be restored to fertility by a restorer (i.e., R line) carrying the restorer gene Rf1 transferred from the D2 nuclear genome. However, the molecular mechanisms of CMS-D2 and its restoration are poorly understood. In this study, a genome-wide comparative transcriptome analysis was performed to identify differentially expressed genes (DEGs) in flower buds among the isogenic fertile R line and sterile A line derived from a backcross population (BC8F1) and the recurrent parent, i.e., the maintainer (B line). A total of 1464 DEGs were identified among the three isogenic lines, and the Rf1-carrying Chr_D05 and its homeologous Chr_A05 had more DEGs than other chromosomes. The results of GO and KEGG enrichment analysis showed differences in circadian rhythm between the fertile and sterile lines. Eleven DEGs were selected for validation using qRT-PCR, confirming the accuracy of the RNA-seq results. Through genome-wide comparative transcriptome analysis, the differential expression profiles of CMS-D2 and its maintainer and restorer lines in Upland cotton were identified. Our results provide an important foundation for further studies into the molecular mechanisms of the interactions between the restorer gene Rf1 and the CMS-D2 cytoplasm.

  7. De novo assembly of a genome-wide transcriptome map of Vicia faba (L.) for transfer cell research.

    Science.gov (United States)

    Arun-Chinnappa, Kiruba S; McCurdy, David W

    2015-01-01

    Vicia faba (L.) is an important cool-season grain legume species used widely in agriculture but also in plant physiology research, particularly as an experimental model to study transfer cell (TC) development. TCs are specialized nutrient transport cells in plants, characterized by invaginated wall ingrowths with amplified plasma membrane surface area enriched with transporter proteins that facilitate nutrient transfer. Many TCs are formed by trans-differentiation from differentiated cells at apoplasmic/symplasmic boundaries in nutrient transport. Adaxial epidermal cells of isolated cotyledons can be induced to form functional TCs, thus providing a valuable experimental system to investigate genetic regulation of TC trans-differentiation. The genome of V. faba is exceedingly large (ca. 13 Gb), however, and limited genomic information is available for this species. To provide a resource for future transcript profiling of epidermal TC differentiation, we have undertaken de novo assembly of a genome-wide transcriptome map for V. faba. Illumina paired-end sequencing of total RNA pooled from different tissues and different stages, including isolated cotyledons induced to form epidermal TCs, generated 69.5 M reads, of which 65.8 M were used for assembly following trimming and quality control. Assembly using a De-Bruijn graph-based approach generated 21,297 contigs, of which 80.6% were successfully annotated against GO terms. The assembly was validated against known V. faba cDNAs held in GenBank, including transcripts previously identified as being specifically expressed in epidermal cells across TC trans-differentiation. This genome-wide transcriptome map therefore provides a valuable tool for future transcript profiling of epidermal TC trans-differentiation, and also enriches the genetic resources available for this important legume crop species.

  8. Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer.

    Science.gov (United States)

    Lesseur, Corina; Diergaarde, Brenda; Olshan, Andrew F; Wünsch-Filho, Victor; Ness, Andrew R; Liu, Geoffrey; Lacko, Martin; Eluf-Neto, José; Franceschi, Silvia; Lagiou, Pagona; Macfarlane, Gary J; Richiardi, Lorenzo; Boccia, Stefania; Polesel, Jerry; Kjaerheim, Kristina; Zaridze, David; Johansson, Mattias; Menezes, Ana M; Curado, Maria Paula; Robinson, Max; Ahrens, Wolfgang; Canova, Cristina; Znaor, Ariana; Castellsagué, Xavier; Conway, David I; Holcátová, Ivana; Mates, Dana; Vilensky, Marta; Healy, Claire M; Szeszenia-Dąbrowska, Neonila; Fabiánová, Eleonóra; Lissowska, Jolanta; Grandis, Jennifer R; Weissler, Mark C; Tajara, Eloiza H; Nunes, Fabio D; de Carvalho, Marcos B; Thomas, Steve; Hung, Rayjean J; Peters, Wilbert H M; Herrero, Rolando; Cadoni, Gabriella; Bueno-de-Mesquita, H Bas; Steffen, Annika; Agudo, Antonio; Shangina, Oxana; Xiao, Xiangjun; Gaborieau, Valérie; Chabrier, Amélie; Anantharaman, Devasena; Boffetta, Paolo; Amos, Christopher I; McKay, James D; Brennan, Paul

    2016-12-01

    We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10(-8)), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10(-9)). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10(-6)) than in HPV-negative (OR = 0.75, P = 0.16) cancers.

  9. INNOVATIVE STRATEGIES TO IDENTIFY M. TUBERCULOSIS ANTIGENS AND EPITOPES USING GENOME-WIDE ANALYSES

    Directory of Open Access Journals (Sweden)

    Annemieke eGeluk

    2014-06-01

    Full Text Available In view of the fact that only a small part of the Mtb expressome has been explored for identification of antigens capable of activating human T-cell responses, which is critically required for the design of better TB vaccination strategies, more emphasis should be placed on innovative ways to discover new Mtb antigens and explore their function at the several stages of infection. Better protective antigens for TB vaccines are urgently needed, also in view of the disappointing results of the MVA85 vaccine which failed to induce additional protection in BCG vaccinated infants [54]. Moreover, immune responses to relevant antigens may be useful to identify TB-specific biomarker signatures. Here we describe the potency of novel tools and strategies to reveal such Mtb antigens. Using proteins specific for different Mtb infection phases, many new antigens of the latency-associated Mtb DosR regulon as well as Rpf proteins, associated with resuscitating TB, were discovered that were recognized by CD4+ and CD8+ T-cells. Furthermore, by employing MHC binding algorithms and bioinformatics combined with high throughput human T-cell screens and tetramers, HLA-class Ia restricted poly-functional CD8+ T-cells were identified in TB patients. Comparable methods, led to the identification of HLA-E-restricted Mtb epitopes recognized by CD8+ T-cells. A genome-wide unbiased antigen discovery approach was applied to analyse the in vivo Mtb gene expression profiles in the lungs of mice, resulting in the identification of IVE-TB antigens, which are expressed during infection in the lung, the main target organ of Mtb. IVE-TB antigens induce strong T cell responses in long-term latently Mtb infected individuals, and represent an interesting new group of TB antigens for vaccination. In summary, new tools have helped expand our view on the Mtb antigenome involved in human cellular immunity and provided new candidates for TB vaccination.

  10. Genome-wide transcriptome analysis of gametophyte development in Physcomitrella patens

    Directory of Open Access Journals (Sweden)

    Xiao Lihong

    2011-12-01

    Full Text Available Abstract Background Regulation of gene expression plays a pivotal role in controlling the development of multicellular plants. To explore the molecular mechanism of plant developmental-stage transition and cell-fate determination, a genome-wide analysis was undertaken of sequential developmental time-points and individual tissue types in the model moss Physcomitrella patens because of the short life cycle and relative structural simplicity of this plant. Results Gene expression was analyzed by digital gene expression tag profiling of samples taken from P. patens protonema at 3, 14 and 24 days, and from leafy shoot tissues at 30 days, after protoplast isolation, and from 14-day-old caulonemal and chloronemal tissues. In total, 4333 genes were identified as differentially displayed. Among these genes, 4129 were developmental-stage specific and 423 were preferentially expressed in either chloronemal or caulonemal tissues. Most of the differentially displayed genes were assigned to functions in organic substance and energy metabolism or macromolecule biosynthetic and catabolic processes based on gene ontology descriptions. In addition, some regulatory genes identified as candidates might be involved in controlling the developmental-stage transition and cell differentiation, namely MYB-like, HB-8, AL3, zinc finger family proteins, bHLH superfamily, GATA superfamily, GATA and bZIP transcription factors, protein kinases, genes related to protein/amino acid methylation, and auxin, ethylene, and cytokinin signaling pathways. Conclusions These genes that show highly dynamic changes in expression during development in P. patens are potential targets for further functional characterization and evolutionary developmental biology studies.

  11. Dissection of the inflammatory bowel disease transcriptome using genome-wide cDNA microarrays.

    Directory of Open Access Journals (Sweden)

    Christine M Costello

    2005-08-01

    Full Text Available BACKGROUND: The differential pathophysiologic mechanisms that trigger and maintain the two forms of inflammatory bowel disease (IBD, Crohn disease (CD, and ulcerative colitis (UC are only partially understood. cDNA microarrays can be used to decipher gene regulation events at a genome-wide level and to identify novel unknown genes that might be involved in perpetuating inflammatory disease progression. METHODS AND FINDINGS: High-density cDNA microarrays representing 33,792 UniGene clusters were prepared. Biopsies were taken from the sigmoid colon of normal controls (n = 11, CD patients (n = 10 and UC patients (n = 10. 33P-radiolabeled cDNA from purified poly(A+ RNA extracted from biopsies (unpooled was hybridized to the arrays. We identified 500 and 272 transcripts differentially regulated in CD and UC, respectively. Interesting hits were independently verified by real-time PCR in a second sample of 100 individuals, and immunohistochemistry was used for exemplary localization. The main findings point to novel molecules important in abnormal immune regulation and the highly disturbed cell biology of colonic epithelial cells in IBD pathogenesis, e.g., CYLD (cylindromatosis, turban tumor syndrome and CDH11 (cadherin 11, type 2. By the nature of the array setup, many of the genes identified were to our knowledge previously uncharacterized, and prediction of the putative function of a subsection of these genes indicate that some could be involved in early events in disease pathophysiology. CONCLUSION: A comprehensive set of candidate genes not previously associated with IBD was revealed, which underlines the polygenic and complex nature of the disease. It points out substantial differences in pathophysiology between CD and UC. The multiple unknown genes identified may stimulate new research in the fields of barrier mechanisms and cell signalling in the context of IBD, and ultimately new therapeutic approaches.

  12. Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia

    NARCIS (Netherlands)

    V.J.M. Verhoeven (Virginie); P.G. Hysi (Pirro); R. Wojciechowski (Robert); Q. Fan (Qiao); J. Guggenheim (Jean); R. Höhn (René); S. MacGregor (Stuart); A.W. Hewit (Alex); A. Nag (Abhishek); C-Y. Cheng (Ching-Yu); E. Yonova-Doing (Ekaterina); X. Zhou (Xin); M.K. Ikram (Kamran); G.H.S. Buitendijk (Gabrielle); G. Mcmahon (George); J.P. Kemp (John); B.S. Pourcain (Beate); C.L. Simpson (Claire); M.J. Mäkelä; T. Lehtimäki (Terho); M. Kähönen (Mika); A.D. Paterson (Andrew); M. Hosseini (Mehran); H.S. Wong (Hoi Suen); L. Xu (Liang); J.B. Jonas; O. Pärssinen (Olavi); J. Wedenoja (Juho); S.P. Yip (Shea Ping); D.W.H. Ho (Daniel); C.P. Pang (Chi); L.J. Chen (Li); K.P. Burdon (Kathryn); J.E. Craig (Jamie); B.E.K. Klein (Barbara); B.E.K. Klein (Barbara); T. Haller (Toomas); A. Metspalu (Andres); C.C. Khor; E.S. Tai (Shyong); T. Aung (Tin); E.N. Vithana (Eranga); W.-T. Tay (Wan-Ting); V.A. Barathi (Veluchamy); P. Chen (Ping); R. Li (Rui); J. Liao (Jie); Y. Zheng (Yuhui); R.T.H. Ong (Rick Twee-Hee); A. Döring (Angela); D.M. Evans (David); N. Timpson (Nicholas); A. Verkerk; T. Meitinger (Thomas); O. Raitakari (Olli); F. Hawthorne (Felicia); T.D. Spector (Timothy); L.C. Karssen (Lennart); M. Pirastu (Mario); D. Murgia (Daniela); W.Q. Ang (Wei); A. Mishra (Aniket); G.W. Montgomery (Grant); C.E. Pennell (Craig); P. Cumberland (Phillippa); I. Cotlarciuc (Ioana); P. Mitchell (Paul); J.J. Wang (Jie Jin); M. Schache (Maria); S. Janmahasathian (Sarayut); R.P. Igo Jr. (Robert); J.H. Lass Jr. (Jonathan); E.Y. Chew (Emily); S.K. Iyengar (Sudha); T.G.M.F. Gorgels (Theo); I. Rudan (Igor); C. Hayward (Caroline); A.F. Wright (Alan); O. Polasek (Ozren); Z. Vatavuk (Zoran); J.F. Wilson (James); B. Fleck (Brian); T. Zeller (Tanja); A. Mirshahi (Alireza); C. Müller (Christian); A.G. Uitterlinden (André); F. Rivadeneira Ramirez (Fernando); J.R. Vingerling (Hans); A. Hofman (Albert); B.A. Oostra (Ben); N. Amin (Najaf); A.A.B. Bergen (Arthur); Y.Y. Teo (Yik Ying); J.S. Rahi (Jugnoo); V. Vitart (Veronique); C. Williams (Cathy); P.N. Baird (Paul); T.Y. Wong (Tien); K. Oexle (Konrad); A.F.H. Pfeiffer (Andreas); D.A. Mackey (David); T.L. Young (Terri); C.M. van Duijn (Cock); S-M. Saw (Seang-Mei); J.E. Bailey-Wilson (Joan); D.E. Stambolian (Dwight); C.C.W. Klaver (Caroline); C.J. Hammond (Christopher)

    2013-01-01

    textabstractRefractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European anc

  13. Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia

    NARCIS (Netherlands)

    V.J.M. Verhoeven (Virginie); P.G. Hysi (Pirro); R. Wojciechowski (Robert); Q. Fan (Qiao); J. Guggenheim (Jean); R. Höhn (René); S. MacGregor (Stuart); A.W. Hewit (Alex); A. Nag (Abhishek); C-Y. Cheng (Ching-Yu); E. Yonova-Doing (Ekaterina); X. Zhou (Xin); M.K. Ikram (Kamran); G.H.S. Buitendijk (Gabrielle); G. Mcmahon (George); J.P. Kemp (John); B.S. Pourcain (Beate); C.L. Simpson (Claire); M.J. Mäkelä; T. Lehtimäki (Terho); M. Kähönen (Mika); A.D. Paterson (Andrew); M. Hosseini (Mehran); H.S. Wong (Hoi Suen); L. Xu (Liang); J.B. Jonas; O. Pärssinen (Olavi); J. Wedenoja (Juho); S.P. Yip (Shea Ping); D.W.H. Ho (Daniel); C.P. Pang (Chi); L.J. Chen (Li); K.P. Burdon (Kathryn); J.E. Craig (Jamie); B.E.K. Klein (Barbara); B.E.K. Klein (Barbara); T. Haller (Toomas); A. Metspalu (Andres); C.C. Khor; E.S. Tai (Shyong); T. Aung (Tin); E.N. Vithana (Eranga); W.-T. Tay (Wan-Ting); V.A. Barathi (Veluchamy); P. Chen (Ping); R. Li (Rui); J. Liao (Jie); Y. Zheng (Yuhui); R.T.H. Ong (Rick Twee-Hee); A. Döring (Angela); D.M. Evans (David); N.J. Timpson (Nicholas); A. Verkerk; T. Meitinger (Thomas); O. Raitakari (Olli); F. Hawthorne (Felicia); T.D. Spector (Timothy); L.C. Karssen (Lennart); M. Pirastu (Mario); D. Murgia (Daniela); W.Q. Ang (Wei); A. Mishra (Aniket); G.W. Montgomery (Grant); C.E. Pennell (Craig); P. Cumberland (Phillippa); I. Cotlarciuc (Ioana); P. Mitchell (Paul); J.J. Wang (Jie Jin); M. Schache (Maria); S. Janmahasathian (Sarayut); R.P. Igo Jr. (Robert); J.H. Lass Jr. (Jonathan); E.Y. Chew (Emily); S.K. Iyengar (Sudha); T.G.M.F. Gorgels (Theo); I. Rudan (Igor); C. Hayward (Caroline); A.F. Wright (Alan); O. Polasek (Ozren); Z. Vatavuk (Zoran); J.F. Wilson (James); B. Fleck (Brian); T. Zeller (Tanja); A. Mirshahi (Alireza); C. Müller (Christian); A.G. Uitterlinden (André); F. Rivadeneira Ramirez (Fernando); J.R. Vingerling (Hans); A. Hofman (Albert); B.A. Oostra (Ben); N. Amin (Najaf); A.A.B. Bergen (Arthur); Y.Y. Teo (Yik Ying); J.S. Rahi (Jugnoo); V. Vitart (Veronique); C. Williams (Cathy); P.N. Baird (Paul); T.Y. Wong (Tien); K. Oexle (Konrad); A.F.H. Pfeiffer (Andreas); D.A. Mackey (David); T.L. Young (Terri); C.M. van Duijn (Cock); S-M. Saw (Seang-Mei); J.E. Bailey-Wilson (Joan); D.E. Stambolian (Dwight); C.C.W. Klaver (Caroline); C.J. Hammond (Christopher)

    2013-01-01

    textabstractRefractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European

  14. Genome-wide transcriptome analysis revealed organelle specific responses to temperature variations in algae

    Science.gov (United States)

    Shin, HyeonSeok; Hong, Seong-Joo; Yoo, Chan; Han, Mi-Ae; Lee, Hookeun; Choi, Hyung-Kyoon; Cho, Suhyung; Lee, Choul-Gyun; Cho, Byung-Kwan

    2016-01-01

    Temperature is a critical environmental factor that affects microalgal growth. However, microalgal coping mechanisms for temperature variations are unclear. Here, we determined changes in transcriptome, total carbohydrate, total fatty acid methyl ester, and fatty acid composition of Tetraselmis sp. KCTC12432BP, a strain with a broad temperature tolerance range, to elucidate the tolerance mechanisms in response to large temperature variations. Owing to unavailability of genome sequence information, de novo transcriptome assembly coupled with BLAST analysis was performed using strand specific RNA-seq data. This resulted in 26,245 protein-coding transcripts, of which 83.7% could be annotated to putative functions. We identified more than 681 genes differentially expressed, suggesting an organelle-specific response to temperature variation. Among these, the genes related to the photosynthetic electron transfer chain, which are localized in the plastid thylakoid membrane, were upregulated at low temperature. However, the transcripts related to the electron transport chain and biosynthesis of phosphatidylethanolamine localized in mitochondria were upregulated at high temperature. These results show that the low energy uptake by repressed photosynthesis under low and high temperature conditions is compensated by different mechanisms, including photosystem I and mitochondrial oxidative phosphorylation, respectively. This study illustrates that microalgae tolerate different temperature conditions through organelle specific mechanisms. PMID:27883062

  15. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

    DEFF Research Database (Denmark)

    O'Dushlaine, Colm; Rossin, Lizzy; Lee, Phil H.

    2015-01-01

    Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from ...

  16. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

    NARCIS (Netherlands)

    O'Dushlaine, Colm; Rossin, Lizzy; Lee, Phil H.; Duncan, Laramie; Parikshak, Neelroop N.; Newhouse, Stephen; Ripke, Stephan; Neale, Benjamin M.; Purcell, Shaun M.; Posthuma, Danielle; Nurnberger, John I.; Lee, S. Hong; Faraone, Stephen V.; Perlis, Roy H.; Mowry, Bryan J.; Thapar, Anita; Goddard, Michael E.; Witte, John S.; Absher, Devin; Agartz, Ingrid; Akil, Huda; Amin, Farooq; Andreassen, Ole A.; Anjorin, Adebayo; Anney, Richard; Anttila, Verneri; Arking, Dan E.; Asherson, Philip; Azevedo, Maria H.; Backlund, Lena; Badner, Judith A.; Bailey, Anthony J.; Banaschewski, Tobias; Barchas, Jack D.; Barnes, Michael R.; Barrett, Thomas B.; Bass, Nicholas; Battaglia, Agatino; Bauer, Michael; Bayes, Monica; Bellivier, Frank; Bergen, Sarah E.; Berrettini, Wade; Betancur, Catalina; Bettecken, Thomas; Biederman, Joseph; Binder, Elisabeth B.; Black, Donald W.; Blackwood, Douglas H. R.; Bloss, Cinnamon S.; Boehnke, Michael; Boomsma, Dorret I.; Breuer, Rene; Bruggeman, Richard; Cormican, Paul; Buccola, Nancy G.; Buitelaar, Jan K.; Bunney, William E.; Buxbaum, Joseph D.; Byerley, William F.; Byrne, Enda M.; Caesar, Sian; Cahn, Wiepke; Cantor, Rita M.; Casas, Miguel; Chakravarti, Aravinda; Chambert, Kimberly; Choudhury, Khalid; Cichon, Sven; Mattheisen, Manuel; Cloninger, C. Robert; Collier, David A.; Cook, Edwin H.; Coon, Hilary; Cormand, Bru; Corvin, Aiden; Coryell, William H.; Craig, David W.; Craig, Ian W.; Crosbie, Jennifer; Cuccaro, Michael L.; Curtis, David; Czamara, Darina; Datta, Susmita; Dawson, Geraldine; Day, Richard; De Geus, Eco J.; Degenhardt, Franziska; Djurovic, Srdjan; Donohoe, Gary J.; Doyle, Alysa E.; Duan, Jubao; Dudbridge, Frank; Duketis, Eftichia; Ebstein, Richard P.; Edenberg, Howard J.; Elia, Josephine; Ennis, Sean; Etain, Bruno; Fanous, Ayman; Farmer, Anne E.; Ferrier, I. Nicol; Flicldnger, Matthew; Fombonne, Eric; Foroud, Tatiana; Frank, Josef; Franke, Barbara; Fraser, Christine; Freedman, Robert; Freimer, Nelson B.; Freitag, Christine M.; Friedl, Marion; Frisen, Louise; Gailagher, Louise; Gejman, Pablo V.; Georgieva, Lyudmila; Gershon, Elliot S.; Giegling, Ina; Gill, Michael; Gordon, Scott D.; Gordon-Smith, Katherine; Green, Elaine K.; Greenwood, Tiffany A.; Grice, Dorothy E.; Gross, Magdalena; Grozeva, Detelina; Guan, Weihua; Gurling, Hugh; De Haan, Lieuwe; Haines, Jonathan L.; Hakonarson, Hakon; Hallmayer, Joachim; Hamilton, Steven P.; Hamshere, Marian L.; Hansen, Thomas F.; Hartmann, Annette M.; Hautzinger, Martin; Heath, Andrew C.; Henders, Anjali K.; Herms, Stefan; Hickie, Ian B.; Hipolito, Maria; Hoefels, Susanne; Holsboer, Florian; Hoogendijk, Witte J.; Hottenga, Jouke-Jan; Hultman, Christina M.; Hus, Vanessa; Ingason, Andres; Ising, Marcus; Jamain, Stephane; Jones, Edward G.; Jones, Ian; Jones, Lisa; Tzeng, Jung-Ying; Kaehler, Anna K.; Kahn, Rene S.; Kandaswamy, Radhika; Keller, Matthew C.; Kennedy, James L.; Kenny, Elaine; Kent, Lindsey; Kim, Yunjung; Kirov, George K.; Klauck, Sabine M.; Klei, Lambertus; Knowles, James A.; Kohli, Martin A.; Koller, Daniel L.; Konte, Bettina; Korszun, Ania; Krabbendam, Lydia; Krasucki, Robert; Kuntsi, Jonna; Kwan, Phoenix; Landen, Mikael; Laengstroem, Niklas; Lathrop, Mark; Lawrence, Jacob; Lawson, William B.; Leboyer, Marion; Ledbetter, David H.; Lencz, Todd; Lesch, Klaus-Peter; Levinson, Douglas F.; Lewis, Cathryn M.; Li, Jun; Lichtenstein, Paul; Lieberman, Jeffrey A.; Lin, Dan-Yu; Linszen, Don H.; Liu, Chunyu; Lohoff, Falk W.; Loo, Sandra K.; Lord, Catherine; Lowe, Jennifer K.; Lucae, Susanne; MacIntyre, Donald J.; Madden, Pamela A. F.; Maestrini, Elena; Magnusson, Patrik K. E.; Mahon, Pamela B.; Maier, Wolfgang; Malhotra, Anil K.; Mane, Shrikant M.; Martin, Christa L.; Martin, Nicholas G.; Matthews, Keith; Mattingsdal, Morten; McCarroll, Steven A.; McGhee, Kevin A.; McGough, James J.; McGrath, Patrick J.; McGuffin, Peter; McInnis, Melvin G.; McIntosh, Andrew; McKinney, Rebecca; McLean, Alan W.; McMahon, Francis J.; McMahon, William M.; McQuillin, Andrew; Medeiros, Helena; Medland, Sarah E.; Meier, Sandra; Melle, Ingrid; Meng, Fan; Meyer, Jobst; Middeldorp, Christel M.; Middleton, Lefkos; Milanova, Vihra; Miranda, Ana; Monaco, Anthony P.; Montgomery, Grant W.; Moran, Jennifer L.; Moreno-De-Luca, Daniel; Morken, Gunnar; Morris, Derek W.; Morrow, Eric M.; Moskvina, Valentina; Muglia, Pierandrea; Muehleisen, Thomas W.; Muir, Walter J.; Mueller-Myhsok, Bertram; Murtha, Michael; Myers, Richard M.; Myin-Germeys, Inez; Neale, Michael C.; Nelson, Stan F.; Nievergelt, Caroline M.; Nikolov, Ivan; Nimgaonkar, Vishwajit; Nolen, Willem A.; Noethen, Markus M.; Nwulia, Evaristus A.; Nyholt, Dale R.; Oades, Robert D.; Olincy, Ann; Oliveira, Guiomar; Olsen, Line; Ophoff, Roel A.; Osby, Urban; Owen, Michael J.; Palotie, Aarno; Parr, Jeremy R.; Paterson, Andrew D.; Pato, Carlos N.; Pato, Michele T.; Penninx, Brenda W.; Pergadia, Michele L.; Pericak-Vance, Margaret A.; Pickard, Benjamin S.; Pimm, Jonathan; Piven, Joseph; Potash, James B.; Poustka, Fritz; Propping, Peter; Puri, Vinay; Quested, Digby J.; Quinn, Emma M.; Ramos-Quiroga, Josep Antoni; Rasmussen, Henrik B.; Raychaudhuri, Soumya; Rehnstroem, Karola; Reif, Andreas; Ribases, Marta; Rice, John P.; Rietschel, Marcella; Roeder, Kathryn; Roeyers, Herbert; Rothenberger, Aribert; Rouleau, Guy; Ruderfer, Douglas; Rujescu, Dan; Sanders, Alan R.; Sanders, Stephan J.; Santangelo, Susan L.; Sergeant, Joseph A.; Schachar, Russell; Schalling, Martin; Schatzberg, Alan F.; Scheftner, William A.; Schellenberg, Gerard D.; Scherer, Stephen W.; Schork, Nicholas J.; Schulze, Thomas G.; Schumacher, Johannes; Schwarz, Markus; Scolnick, Edward; Scott, Laura J.; Shi, Jianxin; Shilling, Paul D.; Shyn, Stanley I.; Silverman, Jeremy M.; Slager, Susan L.; Smalley, Susan L.; Smit, Johannes H.; Smith, Erin N.; Sonuga-Barke, Edmund J. S.; Cair, David St.; State, Matthew; Steffens, Michael; Steinhausen, Hans-Christoph; Strauss, John S.; Strohmaier, Jana; Stroup, T. Scott; Sutdiffe, James S.; Szatmari, Peter; Szelinger, Szabocls; Thirumalai, Srinivasa; Thompson, Robert C.; Todorov, Alexandre A.; Tozzi, Federica; Treutlein, Jens; Uhr, Manfred; Van den Oord, Edwin J. C. G.; Van Grootheest, Gerard; Van Os, Jim; Vicente, Astrid M.; Vieland, Veronica J.; Vincent, John B.; Visscher, Peter M.; Walsh, Christopher A.; Wassink, Thomas H.; Watson, Stanley J.; Weissman, Myrna M.; Werge, Thomas; Wienker, Thomas F.; Wijsman, Ellen M.; Willemsen, Gonneke; Williams, Nigel; Willsey, A. Jeremy; Witt, Stephanie H.; Xu, Wei; Young, Allan H.; Yu, Timothy W.; Zammit, Stanley; Zandi, Peter P.; Zhang, Peng; Zitman, Frans G.; Zoellner, Sebastian; Devlin, Bernie; Kelsoe, John R.; Sklar, Pamela; Daly, Mark J.; O'Donovan, Michael C.; Craddock, Nicholas; Kendler, Kenneth S.; Weiss, Lauren A.; Wray, Naomi R.; Zhao, Zhaoming; Geschwind, Daniel H.; Sullivan, Patrick F.; Smoller, Jordan W.; Holmans, Peter A.; Breen, Gerome

    2015-01-01

    Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from ove

  17. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

    NARCIS (Netherlands)

    Köttgen, Anna; Albrecht, Eva; Teumer, Alexander; Vitart, Veronique; Krumsiek, Jan; Hundertmark, Claudia; Pistis, Giorgio; Ruggiero, Daniela; O'Seaghdha, Conall M; Haller, Toomas; Yang, Qiong; Tanaka, Toshiko; Johnson, Andrew D; Kutalik, Zoltán; Smith, Albert V; Shi, Julia; Struchalin, Maksim; Middelberg, Rita P S; Brown, Morris J; Gaffo, Angelo L; Pirastu, Nicola; Li, Guo; Hayward, Caroline; Zemunik, Tatijana; Huffman, Jennifer; Yengo, Loic; Zhao, Jing Hua; Demirkan, Ayse; Feitosa, Mary F; Liu, Xuan; Malerba, Giovanni; Lopez, Lorna M; van der Harst, Pim; Li, Xinzhong; Kleber, Marcus E; Hicks, Andrew A; Nolte, Ilja M; Johansson, Asa; Murgia, Federico; Wild, Sarah H; Bakker, Stephan J L; Peden, John F; Dehghan, Abbas; Steri, Maristella; Tenesa, Albert; Lagou, Vasiliki; Salo, Perttu; Mangino, Massimo; Rose, Lynda M; Lehtimäki, Terho; Woodward, Owen M; Okada, Yukinori; Tin, Adrienne; Müller, Christian; Oldmeadow, Christopher; Putku, Margus; Czamara, Darina; Kraft, Peter; Frogheri, Laura; Thun, Gian Andri; Grotevendt, Anne; Gislason, Gauti Kjartan; Harris, Tamara B; Launer, Lenore J; McArdle, Patrick; Shuldiner, Alan R; Boerwinkle, Eric; Coresh, Josef; Schmidt, Helena; Schallert, Michael; Martin, Nicholas G; Montgomery, Grant W; Kubo, Michiaki; Nakamura, Yusuke; Tanaka, Toshihiro; Munroe, Patricia B; Samani, Nilesh J; Jacobs, David R; Liu, Kiang; D'Adamo, Pio; Ulivi, Sheila; Rotter, Jerome I; Psaty, Bruce M; Vollenweider, Peter; Waeber, Gerard; Campbell, Susan; Devuyst, Olivier; Navarro, Pau; Kolcic, Ivana; Hastie, Nicholas; Balkau, Beverley; Froguel, Philippe; Esko, Tõnu; Salumets, Andres; Khaw, Kay Tee; Langenberg, Claudia; Wareham, Nicholas J; Isaacs, Aaron; Kraja, Aldi; Zhang, Qunyuan; Wild, Philipp S; Scott, Rodney J; Holliday, Elizabeth G; Org, Elin; Viigimaa, Margus; Bandinelli, Stefania; Metter, Jeffrey E; Lupo, Antonio; Trabetti, Elisabetta; Sorice, Rossella; Döring, Angela; Lattka, Eva; Strauch, Konstantin; Theis, Fabian; Waldenberger, Melanie; Wichmann, H-Erich; Davies, Gail; Gow, Alan J; Bruinenberg, Marcel; Stolk, Ronald P; Kooner, Jaspal S; Zhang, Weihua; Winkelmann, Bernhard R; Boehm, Bernhard O; Lucae, Susanne; Penninx, Brenda W; Smit, Johannes H; Curhan, Gary; Mudgal, Poorva; Plenge, Robert M; Portas, Laura; Persico, Ivana; Kirin, Mirna; Wilson, James F; Mateo Leach, Irene; van Gilst, Wiek H; Goel, Anuj; Ongen, Halit; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G; Imboden, Medea; von Eckardstein, Arnold; Cucca, Francesco; Nagaraja, Ramaiah; Piras, Maria Grazia; Nauck, Matthias; Schurmann, Claudia; Budde, Kathrin; Ernst, Florian; Farrington, Susan M; Theodoratou, Evropi; Prokopenko, Inga; Stumvoll, Michael; Jula, Antti; Perola, Markus; Salomaa, Veikko; Shin, So-Youn; Spector, Tim D; Sala, Cinzia; Ridker, Paul M; Kähönen, Mika; Viikari, Jorma; Hengstenberg, Christian; Nelson, Christopher P; Meschia, James F; Nalls, Michael A; Sharma, Pankaj; Singleton, Andrew B; Kamatani, Naoyuki; Zeller, Tanja; Burnier, Michel; Attia, John; Laan, Maris; Klopp, Norman; Hillege, Hans L; Kloiber, Stefan; Choi, Hyon; Pirastu, Mario; Tore, Silvia; Probst-Hensch, Nicole M; Völzke, Henry; Gudnason, Vilmundur; Parsa, Afshin; Schmidt, Reinhold; Whitfield, John B; Fornage, Myriam; Gasparini, Paolo; Siscovick, David S; Polašek, Ozren; Campbell, Harry; Rudan, Igor; Bouatia-Naji, Nabila; Metspalu, Andres; Loos, Ruth J F; van Duijn, Cornelia M; Borecki, Ingrid B; Ferrucci, Luigi; Gambaro, Giovanni; Deary, Ian J; Wolffenbuttel, Bruce H R; Chambers, John C; März, Winfried; Pramstaller, Peter P; Snieder, Harold; Gyllensten, Ulf; Wright, Alan F; Navis, Gerjan; Watkins, Hugh; Witteman, Jacqueline C M; Sanna, Serena; Schipf, Sabine; Dunlop, Malcolm G; Tönjes, Anke; Ripatti, Samuli; Soranzo, Nicole; Toniolo, Daniela; Chasman, Daniel I; Raitakari, Olli; Kao, W H Linda; Ciullo, Marina; Fox, Caroline S; Caulfield, Mark; Bochud, Murielle; Gieger, Christian

    2013-01-01

    Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with se

  18. Genome-wide association analyses identify variants in developmental genes associated with hypospadias

    DEFF Research Database (Denmark)

    Geller, Frank; Feenstra, Bjarke; Carstensen, Lisbeth

    2014-01-01

    Hypospadias is a common congenital condition in boys in which the urethra opens on the underside of the penis. We performed a genome-wide association study on 1,006 surgery-confirmed hypospadias cases and 5,486 controls from Denmark. After replication genotyping of an additional 1,972 cases and 1...

  19. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

    NARCIS (Netherlands)

    O'Dushlaine, Colm; Rossin, Lizzy; Lee, Phil H.; Duncan, Laramie; Parikshak, Neelroop N.; Newhouse, Stephen; Ripke, Stephan; Neale, Benjamin M.; Purcell, Shaun M.; Posthuma, Danielle; Nurnberger, John I.; Lee, S. Hong; Faraone, Stephen V.; Perlis, Roy H.; Mowry, Bryan J.; Thapar, Anita; Goddard, Michael E.; Witte, John S.; Absher, Devin; Agartz, Ingrid; Akil, Huda; Amin, Farooq; Andreassen, Ole A.; Anjorin, Adebayo; Anney, Richard; Anttila, Verneri; Arking, Dan E.; Asherson, Philip; Azevedo, Maria H.; Backlund, Lena; Badner, Judith A.; Bailey, Anthony J.; Banaschewski, Tobias; Barchas, Jack D.; Barnes, Michael R.; Barrett, Thomas B.; Bass, Nicholas; Battaglia, Agatino; Bauer, Michael; Bayes, Monica; Bellivier, Frank; Bergen, Sarah E.; Berrettini, Wade; Betancur, Catalina; Bettecken, Thomas; Biederman, Joseph; Binder, Elisabeth B.; Black, Donald W.; Blackwood, Douglas H. R.; Bloss, Cinnamon S.; Boehnke, Michael; Boomsma, Dorret I.; Breuer, Rene; Bruggeman, Richard; Cormican, Paul; Buccola, Nancy G.; Buitelaar, Jan K.; Bunney, William E.; Buxbaum, Joseph D.; Byerley, William F.; Byrne, Enda M.; Caesar, Sian; Cahn, Wiepke; Cantor, Rita M.; Casas, Miguel; Chakravarti, Aravinda; Chambert, Kimberly; Choudhury, Khalid; Cichon, Sven; Mattheisen, Manuel; Cloninger, C. Robert; Collier, David A.; Cook, Edwin H.; Coon, Hilary; Cormand, Bru; Corvin, Aiden; Coryell, William H.; Craig, David W.; Craig, Ian W.; Crosbie, Jennifer; Cuccaro, Michael L.; Curtis, David; Czamara, Darina; Datta, Susmita; Dawson, Geraldine; Day, Richard; De Geus, Eco J.; Degenhardt, Franziska; Djurovic, Srdjan; Donohoe, Gary J.; Doyle, Alysa E.; Duan, Jubao; Dudbridge, Frank; Duketis, Eftichia; Ebstein, Richard P.; Edenberg, Howard J.; Elia, Josephine; Ennis, Sean; Etain, Bruno; Fanous, Ayman; Farmer, Anne E.; Ferrier, I. Nicol; Flicldnger, Matthew; Fombonne, Eric; Foroud, Tatiana; Frank, Josef; Franke, Barbara; Fraser, Christine; Freedman, Robert; Freimer, Nelson B.; Freitag, Christine M.; Friedl, Marion; Frisen, Louise; Gailagher, Louise; Gejman, Pablo V.; Georgieva, Lyudmila; Gershon, Elliot S.; Giegling, Ina; Gill, Michael; Gordon, Scott D.; Gordon-Smith, Katherine; Green, Elaine K.; Greenwood, Tiffany A.; Grice, Dorothy E.; Gross, Magdalena; Grozeva, Detelina; Guan, Weihua; Gurling, Hugh; De Haan, Lieuwe; Haines, Jonathan L.; Hakonarson, Hakon; Hallmayer, Joachim; Hamilton, Steven P.; Hamshere, Marian L.; Hansen, Thomas F.; Hartmann, Annette M.; Hautzinger, Martin; Heath, Andrew C.; Henders, Anjali K.; Herms, Stefan; Hickie, Ian B.; Hipolito, Maria; Hoefels, Susanne; Holsboer, Florian; Hoogendijk, Witte J.; Hottenga, Jouke-Jan; Hultman, Christina M.; Hus, Vanessa; Ingason, Andres; Ising, Marcus; Jamain, Stephane; Jones, Edward G.; Jones, Ian; Jones, Lisa; Tzeng, Jung-Ying; Kaehler, Anna K.; Kahn, Rene S.; Kandaswamy, Radhika; Keller, Matthew C.; Kennedy, James L.; Kenny, Elaine; Kent, Lindsey; Kim, Yunjung; Kirov, George K.; Klauck, Sabine M.; Klei, Lambertus; Knowles, James A.; Kohli, Martin A.; Koller, Daniel L.; Konte, Bettina; Korszun, Ania; Krabbendam, Lydia; Krasucki, Robert; Kuntsi, Jonna; Kwan, Phoenix; Landen, Mikael; Laengstroem, Niklas; Lathrop, Mark; Lawrence, Jacob; Lawson, William B.; Leboyer, Marion; Ledbetter, David H.; Lencz, Todd; Lesch, Klaus-Peter; Levinson, Douglas F.; Lewis, Cathryn M.; Li, Jun; Lichtenstein, Paul; Lieberman, Jeffrey A.; Lin, Dan-Yu; Linszen, Don H.; Liu, Chunyu; Lohoff, Falk W.; Loo, Sandra K.; Lord, Catherine; Lowe, Jennifer K.; Lucae, Susanne; MacIntyre, Donald J.; Madden, Pamela A. F.; Maestrini, Elena; Magnusson, Patrik K. E.; Mahon, Pamela B.; Maier, Wolfgang; Malhotra, Anil K.; Mane, Shrikant M.; Martin, Christa L.; Martin, Nicholas G.; Matthews, Keith; Mattingsdal, Morten; McCarroll, Steven A.; McGhee, Kevin A.; McGough, James J.; McGrath, Patrick J.; McGuffin, Peter; McInnis, Melvin G.; McIntosh, Andrew; McKinney, Rebecca; McLean, Alan W.; McMahon, Francis J.; McMahon, William M.; McQuillin, Andrew; Medeiros, Helena; Medland, Sarah E.; Meier, Sandra; Melle, Ingrid; Meng, Fan; Meyer, Jobst; Middeldorp, Christel M.; Middleton, Lefkos; Milanova, Vihra; Miranda, Ana; Monaco, Anthony P.; Montgomery, Grant W.; Moran, Jennifer L.; Moreno-De-Luca, Daniel; Morken, Gunnar; Morris, Derek W.; Morrow, Eric M.; Moskvina, Valentina; Muglia, Pierandrea; Muehleisen, Thomas W.; Muir, Walter J.; Mueller-Myhsok, Bertram; Murtha, Michael; Myers, Richard M.; Myin-Germeys, Inez; Neale, Michael C.; Nelson, Stan F.; Nievergelt, Caroline M.; Nikolov, Ivan; Nimgaonkar, Vishwajit; Nolen, Willem A.; Noethen, Markus M.

    Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from

  20. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function

    NARCIS (Netherlands)

    D.B. Hancock (Dana); M. Eijgelsheim (Mark); J.B. Wilk (Jemma); S.A. Gharib (Sina); L.R. Loehr (Laura); K. Marciante (Kristin); N. Franceschini (Nora); Y.M.T.A. van Durme; T.H. Chen; R.G. Barr (Graham); M.B. Schabath (Matthew); D.J. Couper (David); G.G. Brusselle (Guy); B.M. Psaty (Bruce); P. Tikka-Kleemola (Päivi); J.I. Rotter (Jerome); A.G. Uitterlinden (André); A. Hofman (Albert); N.M. Punjabi (Naresh); F. Rivadeneira Ramirez (Fernando); A.C. Morrison (Alanna); P.L. Enright (Paul); K.E. North (Kari); S.R. Heckbert (Susan); T. Lumley (Thomas); B.H.Ch. Stricker (Bruno); G.T. O'Connor (George); S.J. London (Stephanie)

    2010-01-01

    textabstractSpirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV1) and it

  1. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

    NARCIS (Netherlands)

    Köttgen, Anna; Albrecht, Eva; Teumer, Alexander; Vitart, Veronique; Krumsiek, Jan; Hundertmark, Claudia; Pistis, Giorgio; Ruggiero, Daniela; O'Seaghdha, Conall M; Haller, Toomas; Yang, Qiong; Tanaka, Toshiko; Johnson, Andrew D; Kutalik, Zoltán; Smith, Albert V; Shi, Julia; Struchalin, Maksim; Middelberg, Rita P S; Brown, Morris J; Gaffo, Angelo L; Pirastu, Nicola; Li, Guo; Hayward, Caroline; Zemunik, Tatijana; Huffman, Jennifer; Yengo, Loic; Zhao, Jing Hua; Demirkan, Ayse; Feitosa, Mary F; Liu, Xuan; Malerba, Giovanni; Lopez, Lorna M; van der Harst, Pim; Li, Xinzhong; Kleber, Marcus E; Hicks, Andrew A; Nolte, Ilja M; Johansson, Asa; Murgia, Federico; Wild, Sarah H; Bakker, Stephan J L; Peden, John F; Dehghan, Abbas; Steri, Maristella; Tenesa, Albert; Lagou, Vasiliki; Salo, Perttu; Mangino, Massimo; Rose, Lynda M; Lehtimäki, Terho; Woodward, Owen M; Okada, Yukinori; Tin, Adrienne; Müller, Christian; Oldmeadow, Christopher; Putku, Margus; Czamara, Darina; Kraft, Peter; Frogheri, Laura; Thun, Gian Andri; Grotevendt, Anne; Gislason, Gauti Kjartan; Harris, Tamara B; Launer, Lenore J; McArdle, Patrick; Shuldiner, Alan R; Boerwinkle, Eric; Coresh, Josef; Schmidt, Helena; Schallert, Michael; Martin, Nicholas G; Montgomery, Grant W; Kubo, Michiaki; Nakamura, Yusuke; Tanaka, Toshihiro; Munroe, Patricia B; Samani, Nilesh J; Jacobs, David R; Liu, Kiang; D'Adamo, Pio; Ulivi, Sheila; Rotter, Jerome I; Psaty, Bruce M; Vollenweider, Peter; Waeber, Gerard; Campbell, Susan; Devuyst, Olivier; Navarro, Pau; Kolcic, Ivana; Hastie, Nicholas; Balkau, Beverley; Froguel, Philippe; Esko, Tõnu; Salumets, Andres; Khaw, Kay Tee; Langenberg, Claudia; Wareham, Nicholas J; Isaacs, Aaron; Kraja, Aldi; Zhang, Qunyuan; Wild, Philipp S; Scott, Rodney J; Holliday, Elizabeth G; Org, Elin; Viigimaa, Margus; Bandinelli, Stefania; Metter, Jeffrey E; Lupo, Antonio; Trabetti, Elisabetta; Sorice, Rossella; Döring, Angela; Lattka, Eva; Strauch, Konstantin; Theis, Fabian; Waldenberger, Melanie; Wichmann, H-Erich; Davies, Gail; Gow, Alan J; Bruinenberg, Marcel; Stolk, Ronald P; Kooner, Jaspal S; Zhang, Weihua; Winkelmann, Bernhard R; Boehm, Bernhard O; Lucae, Susanne; Penninx, Brenda W; Smit, Johannes H; Curhan, Gary; Mudgal, Poorva; Plenge, Robert M; Portas, Laura; Persico, Ivana; Kirin, Mirna; Wilson, James F; Mateo Leach, Irene; van Gilst, Wiek H; Goel, Anuj; Ongen, Halit; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G; Imboden, Medea; von Eckardstein, Arnold; Cucca, Francesco; Nagaraja, Ramaiah; Piras, Maria Grazia; Nauck, Matthias; Schurmann, Claudia; Budde, Kathrin; Ernst, Florian; Farrington, Susan M; Theodoratou, Evropi; Prokopenko, Inga; Stumvoll, Michael; Jula, Antti; Perola, Markus; Salomaa, Veikko; Shin, So-Youn; Spector, Tim D; Sala, Cinzia; Ridker, Paul M; Kähönen, Mika; Viikari, Jorma; Hengstenberg, Christian; Nelson, Christopher P; Meschia, James F; Nalls, Michael A; Sharma, Pankaj; Singleton, Andrew B; Kamatani, Naoyuki; Zeller, Tanja; Burnier, Michel; Attia, John; Laan, Maris; Klopp, Norman; Hillege, Hans L; Kloiber, Stefan; Choi, Hyon; Pirastu, Mario; Tore, Silvia; Probst-Hensch, Nicole M; Völzke, Henry; Gudnason, Vilmundur; Parsa, Afshin; Schmidt, Reinhold; Whitfield, John B; Fornage, Myriam; Gasparini, Paolo; Siscovick, David S; Polašek, Ozren; Campbell, Harry; Rudan, Igor; Bouatia-Naji, Nabila; Metspalu, Andres; Loos, Ruth J F; van Duijn, Cornelia M; Borecki, Ingrid B; Ferrucci, Luigi; Gambaro, Giovanni; Deary, Ian J; Wolffenbuttel, Bruce H R; Chambers, John C; März, Winfried; Pramstaller, Peter P; Snieder, Harold; Gyllensten, Ulf; Wright, Alan F; Navis, Gerjan; Watkins, Hugh; Witteman, Jacqueline C M; Sanna, Serena; Schipf, Sabine; Dunlop, Malcolm G; Tönjes, Anke; Ripatti, Samuli; Soranzo, Nicole; Toniolo, Daniela; Chasman, Daniel I; Raitakari, Olli; Kao, W H Linda; Ciullo, Marina; Fox, Caroline S; Caulfield, Mark; Bochud, Murielle; Gieger, Christian

    Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with

  2. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

    NARCIS (Netherlands)

    O'Dushlaine, Colm; Rossin, Lizzy; Lee, Phil H.; Duncan, Laramie; Parikshak, Neelroop N.; Newhouse, Stephen; Ripke, Stephan; Neale, Benjamin M.; Purcell, Shaun M.; Posthuma, Danielle; Nurnberger, John I.; Lee, S. Hong; Faraone, Stephen V.; Perlis, Roy H.; Mowry, Bryan J.; Thapar, Anita; Goddard, Michael E.; Witte, John S.; Absher, Devin; Agartz, Ingrid; Akil, Huda; Amin, Farooq; Andreassen, Ole A.; Anjorin, Adebayo; Anney, Richard; Anttila, Verneri; Arking, Dan E.; Asherson, Philip; Azevedo, Maria H.; Backlund, Lena; Badner, Judith A.; Bailey, Anthony J.; Banaschewski, Tobias; Barchas, Jack D.; Barnes, Michael R.; Barrett, Thomas B.; Bass, Nicholas; Battaglia, Agatino; Bauer, Michael; Bayes, Monica; Bellivier, Frank; Bergen, Sarah E.; Berrettini, Wade; Betancur, Catalina; Bettecken, Thomas; Biederman, Joseph; Binder, Elisabeth B.; Black, Donald W.; Blackwood, Douglas H. R.; Bloss, Cinnamon S.; Boehnke, Michael; Boomsma, Dorret I.; Breuer, Rene; Bruggeman, Richard; Cormican, Paul; Buccola, Nancy G.; Buitelaar, Jan K.; Bunney, William E.; Buxbaum, Joseph D.; Byerley, William F.; Byrne, Enda M.; Caesar, Sian; Cahn, Wiepke; Cantor, Rita M.; Casas, Miguel; Chakravarti, Aravinda; Chambert, Kimberly; Choudhury, Khalid; Cichon, Sven; Mattheisen, Manuel; Cloninger, C. Robert; Collier, David A.; Cook, Edwin H.; Coon, Hilary; Cormand, Bru; Corvin, Aiden; Coryell, William H.; Craig, David W.; Craig, Ian W.; Crosbie, Jennifer; Cuccaro, Michael L.; Curtis, David; Czamara, Darina; Datta, Susmita; Dawson, Geraldine; Day, Richard; De Geus, Eco J.; Degenhardt, Franziska; Djurovic, Srdjan; Donohoe, Gary J.; Doyle, Alysa E.; Duan, Jubao; Dudbridge, Frank; Duketis, Eftichia; Ebstein, Richard P.; Edenberg, Howard J.; Elia, Josephine; Ennis, Sean; Etain, Bruno; Fanous, Ayman; Farmer, Anne E.; Ferrier, I. Nicol; Flicldnger, Matthew; Fombonne, Eric; Foroud, Tatiana; Frank, Josef; Franke, Barbara; Fraser, Christine; Freedman, Robert; Freimer, Nelson B.; Freitag, Christine M.; Friedl, Marion; Frisen, Louise; Gailagher, Louise; Gejman, Pablo V.; Georgieva, Lyudmila; Gershon, Elliot S.; Giegling, Ina; Gill, Michael; Gordon, Scott D.; Gordon-Smith, Katherine; Green, Elaine K.; Greenwood, Tiffany A.; Grice, Dorothy E.; Gross, Magdalena; Grozeva, Detelina; Guan, Weihua; Gurling, Hugh; De Haan, Lieuwe; Haines, Jonathan L.; Hakonarson, Hakon; Hallmayer, Joachim; Hamilton, Steven P.; Hamshere, Marian L.; Hansen, Thomas F.; Hartmann, Annette M.; Hautzinger, Martin; Heath, Andrew C.; Henders, Anjali K.; Herms, Stefan; Hickie, Ian B.; Hipolito, Maria; Hoefels, Susanne; Holsboer, Florian; Hoogendijk, Witte J.; Hottenga, Jouke-Jan; Hultman, Christina M.; Hus, Vanessa; Ingason, Andres; Ising, Marcus; Jamain, Stephane; Jones, Edward G.; Jones, Ian; Jones, Lisa; Tzeng, Jung-Ying; Kaehler, Anna K.; Kahn, Rene S.; Kandaswamy, Radhika; Keller, Matthew C.; Kennedy, James L.; Kenny, Elaine; Kent, Lindsey; Kim, Yunjung; Kirov, George K.; Klauck, Sabine M.; Klei, Lambertus; Knowles, James A.; Kohli, Martin A.; Koller, Daniel L.; Konte, Bettina; Korszun, Ania; Krabbendam, Lydia; Krasucki, Robert; Kuntsi, Jonna; Kwan, Phoenix; Landen, Mikael; Laengstroem, Niklas; Lathrop, Mark; Lawrence, Jacob; Lawson, William B.; Leboyer, Marion; Ledbetter, David H.; Lencz, Todd; Lesch, Klaus-Peter; Levinson, Douglas F.; Lewis, Cathryn M.; Li, Jun; Lichtenstein, Paul; Lieberman, Jeffrey A.; Lin, Dan-Yu; Linszen, Don H.; Liu, Chunyu; Lohoff, Falk W.; Loo, Sandra K.; Lord, Catherine; Lowe, Jennifer K.; Lucae, Susanne; MacIntyre, Donald J.; Madden, Pamela A. F.; Maestrini, Elena; Magnusson, Patrik K. E.; Mahon, Pamela B.; Maier, Wolfgang; Malhotra, Anil K.; Mane, Shrikant M.; Martin, Christa L.; Martin, Nicholas G.; Matthews, Keith; Mattingsdal, Morten; McCarroll, Steven A.; McGhee, Kevin A.; McGough, James J.; McGrath, Patrick J.; McGuffin, Peter; McInnis, Melvin G.; McIntosh, Andrew; McKinney, Rebecca; McLean, Alan W.; McMahon, Francis J.; McMahon, William M.; McQuillin, Andrew; Medeiros, Helena; Medland, Sarah E.; Meier, Sandra; Melle, Ingrid; Meng, Fan; Meyer, Jobst; Middeldorp, Christel M.; Middleton, Lefkos; Milanova, Vihra; Miranda, Ana; Monaco, Anthony P.; Montgomery, Grant W.; Moran, Jennifer L.; Moreno-De-Luca, Daniel; Morken, Gunnar; Morris, Derek W.; Morrow, Eric M.; Moskvina, Valentina; Muglia, Pierandrea; Muehleisen, Thomas W.; Muir, Walter J.; Mueller-Myhsok, Bertram; Murtha, Michael; Myers, Richard M.; Myin-Germeys, Inez; Neale, Michael C.; Nelson, Stan F.; Nievergelt, Caroline M.; Nikolov, Ivan; Nimgaonkar, Vishwajit; Nolen, Willem A.; Noethen, Markus M.; Nwulia, Evaristus A.; Nyholt, Dale R.; Oades, Robert D.; Olincy, Ann; Oliveira, Guiomar; Olsen, Line; Ophoff, Roel A.; Osby, Urban; Owen, Michael J.; Palotie, Aarno; Parr, Jeremy R.; Paterson, Andrew D.; Pato, Carlos N.; Pato, Michele T.; Penninx, Brenda W.; Pergadia, Michele L.; Pericak-Vance, Margaret A.; Pickard, Benjamin S.; Pimm, Jonathan; Piven, Joseph; Potash, James B.; Poustka, Fritz; Propping, Peter; Puri, Vinay; Quested, Digby J.; Quinn, Emma M.; Ramos-Quiroga, Josep Antoni; Rasmussen, Henrik B.; Raychaudhuri, Soumya; Rehnstroem, Karola; Reif, Andreas; Ribases, Marta; Rice, John P.; Rietschel, Marcella; Roeder, Kathryn; Roeyers, Herbert; Rothenberger, Aribert; Rouleau, Guy; Ruderfer, Douglas; Rujescu, Dan; Sanders, Alan R.; Sanders, Stephan J.; Santangelo, Susan L.; Sergeant, Joseph A.; Schachar, Russell; Schalling, Martin; Schatzberg, Alan F.; Scheftner, William A.; Schellenberg, Gerard D.; Scherer, Stephen W.; Schork, Nicholas J.; Schulze, Thomas G.; Schumacher, Johannes; Schwarz, Markus; Scolnick, Edward; Scott, Laura J.; Shi, Jianxin; Shilling, Paul D.; Shyn, Stanley I.; Silverman, Jeremy M.; Slager, Susan L.; Smalley, Susan L.; Smit, Johannes H.; Smith, Erin N.; Sonuga-Barke, Edmund J. S.; Cair, David St.; State, Matthew; Steffens, Michael; Steinhausen, Hans-Christoph; Strauss, John S.; Strohmaier, Jana; Stroup, T. Scott; Sutdiffe, James S.; Szatmari, Peter; Szelinger, Szabocls; Thirumalai, Srinivasa; Thompson, Robert C.; Todorov, Alexandre A.; Tozzi, Federica; Treutlein, Jens; Uhr, Manfred; Van den Oord, Edwin J. C. G.; Van Grootheest, Gerard; Van Os, Jim; Vicente, Astrid M.; Vieland, Veronica J.; Vincent, John B.; Visscher, Peter M.; Walsh, Christopher A.; Wassink, Thomas H.; Watson, Stanley J.; Weissman, Myrna M.; Werge, Thomas; Wienker, Thomas F.; Wijsman, Ellen M.; Willemsen, Gonneke; Williams, Nigel; Willsey, A. Jeremy; Witt, Stephanie H.; Xu, Wei; Young, Allan H.; Yu, Timothy W.; Zammit, Stanley; Zandi, Peter P.; Zhang, Peng; Zitman, Frans G.; Zoellner, Sebastian; Devlin, Bernie; Kelsoe, John R.; Sklar, Pamela; Daly, Mark J.; O'Donovan, Michael C.; Craddock, Nicholas; Kendler, Kenneth S.; Weiss, Lauren A.; Wray, Naomi R.; Zhao, Zhaoming; Geschwind, Daniel H.; Sullivan, Patrick F.; Smoller, Jordan W.; Holmans, Peter A.; Breen, Gerome

    2015-01-01

    Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from ove

  3. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function

    NARCIS (Netherlands)

    D.B. Hancock (Dana); M. Eijgelsheim (Mark); J.B. Wilk (Jemma); S.A. Gharib (Sina); L.R. Loehr (Laura); K. Marciante (Kristin); N. Franceschini (Nora); Y.M.T.A. van Durme; T.H. Chen; R.G. Barr (Graham); M.B. Schabath (Matthew); D.J. Couper (David); G.G. Brusselle (Guy); B.M. Psaty (Bruce); P. Tikka-Kleemola (Päivi); J.I. Rotter (Jerome); A.G. Uitterlinden (André); A. Hofman (Albert); N.M. Punjabi (Naresh); F. Rivadeneira Ramirez (Fernando); A.C. Morrison (Alanna); P.L. Enright (Paul); K.E. North (Kari); S.R. Heckbert (Susan); T. Lumley (Thomas); B.H.Ch. Stricker (Bruno); G.T. O'Connor (George); S.J. London (Stephanie)

    2010-01-01

    textabstractSpirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV1) and

  4. Genome-wide meta-analyses of smoking behaviors in African Americans.

    Science.gov (United States)

    David, S P; Hamidovic, A; Chen, G K; Bergen, A W; Wessel, J; Kasberger, J L; Brown, W M; Petruzella, S; Thacker, E L; Kim, Y; Nalls, M A; Tranah, G J; Sung, Y J; Ambrosone, C B; Arnett, D; Bandera, E V; Becker, D M; Becker, L; Berndt, S I; Bernstein, L; Blot, W J; Broeckel, U; Buxbaum, S G; Caporaso, N; Casey, G; Chanock, S J; Deming, S L; Diver, W R; Eaton, C B; Evans, D S; Evans, M K; Fornage, M; Franceschini, N; Harris, T B; Henderson, B E; Hernandez, D G; Hitsman, B; Hu, J J; Hunt, S C; Ingles, S A; John, E M; Kittles, R; Kolb, S; Kolonel, L N; Le Marchand, L; Liu, Y; Lohman, K K; McKnight, B; Millikan, R C; Murphy, A; Neslund-Dudas, C; Nyante, S; Press, M; Psaty, B M; Rao, D C; Redline, S; Rodriguez-Gil, J L; Rybicki, B A; Signorello, L B; Singleton, A B; Smoller, J; Snively, B; Spring, B; Stanford, J L; Strom, S S; Swan, G E; Taylor, K D; Thun, M J; Wilson, A F; Witte, J S; Yamamura, Y; Yanek, L R; Yu, K; Zheng, W; Ziegler, R G; Zonderman, A B; Jorgenson, E; Haiman, C A; Furberg, H

    2012-05-22

    The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

  5. Genome-wide transcriptomic alterations induced by ethanol treatment in human dental pulp stem cells (DPSCs

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    Omar Khalid

    2014-12-01

    Full Text Available Human dental pulp stem cells (DPSCs isolated from adult dental pulp are multipotent mesenchymal stem cells that can be directed to differentiate into osteogenic/odontogenic cells and also trans-differentiate into neuronal cells. The utility of DPSC has been explored in odontogenic differentiation for tooth regeneration. Alcohol abuse appears to lead to periodontal disease, tooth decay and mouth sores that are potentially precancerous. Persons who abuse alcohol are at high risk of having seriously deteriorated teeth, gums and compromised oral health in general. It is currently unknown if alcohol exposure has any impact on adult stem cell maintenance, stem cell fate determination and plasticity, and stem cell niche environment. Here we provide detailed experimental methods, analysis and information associated with our data deposited into Gene Expression Omnibus (GEO under GSE57255. Our data provide transcriptomic changes that are occurring by EtOH treatment of DPSCs at 24-hour and 48-hour time point.

  6. Insight in genome-wide association of metabolite quantitative traits by exome sequence analyses.

    Science.gov (United States)

    Demirkan, Ayşe; Henneman, Peter; Verhoeven, Aswin; Dharuri, Harish; Amin, Najaf; van Klinken, Jan Bert; Karssen, Lennart C; de Vries, Boukje; Meissner, Axel; Göraler, Sibel; van den Maagdenberg, Arn M J M; Deelder, André M; C 't Hoen, Peter A; van Duijn, Cornelia M; van Dijk, Ko Willems

    2015-01-01

    Metabolite quantitative traits carry great promise for epidemiological studies, and their genetic background has been addressed using Genome-Wide Association Studies (GWAS). Thus far, the role of less common variants has not been exhaustively studied. Here, we set out a GWAS for metabolite quantitative traits in serum, followed by exome sequence analysis to zoom in on putative causal variants in the associated genes. 1H Nuclear Magnetic Resonance (1H-NMR) spectroscopy experiments yielded successful quantification of 42 unique metabolites in 2,482 individuals from The Erasmus Rucphen Family (ERF) study. Heritability of metabolites were estimated by SOLAR. GWAS was performed by linear mixed models, using HapMap imputations. Based on physical vicinity and pathway analyses, candidate genes were screened for coding region variation using exome sequence data. Heritability estimates for metabolites ranged between 10% and 52%. GWAS replicated three known loci in the metabolome wide significance: CPS1 with glycine (P-value  = 1.27×10-32), PRODH with proline (P-value  = 1.11×10-19), SLC16A9 with carnitine level (P-value  = 4.81×10-14) and uncovered a novel association between DMGDH and dimethyl-glycine (P-value  = 1.65×10-19) level. In addition, we found three novel, suggestively significant loci: TNP1 with pyruvate (P-value  = 1.26×10-8), KCNJ16 with 3-hydroxybutyrate (P-value  = 1.65×10-8) and 2p12 locus with valine (P-value  = 3.49×10-8). Exome sequence analysis identified potentially causal coding and regulatory variants located in the genes CPS1, KCNJ2 and PRODH, and revealed allelic heterogeneity for CPS1 and PRODH. Combined GWAS and exome analyses of metabolites detected by high-resolution 1H-NMR is a robust approach to uncover metabolite quantitative trait loci (mQTL), and the likely causative variants in these loci. It is anticipated that insight in the genetics of intermediate phenotypes will provide additional insight into the

  7. Insight in genome-wide association of metabolite quantitative traits by exome sequence analyses.

    Directory of Open Access Journals (Sweden)

    Ayşe Demirkan

    2015-01-01

    Full Text Available Metabolite quantitative traits carry great promise for epidemiological studies, and their genetic background has been addressed using Genome-Wide Association Studies (GWAS. Thus far, the role of less common variants has not been exhaustively studied. Here, we set out a GWAS for metabolite quantitative traits in serum, followed by exome sequence analysis to zoom in on putative causal variants in the associated genes. 1H Nuclear Magnetic Resonance (1H-NMR spectroscopy experiments yielded successful quantification of 42 unique metabolites in 2,482 individuals from The Erasmus Rucphen Family (ERF study. Heritability of metabolites were estimated by SOLAR. GWAS was performed by linear mixed models, using HapMap imputations. Based on physical vicinity and pathway analyses, candidate genes were screened for coding region variation using exome sequence data. Heritability estimates for metabolites ranged between 10% and 52%. GWAS replicated three known loci in the metabolome wide significance: CPS1 with glycine (P-value  = 1.27×10-32, PRODH with proline (P-value  = 1.11×10-19, SLC16A9 with carnitine level (P-value  = 4.81×10-14 and uncovered a novel association between DMGDH and dimethyl-glycine (P-value  = 1.65×10-19 level. In addition, we found three novel, suggestively significant loci: TNP1 with pyruvate (P-value  = 1.26×10-8, KCNJ16 with 3-hydroxybutyrate (P-value  = 1.65×10-8 and 2p12 locus with valine (P-value  = 3.49×10-8. Exome sequence analysis identified potentially causal coding and regulatory variants located in the genes CPS1, KCNJ2 and PRODH, and revealed allelic heterogeneity for CPS1 and PRODH. Combined GWAS and exome analyses of metabolites detected by high-resolution 1H-NMR is a robust approach to uncover metabolite quantitative trait loci (mQTL, and the likely causative variants in these loci. It is anticipated that insight in the genetics of intermediate phenotypes will provide additional insight

  8. Genome-wide transcriptome and proteome analysis on different developmental stages of Cordyceps militaris.

    Directory of Open Access Journals (Sweden)

    Yalin Yin

    Full Text Available BACKGROUND: Cordyceps militaris, an ascomycete caterpillar fungus, has been used as a traditional Chinese medicine for many years owing to its anticancer and immunomodulatory activities. Currently, artificial culturing of this beneficial fungus has been widely used and can meet the market, but systematic molecular studies on the developmental stages of cultured C. militaris at transcriptional and translational levels have not been determined. METHODOLOGY/PRINCIPAL FINDINGS: We utilized high-throughput Illumina sequencing to obtain the transcriptomes of C. militaris mycelium and fruiting body. All clean reads were mapped to C. militaris genome and most of the reads showed perfect coverage. Alternative splicing and novel transcripts were predicted to enrich the database. Gene expression analysis revealed that 2,113 genes were up-regulated in mycelium and 599 in fruiting body. Gene Ontology (GO and Kyoto Encyclopedia of Genes and Genomes (KEGG analysis were performed to analyze the genes with expression differences. Moreover, the putative cordycepin metabolism difference between different developmental stages was studied. In addition, the proteome data of mycelium and fruiting body were obtained by one-dimensional gel electrophoresis (1-DGE coupled with nano-electrospray ionization liquid chromatography tandem mass spectrometry (nESI-LC-MS/MS. 359 and 214 proteins were detected from mycelium and fruiting body respectively. GO, KEGG and Cluster of Orthologous Groups (COG analysis were further conducted to better understand their difference. We analyzed the amounts of some noteworthy proteins in these two samples including lectin, superoxide dismutase, glycoside hydrolase and proteins involved in cordycepin metabolism, providing important information for further protein studies. CONCLUSIONS/SIGNIFICANCE: The results reveal the difference in gene expression between the mycelium and fruiting body of artificially cultivated C. militaris by transcriptome

  9. Genome-Wide Transcriptome and Proteome Analysis on Different Developmental Stages of Cordyceps militaris

    Science.gov (United States)

    Yin, Yalin; Yu, Guojun; Chen, Yijie; Jiang, Shuai; Wang, Man; Jin, Yanxia; Lan, Xianqing; Liang, Yi; Sun, Hui

    2012-01-01

    Background Cordyceps militaris, an ascomycete caterpillar fungus, has been used as a traditional Chinese medicine for many years owing to its anticancer and immunomodulatory activities. Currently, artificial culturing of this beneficial fungus has been widely used and can meet the market, but systematic molecular studies on the developmental stages of cultured C. militaris at transcriptional and translational levels have not been determined. Methodology/Principal Findings We utilized high-throughput Illumina sequencing to obtain the transcriptomes of C. militaris mycelium and fruiting body. All clean reads were mapped to C. militaris genome and most of the reads showed perfect coverage. Alternative splicing and novel transcripts were predicted to enrich the database. Gene expression analysis revealed that 2,113 genes were up-regulated in mycelium and 599 in fruiting body. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to analyze the genes with expression differences. Moreover, the putative cordycepin metabolism difference between different developmental stages was studied. In addition, the proteome data of mycelium and fruiting body were obtained by one-dimensional gel electrophoresis (1-DGE) coupled with nano-electrospray ionization liquid chromatography tandem mass spectrometry (nESI-LC-MS/MS). 359 and 214 proteins were detected from mycelium and fruiting body respectively. GO, KEGG and Cluster of Orthologous Groups (COG) analysis were further conducted to better understand their difference. We analyzed the amounts of some noteworthy proteins in these two samples including lectin, superoxide dismutase, glycoside hydrolase and proteins involved in cordycepin metabolism, providing important information for further protein studies. Conclusions/Significance The results reveal the difference in gene expression between the mycelium and fruiting body of artificially cultivated C. militaris by transcriptome and proteome

  10. Genome wide transcriptome analysis of dendritic cells identifies genes with altered expression in psoriasis.

    Directory of Open Access Journals (Sweden)

    Kata Filkor

    Full Text Available Activation of dendritic cells by different pathogens induces the secretion of proinflammatory mediators resulting in local inflammation. Importantly, innate immunity must be properly controlled, as its continuous activation leads to the development of chronic inflammatory diseases such as psoriasis. Lipopolysaccharide (LPS or peptidoglycan (PGN induced tolerance, a phenomenon of transient unresponsiveness of cells to repeated or prolonged stimulation, proved valuable model for the study of chronic inflammation. Thus, the aim of this study was the identification of the transcriptional diversity of primary human immature dendritic cells (iDCs upon PGN induced tolerance. Using SAGE-Seq approach, a tag-based transcriptome sequencing method, we investigated gene expression changes of primary human iDCs upon stimulation or restimulation with Staphylococcus aureus derived PGN, a widely used TLR2 ligand. Based on the expression pattern of the altered genes, we identified non-tolerizeable and tolerizeable genes. Gene Ontology (GO and Kyoto Encyclopedia of Genes and Genomes (Kegg analysis showed marked enrichment of immune-, cell cycle- and apoptosis related genes. In parallel to the marked induction of proinflammatory mediators, negative feedback regulators of innate immunity, such as TNFAIP3, TNFAIP8, Tyro3 and Mer are markedly downregulated in tolerant cells. We also demonstrate, that the expression pattern of TNFAIP3 and TNFAIP8 is altered in both lesional, and non-lesional skin of psoriatic patients. Finally, we show that pretreatment of immature dendritic cells with anti-TNF-α inhibits the expression of IL-6 and CCL1 in tolerant iDCs and partially releases the suppression of TNFAIP8. Our findings suggest that after PGN stimulation/restimulation the host cell utilizes different mechanisms in order to maintain critical balance between inflammation and tolerance. Importantly, the transcriptome sequencing of stimulated/restimulated iDCs identified

  11. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function.

    Science.gov (United States)

    Hancock, Dana B; Eijgelsheim, Mark; Wilk, Jemma B; Gharib, Sina A; Loehr, Laura R; Marciante, Kristin D; Franceschini, Nora; van Durme, Yannick M T A; Chen, Ting-Hsu; Barr, R Graham; Schabath, Matthew B; Couper, David J; Brusselle, Guy G; Psaty, Bruce M; van Duijn, Cornelia M; Rotter, Jerome I; Uitterlinden, André G; Hofman, Albert; Punjabi, Naresh M; Rivadeneira, Fernando; Morrison, Alanna C; Enright, Paul L; North, Kari E; Heckbert, Susan R; Lumley, Thomas; Stricker, Bruno H C; O'Connor, George T; London, Stephanie J

    2010-01-01

    Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV(1)) and its ratio to forced vital capacity (FEV(1)/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV(1)/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV(1) (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 x 10(-8)) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.

  12. Genome-wide primary transcriptome analysis of H2-producing archaeon Thermococcus onnurineus NA1

    Science.gov (United States)

    Cho, Suhyung; Kim, Min-Sik; Jeong, Yujin; Lee, Bo-Rahm; Lee, Jung-Hyun; Kang, Sung Gyun; Cho, Byung-Kwan

    2017-01-01

    In spite of their pivotal roles in transcriptional and post-transcriptional processes, the regulatory elements of archaeal genomes are not yet fully understood. Here, we determine the primary transcriptome of the H2-producing archaeon Thermococcus onnurineus NA1. We identified 1,082 purine-rich transcription initiation sites along with well-conserved TATA box, A-rich B recognition element (BRE), and promoter proximal element (PPE) motif in promoter regions, a high pyrimidine nucleotide content (T/C) at the −1 position, and Shine-Dalgarno (SD) motifs (GGDGRD) in 5′ untranslated regions (5′ UTRs). Along with differential transcript levels, 117 leaderless genes and 86 non-coding RNAs (ncRNAs) were identified, representing diverse cellular functions and potential regulatory functions under the different growth conditions. Interestingly, we observed low GC content in ncRNAs for RNA-based regulation via unstructured forms or interaction with other cellular components. Further comparative analysis of T. onnurineus upstream regulatory sequences with those of closely related archaeal genomes demonstrated that transcription of orthologous genes are initiated by highly conserved promoter sequences, however their upstream sequences for transcriptional and translational regulation are largely diverse. These results provide the genetic information of T. onnurineus for its future application in metabolic engineering. PMID:28216628

  13. Stepwise Evolution of Coral Biomineralization Revealed with Genome-Wide Proteomics and Transcriptomics.

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    Takeshi Takeuchi

    Full Text Available Despite the importance of stony corals in many research fields related to global issues, such as marine ecology, climate change, paleoclimatogy, and metazoan evolution, very little is known about the evolutionary origin of coral skeleton formation. In order to investigate the evolution of coral biomineralization, we have identified skeletal organic matrix proteins (SOMPs in the skeletal proteome of the scleractinian coral, Acropora digitifera, for which large genomic and transcriptomic datasets are available. Scrupulous gene annotation was conducted based on comparisons of functional domain structures among metazoans. We found that SOMPs include not only coral-specific proteins, but also protein families that are widely conserved among cnidarians and other metazoans. We also identified several conserved transmembrane proteins in the skeletal proteome. Gene expression analysis revealed that expression of these conserved genes continues throughout development. Therefore, these genes are involved not only skeleton formation, but also in basic cellular functions, such as cell-cell interaction and signaling. On the other hand, genes encoding coral-specific proteins, including extracellular matrix domain-containing proteins, galaxins, and acidic proteins, were prominently expressed in post-settlement stages, indicating their role in skeleton formation. Taken together, the process of coral skeleton formation is hypothesized as: 1 formation of initial extracellular matrix between epithelial cells and substrate, employing pre-existing transmembrane proteins; 2 additional extracellular matrix formation using novel proteins that have emerged by domain shuffling and rapid molecular evolution and; 3 calcification controlled by coral-specific SOMPs.

  14. Stepwise Evolution of Coral Biomineralization Revealed with Genome-Wide Proteomics and Transcriptomics.

    Science.gov (United States)

    Takeuchi, Takeshi; Yamada, Lixy; Shinzato, Chuya; Sawada, Hitoshi; Satoh, Noriyuki

    2016-01-01

    Despite the importance of stony corals in many research fields related to global issues, such as marine ecology, climate change, paleoclimatogy, and metazoan evolution, very little is known about the evolutionary origin of coral skeleton formation. In order to investigate the evolution of coral biomineralization, we have identified skeletal organic matrix proteins (SOMPs) in the skeletal proteome of the scleractinian coral, Acropora digitifera, for which large genomic and transcriptomic datasets are available. Scrupulous gene annotation was conducted based on comparisons of functional domain structures among metazoans. We found that SOMPs include not only coral-specific proteins, but also protein families that are widely conserved among cnidarians and other metazoans. We also identified several conserved transmembrane proteins in the skeletal proteome. Gene expression analysis revealed that expression of these conserved genes continues throughout development. Therefore, these genes are involved not only skeleton formation, but also in basic cellular functions, such as cell-cell interaction and signaling. On the other hand, genes encoding coral-specific proteins, including extracellular matrix domain-containing proteins, galaxins, and acidic proteins, were prominently expressed in post-settlement stages, indicating their role in skeleton formation. Taken together, the process of coral skeleton formation is hypothesized as: 1) formation of initial extracellular matrix between epithelial cells and substrate, employing pre-existing transmembrane proteins; 2) additional extracellular matrix formation using novel proteins that have emerged by domain shuffling and rapid molecular evolution and; 3) calcification controlled by coral-specific SOMPs.

  15. Genome-wide Mapping of Transcriptional Start Sites Defines an Extensive Leaderless Transcriptome in Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Teresa Cortes

    2013-11-01

    Full Text Available Deciphering physiological changes that mediate transition of Mycobacterium tuberculosis between replicating and nonreplicating states is essential to understanding how the pathogen can persist in an individual host for decades. We have combined RNA sequencing (RNA-seq of 5′ triphosphate-enriched libraries with regular RNA-seq to characterize the architecture and expression of M. tuberculosis promoters. We identified over 4,000 transcriptional start sites (TSSs. Strikingly, for 26% of the genes with a primary TSS, the site of transcriptional initiation overlapped with the annotated start codon, generating leaderless transcripts lacking a 5′ UTR and, hence, the Shine-Dalgarno sequence commonly used to initiate ribosomal engagement in eubacteria. Genes encoding proteins with active growth functions were markedly depleted from the leaderless transcriptome, and there was a significant increase in the overall representation of leaderless mRNAs in a starvation model of growth arrest. The high percentage of leaderless genes may have particular importance in the physiology of nonreplicating M. tuberculosis.

  16. Genome-wide association analyses using electronic health records identify new loci influencing blood pressure variation.

    Science.gov (United States)

    Hoffmann, Thomas J; Ehret, Georg B; Nandakumar, Priyanka; Ranatunga, Dilrini; Schaefer, Catherine; Kwok, Pui-Yan; Iribarren, Carlos; Chakravarti, Aravinda; Risch, Neil

    2017-01-01

    Longitudinal electronic health records on 99,785 Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort individuals provided 1,342,814 systolic and diastolic blood pressure measurements for a genome-wide association study on long-term average systolic, diastolic, and pulse pressure. We identified 39 new loci among 75 genome-wide significant loci (P ≤ 5 × 10(-8)), with most replicating in the combined International Consortium for Blood Pressure (ICBP; n = 69,396) and UK Biobank (UKB; n = 152,081) studies. Combining GERA with ICBP yielded 36 additional new loci, with most replicating in UKB. Combining all three studies (n = 321,262) yielded 241 additional genome-wide significant loci, although no replication sample was available for these. All associated loci explained 2.9%, 2.5%, and 3.1% of variation in systolic, diastolic, and pulse pressure, respectively, in GERA non-Hispanic whites. Using multiple blood pressure measurements in GERA doubled the variance explained. A normalized risk score was associated with time to onset of hypertension (hazards ratio = 1.18, P = 8.2 × 10(-45)). Expression quantitative trait locus analysis of blood pressure loci showed enrichment in aorta and tibial artery.

  17. Genome-wide pathway association studies of multiple correlated quantitative phenotypes using principle component analyses.

    Directory of Open Access Journals (Sweden)

    Feng Zhang

    Full Text Available Genome-wide pathway association studies provide novel insight into the biological mechanism underlying complex diseases. Current pathway association studies primarily focus on single important disease phenotype, which is sometimes insufficient to characterize the clinical manifestations of complex diseases. We present a multi-phenotypes pathway association study(MPPAS approach using principle component analysis(PCA. In our approach, PCA is first applied to multiple correlated quantitative phenotypes for extracting a set of orthogonal phenotypic components. The extracted phenotypic components are then used for pathway association analysis instead of original quantitative phenotypes. Four statistics were proposed for PCA-based MPPAS in this study. Simulations using the real data from the HapMap project were conducted to evaluate the power and type I error rates of PCA-based MPPAS under various scenarios considering sample sizes, additive and interactive genetic effects. A real genome-wide association study data set of bone mineral density (BMD at hip and spine were also analyzed by PCA-based MPPAS. Simulation studies illustrated the performance of PCA-based MPPAS for identifying the causal pathways underlying complex diseases. Genome-wide MPPAS of BMD detected associations between BMD and KENNY_CTNNB1_TARGETS_UP as well as LONGEVITYPATHWAY pathways in this study. We aim to provide a applicable MPPAS approach, which may help to gain deep understanding the potential biological mechanism of association results for complex diseases.

  18. Genome-wide association analyses for fatty acid composition in porcine muscle and abdominal fat tissues.

    Directory of Open Access Journals (Sweden)

    Bin Yang

    Full Text Available Fatty acid composition is an important phenotypic trait in pigs as it affects nutritional, technical and sensory quality of pork. Here, we reported a genome-wide association study (GWAS for fatty acid composition in the longissimus muscle and abdominal fat tissues of 591 White Duroc×Erhualian F2 animals and in muscle samples of 282 Chinese Sutai pigs. A total of 46 loci surpassing the suggestive significance level were identified on 15 pig chromosomes (SSC for 12 fatty acids, revealing the complex genetic architecture of fatty acid composition in pigs. Of the 46 loci, 15 on SSC5, 7, 14 and 16 reached the genome-wide significance level. The two most significant SNPs were ss131535508 (P = 2.48×10(-25 at 41.39 Mb on SSC16 for C20∶0 in abdominal fat and ss478935891 (P = 3.29×10(-13 at 121.31 Mb on SSC14 for muscle C18∶0. A meta-analysis of GWAS identified 4 novel loci and enhanced the association strength at 6 loci compared to those evidenced in a single population, suggesting the presence of common underlying variants. The longissimus muscle and abdominal fat showed consistent association profiles at most of the identified loci and distinct association signals at several loci. All loci have specific effects on fatty acid composition, except for two loci on SSC4 and SSC7 affecting multiple fatness traits. Several promising candidate genes were found in the neighboring regions of the lead SNPs at the genome-wide significant loci, such as SCD for C18∶0 and C16∶1 on SSC14 and ELOVL7 for C20∶0 on SSC16. The findings provide insights into the molecular basis of fatty acid composition in pigs, and would benefit the final identification of the underlying mutations.

  19. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis

    Science.gov (United States)

    Liu, Xiangdong; Invernizzi, Pietro; Lu, Yue; Kosoy, Roman; Lu, Yan; Bianchi, Ilaria; Podda, Mauro; Xu, Chun; Xie, Gang; Macciardi, Fabio; Selmi, Carlo; Lupoli, Sara; Shigeta, Russell; Ransom, Michael; Lleo, Ana; Lee, Annette T; Mason, Andrew L; Myers, Robert P; Peltekian, Kevork M; Ghent, Cameron N; Bernuzzi, Francesca; Zuin, Massimo; Rosina, Floriano; Borghesio, Elisabetta; Floreani, Annarosa; Lazzari, Roberta; Niro, Grazia; Andriulli, Angelo; Muratori, Luigi; Muratori, Paolo; Almasio, Piero L; Andreone, Pietro; Margotti, Marzia; Brunetto, Maurizia; Coco, Barbara; Alvaro, Domenico; Bragazzi, Maria C; Marra, Fabio; Pisano, Alessandro; Rigamonti, Cristina; Colombo, Massimo; Marzioni, Marco; Benedetti, Antonio; Fabris, Luca; Strazzabosco, Mario; Portincasa, Piero; Palmieri, Vincenzo O; Tiribelli, Claudio; Croce, Lory; Bruno, Savino; Rossi, Sonia; Vinci, Maria; Prisco, Cleofe; Mattalia, Alberto; Toniutto, Pierluigi; Picciotto, Antonio; Galli, Andrea; Ferrari, Carlo; Colombo, Silvia; Casella, Giovanni; Morini, Lorenzo; Caporaso, Nicola; Colli, Agostino; Spinzi, Giancarlo; Montanari, Renzo; Gregersen, Peter K; Heathcote, E Jenny; Hirschfield, Gideon M; Siminovitch, Katherine A; Amos, Christopher I; Gershwin, M Eric; Seldin, Michael F

    2011-01-01

    A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 × 10–11, odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 × 10–10, OR = 1.63) and 17q12-21 (P = 1.7 × 10–10, OR = 1.38). PMID:20639880

  20. Systematic Identification and Assessment of Therapeutic Targets for Breast Cancer Based on Genome-Wide RNA Interference Transcriptomes

    Directory of Open Access Journals (Sweden)

    Yang Liu

    2017-02-01

    Full Text Available With accumulating public omics data, great efforts have been made to characterize the genetic heterogeneity of breast cancer. However, identifying novel targets and selecting the best from the sizeable lists of candidate targets is still a key challenge for targeted therapy, largely owing to the lack of economical, efficient and systematic discovery and assessment to prioritize potential therapeutic targets. Here, we describe an approach that combines the computational evaluation and objective, multifaceted assessment to systematically identify and prioritize targets for biological validation and therapeutic exploration. We first establish the reference gene expression profiles from breast cancer cell line MCF7 upon genome-wide RNA interference (RNAi of a total of 3689 genes, and the breast cancer query signatures using RNA-seq data generated from tissue samples of clinical breast cancer patients in the Cancer Genome Atlas (TCGA. Based on gene set enrichment analysis, we identified a set of 510 genes that when knocked down could significantly reverse the transcriptome of breast cancer state. We then perform multifaceted assessment to analyze the gene set to prioritize potential targets for gene therapy. We also propose drug repurposing opportunities and identify potentially druggable proteins that have been poorly explored with regard to the discovery of small-molecule modulators. Finally, we obtained a small list of candidate therapeutic targets for four major breast cancer subtypes, i.e., luminal A, luminal B, HER2+ and triple negative breast cancer. This RNAi transcriptome-based approach can be a helpful paradigm for relevant researches to identify and prioritize candidate targets for experimental validation.

  1. Gene set analyses of genome-wide association studies on 49 quantitative traits measured in a single genetic epidemiology dataset.

    Science.gov (United States)

    Kim, Jihye; Kwon, Ji-Sun; Kim, Sangsoo

    2013-09-01

    Gene set analysis is a powerful tool for interpreting a genome-wide association study result and is gaining popularity these days. Comparison of the gene sets obtained for a variety of traits measured from a single genetic epidemiology dataset may give insights into the biological mechanisms underlying these traits. Based on the previously published single nucleotide polymorphism (SNP) genotype data on 8,842 individuals enrolled in the Korea Association Resource project, we performed a series of systematic genome-wide association analyses for 49 quantitative traits of basic epidemiological, anthropometric, or blood chemistry parameters. Each analysis result was subjected to subsequent gene set analyses based on Gene Ontology (GO) terms using gene set analysis software, GSA-SNP, identifying a set of GO terms significantly associated to each trait (pcorr neuronal or nerve systems.

  2. Traumatic Brain Injury Induces Genome-Wide Transcriptomic, Methylomic, and Network Perturbations in Brain and Blood Predicting Neurological Disorders

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    Qingying Meng

    2017-02-01

    Full Text Available The complexity of the traumatic brain injury (TBI pathology, particularly concussive injury, is a serious obstacle for diagnosis, treatment, and long-term prognosis. Here we utilize modern systems biology in a rodent model of concussive injury to gain a thorough view of the impact of TBI on fundamental aspects of gene regulation, which have the potential to drive or alter the course of the TBI pathology. TBI perturbed epigenomic programming, transcriptional activities (expression level and alternative splicing, and the organization of genes in networks centered around genes such as Anax2, Ogn, and Fmod. Transcriptomic signatures in the hippocampus are involved in neuronal signaling, metabolism, inflammation, and blood function, and they overlap with those in leukocytes from peripheral blood. The homology between genomic signatures from blood and brain elicited by TBI provides proof of concept information for development of biomarkers of TBI based on composite genomic patterns. By intersecting with human genome-wide association studies, many TBI signature genes and network regulators identified in our rodent model were causally associated with brain disorders with relevant link to TBI. The overall results show that concussive brain injury reprograms genes which could lead to predisposition to neurological and psychiatric disorders, and that genomic information from peripheral leukocytes has the potential to predict TBI pathogenesis in the brain.

  3. Traumatic Brain Injury Induces Genome-Wide Transcriptomic, Methylomic, and Network Perturbations in Brain and Blood Predicting Neurological Disorders.

    Science.gov (United States)

    Meng, Qingying; Zhuang, Yumei; Ying, Zhe; Agrawal, Rahul; Yang, Xia; Gomez-Pinilla, Fernando

    2017-02-01

    The complexity of the traumatic brain injury (TBI) pathology, particularly concussive injury, is a serious obstacle for diagnosis, treatment, and long-term prognosis. Here we utilize modern systems biology in a rodent model of concussive injury to gain a thorough view of the impact of TBI on fundamental aspects of gene regulation, which have the potential to drive or alter the course of the TBI pathology. TBI perturbed epigenomic programming, transcriptional activities (expression level and alternative splicing), and the organization of genes in networks centered around genes such as Anax2, Ogn, and Fmod. Transcriptomic signatures in the hippocampus are involved in neuronal signaling, metabolism, inflammation, and blood function, and they overlap with those in leukocytes from peripheral blood. The homology between genomic signatures from blood and brain elicited by TBI provides proof of concept information for development of biomarkers of TBI based on composite genomic patterns. By intersecting with human genome-wide association studies, many TBI signature genes and network regulators identified in our rodent model were causally associated with brain disorders with relevant link to TBI. The overall results show that concussive brain injury reprograms genes which could lead to predisposition to neurological and psychiatric disorders, and that genomic information from peripheral leukocytes has the potential to predict TBI pathogenesis in the brain.

  4. Genome-Wide Host-Pathogen Interaction Unveiled by Transcriptomic Response of Diamondback Moth to Fungal Infection.

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    Zhen-Jian Chu

    Full Text Available Genome-wide insight into insect pest response to the infection of Beauveria bassiana (fungal insect pathogen is critical for genetic improvement of fungal insecticides but has been poorly explored. We constructed three pairs of transcriptomes of Plutella xylostella larvae at 24, 36 and 48 hours post treatment of infection (hptI and of control (hptC for insight into the host-pathogen interaction at genomic level. There were 2143, 3200 and 2967 host genes differentially expressed at 24, 36 and 48 hptI/hptC respectively. These infection-responsive genes (~15% of the host genome were enriched in various immune processes, such as complement and coagulation cascades, protein digestion and absorption, and drug metabolism-cytochrome P450. Fungal penetration into cuticle and host defense reaction began at 24 hptI, followed by most intensive host immune response at 36 hptI and attenuated immunity at 48 hptI. Contrastingly, 44% of fungal genes were differentially expressed in the infection course and enriched in several biological processes, such as antioxidant activity, peroxidase activity and proteolysis. There were 1636 fungal genes co-expressed during 24-48 hptI, including 116 encoding putative secretion proteins. Our results provide novel insights into the insect-pathogen interaction and help to probe molecular mechanisms involved in the fungal infection to the global pest.

  5. Genome-Wide Gene Expression Profile Analyses Identify CTTN as a Potential Prognostic Marker in Esophageal Cancer

    OpenAIRE

    2014-01-01

    Aim Esophageal squamous cell carcinoma (ESCC) is one of the most common fatal malignances of the digestive tract. Its prognosis is poor mainly due to the lack of reliable markers for early detection and prognostic prediction. Here we aim to identify the molecules involved in ESCC carcinogenesis and those as potential markers for prognosis and as new molecular therapeutic targets. Methods We performed genome-wide gene expression profile analyses of 10 primary ESCCs and their adjacent normal ti...

  6. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

    DEFF Research Database (Denmark)

    Okbay, Aysu; Baselmans, Bart M L; De Neve, Jan-Emmanuel

    2016-01-01

    Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted...... genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated...... with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us...

  7. Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy

    DEFF Research Database (Denmark)

    Luca, Gianina; Haba-Rubio, José; Dauvilliers, Yves

    2013-01-01

    diagnosed according to International Classification of Sleep Disorders-2. Demographic and clinical characteristics, polysomnography and multiple sleep latency test data, hypocretin-1 levels, and genome-wide genotypes were available. We found a significantly lower age at sleepiness onset (men versus women...... diagnostic delay were young age at diagnosis, cataplexy as the first symptom and higher frequency of cataplexy attacks. The mean multiple sleep latency negatively correlated with Epworth Sleepiness Scale (ESS) and with the number of sleep-onset rapid eye movement periods (SOREMPs), but none...... of the polysomnographic variables was associated with subjective or objective measures of sleepiness. Variant rs2859998 in UBXN2B gene showed a strong association (P = 1.28E-07) with the age at onset of excessive daytime sleepiness, and rs12425451 near the transcription factor TEAD4 (P = 1.97E-07) with the age at onset...

  8. Genome-wide analyses of recombination suggest that Giardia intestinalis assemblages represent different species.

    Science.gov (United States)

    Xu, Feifei; Jerlström-Hultqvist, Jon; Andersson, Jan O

    2012-10-01

    Giardia intestinalis is a major cause of waterborne enteric disease in humans. The species is divided into eight assemblages suggested to represent separate Giardia species based on host specificities and the genetic divergence of marker genes. We have investigated whether genome-wide recombination occurs between assemblages using the three available G. intestinalis genomes. First, the relative nonsynonymous substitution rates of the homologs were compared for 4,009 positional homologs. The vast majority of these comparisons indicate genetic isolation without interassemblage recombinations. Only a region of 6 kbp suggests genetic exchange between assemblages A and E, followed by gene conversion events. Second, recombination-detecting software fails to identify within-gene recombination between the different assemblages for most of the homologs. Our results indicate very low frequency of recombination between the syntenic core genes, suggesting that G. intestinalis assemblages are genetically isolated lineages and thus should be viewed as separated Giardia species.

  9. Genome-wide association analyses identify SPOCK as a key novel gene underlying age at menarche.

    Directory of Open Access Journals (Sweden)

    Yao-Zhong Liu

    2009-03-01

    Full Text Available For females, menarche is a most significant physiological event. Age at menarche (AAM is a trait with high genetic determination and is associated with major complex diseases in women. However, specific genes for AAM variation are largely unknown. To identify genetic factors underlying AAM variation, a genome-wide association study (GWAS examining about 380,000 SNPs was conducted in 477 Caucasian women. A follow-up replication study was performed to validate our major GWAS findings using two independent Caucasian cohorts with 854 siblings and 762 unrelated subjects, respectively, and one Chinese cohort of 1,387 unrelated subjects--all females. Our GWAS identified a novel gene, SPOCK (Sparc/Osteonectin, CWCV, and Kazal-like domains proteoglycan, which had seven SNPs associated with AAM with genome-wide false discovery rate (FDR q<0.05. Six most significant SNPs of the gene were selected for validation in three independent replication cohorts. All of the six SNPs were replicated in at least one cohort. In particular, SNPs rs13357391 and rs1859345 were replicated both within and across different ethnic groups in all three cohorts, with p values of 5.09 x 10(-3 and 4.37 x 10(-3, respectively, in the Chinese cohort and combined p values (obtained by Fisher's method of 5.19 x 10(-5 and 1.02 x 10(-4, respectively, in all three replication cohorts. Interestingly, SPOCK can inhibit activation of MMP-2 (matrix metalloproteinase-2, a key factor promoting endometrial menstrual breakdown and onset of menstrual bleeding. Our findings, together with the functional relevance, strongly supported that the SPOCK gene underlies variation of AAM.

  10. Multiplex and genome-wide analyses reveal distinctive properties of KIR+ and CD56+ T cells in human blood.

    Science.gov (United States)

    Chan, Wing Keung; Rujkijyanont, Piya; Neale, Geoffrey; Yang, Jie; Bari, Rafijul; Das Gupta, Neha; Holladay, Martha; Rooney, Barbara; Leung, Wing

    2013-08-15

    Killer cell Ig-like receptors (KIRs) on NK cells have been linked to a wide spectrum of health conditions such as chronic infections, autoimmune diseases, pregnancy complications, cancers, and transplant failures. A small subset of effector memory T cells also expresses KIRs. In this study, we use modern analytic tools including genome-wide and multiplex molecular, phenotypic, and functional assays to characterize the KIR(+) T cells in human blood. We find that KIR(+) T cells primarily reside in the CD56(+) T population that is distinctively DNAM-1(high) with a genome-wide quiescent transcriptome, short telomere, and limited TCR excision circles. During CMV reactivation in bone marrow transplant recipients, KIR(+)CD56(+) T cells rapidly expanded in real-time but not KIR(+)CD56(-) T cells or KIR(+) NK cells. In CMV(+) asymptomatic donors, as much as 50% of CD56(+) T cells are KIR(+), and most are distinguishably KIR2DL2/3(+)NKG2C(+)CD57(+). Functionally, the KIR(+)CD56(+) T cell subset lyses cancer cells and CMVpp65-pulsed target cells in a dual KIR-dependent and TCR-dependent manner. Analysis of metabolic transcriptome confirms the immunological memory status of KIR(+)CD56(+) T cells in contrast to KIR(-)CD56(+) T cells that are more active in energy metabolism and effector differentiation. KIR(-)CD56(+) T cells have >25-fold higher level of expression of RORC than the KIR(+) counterpart and are a previously unknown producer of IL-13 rather than IL-17 in multiplex cytokine arrays. Our data provide fundamental insights into KIR(+) T cells biologically and clinically.

  11. Multistage genome-wide association meta-analyses identified two new loci for bone mineral density.

    Science.gov (United States)

    Zhang, Lei; Choi, Hyung Jin; Estrada, Karol; Leo, Paul J; Li, Jian; Pei, Yu-Fang; Zhang, Yinping; Lin, Yong; Shen, Hui; Liu, Yao-Zhong; Liu, Yongjun; Zhao, Yingchun; Zhang, Ji-Gang; Tian, Qing; Wang, Yu-ping; Han, Yingying; Ran, Shu; Hai, Rong; Zhu, Xue-Zhen; Wu, Shuyan; Yan, Han; Liu, Xiaogang; Yang, Tie-Lin; Guo, Yan; Zhang, Feng; Guo, Yan-fang; Chen, Yuan; Chen, Xiangding; Tan, Lijun; Zhang, Lishu; Deng, Fei-Yan; Deng, Hongyi; Rivadeneira, Fernando; Duncan, Emma L; Lee, Jong Young; Han, Bok Ghee; Cho, Nam H; Nicholson, Geoffrey C; McCloskey, Eugene; Eastell, Richard; Prince, Richard L; Eisman, John A; Jones, Graeme; Reid, Ian R; Sambrook, Philip N; Dennison, Elaine M; Danoy, Patrick; Yerges-Armstrong, Laura M; Streeten, Elizabeth A; Hu, Tian; Xiang, Shuanglin; Papasian, Christopher J; Brown, Matthew A; Shin, Chan Soo; Uitterlinden, André G; Deng, Hong-Wen

    2014-04-01

    Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10(-8)) level: 14q24.2 (rs227425, P-value 3.98 × 10(-13), SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10(-9), CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n = 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.

  12. Genome-wide Annotation, Identification, and Global Transcriptomic Analysis of Regulatory or Small RNA Gene Expression in Staphylococcus aureus

    Directory of Open Access Journals (Sweden)

    Ronan K. Carroll

    2016-02-01

    Full Text Available In Staphylococcus aureus, hundreds of small regulatory or small RNAs (sRNAs have been identified, yet this class of molecule remains poorly understood and severely understudied. sRNA genes are typically absent from genome annotation files, and as a consequence, their existence is often overlooked, particularly in global transcriptomic studies. To facilitate improved detection and analysis of sRNAs in S. aureus, we generated updated GenBank files for three commonly used S. aureus strains (MRSA252, NCTC 8325, and USA300, in which we added annotations for >260 previously identified sRNAs. These files, the first to include genome-wide annotation of sRNAs in S. aureus, were then used as a foundation to identify novel sRNAs in the community-associated methicillin-resistant strain USA300. This analysis led to the discovery of 39 previously unidentified sRNAs. Investigating the genomic loci of the newly identified sRNAs revealed a surprising degree of inconsistency in genome annotation in S. aureus, which may be hindering the analysis and functional exploration of these elements. Finally, using our newly created annotation files as a reference, we perform a global analysis of sRNA gene expression in S. aureus and demonstrate that the newly identified tsr25 is the most highly upregulated sRNA in human serum. This study provides an invaluable resource to the S. aureus research community in the form of our newly generated annotation files, while at the same time presenting the first examination of differential sRNA expression in pathophysiologically relevant conditions.

  13. Combination analysis of genome-wide association and transcriptome sequencing of residual feed intake in quality chickens.

    Science.gov (United States)

    Xu, Zhenqiang; Ji, Congliang; Zhang, Yan; Zhang, Zhe; Nie, Qinghua; Xu, Jiguo; Zhang, Dexiang; Zhang, Xiquan

    2016-08-09

    Residual feed intake (RFI) is a powerful indicator for energy utilization efficiency and responds to selection. Low RFI selection enables a reduction in feed intake without affecting growth performance. However, the effective variants or major genes dedicated to phenotypic differences in RFI in quality chickens are unclear. Therefore, a genome-wide association study (GWAS) and RNA sequencing were performed on RFI to identify genetic variants and potential candidate genes associated with energy improvement. A lower average daily feed intake was found in low-RFI birds compared to high-RFI birds. The heritability of RFI measured from 44 to 83 d of age was 0.35. GWAS showed that 32 of the significant single nucleotide polymorphisms (SNPs) associated with the RFI (P < 10(-4)) accounted for 53.01 % of the additive genetic variance. More than half of the effective SNPs were located in a 1 Mb region (16.3-17.3 Mb) of chicken (Gallus gallus) chromosome (GGA) 12. Thus, focusing on this region should enable a deeper understanding of energy utilization. RNA sequencing was performed to profile the liver transcriptomes of four male chickens selected from the high and low tails of the RFI. One hundred and sixteen unique genes were identified as differentially expressed genes (DEGs). Some of these genes were relevant to appetite, cell activities, and fat metabolism, such as CCKAR, HSP90B1, and PCK1. Some potential genes within the 500 Kb flanking region of the significant RFI-related SNPs detected in GWAS (i.e., MGP, HIST1H110, HIST1H2A4L3, OC3, NR0B2, PER2, ST6GALNAC2, and G0S2) were also identified as DEGs in chickens with divergent RFIs. The GWAS findings showed that the 1 Mb narrow region of GGA12 should be important because it contained genes involved in energy-consuming processes, such as lipogenesis, social behavior, and immunity. Similar results were obtained in the transcriptome sequencing experiments. In general, low-RFI birds seemed to optimize energy employment

  14. Genome-wide methylome analyses reveal novel epigenetic regulation patterns in schizophrenia and bipolar disorder.

    Science.gov (United States)

    Li, Yongsheng; Camarillo, Cynthia; Xu, Juan; Arana, Tania Bedard; Xiao, Yun; Zhao, Zheng; Chen, Hong; Ramirez, Mercedes; Zavala, Juan; Escamilla, Michael A; Armas, Regina; Mendoza, Ricardo; Ontiveros, Alfonso; Nicolini, Humberto; Magaña, Alvaro Antonio Jerez; Rubin, Lewis P; Li, Xia; Xu, Chun

    2015-01-01

    Schizophrenia (SZ) and bipolar disorder (BP) are complex genetic disorders. Their appearance is also likely informed by as yet only partially described epigenetic contributions. Using a sequencing-based method for genome-wide analysis, we quantitatively compared the blood DNA methylation landscapes in SZ and BP subjects to control, both in an understudied population, Hispanics along the US-Mexico border. Remarkably, we identified thousands of differentially methylated regions for SZ and BP preferentially located in promoters 3'-UTRs and 5'-UTRs of genes. Distinct patterns of aberrant methylation of promoter sequences were located surrounding transcription start sites. In these instances, aberrant methylation occurred in CpG islands (CGIs) as well as in flanking regions as well as in CGI sparse promoters. Pathway analysis of genes displaying these distinct aberrant promoter methylation patterns showed enhancement of epigenetic changes in numerous genes previously related to psychiatric disorders and neurodevelopment. Integration of gene expression data further suggests that in SZ aberrant promoter methylation is significantly associated with altered gene transcription. In particular, we found significant associations between (1) promoter CGIs hypermethylation with gene repression and (2) CGI 3'-shore hypomethylation with increased gene expression. Finally, we constructed a specific methylation analysis platform that facilitates viewing and comparing aberrant genome methylation in human neuropsychiatric disorders.

  15. Genome-Wide Methylome Analyses Reveal Novel Epigenetic Regulation Patterns in Schizophrenia and Bipolar Disorder

    Directory of Open Access Journals (Sweden)

    Yongsheng Li

    2015-01-01

    Full Text Available Schizophrenia (SZ and bipolar disorder (BP are complex genetic disorders. Their appearance is also likely informed by as yet only partially described epigenetic contributions. Using a sequencing-based method for genome-wide analysis, we quantitatively compared the blood DNA methylation landscapes in SZ and BP subjects to control, both in an understudied population, Hispanics along the US-Mexico border. Remarkably, we identified thousands of differentially methylated regions for SZ and BP preferentially located in promoters 3′-UTRs and 5′-UTRs of genes. Distinct patterns of aberrant methylation of promoter sequences were located surrounding transcription start sites. In these instances, aberrant methylation occurred in CpG islands (CGIs as well as in flanking regions as well as in CGI sparse promoters. Pathway analysis of genes displaying these distinct aberrant promoter methylation patterns showed enhancement of epigenetic changes in numerous genes previously related to psychiatric disorders and neurodevelopment. Integration of gene expression data further suggests that in SZ aberrant promoter methylation is significantly associated with altered gene transcription. In particular, we found significant associations between (1 promoter CGIs hypermethylation with gene repression and (2 CGI 3′-shore hypomethylation with increased gene expression. Finally, we constructed a specific methylation analysis platform that facilitates viewing and comparing aberrant genome methylation in human neuropsychiatric disorders.

  16. BioSMACK: a linux live CD for genome-wide association analyses.

    Science.gov (United States)

    Hong, Chang Bum; Kim, Young Jin; Moon, Sanghoon; Shin, Young-Ah; Go, Min Jin; Kim, Dong-Joon; Lee, Jong-Young; Cho, Yoon Shin

    2012-01-01

    Recent advances in high-throughput genotyping technologies have enabled us to conduct a genome-wide association study (GWAS) on a large cohort. However, analyzing millions of single nucleotide polymorphisms (SNPs) is still a difficult task for researchers conducting a GWAS. Several difficulties such as compatibilities and dependencies are often encountered by researchers using analytical tools, during the installation of software. This is a huge obstacle to any research institute without computing facilities and specialists. Therefore, a proper research environment is an urgent need for researchers working on GWAS. We developed BioSMACK to provide a research environment for GWAS that requires no configuration and is easy to use. BioSMACK is based on the Ubuntu Live CD that offers a complete Linux-based operating system environment without installation. Moreover, we provide users with a GWAS manual consisting of a series of guidelines for GWAS and useful examples. BioSMACK is freely available at http://ksnp.cdc. go.kr/biosmack.

  17. Genome-Wide Association Analyses Point to Candidate Genes for Electric Shock Avoidance in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Mirjam Appel

    Full Text Available Electric shock is a common stimulus for nociception-research and the most widely used reinforcement in aversive associative learning experiments. Yet, nothing is known about the mechanisms it recruits at the periphery. To help fill this gap, we undertook a genome-wide association analysis using 38 inbred Drosophila melanogaster strains, which avoided shock to varying extents. We identified 514 genes whose expression levels and/ or sequences co-varied with shock avoidance scores. We independently scrutinized 14 of these genes using mutants, validating the effect of 7 of them on shock avoidance. This emphasizes the value of our candidate gene list as a guide for follow-up research. In addition, by integrating our association results with external protein-protein interaction data we obtained a shock avoidance-associated network of 38 genes. Both this network and the original candidate list contained a substantial number of genes that affect mechanosensory bristles, which are hair-like organs distributed across the fly's body. These results may point to a potential role for mechanosensory bristles in shock sensation. Thus, we not only provide a first list of candidate genes for shock avoidance, but also point to an interesting new hypothesis on nociceptive mechanisms.

  18. Genome-Wide Methylome Analyses Reveal Novel Epigenetic Regulation Patterns in Schizophrenia and Bipolar Disorder

    Science.gov (United States)

    Li, Yongsheng; Camarillo, Cynthia; Xu, Juan; Arana, Tania Bedard; Xiao, Yun; Zhao, Zheng; Chen, Hong; Ramirez, Mercedes; Zavala, Juan; Escamilla, Michael A.; Armas, Regina; Mendoza, Ricardo; Ontiveros, Alfonso; Nicolini, Humberto; Jerez Magaña, Alvaro Antonio; Rubin, Lewis P.; Li, Xia; Xu, Chun

    2015-01-01

    Schizophrenia (SZ) and bipolar disorder (BP) are complex genetic disorders. Their appearance is also likely informed by as yet only partially described epigenetic contributions. Using a sequencing-based method for genome-wide analysis, we quantitatively compared the blood DNA methylation landscapes in SZ and BP subjects to control, both in an understudied population, Hispanics along the US-Mexico border. Remarkably, we identified thousands of differentially methylated regions for SZ and BP preferentially located in promoters 3′-UTRs and 5′-UTRs of genes. Distinct patterns of aberrant methylation of promoter sequences were located surrounding transcription start sites. In these instances, aberrant methylation occurred in CpG islands (CGIs) as well as in flanking regions as well as in CGI sparse promoters. Pathway analysis of genes displaying these distinct aberrant promoter methylation patterns showed enhancement of epigenetic changes in numerous genes previously related to psychiatric disorders and neurodevelopment. Integration of gene expression data further suggests that in SZ aberrant promoter methylation is significantly associated with altered gene transcription. In particular, we found significant associations between (1) promoter CGIs hypermethylation with gene repression and (2) CGI 3′-shore hypomethylation with increased gene expression. Finally, we constructed a specific methylation analysis platform that facilitates viewing and comparing aberrant genome methylation in human neuropsychiatric disorders. PMID:25734057

  19. Genome-Wide Association Analyses Point to Candidate Genes for Electric Shock Avoidance in Drosophila melanogaster.

    Science.gov (United States)

    Appel, Mirjam; Scholz, Claus-Jürgen; Müller, Tobias; Dittrich, Marcus; König, Christian; Bockstaller, Marie; Oguz, Tuba; Khalili, Afshin; Antwi-Adjei, Emmanuel; Schauer, Tamas; Margulies, Carla; Tanimoto, Hiromu; Yarali, Ayse

    2015-01-01

    Electric shock is a common stimulus for nociception-research and the most widely used reinforcement in aversive associative learning experiments. Yet, nothing is known about the mechanisms it recruits at the periphery. To help fill this gap, we undertook a genome-wide association analysis using 38 inbred Drosophila melanogaster strains, which avoided shock to varying extents. We identified 514 genes whose expression levels and/ or sequences co-varied with shock avoidance scores. We independently scrutinized 14 of these genes using mutants, validating the effect of 7 of them on shock avoidance. This emphasizes the value of our candidate gene list as a guide for follow-up research. In addition, by integrating our association results with external protein-protein interaction data we obtained a shock avoidance-associated network of 38 genes. Both this network and the original candidate list contained a substantial number of genes that affect mechanosensory bristles, which are hair-like organs distributed across the fly's body. These results may point to a potential role for mechanosensory bristles in shock sensation. Thus, we not only provide a first list of candidate genes for shock avoidance, but also point to an interesting new hypothesis on nociceptive mechanisms.

  20. Genome-wide analyses of Epstein-Barr virus reveal conserved RNA structures and a novel stable intronic sequence RNA

    OpenAIRE

    2013-01-01

    Background Epstein-Barr virus (EBV) is a human herpesvirus implicated in cancer and autoimmune disorders. Little is known concerning the roles of RNA structure in this important human pathogen. This study provides the first comprehensive genome-wide survey of RNA and RNA structure in EBV. Results Novel EBV RNAs and RNA structures were identified by computational modeling and RNA-Seq analyses of EBV. Scans of the genomic sequences of four EBV strains (EBV-1, EBV-2, GD1, and GD2) and of the clo...

  1. Genome-wide transcriptomic analysis of the response to nitrogen limitation in Streptomyces coelicolor A3(2

    Directory of Open Access Journals (Sweden)

    Efthimiou Georgios

    2011-03-01

    Full Text Available Abstract Background The present study represents a genome-wide transcriptomic analysis of the response of the model streptomycete Streptomyces coelicolor A3(2 M145 to fermentor culture in Modified Evans Media limited, respectively, for nitrogen, phosphate and carbon undertaken as part of the ActinoGEN consortium to provide a publicly available reference microarray dataset. Findings A microarray dataset using samples from two replicate cultures for each nutrient limitation was generated. In this report our analysis has focused on the genes which are significantly differentially expressed, as determined by Rank Products Analysis, between samples from matched time points correlated by growth phase for the three pairs of differently limited culture datasets. With a few exceptions, genes are only significantly differentially expressed between the N6/N7 time points and their corresponding time points in the C and P-limited cultures, with the vast majority of the differentially expressed genes being more highly expressed in the N-limited cultures. Our analysis of these genes indicated expression of several members of the GlnR regulon are induced upon nitrogen limitation, as assayed for by [NH4+] measurements, and we are able to identify several additional genes not present in the GlnR regulon whose expression is induced in response to nitrogen limitation. We also note SCO3327 which encodes a small protein (32 amino acid residues unusually rich in the basic amino acids lysine (31.25% and arginine (25% is significantly differentially expressed in the nitrogen limited cultures. Additionally, we investigate the expression of known members of the GlnR regulon and the relationship between gene organization and expression for the SCO2486-SCO2487 and SCO5583-SCO5585 operons. Conclusions We provide a list of genes whose expression is differentially expressed in low nitrogen culture conditions, including a putative nitrogen storage protein encoded by SCO3327

  2. Genome-wide meta-analyses identify multiple loci associated with smoking behavior

    NARCIS (Netherlands)

    H. Furberg (Helena); Y. Kim (Yunjung); J. Dackor (Jennifer); E.A. Boerwinkle (Eric); N. Franceschini (Nora); D. Ardissino (Diego); L. Bernardinelli (Luisa); P.M. Mannucci (Pier); F. Mauri (Francesco); P.A. Merlini (Piera); D. Absher (Devin); T.L. Assimes (Themistocles); S.P. Fortmann (Stephen); C. Iribarren (Carlos); J.W. Knowles (Joshua); T. Quertermous (Thomas); L. Ferrucci (Luigi); T. Tanaka (Toshiko); J.C. Bis (Joshua); T. Haritunians (Talin); B. McKnight (Barbara); B.M. Psaty (Bruce); K.D. Taylor (Kent); E.L. Thacker (Evan); P. Almgren (Peter); L. Groop (Leif); C. Ladenvall (Claes); M. Boehnke (Michael); A.U. Jackson (Anne); K.L. Mohlke (Karen); H.M. Stringham (Heather); J. Tuomilehto (Jaakko); E.J. Benjamin (Emelia); S.J. Hwang; D. Levy (Daniel); S.R. Preis; R.S. Vasan (Ramachandran Srini); J. Duan (Jubao); P.V. Gejman (Pablo); D.F. Levinson (Douglas); A.R. Sanders (Alan); J. Shi (Jianxin); E.H. Lips (Esther); J.D. McKay (James); A. Agudo (Antonio); L. Barzan (Luigi); V. Bencko (Vladimir); S. Benhamou (Simone); X. Castellsagué (Xavier); C. Canova (Cristina); D.I. Conway (David); E. Fabianova (Eleonora); L. Foretova (Lenka); V. Janout (Vladimir); C.M. Healy (Claire); I. Holcátová (Ivana); K. Kjaerheim (Kristina); P. Lagiou; J. Lissowska (Jolanta); R. Lowry (Ray); T.V. MacFarlane (Tatiana); D. Mates (Dana); L. Richiardi (Lorenzo); P. Rudnai (Peter); N. Szeszenia-Dabrowska (Neonilia); D. Zaridze; A. Znaor (Ariana); M. Lathrop (Mark); P. Brennan (Paul); S. Bandinelli (Stefania); T.M. Frayling (Timothy); J.M. Guralnik (Jack); Y. Milaneschi (Yuri); J.R.B. Perry (John); D. Altshuler (David); R. Elosua (Roberto); S. Kathiresan (Sekar); G. Lucas (Gavin); O. Melander (Olle); V. Salomaa (Veikko); S.M. Schwartz (Stephen); B.F. Voight (Benjamin); B.W.J.H. Penninx (Brenda); J.H. Smit (Johannes); N. Vogelzangs (Nicole); D.I. Boomsma (Dorret); E.J.C. de Geus (Eco); J.M. Vink (Jacqueline); G.A.H.M. Willemsen (Gonneke); S.J. Chanock (Stephen); F. Gu (Fangyi); S.E. Hankinson (Susan); D. Hunter (David); A. Hofman (Albert); H.W. Tiemeier (Henning); A.G. Uitterlinden (André); P. Tikka-Kleemola (Päivi); S. Walter (Stefan); D.I. Chasman (Daniel); B.M. Everett (Brendan); G. Pare (Guillaume); P.M. Ridker (Paul); M.D. Li (Ming); H.H. Maes (Hermine); J. Audrain-Mcgovern (Janet); D. Posthuma (Danielle); L.M. Thornton (Laura); C. Lerman (Caryn); J. Kaprio (Jaakko); J.E. Rose (Jed); J.P.A. Ioannidis (John); P. Kraft (Peter); D.Y. Lin (Dan); P.F. Sullivan (Patrick); C.J. O'Donnell (Christopher)

    2010-01-01

    textabstractConsistent but indirect evidence has implicated genetic factors in smoking behavior. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (

  3. Comparison of Genome-Wide Association Methods in Analyses of Admixed Populations with Complex Familial Relationships

    DEFF Research Database (Denmark)

    Kadri, Naveen; Guldbrandtsen, Bernt; Sørensen, Peter;

    2014-01-01

    ) levels. We also compared type-I error rates among models in analyses of publicly available human and dog datasets. The models corrected for none, one, or both structure levels. Correction for K was performed with linear mixed models incorporating familial relationships estimated from pedigrees or genetic......Population structure is known to cause false-positive detection in association studies. We compared the power, precision, and type-I error rates of various association models in analyses of a simulated dataset with structure at the population (admixture from two populations; P) and family (K...... corrected for P. In contrast, correction for P alone in linear models was insufficient. The power and precision of linear mixed models with and without correction for P were similar. Furthermore, power, precision, and type-I error rate were comparable in linear mixed models incorporating pedigree...

  4. Genome-wide identification and expression analyses of cytochrome P450 genes in mulberry (Morus notabilis)

    Institute of Scientific and Technical Information of China (English)

    Bi Ma; Yiwei Luo; Ling Jia; Xiwu Qi; Qiwei Zeng; Zhonghuai Xiang; Ningjia He

    2014-01-01

    Cytochrome P450s play critical roles in the biosyn-thesis of physiological y important compounds in plants. These compounds often act as defense toxins to prevent herbivory. In the present study, a total of 174 P450 genes of mulberry (Morus notabilis C.K.Schn) were identified based on bioinfor-matics analyses. These mulberry P450 genes were divided into nine clans and 47 families and were found to be expressed in a tissue-preferential manner. These genes were compared to the P450 genes in Arabidopsis thaliana. Families CYP80, CYP92, CYP728, CYP733, CYP736, and CYP749 were found to exist in mulberry, and they may play important roles in the biosynthesis of mulberry secondary metabolites. Analyses of the functional and metabolic pathways of these genes indicated that mulberry P450 genes may participate in the metabolism of lipids, other secondary metabolites, xenobiotics, amino acids, cofactors, vitamins, terpenoids, and polyketides. These results provide a foundation for understanding of the structures and biological functions of mulberry P450 genes.

  5. Genome-wide analyses of HTLV-1aD strains from Cape Verde, Africa

    Science.gov (United States)

    Zanella, Louise; de Pina-Araujo I, Isabel; Morgado, Mariza G; Vicente, Ana Carolina

    2016-01-01

    We characterised and reported the first full-length genomes of Human T-cell Lymphotropic Virus Type 1 subgroup HTLV-1aD (CV21 and CV79). This subgroup is one of the major determinants of HTLV-1 infections in North and West Africa, and recombinant strains involving this subgroup have been recently demonstrated. The CV21 and CV79 strains from Cape Verde/Africa were characterised as pure HTLV-1aD genomes, comparative analyses including HTLV-1 subtypes and subgroups revealed HTLV-1aD signatures in the envelope, pol, and pX regions. These genomes provide original information that will contribute to further studies on HTLV-1a epidemiology and evolution. PMID:27653363

  6. Genetic variants associated with subjective well-being, depressive symptoms and neuroticism identified through genome-wide analyses

    Science.gov (United States)

    Derringer, Jaime; Gratten, Jacob; Lee, James J; Liu, Jimmy Z; de Vlaming, Ronald; Ahluwalia, Tarunveer S; Buchwald, Jadwiga; Cavadino, Alana; Frazier-Wood, Alexis C; Davies, Gail; Furlotte, Nicholas A; Garfield, Victoria; Geisel, Marie Henrike; Gonzalez, Juan R; Haitjema, Saskia; Karlsson, Robert; van der Laan, Sander W; Ladwig, Karl-Heinz; Lahti, Jari; van der Lee, Sven J; Miller, Michael B; Lind, Penelope A; Liu, Tian; Matteson, Lindsay; Mihailov, Evelin; Minica, Camelia C; Nolte, Ilja M; Mook-Kanamori, Dennis O; van der Most, Peter J; Oldmeadow, Christopher; Qian, Yong; Raitakari, Olli; Rawal, Rajesh; Realo, Anu; Rueedi, Rico; Schmidt, Börge; Smith, Albert V; Stergiakouli, Evie; Tanaka, Toshiko; Taylor, Kent; Thorleifsson, Gudmar; Wedenoja, Juho; Wellmann, Juergen; Westra, Harm-Jan; Willems, Sara M; Zhao, Wei; Amin, Najaf; Bakshi, Andrew; Bergmann, Sven; Bjornsdottir, Gyda; Boyle, Patricia A; Cherney, Samantha; Cox, Simon R; Davis, Oliver S P; Ding, Jun; Direk, Nese; Eibich, Peter; Emeny, Rebecca T; Fatemifar, Ghazaleh; Faul, Jessica D; Ferrucci, Luigi; Forstner, Andreas J; Gieger, Christian; Gupta, Richa; Harris, Tamara B; Harris, Juliette M; Holliday, Elizabeth G; Hottenga, Jouke-Jan; De Jager, Philip L; Kaakinen, Marika A; Kajantie, Eero; Karhunen, Ville; Kolcic, Ivana; Kumari, Meena; Launer, Lenore J; Franke, Lude; Li-Gao, Ruifang; Liewald, David C; Koini, Marisa; Loukola, Anu; Marques-Vidal, Pedro; Montgomery, Grant W; Mosing, Miriam A; Paternoster, Lavinia; Pattie, Alison; Petrovic, Katja E; Pulkki-Råback, Laura; Quaye, Lydia; Räikkönen, Katri; Rudan, Igor; Scott, Rodney J; Smith, Jennifer A; Sutin, Angelina R; Trzaskowski, Maciej; Vinkhuyzen, Anna E; Yu, Lei; Zabaneh, Delilah; Attia, John R; Bennett, David A; Berger, Klaus; Bertram, Lars; Boomsma, Dorret I; Snieder, Harold; Chang, Shun-Chiao; Cucca, Francesco; Deary, Ian J; van Duijn, Cornelia M; Eriksson, Johan G; Bültmann, Ute; de Geus, Eco J C; Groenen, Patrick J F; Gudnason, Vilmundur; Hansen, Torben; Hartman, Catharine A; Haworth, Claire M A; Hayward, Caroline; Heath, Andrew C; Hinds, David A; Hyppönen, Elina; Iacono, William G; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L R; Keltikangas-Järvinen, Liisa; Kraft, Peter; Kubzansky, Laura D; Lehtimäki, Terho; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; Metspalu, Andres; Mills, Melinda; de Mutsert, Renée; Oldehinkel, Albertine J; Pasterkamp, Gerard; Pedersen, Nancy L; Plomin, Robert; Polasek, Ozren; Power, Christine; Rich, Stephen S; Rosendaal, Frits R; den Ruijter, Hester M; Schlessinger, David; Schmidt, Helena; Svento, Rauli; Schmidt, Reinhold; Alizadeh, Behrooz Z; Sørensen, Thorkild I A; Spector, Tim D; Starr, John M; Stefansson, Kari; Steptoe, Andrew; Terracciano, Antonio; Thorsteinsdottir, Unnur; Thurik, A Roy; Timpson, Nicholas J; Tiemeier, Henning; Uitterlinden, André G; Vollenweider, Peter; Wagner, Gert G; Weir, David R; Yang, Jian; Conley, Dalton C; Smith, George Davey; Hofman, Albert; Johannesson, Magnus; Laibson, David I; Medland, Sarah E; Meyer, Michelle N; Pickrell, Joseph K; Esko, Tõnu; Krueger, Robert F; Beauchamp, Jonathan P; Koellinger, Philipp D; Benjamin, Daniel J; Bartels, Meike; Cesarini, David

    2016-01-01

    We conducted genome-wide association studies of three phenotypes: subjective well-being (N = 298,420), depressive symptoms (N = 161,460), and neuroticism (N = 170,910). We identified three variants associated with subjective well-being, two with depressive symptoms, and eleven with neuroticism, including two inversion polymorphisms. The two depressive symptoms loci replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings, and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are strongly enriched for association. PMID:27089181

  7. Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria.

    Directory of Open Access Journals (Sweden)

    Hong Liu

    Full Text Available BACKGROUND: As a genetic disorder of abnormal pigmentation, the molecular basis of dyschromatosis universalis hereditaria (DUH had remained unclear until recently when ABCB6 was reported as a causative gene of DUH. METHODOLOGY: We performed genome-wide linkage scan using Illumina Human 660W-Quad BeadChip and exome sequencing analyses using Agilent SureSelect Human All Exon Kits in a multiplex Chinese DUH family to identify the pathogenic mutations and verified the candidate mutations using Sanger sequencing. Quantitative RT-PCR and Immunohistochemistry was performed to verify the expression of the pathogenic gene, Zebrafish was also used to confirm the functional role of ABCB6 in melanocytes and pigmentation. RESULTS: Genome-wide linkage (assuming autosomal dominant inheritance mode and exome sequencing analyses identified ABCB6 as the disease candidate gene by discovering a coding mutation (c.1358C>T; p.Ala453Val that co-segregates with the disease phenotype. Further mutation analysis of ABCB6 in four other DUH families and two sporadic cases by Sanger sequencing confirmed the mutation (c.1358C>T; p.Ala453Val and discovered a second, co-segregating coding mutation (c.964A>C; p.Ser322Lys in one of the four families. Both mutations were heterozygous in DUH patients and not present in the 1000 Genome Project and dbSNP database as well as 1,516 unrelated Chinese healthy controls. Expression analysis in human skin and mutagenesis interrogation in zebrafish confirmed the functional role of ABCB6 in melanocytes and pigmentation. Given the involvement of ABCB6 mutations in coloboma, we performed ophthalmological examination of the DUH carriers of ABCB6 mutations and found ocular abnormalities in them. CONCLUSION: Our study has advanced our understanding of DUH pathogenesis and revealed the shared pathological mechanism between pigmentary DUH and ocular coloboma.

  8. Genome-Wide Identification, Evolutionary, and Expression Analyses of Histone H3 Variants in Plants

    Directory of Open Access Journals (Sweden)

    Jinteng Cui

    2015-01-01

    Full Text Available Histone variants alter the nucleosome structure and play important roles in chromosome segregation, transcription, DNA repair, and sperm compaction. Histone H3 is encoded by many genes in most eukaryotic species and is the histone that contains the largest variety of posttranslational modifications. Compared with the metazoan H3 variants, little is known about the complex evolutionary history of H3 variants proteins in plants. Here, we study the identification, evolutionary, and expression analyses of histone H3 variants from genomes in major branches in the plant tree of life. Firstly we identified all the histone three related (HTR genes from the examined genomes, then we classified the four groups variants: centromeric H3, H3.1, H3.3 and H3-like, by phylogenetic analysis, intron information, and alignment. We further demonstrated that the H3 variants have evolved under strong purifying selection, indicating the conservation of HTR proteins. Expression analysis revealed that the HTR has a wide expression profile in maize and rice development and plays important roles in development.

  9. An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype

    NARCIS (Netherlands)

    Direk, Nese; Williams, Stephanie; Smith, Jennifer A.; Ripke, Stephan; Air, Tracy; Amare, Azmeraw T.; Amin, Najaf; Baune, Bernhard T.; Bennett, David A.; Blackwood, Douglas H. R.; Boomsma, Dorret; Breen, Gerome; Buttenschon, Henriette N.; Byrne, Enda M.; Borglum, Anders D.; Castelao, Enrique; Cichon, Sven; Clarke, Toni-Kim; Cornelis, Marilyn C.; Dannlowski, Udo; De Jager, Philip L.; Demirkan, Ayse; Domenici, Enrico; van Duijn, Cornelia M.; Dunn, Erin C.; Eriksson, Johan G.; Esko, Tonu; Faul, Jessica D.; Ferrucci, Luigi; Fornage, Myriam; de Geus, Eco; Gill, Michael; Gordon, Scott D.; Grabe, Hans Joergen; van Grootheest, Gerard; Hamilton, Steven P.; Hartman, Catharina A.; Heath, Andrew C.; Hek, Karin; Hofman, Albert; Homuth, Georg; Horn, Carsten; Hottenga, Jouke Jan; Kardia, Sharon L. R.; Kloiber, Stefan; Koenen, Karestan; Kutalik, Zoltan; Ladwig, Karl-Heinz; Lahti, Jari; Levinson, Douglas F.; Lewis, Cathryn M.; Lewis, Glyn; Li, Qingqin S.; Llewellyn, David J.; Lucae, Susanne; Lunetta, Kathryn L.; MacIntyre, Donald J.; Madden, Pamela; Martin, Nicholas G.; McIntosh, Andrew M.; Metspalu, Andres; Milaneschi, Yuri; Montgomery, Grant W.; Mors, Ole; Mosley, Thomas H.; Murabito, Joanne M.; Mueller-Myhsok, Bertram; Nothen, Markus M.; Nyholt, Dale R.; O'Donovan, Michael C.; Penninx, Brenda W.; Pergadia, Michele L.; Perlis, Roy; Potash, James B.; Preisig, Martin; Purcell, Shaun M.; Quiroz, Jorge A.; Raikkonen, Katri; Rice, John P.; Rietschel, Marcella; Rivera, Margarita; Schulze, Thomas G.; Shi, Jianxin; Shyn, Stanley; Sinnamon, Grant C.; Smit, Johannes H.; Smoller, Jordan W.; Snieder, Harold; Tanaka, Toshiko; Tansey, Katherine E.; Teumer, Alexander; Uher, Rudolf; Umbricht, Daniel; Van der Auwera, Sandra; Ware, Erin B.; Weir, David R.; Weissman, Myrna M.; Willemsen, Gonneke; Yang, Jingyun; Zhao, Wei; Tiemeier, Henning; Sullivan, Patrick F.

    2017-01-01

    BACKGROUND: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide

  10. Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function

    Science.gov (United States)

    Tang, Wenbo; Kowgier, Matthew; Loth, Daan W.; Soler Artigas, María; Joubert, Bonnie R.; Hodge, Emily; Gharib, Sina A.; Smith, Albert V.; Ruczinski, Ingo; Gudnason, Vilmundur; Mathias, Rasika A.; Harris, Tamara B.; Hansel, Nadia N.; Launer, Lenore J.; Barnes, Kathleen C.; Hansen, Joyanna G.; Albrecht, Eva; Aldrich, Melinda C.; Allerhand, Michael; Barr, R. Graham; Brusselle, Guy G.; Couper, David J.; Curjuric, Ivan; Davies, Gail; Deary, Ian J.; Dupuis, Josée; Fall, Tove; Foy, Millennia; Franceschini, Nora; Gao, Wei; Gläser, Sven; Gu, Xiangjun; Hancock, Dana B.; Heinrich, Joachim; Hofman, Albert; Imboden, Medea; Ingelsson, Erik; James, Alan; Karrasch, Stefan; Koch, Beate; Kritchevsky, Stephen B.; Kumar, Ashish; Lahousse, Lies; Li, Guo; Lind, Lars; Lindgren, Cecilia; Liu, Yongmei; Lohman, Kurt; Lumley, Thomas; McArdle, Wendy L.; Meibohm, Bernd; Morris, Andrew P.; Morrison, Alanna C.; Musk, Bill; North, Kari E.; Palmer, Lyle J.; Probst-Hensch, Nicole M.; Psaty, Bruce M.; Rivadeneira, Fernando; Rotter, Jerome I.; Schulz, Holger; Smith, Lewis J.; Sood, Akshay; Starr, John M.; Strachan, David P.; Teumer, Alexander; Uitterlinden, André G.; Völzke, Henry; Voorman, Arend; Wain, Louise V.; Wells, Martin T.; Wilk, Jemma B.; Williams, O. Dale; Heckbert, Susan R.; Stricker, Bruno H.; London, Stephanie J.; Fornage, Myriam; Tobin, Martin D.; O′Connor, George T.; Hall, Ian P.; Cassano, Patricia A.

    2014-01-01

    Background Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. Methods We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. Results The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10-7). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. Conclusions In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function. PMID:24983941

  11. Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

    Directory of Open Access Journals (Sweden)

    Wenbo Tang

    Full Text Available Genome-wide association studies (GWAS have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1 in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7. In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8 at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

  12. Genome-Wide Analyses Suggest Mechanisms Involving Early B-Cell Development in Canine IgA Deficiency

    Science.gov (United States)

    Frankowiack, Marcel; Kierczak, Marcin; Bergvall, Kerstin; Axelsson, Erik; Tintle, Linda; Marti, Eliane; Roosje, Petra; Leeb, Tosso; Hedhammar, Åke; Hammarström, Lennart; Lindblad-Toh, Kerstin

    2015-01-01

    Immunoglobulin A deficiency (IgAD) is the most common primary immune deficiency disorder in both humans and dogs, characterized by recurrent mucosal tract infections and a predisposition for allergic and other immune mediated diseases. In several dog breeds, low IgA levels have been observed at a high frequency and with a clinical resemblance to human IgAD. In this study, we used genome-wide association studies (GWAS) to identify genomic regions associated with low IgA levels in dogs as a comparative model for human IgAD. We used a novel percentile groups-approach to establish breed-specific cut-offs and to perform analyses in a close to continuous manner. GWAS performed in four breeds prone to low IgA levels (German shepherd, Golden retriever, Labrador retriever and Shar-Pei) identified 35 genomic loci suggestively associated (p IgA levels. In German shepherd, three genomic regions (candidate genes include KIRREL3 and SERPINA9) were genome-wide significantly associated (p IgA levels. A ~20kb long haplotype on CFA28, significantly associated (p = 0.0005) to IgA levels in Shar-Pei, was positioned within the first intron of the gene SLIT1. Both KIRREL3 and SLIT1 are highly expressed in the central nervous system and in bone marrow and are potentially important during B-cell development. SERPINA9 expression is restricted to B-cells and peaks at the time-point when B-cells proliferate into antibody-producing plasma cells. The suggestively associated regions were enriched for genes in Gene Ontology gene sets involving inflammation and early immune cell development. PMID:26225558

  13. Cross-Disorder Genome-Wide Analyses Suggest a Complex Genetic Relationship Between Tourette Syndrome and Obsessive-Compulsive Disorder

    Science.gov (United States)

    Yu, Dongmei; Mathews, Carol A.; Scharf, Jeremiah M.; Neale, Benjamin M.; Davis, Lea K.; Gamazon, Eric R.; Derks, Eske M.; Evans, Patrick; Edlund, Christopher K.; Crane, Jacquelyn; Fagerness, Jesen A.; Osiecki, Lisa; Gallagher, Patience; Gerber, Gloria; Haddad, Stephen; Illmann, Cornelia; McGrath, Lauren M.; Mayerfeld, Catherine; Arepalli, Sampath; Barlassina, Cristina; Barr, Cathy L.; Bellodi, Laura; Benarroch, Fortu; Berrió, Gabriel Bedoya; Bienvenu, O. Joseph; Black, Donald; Bloch, Michael H.; Brentani, Helena; Bruun, Ruth D.; Budman, Cathy L.; Camarena, Beatriz; Campbell, Desmond D.; Cappi, Carolina; Cardona Silgado, Julio C.; Cavallini, Maria C.; Chavira, Denise A.; Chouinard, Sylvain; Cook, Edwin H.; Cookson, M. R.; Coric, Vladimir; Cullen, Bernadette; Cusi, Daniele; Delorme, Richard; Denys, Damiaan; Dion, Yves; Eapen, Valsama; Egberts, Karin; Falkai, Peter; Fernandez, Thomas; Fournier, Eduardo; Garrido, Helena; Geller, Daniel; Gilbert, Donald; Girard, Simon L.; Grabe, Hans J.; Grados, Marco A.; Greenberg, Benjamin D.; Gross-Tsur, Varda; Grünblatt, Edna; Hardy, John; Heiman, Gary A.; Hemmings, Sian M.J.; Herrera, Luis D.; Hezel, Dianne M.; Hoekstra, Pieter J.; Jankovic, Joseph; Kennedy, James L.; King, Robert A.; Konkashbaev, Anuar I.; Kremeyer, Barbara; Kurlan, Roger; Lanzagorta, Nuria; Leboyer, Marion; Leckman, James F.; Lennertz, Leonhard; Liu, Chunyu; Lochner, Christine; Lowe, Thomas L.; Lupoli, Sara; Macciardi, Fabio; Maier, Wolfgang; Manunta, Paolo; Marconi, Maurizio; McCracken, James T.; Mesa Restrepo, Sandra C.; Moessner, Rainald; Moorjani, Priya; Morgan, Jubel; Muller, Heike; Murphy, Dennis L.; Naarden, Allan L.; Ochoa, William Cornejo; Ophoff, Roel A.; Pakstis, Andrew J.; Pato, Michele T.; Pato, Carlos N.; Piacentini, John; Pittenger, Christopher; Pollak, Yehuda; Rauch, Scott L.; Renner, Tobias; Reus, Victor I.; Richter, Margaret A.; Riddle, Mark A.; Robertson, Mary M.; Romero, Roxana; Rosário, Maria C.; Rosenberg, David; Ruhrmann, Stephan; Sabatti, Chiara; Salvi, Erika; Sampaio, Aline S.; Samuels, Jack; Sandor, Paul; Service, Susan K.; Sheppard, Brooke; Singer, Harvey S.; Smit, Jan H.; Stein, Dan J.; Strengman, Eric; Tischfield, Jay A.; Turiel, Maurizio; Valencia Duarte, Ana V.; Vallada, Homero; Veenstra-VanderWeele, Jeremy; Walitza, Susanne; Walkup, John; Wang, Ying; Weale, Mike; Weiss, Robert; Wendland, Jens R.; Westenberg, Herman G.M.; Yao, Yin; Hounie, Ana G.; Miguel, Euripedes C.; Nicolini, Humberto; Wagner, Michael; Ruiz-Linares, Andres; Cath, Danielle C.; McMahon, William; Posthuma, Danielle; Oostra, Ben A.; Nestadt, Gerald; Rouleau, Guy A.; Purcell, Shaun; Jenike, Michael A.; Heutink, Peter; Hanna, Gregory L.; Conti, David V.; Arnold, Paul D.; Freimer, Nelson; Stewart, S. Evelyn; Knowles, James A.; Cox, Nancy J.; Pauls, David L.

    2014-01-01

    Obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS) are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. Here, we report a combined genome-wide association study (GWAS) of TS and OCD in 2723 cases (1310 with OCD, 834 with TS, 579 with OCD plus TS/chronic tics (CT)), 5667 ancestry-matched controls, and 290 OCD parent-child trios. Although no individual single nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels, i.e. expression quantitative loci (eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10−4), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, TS had a smaller, non-significant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and TS/CT were included in the analysis (p=0.01). Previous work has shown that TS and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of TS and OCD. Furthermore, OCD with co-occurring TS/CT may have different underlying genetic susceptibility compared to OCD alone. PMID:25158072

  14. Genome-wide DNA promoter methylation and transcriptome analysis in human adipose tissue unravels novel candidate genes for obesity

    OpenAIRE

    Maria Keller; Lydia Hopp; Xuanshi Liu; Tobias Wohland; Kerstin Rohde; Raffaella Cancello; Matthias Klös; Karl Bacos; Matthias Kern; Fabian Eichelmann; Arne Dietrich; Michael R Schön; Daniel Gärtner; Tobias Lohmann; Miriam Dreßler

    2017-01-01

    Objective/methods: DNA methylation plays an important role in obesity and related metabolic complications. We examined genome-wide DNA promoter methylation along with mRNA profiles in paired samples of human subcutaneous adipose tissue (SAT) and omental visceral adipose tissue (OVAT) from non-obese vs. obese individuals. Results: We identified negatively correlated methylation and expression of several obesity-associated genes in our discovery dataset and in silico replicated ETV6 in two i...

  15. Transcriptome kinetics is governed by a genome-wide coupling of mRNA production and degradation: a role for RNA Pol II.

    Directory of Open Access Journals (Sweden)

    Ophir Shalem

    2011-09-01

    Full Text Available Transcriptome dynamics is governed by two opposing processes, mRNA production and degradation. Recent studies found that changes in these processes are frequently coordinated and that the relationship between them shapes transcriptome kinetics. Specifically, when transcription changes are counter-acted with changes in mRNA stability, transient fast-relaxing transcriptome kinetics is observed. A possible molecular mechanism underlying such coordinated regulation might lay in two RNA polymerase (Pol II subunits, Rpb4 and Rpb7, which are recruited to mRNAs during transcription and later affect their degradation in the cytoplasm. Here we used a yeast strain carrying a mutant Pol II which poorly recruits these subunits. We show that this mutant strain is impaired in its ability to modulate mRNA stability in response to stress. The normal negative coordinated regulation is lost in the mutant, resulting in abnormal transcriptome profiles both with respect to magnitude and kinetics of responses. These results reveal an important role for Pol II, in regulation of both mRNA synthesis and degradation, and also in coordinating between them. We propose a simple model for production-degradation coupling that accounts for our observations. The model shows how a simple manipulation of the rates of co-transcriptional mRNA imprinting by Pol II may govern genome-wide transcriptome kinetics in response to environmental changes.

  16. Genome-wide transcriptome analysis of the plant pathogen Xanthomonas identifies sRNAs with putative virulence functions

    Science.gov (United States)

    Schmidtke, Cornelius; Findeiß, Sven; Sharma, Cynthia M.; Kuhfuß, Juliane; Hoffmann, Steve; Vogel, Jörg; Stadler, Peter F.; Bonas, Ulla

    2012-01-01

    The Gram-negative plant-pathogenic bacterium Xanthomonas campestris pv. vesicatoria (Xcv) is an important model to elucidate the mechanisms involved in the interaction with the host. To gain insight into the transcriptome of the Xcv strain 85–10, we took a differential RNA sequencing (dRNA-seq) approach. Using a novel method to automatically generate comprehensive transcription start site (TSS) maps we report 1421 putative TSSs in the Xcv genome. Genes in Xcv exhibit a poorly conserved −10 promoter element and no consensus Shine-Dalgarno sequence. Moreover, 14% of all mRNAs are leaderless and 13% of them have unusually long 5′-UTRs. Northern blot analyses confirmed 16 intergenic small RNAs and seven cis-encoded antisense RNAs in Xcv. Expression of eight intergenic transcripts was controlled by HrpG and HrpX, key regulators of the Xcv type III secretion system. More detailed characterization identified sX12 as a small RNA that controls virulence of Xcv by affecting the interaction of the pathogen and its host plants. The transcriptional landscape of Xcv is unexpectedly complex, featuring abundant antisense transcripts, alternative TSSs and clade-specific small RNAs. PMID:22080557

  17. Systems genetics of obesity in an F2 pig model by genome-wide association, genetic network and pathway analyses

    Directory of Open Access Journals (Sweden)

    Lisette J. A. Kogelman

    2014-07-01

    Full Text Available Obesity is a complex condition with world-wide exponentially rising prevalence rates, linked with severe diseases like Type 2 Diabetes. Economic and welfare consequences have led to a raised interest in a better understanding of the biological and genetic background. To date, whole genome investigations focusing on single genetic variants have achieved limited success, and the importance of including genetic interactions is becoming evident. Here, the aim was to perform an integrative genomic analysis in an F2 pig resource population that was constructed with an aim to maximize genetic variation of obesity-related phenotypes and genotyped using the 60K SNP chip. Firstly, Genome Wide Association (GWA analysis was performed on the Obesity Index to locate candidate genomic regions that were further validated using combined Linkage Disequilibrium Linkage Analysis and investigated by evaluation of haplotype blocks. We built Weighted Interaction SNP Hub (WISH and differentially wired (DW networks using genotypic correlations amongst obesity-associated SNPs resulting from GWA analysis. GWA results and SNP modules detected by WISH and DW analyses were further investigated by functional enrichment analyses. The functional annotation of SNPs revealed several genes associated with obesity, e.g. NPC2 and OR4D10. Moreover, gene enrichment analyses identified several significantly associated pathways, over and above the GWA study results, that may influence obesity and obesity related diseases, e.g. metabolic processes. WISH networks based on genotypic correlations allowed further identification of various gene ontology terms and pathways related to obesity and related traits, which were not identified by the GWA study. In conclusion, this is the first study to develop a (genetic obesity index and employ systems genetics in a porcine model to provide important insights into the complex genetic architecture associated with obesity and many biological pathways

  18. Systems genetics of obesity in an F2 pig model by genome-wide association, genetic network, and pathway analyses.

    Science.gov (United States)

    Kogelman, Lisette J A; Pant, Sameer D; Fredholm, Merete; Kadarmideen, Haja N

    2014-01-01

    Obesity is a complex condition with world-wide exponentially rising prevalence rates, linked with severe diseases like Type 2 Diabetes. Economic and welfare consequences have led to a raised interest in a better understanding of the biological and genetic background. To date, whole genome investigations focusing on single genetic variants have achieved limited success, and the importance of including genetic interactions is becoming evident. Here, the aim was to perform an integrative genomic analysis in an F2 pig resource population that was constructed with an aim to maximize genetic variation of obesity-related phenotypes and genotyped using the 60K SNP chip. Firstly, Genome Wide Association (GWA) analysis was performed on the Obesity Index to locate candidate genomic regions that were further validated using combined Linkage Disequilibrium Linkage Analysis and investigated by evaluation of haplotype blocks. We built Weighted Interaction SNP Hub (WISH) and differentially wired (DW) networks using genotypic correlations amongst obesity-associated SNPs resulting from GWA analysis. GWA results and SNP modules detected by WISH and DW analyses were further investigated by functional enrichment analyses. The functional annotation of SNPs revealed several genes associated with obesity, e.g., NPC2 and OR4D10. Moreover, gene enrichment analyses identified several significantly associated pathways, over and above the GWA study results, that may influence obesity and obesity related diseases, e.g., metabolic processes. WISH networks based on genotypic correlations allowed further identification of various gene ontology terms and pathways related to obesity and related traits, which were not identified by the GWA study. In conclusion, this is the first study to develop a (genetic) obesity index and employ systems genetics in a porcine model to provide important insights into the complex genetic architecture associated with obesity and many biological pathways that underlie

  19. Deciphering the cryptic genome: genome-wide analyses of the rice pathogen Fusarium fujikuroi reveal complex regulation of secondary metabolism and novel metabolites.

    Directory of Open Access Journals (Sweden)

    Philipp Wiemann

    Full Text Available The fungus Fusarium fujikuroi causes "bakanae" disease of rice due to its ability to produce gibberellins (GAs, but it is also known for producing harmful mycotoxins. However, the genetic capacity for the whole arsenal of natural compounds and their role in the fungus' interaction with rice remained unknown. Here, we present a high-quality genome sequence of F. fujikuroi that was assembled into 12 scaffolds corresponding to the 12 chromosomes described for the fungus. We used the genome sequence along with ChIP-seq, transcriptome, proteome, and HPLC-FTMS-based metabolome analyses to identify the potential secondary metabolite biosynthetic gene clusters and to examine their regulation in response to nitrogen availability and plant signals. The results indicate that expression of most but not all gene clusters correlate with proteome and ChIP-seq data. Comparison of the F. fujikuroi genome to those of six other fusaria revealed that only a small number of gene clusters are conserved among these species, thus providing new insights into the divergence of secondary metabolism in the genus Fusarium. Noteworthy, GA biosynthetic genes are present in some related species, but GA biosynthesis is limited to F. fujikuroi, suggesting that this provides a selective advantage during infection of the preferred host plant rice. Among the genome sequences analyzed, one cluster that includes a polyketide synthase gene (PKS19 and another that includes a non-ribosomal peptide synthetase gene (NRPS31 are unique to F. fujikuroi. The metabolites derived from these clusters were identified by HPLC-FTMS-based analyses of engineered F. fujikuroi strains overexpressing cluster genes. In planta expression studies suggest a specific role for the PKS19-derived product during rice infection. Thus, our results indicate that combined comparative genomics and genome-wide experimental analyses identified novel genes and secondary metabolites that contribute to the evolutionary

  20. Deciphering the Cryptic Genome: Genome-wide Analyses of the Rice Pathogen Fusarium fujikuroi Reveal Complex Regulation of Secondary Metabolism and Novel Metabolites

    Science.gov (United States)

    Studt, Lena; Niehaus, Eva-Maria; Espino, Jose J.; Huß, Kathleen; Michielse, Caroline B.; Albermann, Sabine; Wagner, Dominik; Bergner, Sonja V.; Connolly, Lanelle R.; Fischer, Andreas; Reuter, Gunter; Kleigrewe, Karin; Bald, Till; Wingfield, Brenda D.; Ophir, Ron; Freeman, Stanley; Hippler, Michael; Smith, Kristina M.; Brown, Daren W.; Proctor, Robert H.; Münsterkötter, Martin; Freitag, Michael; Humpf, Hans-Ulrich; Güldener, Ulrich; Tudzynski, Bettina

    2013-01-01

    The fungus Fusarium fujikuroi causes “bakanae” disease of rice due to its ability to produce gibberellins (GAs), but it is also known for producing harmful mycotoxins. However, the genetic capacity for the whole arsenal of natural compounds and their role in the fungus' interaction with rice remained unknown. Here, we present a high-quality genome sequence of F. fujikuroi that was assembled into 12 scaffolds corresponding to the 12 chromosomes described for the fungus. We used the genome sequence along with ChIP-seq, transcriptome, proteome, and HPLC-FTMS-based metabolome analyses to identify the potential secondary metabolite biosynthetic gene clusters and to examine their regulation in response to nitrogen availability and plant signals. The results indicate that expression of most but not all gene clusters correlate with proteome and ChIP-seq data. Comparison of the F. fujikuroi genome to those of six other fusaria revealed that only a small number of gene clusters are conserved among these species, thus providing new insights into the divergence of secondary metabolism in the genus Fusarium. Noteworthy, GA biosynthetic genes are present in some related species, but GA biosynthesis is limited to F. fujikuroi, suggesting that this provides a selective advantage during infection of the preferred host plant rice. Among the genome sequences analyzed, one cluster that includes a polyketide synthase gene (PKS19) and another that includes a non-ribosomal peptide synthetase gene (NRPS31) are unique to F. fujikuroi. The metabolites derived from these clusters were identified by HPLC-FTMS-based analyses of engineered F. fujikuroi strains overexpressing cluster genes. In planta expression studies suggest a specific role for the PKS19-derived product during rice infection. Thus, our results indicate that combined comparative genomics and genome-wide experimental analyses identified novel genes and secondary metabolites that contribute to the evolutionary success of F

  1. Genome-wide and molecular evolution analyses of the phospholipase D gene family in Poplar and Grape.

    Science.gov (United States)

    Liu, Qi; Zhang, Chiyu; Yang, Yongping; Hu, Xiangyang

    2010-06-18

    The Phospholipase D (PLD) family plays an important role in the regulation of cellular processes in plants, including abscisic acid signaling, programmed cell death, root hair patterning, root growth, freezing tolerance and other stress responses. PLD genes constitute an important gene family in higher plants. However, until now our knowledge concerning the PLD gene family members and their evolutionary relationship in woody plants such as Poplar and Grape has been limited. In this study, we have provided a genome-wide analysis of the PLD gene family in Poplar and Grape. Eighteen and eleven members of the PLD gene family were identified in Poplar and Grape respectively. Phylogenetic and gene structure analyses showed that the PLD gene family can be divided into 6 subgroups: alpha, beta/gamma, delta, epsilon, zeta, and phi, and that the 6 PLD subgroups originated from 4 original ancestors through a series of gene duplications. Interestingly, the majority of the PLD genes from both Poplar (76.5%, 13/17) and Grape (90.9%, 10/11) clustered closely together in the phylogenetic tree to the extent that their evolutionary relationship appears more tightly linked to each other, at least in terms of the PLD gene family, than it does to either Arabidopsis or rice. Five pairs of duplicated PLD genes were identified in Poplar, more than those in Grape, suggesting that frequent gene duplications occurred after these species diverged, resulting in a rapid expansion of the PLD gene family in Poplar. The majority of the gene duplications in Poplar were caused by segmental duplication and were distinct from those in Arabidopsis, rice and Grape. Additionally, the gene duplications in Poplar were estimated to have occurred from 11.31 to 13.76 million years ago, which are later than those that occurred in the other three plant species. Adaptive evolution analysis showed that positive selection contributed to the evolution of the PXPH- and SP-PLDs, whereas purifying selection has driven

  2. Genome-wide and molecular evolution analyses of the phospholipase D gene family in Poplar and Grape

    Directory of Open Access Journals (Sweden)

    Yang Yongping

    2010-06-01

    Full Text Available Abstract Background The Phospholipase D (PLD family plays an important role in the regulation of cellular processes in plants, including abscisic acid signaling, programmed cell death, root hair patterning, root growth, freezing tolerance and other stress responses. PLD genes constitute an important gene family in higher plants. However, until now our knowledge concerning the PLD gene family members and their evolutionary relationship in woody plants such as Poplar and Grape has been limited. Results In this study, we have provided a genome-wide analysis of the PLD gene family in Poplar and Grape. Eighteen and eleven members of the PLD gene family were identified in Poplar and Grape respectively. Phylogenetic and gene structure analyses showed that the PLD gene family can be divided into 6 subgroups: α, β/γ, δ, ε, ζ, and φ, and that the 6 PLD subgroups originated from 4 original ancestors through a series of gene duplications. Interestingly, the majority of the PLD genes from both Poplar (76.5%, 13/17 and Grape (90.9%, 10/11 clustered closely together in the phylogenetic tree to the extent that their evolutionary relationship appears more tightly linked to each other, at least in terms of the PLD gene family, than it does to either Arabidopsis or rice. Five pairs of duplicated PLD genes were identified in Poplar, more than those in Grape, suggesting that frequent gene duplications occurred after these species diverged, resulting in a rapid expansion of the PLD gene family in Poplar. The majority of the gene duplications in Poplar were caused by segmental duplication and were distinct from those in Arabidopsis, rice and Grape. Additionally, the gene duplications in Poplar were estimated to have occurred from 11.31 to 13.76 million years ago, which are later than those that occurred in the other three plant species. Adaptive evolution analysis showed that positive selection contributed to the evolution of the PXPH- and SP-PLDs, whereas

  3. Genome-wide gene expression profile analyses identify CTTN as a potential prognostic marker in esophageal cancer.

    Directory of Open Access Journals (Sweden)

    Pei Lu

    Full Text Available AIM: Esophageal squamous cell carcinoma (ESCC is one of the most common fatal malignances of the digestive tract. Its prognosis is poor mainly due to the lack of reliable markers for early detection and prognostic prediction. Here we aim to identify the molecules involved in ESCC carcinogenesis and those as potential markers for prognosis and as new molecular therapeutic targets. METHODS: We performed genome-wide gene expression profile analyses of 10 primary ESCCs and their adjacent normal tissues by cDNA microarrays representing 47,000 transcripts and variants. Candidate genes were then validated by semi quantitative reverse transcription-PCR (RT-PCR, tissue microarrays (TMAs and immunohistochemistry (IHC staining. RESULTS: Using an arbitrary cutoff line of signal log ratio of ≥1.5 or ≤-1.5, we observed 549 up-regulated genes and 766 down-regulated genes in ESCCs compared with normal esophageal tissues. The functions of 302 differentially expressed genes were associated with cell metabolism, cell adhesion and immune response. Several candidate deregulated genes including four overexpressed (CTTN, DMRT2, MCM10 and SCYA26 and two underexpressed (HMGCS2 and SORBS2 were subsequently verified, which can be served as biomarkers for ESCC. Moreover, overexpression of cortactin (CTTN was observed in 126/198 (63.6% of ESCC cases and was significantly associated with lymph node metastasis (P = 0.000, pathologic stage (P = 0.000 and poor survival (P<0.001 of ESCC patients. Furthermore, a significant correlation between CTTN overexpression and shorter disease-specific survival rate was found in different subgroups of ESCC patient stratified by the pathologic stage (P<0.05. CONCLUSION: Our data provide valuable information for establishing molecules as candidates for prognostic and/or as therapeutic targets.

  4. Discovery of germline-related genes in Cephalochordate amphioxus: A genome wide survey using genome annotation and transcriptome data.

    Science.gov (United States)

    Yue, Jia-Xing; Li, Kun-Lung; Yu, Jr-Kai

    2015-12-01

    The generation of germline cells is a critical process in the reproduction of multicellular organisms. Studies in animal models have identified a common repertoire of genes that play essential roles in primordial germ cell (PGC) formation. However, comparative studies also indicate that the timing and regulation of this core genetic program vary considerably in different animals, raising the intriguing questions regarding the evolution of PGC developmental mechanisms in metazoans. Cephalochordates (commonly called amphioxus or lancelets) represent one of the invertebrate chordate groups and can provide important information about the evolution of developmental mechanisms in the chordate lineage. In this study, we used genome and transcriptome data to identify germline-related genes in two distantly related cephalochordate species, Branchiostoma floridae and Asymmetron lucayanum. Branchiostoma and Asymmetron diverged more than 120 MYA, and the most conspicuous difference between them is their gonadal morphology. We used important germline developmental genes in several model animals to search the amphioxus genome and transcriptome dataset for conserved homologs. We also annotated the assembled transcriptome data using Gene Ontology (GO) terms to facilitate the discovery of putative genes associated with germ cell development and reproductive functions in amphioxus. We further confirmed the expression of 14 genes in developing oocytes or mature eggs using whole mount in situ hybridization, suggesting their potential functions in amphioxus germ cell development. The results of this global survey provide a useful resource for testing potential functions of candidate germline-related genes in cephalochordates and for investigating differences in gonad developmental mechanisms between Branchiostoma and Asymmetron species.

  5. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

    NARCIS (Netherlands)

    Kar, S.P.; Beesley, J.; Olama, A. Amin Al; Michailidou, K.; Tyrer, J.; Kote-Jarai, Z.; Lawrenson, K.; Lindstrom, S.; Ramus, S.J.; Thompson, D.J.; Kibel, A.S.; Dansonka-Mieszkowska, A.; Michael, A.; Dieffenbach, A.K.; Gentry-Maharaj, A.; Whittemore, A.S.; Wolk, A.; Monteiro, A.; Peixoto, A.; Kierzek, A.; Cox, A; Rudolph, A.; Gonzalez-Neira, A.; Wu, A.H.; Lindblom, A.; Swerdlow, A.; Ziogas, A.; Ekici, A.B.; Burwinkel, B.; Karlan, B.Y.; Nordestgaard, B.G.; Blomqvist, C.; Phelan, C.; McLean, C.; Pearce, C.L.; Vachon, C.; Cybulski, C.; Slavov, C.; Stegmaier, C.; Maier, C.; Ambrosone, C.B.; Hogdall, C.K.; Teerlink, C.C.; Kang, D.; Tessier, D.C.; Schaid, D.J.; Stram, D.O.; Cramer, D.W; Neal, D.E.; Eccles, D.; Flesch-Janys, D.; Edwards, D.R.; Wokozorczyk, D.; Levine, D.A.; Yannoukakos, D.; Sawyer, E.J.; Bandera, E.V.; Poole, E.M.; Goode, E.L.; Khusnutdinova, E.; Hogdall, E.; Song, F.; Bruinsma, F.; Heitz, F.; Modugno, F.; Hamdy, F.C.; Wiklund, F.; Giles, G.G.; Olsson, H.; Wildiers, H.; Ulmer, H.U.; Pandha, H.; Risch, H.A.; Darabi, H.; Salvesen, H.B.; Nevanlinna, H.; Gronberg, H.; Brenner, H.; Brauch, H.; Anton-Culver, H.; Song, H.; Lim, H.Y.; McNeish, I.; Campbell, I.; Vergote, I.; Gronwald, J.; Lubinski, J.; Stanford, J.L.; Benitez, J.; Doherty, J.A.; Permuth, J.B.; Chang-Claude, J.; Donovan, J.L.; Dennis, J.; Schildkraut, J.M.; Schleutker, J.; Hopper, J.L.; Kupryjanczyk, J.; Park, J.Y.; Figueroa, J.; Kiemeney, L.A.; Massuger, L.F.A.G.

    2016-01-01

    Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and

  6. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

    NARCIS (Netherlands)

    A. Okbay (Aysu); Baselmans, B.M.L. (Bart M.L.); J.E. de Neve (Jan-Emmanuel); P. Turley (Patrick); M. Nivard (Michel); Fontana, M.A. (Mark Alan); Meddens, S.F.W. (S. Fleur W.); Linnér, R.K. (Richard Karlsson); Rietveld, C.A. (Cornelius A); J. Derringer; J. Gratten (Jacob); J.J. Lee (James J.); Liu, J.Z. (Jimmy Z); R. De Vlaming (Ronald); SAhluwalia, T. (Tarunveer); Buchwald, J. (Jadwiga); A. Cavadino (Alana); A.C. Frazier-Wood (Alexis C.); Furlotte, N.A. (Nicholas A); Garfield, V. (Victoria); Geisel, M.H. (Marie Henrike); J.R. Gonzalez (Juan R.); Haitjema, S. (Saskia); R. Karlsson (Robert); Der Laan, S.W. (Sander Wvan); K.-H. Ladwig (Karl-Heinz); J. Lahti (Jari); S. van der Lee (Sven); P.A. Lind (Penelope); Liu, T. (Tian); Matteson, L. (Lindsay); E. Mihailov (Evelin); M. Miller (Mike); CMinica, C. (Camelia); MNolte, I. (Ilja); D.O. Mook-Kanamori (Dennis); P.J. van der Most (Peter); C. Oldmeadow (Christopher); Y. Qian (Yong); O. Raitakari (Olli); R. Rawal (R.); A. Realo; Rueedi, R. (Rico); Schmidt, B. (Börge); A.V. Smith (Albert Vernon); E. Stergiakouli (Evangelia); T. Tanaka (Toshiko); K.D. Taylor (Kent); Wedenoja, J. (Juho); Wellmann, J. (Juergen); H.J. Westra (Harm-Jan); MWillems, S. (Sara); Zhao, W. (Wei); L.C. Study (LifeLines Cohort); N. Amin (Najaf); Bakshi, A. (Andrew); P.A. Boyle (Patricia); Cherney, S. (Samantha); Cox, S.R. (Simon R); G. Davies (Gail); O.S.P. Davis (Oliver S.); J. Ding (Jun); N. Direk (Nese); Eibich, P. (Peter); R. Emeny (Rebecca); Fatemifar, G. (Ghazaleh); J.D. Faul; L. Ferrucci (Luigi); A.J. Forstner; C. Gieger (Christian); Gupta, R. (Richa); T.B. Harris (Tamara B.); J.M. Harris (Juliette); E.G. Holliday (Elizabeth); J.J. Hottenga (Jouke Jan); P.L. de Jager (Philip); M. Kaakinen (Marika); E. Kajantie (Eero); Karhunen, V. (Ville); I. Kolcic (Ivana); M. Kumari (Meena); L.J. Launer (Lenore); L. Franke (Lude); Li-Gao, R. (Ruifang); Koini, M. (Marisa); A. Loukola (Anu); P. Marques-Vidal; G.W. Montgomery (Grant); M. Mosing (Miriam); L. Paternoster (Lavinia); A. Pattie (Alison); K. Petrovic (Katja); Pulkki-R'back, L. (Laura); L. Quaye (Lydia); R'ikkönen, K. (Katri); I. Rudan (Igor); R. Scott (Rodney); J.A. Smith (Jennifer A); A.R. Sutin; Trzaskowski, M. (Maciej); Vinkhuyze, A.E. (Anna E.); L. Yu (Lei); D. Zabaneh (Delilah); J. Attia (John); D.A. Bennett (David A.); Berger, K. (Klaus); L. Bertram (Lars); D.I. Boomsma (Dorret); H. Snieder (Harold); Chang, S.-C. (Shun-Chiao); F. Cucca (Francesco); I.J. Deary (Ian J.); C.M. van Duijn (Cock); K. Hagen (Knut); U. Bültmann (Ute); E.J. Geus (Eeco); P.J.F. Groenen (Patrick); V. Gudnason (Vilmundur); T. Hansen (T.); Hartman, C.A. (Catharine A); C.M.A. Haworth (Claire M.); C. Hayward (Caroline); A.C. Heath (Andrew C.); D.A. Hinds (David A.); E. Hypponen (Elina); W.G. Iacono (William); M.-R. Jarvelin (Marjo-Riitta); K.-H. JöCkel (Karl-Heinz); J. Kaprio (Jaakko); S.L.R. Kardia (Sharon); Keltikangas-J'rvinen, L. (Liisa); P. Kraft (Peter); Kubzansky, L.D. (Laura D.); Lehtim'ki, T. (Terho); P.K. Magnusson (Patrik); N.G. Martin (Nicholas); M. McGue (Matt); A. Metspalu (Andres); M. Mills (Melinda); R. de Mutsert (Reneé); A.J. Oldehinkel (Albertine); G. Pasterkamp (Gerard); N.L. Pedersen (Nancy); R. Plomin (Robert); O. Polasek (Ozren); C. Power (Christopher); S.S. Rich (Stephen); F.R. Rosendaal (Frits); H.M. den Ruijter (Hester ); Schlessinger, D. (David); R. Schmidt (Reinhold); R. Svento (Rauli); R. Schmidt (Reinhold); B.Z. Alizadeh (Behrooz); T.I.A. Sørensen (Thorkild); DSpector, T. (Tim); Steptoe, A. (Andrew); A. Terracciano; A.R. Thurik (Roy); N. Timpson (Nicholas); H.W. Tiemeier (Henning); A.G. Uitterlinden (André); P. Vollenweider (Peter); Wagner, G.G. (Gert G.); D.R. Weir (David); J. Yang (Joanna); Conley, D.C. (Dalton C.); G.D. Smith; Hofman, A. (Albert); M. Johannesson (Magnus); D. Laibson (David); S.E. Medland (Sarah Elizabeth); M.N. Meyer (Michelle N.); Pickrell, J.K. (Joseph K.); Esko, T. (T'nu); R.F. Krueger; J.P. Beauchamp (Jonathan); Ph.D. Koellinger (Philipp); D.J. Benjamin (Daniel J.); M. Bartels (Meike); D. Cesarini (David)

    2016-01-01

    textabstractVery few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. W

  7. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

    NARCIS (Netherlands)

    Okbay, Aysu; Baselmans, Bart M L; De Neve, Jan-Emmanuel; Turley, Patrick; Nivard, Michel G; Fontana, Mark Alan; Meddens, S Fleur W; Linnér, Richard Karlsson; Rietveld, Cornelius A; Derringer, Jaime; Gratten, Jacob; Lee, James J; Liu, Jimmy Z; de Vlaming, Ronald; Ahluwalia, Tarunveer S; Buchwald, Jadwiga; Cavadino, Alana; Frazier-Wood, Alexis C; Furlotte, Nicholas A; Garfield, Victoria; Geisel, Marie Henrike; Gonzalez, Juan R; Haitjema, Saskia; Karlsson, Robert; van der Laan, Sander W; Ladwig, Karl-Heinz; Lahti, Jari; van der Lee, Sven J; Lind, Penelope A; Liu, Tian; Matteson, Lindsay; Mihailov, Evelin; Miller, Michael B; Minica, Camelia C; Nolte, Ilja M; Mook-Kanamori, Dennis; van der Most, Peter J; Oldmeadow, Christopher; Qian, Yong; Raitakari, Olli; Rawal, Rajesh; Realo, Anu; Rueedi, Rico; Schmidt, Börge; Smith, Albert V; Stergiakouli, Evie; Tanaka, Toshiko; Taylor, Kent; Wedenoja, Juho; Wellmann, Juergen; Westra, Harm-Jan; Willems, Sara M; Zhao, Wei; Amin, Najaf; Bakshi, Andrew; Boyle, Patricia A; Cherney, Samantha; Cox, Simon R; Davies, Gail; Davis, Oliver S P; Ding, Jun; Direk, Nese; Eibich, Peter; Emeny, Rebecca T; Fatemifar, Ghazaleh; Faul, Jessica D; Ferrucci, Luigi; Forstner, Andreas; Gieger, Christian; Gupta, Richa; Harris, Tamara B; Harris, Juliette M; Holliday, Elizabeth G; Hottenga, Jouke-Jan; De Jager, Philip L; Kaakinen, Marika A; Kajantie, Eero; Karhunen, Ville; Kolcic, Ivana; Kumari, Meena; Launer, Lenore J; Franke, Lude; Li-Gao, Ruifang; Koini, Marisa; Loukola, Anu; Marques-Vidal, Pedro; Montgomery, Grant W; Mosing, Miriam A; Paternoster, Lavinia; Pattie, Alison; Petrovic, Katja E; Pulkki-Råback, Laura; Quaye, Lydia; Räikkönen, Katri; Rudan, Igor; Scott, Rodney J; Smith, Jennifer A; Sutin, Angelina R; Trzaskowski, Maciej; Vinkhuyzen, Anna E; Yu, Lei; Zabaneh, Delilah; Attia, John R; Bennett, David A; Berger, Klaus; Bertram, Lars; Boomsma, Dorret I; Snieder, Harold; Chang, Shun-Chiao; Cucca, Francesco; Deary, Ian J; van Duijn, Cornelia M; Eriksson, Johan G; Bültmann, Ute; de Geus, Eco J C; Groenen, Patrick J F; Gudnason, Vilmundur; Hansen, Torben; Hartman, Catharine A; Haworth, Claire M A; Hayward, Caroline; Heath, Andrew C; Hinds, David A; Hyppönen, Elina; Iacono, William G; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L R; Keltikangas-Järvinen, Liisa; Kraft, Peter; Kubzansky, Laura D; Lehtimäki, Terho; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; Metspalu, Andres; Mills, Melinda; de Mutsert, Renée; Oldehinkel, Albertine J; Pasterkamp, Gerard; Pedersen, Nancy L; Plomin, Robert; Polasek, Ozren; Power, Christine; Rich, Stephen S; Rosendaal, Frits R; den Ruijter, Hester M; Schlessinger, David; Schmidt, Helena; Svento, Rauli; Schmidt, Reinhold; Alizadeh, Behrooz; Sørensen, Thorkild I A; Spector, Tim D; Steptoe, Andrew; Terracciano, Antonio; Thurik, A Roy; Timpson, Nicholas J; Tiemeier, Henning; Uitterlinden, André G; Vollenweider, Peter; Wagner, Gert G; Weir, David R; Yang, Jian; Conley, Dalton C; Smith, George Davey; Hofman, Albert; Johannesson, Magnus; Laibson, David I; Medland, Sarah E; Meyer, Michelle N; Pickrell, Joseph K; Esko, Tõnu; Krueger, Robert F; Beauchamp, Jonathan P; Koellinger, Philipp D; Benjamin, Daniel J; Bartels, Meike; Cesarini, David

    2016-01-01

    Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted

  8. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

    NARCIS (Netherlands)

    Okbay, Aysu; Baselmans, Bart M L; De Neve, Jan-Emmanuel; Turley, Patrick; Nivard, Michel G; Fontana, Mark Alan; Meddens, S Fleur W; Linnér, Richard Karlsson; Rietveld, Cornelius A; Derringer, Jaime; Gratten, Jacob; Lee, James J; Liu, Jimmy Z; de Vlaming, Ronald; Ahluwalia, Tarunveer S; Buchwald, Jadwiga; Cavadino, Alana; Frazier-Wood, Alexis C; Furlotte, Nicholas A; Garfield, Victoria; Geisel, Marie Henrike; Gonzalez, Juan R; Haitjema, Saskia; Karlsson, Robert; van der Laan, Sander W; Ladwig, Karl-Heinz; Lahti, Jari; van der Lee, Sven J; Lind, Penelope A; Liu, Tian; Matteson, Lindsay; Mihailov, Evelin; Miller, Michael B; Minica, Camelia C; Nolte, Ilja M; Mook-Kanamori, Dennis; van der Most, Peter J; Oldmeadow, Christopher; Qian, Yong; Raitakari, Olli; Rawal, Rajesh; Realo, Anu; Rueedi, Rico; Schmidt, Börge; Smith, Albert V; Stergiakouli, Evie; Tanaka, Toshiko; Taylor, Kent; Wedenoja, Juho; Wellmann, Juergen; Westra, Harm-Jan; Willems, Sara M; Zhao, Wei; Amin, Najaf; Bakshi, Andrew; Boyle, Patricia A; Cherney, Samantha; Cox, Simon R; Davies, Gail; Davis, Oliver S P; Ding, Jun; Direk, Nese; Eibich, Peter; Emeny, Rebecca T; Fatemifar, Ghazaleh; Faul, Jessica D; Ferrucci, Luigi; Forstner, Andreas; Gieger, Christian; Gupta, Richa; Harris, Tamara B; Harris, Juliette M; Holliday, Elizabeth G; Hottenga, Jouke-Jan; De Jager, Philip L; Kaakinen, Marika A; Kajantie, Eero; Karhunen, Ville; Kolcic, Ivana; Kumari, Meena; Launer, Lenore J; Franke, Lude; Li-Gao, Ruifang; Koini, Marisa; Loukola, Anu; Marques-Vidal, Pedro; Montgomery, Grant W; Mosing, Miriam A; Paternoster, Lavinia; Pattie, Alison; Petrovic, Katja E; Pulkki-Råback, Laura; Quaye, Lydia; Räikkönen, Katri; Rudan, Igor; Scott, Rodney J; Smith, Jennifer A; Sutin, Angelina R; Trzaskowski, Maciej; Vinkhuyzen, Anna E; Yu, Lei; Zabaneh, Delilah; Attia, John R; Bennett, David A; Berger, Klaus; Bertram, Lars; Boomsma, Dorret I; Snieder, Harold; Chang, Shun-Chiao; Cucca, Francesco; Deary, Ian J; van Duijn, Cornelia M; Eriksson, Johan G; Bültmann, Ute; de Geus, Eco J C; Groenen, Patrick J F; Gudnason, Vilmundur; Hansen, Torben; Hartman, Catharine A; Haworth, Claire M A; Hayward, Caroline; Heath, Andrew C; Hinds, David A; Hyppönen, Elina; Iacono, William G; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L R; Keltikangas-Järvinen, Liisa; Kraft, Peter; Kubzansky, Laura D; Lehtimäki, Terho; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; Metspalu, Andres; Mills, Melinda; de Mutsert, Renée; Oldehinkel, Albertine J; Pasterkamp, Gerard|info:eu-repo/dai/nl/138488304; Pedersen, Nancy L; Plomin, Robert; Polasek, Ozren; Power, Christine; Rich, Stephen S; Rosendaal, Frits R; den Ruijter, Hester M|info:eu-repo/dai/nl/304123846; Schlessinger, David; Schmidt, Helena; Svento, Rauli; Schmidt, Reinhold; Alizadeh, Behrooz Z|info:eu-repo/dai/nl/274070057; Sørensen, Thorkild I A; Spector, Tim D; Steptoe, Andrew; Terracciano, Antonio; Thurik, A Roy; Timpson, Nicholas J; Tiemeier, Henning; Uitterlinden, André G; Vollenweider, Peter; Wagner, Gert G; Weir, David R; Yang, Jian; Conley, Dalton C; Smith, George Davey; Hofman, Albert; Johannesson, Magnus; Laibson, David I; Medland, Sarah E; Meyer, Michelle N; Pickrell, Joseph K; Esko, Tõnu; Krueger, Robert F; Beauchamp, Jonathan P; Koellinger, Philipp D; Benjamin, Daniel J; Bartels, Meike; Cesarini, David

    2016-01-01

    Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted

  9. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

    Science.gov (United States)

    Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted ...

  10. Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets

    NARCIS (Netherlands)

    Wain, Louise V.; Shrine, Nick R. G.; Artigas, Maria Soler; Erzurumluoglu, A Mesut; Noyvert, Boris; Bossini-Castillo, Lara; Obeidat, Ma'en; Henrys, Amanda P.; Portelli, Michael A.; Hall, Robert J; Billington, Charlotte K.; Rimington, Tracy L; Fenech, Anthony G; John, Catherine; Blake, Tineka; Jackson, Victoria E.; Allen, Richard J; Prins, Bram P.; Campbell, Archie; Porteous, David J.; Jarvelin, Marjo-Riitta; Wielscher, Matthias; Jamess, Alan L.; Hui, Jennie; Wareham, Nicholas J.; Zhao, Jing Hua; Wilson, James F.; Joshi, Peter K.; Stubbe, Beate; Rawal, Rajesh; Schulz, Holger; Imboden, Medea; Probst-Hensch, Nicole M.; Karrasch, Stefan; Gieger, Christian; Deary, Ian J.; Harris, Sarah E.; Marten, Jonathan; Rudan, Igor; Enroth, Stefan; Gyllensten, Ulf; Kerr, Shona M.; Polasek, Ozren; Kahonen, Mika; Surakka, Ida; Vitart, Veronique; Hayward, Caroline; Lehtimaki, Terho; Raitakari, Olli T.; Evans, David M.; Henderson, A. John; Pennell, Craig E.; Wang, Carol A.; Sly, Peter D.; Wan, Emily S; Busch, Robert; Hobbs, Brian D; Litonjua, Augusto; Sparrow, David W; Gulsvik, Amund; Bakke, Per S.; Crapo, James D.; Beaty, Terri H.; Hansel, Nadia N.; Mathias, Rasika A.; Ruczinski, Ingo; Barnes, Kathleen C.; Bosse, Yohan; Joubert, Philippe; van den Berge, Maarten; Brandsma, Corry-Anke; Pare, Peter D.; Sin, Don; Nickle, David C.; Hao, Ke; Gottesman, Omri; Dewey, Frederick E; Bruse, Shannon E; Carey, David J.; Kirchner, H Lester; Jonsson, Stefan; Thorleifsson, Gudmar; Jonsdottir, Ingileif; Gislason, Thorarinn; Stefansson, Kari; Schurmann, Claudia; Nadkarni, Girish N; Bottinger, Erwin P.; Loos, Ruth J. F.; Walters, Robin G.; Chen, Zhengming; Millwood, Iona Y; Vaucher, Julien; Kurmi, Om P; Li, Liming; Hansell, Anna L.; Brightling, Chris; Zeggini, Eleftheria; Cho, Michael H.; Silverman, Edwin K.; Sayers, Ian; Trynka, Gosia; Morris, Andrew P.; Strachan, David P.; Halls, Ian P.; Tobin, Martin D.

    2017-01-01

    Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 in

  11. Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets

    NARCIS (Netherlands)

    Wain, Louise V; Shrine, Nick; Artigas, María Soler; Erzurumluoglu, A Mesut; Noyvert, Boris; Bossini-Castillo, Lara; Obeidat, Ma'en; Henry, Amanda P; Portelli, Michael A; Hall, Robert J; Billington, Charlotte K; Rimington, Tracy L; Fenech, Anthony G; John, Catherine; Blake, Tineka; Jackson, Victoria E; Allen, Richard J; Prins, Bram P; Campbell, Archie; Porteous, David J; Jarvelin, Marjo-Riitta; Wielscher, Matthias; James, Alan L; Hui, Jennie; Wareham, Nicholas J; Zhao, Jing Hua; Wilson, James F; Joshi, Peter K; Stubbe, Beate; Rawal, Rajesh; Schulz, Holger; Imboden, Medea; Probst-Hensch, Nicole M; Karrasch, Stefan; Gieger, Christian; Deary, Ian J; Harris, Sarah E; Marten, Jonathan; Rudan, Igor; Enroth, Stefan; Gyllensten, Ulf; Kerr, Shona M; Polasek, Ozren; Kähönen, Mika; Surakka, Ida; Vitart, Veronique; Hayward, Caroline; Lehtimäki, Terho; Raitakari, Olli T; Evans, David M; Henderson, A John; Pennell, Craig E; Wang, Carol A; Sly, Peter D; Wan, Emily S; Busch, Robert; Hobbs, Brian D; Litonjua, Augusto A; Sparrow, David W; Gulsvik, Amund; Bakke, Per S; Crapo, James D; Beaty, Terri H; Hansel, Nadia N; Mathias, Rasika A; Ruczinski, Ingo; Barnes, Kathleen C; Bossé, Yohan; Joubert, Philippe; van den Berge, Maarten; Brandsma, Corry-Anke; Paré, Peter D; Sin, Don D; Nickle, David C; Hao, Ke; Gottesman, Omri; Dewey, Frederick E; Bruse, Shannon E; Carey, David J; Kirchner, H Lester; Jonsson, Stefan; Thorleifsson, Gudmar; Jonsdottir, Ingileif; Gislason, Thorarinn; Stefansson, Kari; Schurmann, Claudia; Nadkarni, Girish; Bottinger, Erwin P; Loos, Ruth J F; Walters, Robin G; Chen, Zhengming; Millwood, Iona Y; Vaucher, Julien; Kurmi, Om P; Li, Liming; Hansell, Anna L; Brightling, Chris; Zeggini, Eleftheria; Cho, Michael H; Silverman, Edwin K; Sayers, Ian; Trynka, Gosia; Morris, Andrew P; Strachan, David P; Hall, Ian P; Tobin, Martin D

    2017-01-01

    Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 in

  12. Genome-wide association analyses in Han Chinese identify two new susceptibility loci for amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Deng, Min; Wei, Ling; Zuo, Xianbo; Tian, Yanghua; Xie, Fei; Hu, Panpan; Zhu, Chunyan; Yu, Fengqiong; Meng, Yu; Wang, Honghao; Zhang, Fangfang; Ma, Huijuan; Ye, Rong; Cheng, Huaidong; Du, Jing; Dong, Wenwen; Zhou, Shanshan; Wang, Changqing; Wang, Yu; Wang, Jingye; Chen, Xianwen; Sun, Zhongwu; Zhou, Nong; Jiang, Yubao; Liu, Xiuxiu; Li, Xiaogang; Zhang, Nan; Liu, Na; Guan, Yingjun; Han, Yongsheng; Han, Yongzhu; Lv, Xinyi; Fu, Yu; Yu, Hui; Xi, Chunhua; Xie, Dandan; Zhao, Qiyuan; Xie, Peng; Wang, Xin; Zhang, Zhijun; Shen, Lu; Cui, Yong; Yin, Xianyong; Cheng, Hui; Liang, Bo; Zheng, Xiaodong; Lee, Tatia M. C.; Chen, Gang; Zhou, Fusheng; Veldink, Hendrik; Robberecht, Wim; Landers, John E.; Andersen, Peter M.; Al-Chalabi, Ammar; Shaw, Chris; Liu, Chunfeng; Tang, Beisha; Xiao, Shangxi; Robertson, Janice; Zhang, Fengyu; van den Berg, Leonard H.; Sun, Liangdan; Liu, Jianjun; Yang, Sen; Ju, Xiaodong; Wang, Kai; Zhang, Xuejun

    2013-01-01

    To identify susceptibility genes for amyotrophic lateral sclerosis (ALS), we conducted a genome-wide association study (GWAS) in 506 individuals with sporadic ALS and 1,859 controls of Han Chinese ancestry. Ninety top SNPs suggested by the current GWAS and 6 SNPs identified by previous GWAS were ana

  13. Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer.

    Science.gov (United States)

    Gong, Jian; Hutter, Carolyn M; Newcomb, Polly A; Ulrich, Cornelia M; Bien, Stephanie A; Campbell, Peter T; Baron, John A; Berndt, Sonja I; Bezieau, Stephane; Brenner, Hermann; Casey, Graham; Chan, Andrew T; Chang-Claude, Jenny; Du, Mengmeng; Duggan, David; Figueiredo, Jane C; Gallinger, Steven; Giovannucci, Edward L; Haile, Robert W; Harrison, Tabitha A; Hayes, Richard B; Hoffmeister, Michael; Hopper, John L; Hudson, Thomas J; Jeon, Jihyoun; Jenkins, Mark A; Kocarnik, Jonathan; Küry, Sébastien; Le Marchand, Loic; Lin, Yi; Lindor, Noralane M; Nishihara, Reiko; Ogino, Shuji; Potter, John D; Rudolph, Anja; Schoen, Robert E; Schrotz-King, Petra; Seminara, Daniela; Slattery, Martha L; Thibodeau, Stephen N; Thornquist, Mark; Toth, Reka; Wallace, Robert; White, Emily; Jiao, Shuo; Lemire, Mathieu; Hsu, Li; Peters, Ulrike

    2016-10-01

    Genome-wide association studies (GWAS) have identified many genetic susceptibility loci for colorectal cancer (CRC). However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76×10-8; permuted p-value 3.51x10-8) region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74-0.91]; P = 2.1×10-4) and TT genotypes (OR,0.62 [95% CI, 0.51-0.75]; P = 1.3×10-6) but not associated among those with the CC genotype (p = 0.059). No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk.

  14. Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer.

    Directory of Open Access Journals (Sweden)

    Jian Gong

    2016-10-01

    Full Text Available Genome-wide association studies (GWAS have identified many genetic susceptibility loci for colorectal cancer (CRC. However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO. Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76×10-8; permuted p-value 3.51x10-8 region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74-0.91]; P = 2.1×10-4 and TT genotypes (OR,0.62 [95% CI, 0.51-0.75]; P = 1.3×10-6 but not associated among those with the CC genotype (p = 0.059. No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk.

  15. Genome-wide analysis of primary CD4+ and CD8+ T cell transcriptomes shows evidence for a network of enriched pathways associated with HIV disease

    Directory of Open Access Journals (Sweden)

    Wang Bin

    2011-03-01

    Full Text Available Abstract Background HIV preferentially infects CD4+ T cells, and the functional impairment and numerical decline of CD4+ and CD8+ T cells characterize HIV disease. The numerical decline of CD4+ and CD8+ T cells affects the optimal ratio between the two cell types necessary for immune regulation. Therefore, this work aimed to define the genomic basis of HIV interactions with the cellular transcriptome of both CD4+ and CD8+ T cells. Results Genome-wide transcriptomes of primary CD4+ and CD8+ T cells from HIV+ patients were analyzed at different stages of HIV disease using Illumina microarray. For each cell subset, pairwise comparisons were performed and differentially expressed (DE genes were identified (fold change >2 and B-statistic >0 followed by quantitative PCR validation. Gene ontology (GO analysis of DE genes revealed enriched categories of complement activation, actin filament, proteasome core and proton-transporting ATPase complex. By gene set enrichment analysis (GSEA, a network of enriched pathways functionally connected by mitochondria was identified in both T cell subsets as a transcriptional signature of HIV disease progression. These pathways ranged from metabolism and energy production (TCA cycle and OXPHOS to mitochondria meditated cell apoptosis and cell cycle dysregulation. The most unique and significant feature of our work was that the non-progressing status in HIV+ long-term non-progressors was associated with MAPK, WNT, and AKT pathways contributing to cell survival and anti-viral responses. Conclusions These data offer new comparative insights into HIV disease progression from the aspect of HIV-host interactions at the transcriptomic level, which will facilitate the understanding of the genetic basis of transcriptomic interaction of HIV in vivo and how HIV subverts the human gene machinery at the individual cell type level.

  16. Genome-Wide Transcriptome Profiling of Mycobacterium smegmatis MC² 155 Cultivated in Minimal Media Supplemented with Cholesterol, Androstenedione or Glycerol.

    Science.gov (United States)

    Li, Qun; Ge, Fanglan; Tan, Yunya; Zhang, Guangxiang; Li, Wei

    2016-05-07

    Mycobacterium smegmatis strain MC² 155 is an attractive model organism for the study of M. tuberculosis and other mycobacterial pathogens, as it can grow well using cholesterol as a carbon resource. However, its global transcriptomic response remains largely unrevealed. In this study, M. smegmatis MC² 155 cultivated in androstenedione, cholesterol and glycerol supplemented media were collected separately for a RNA-Sequencing study. The results showed that 6004, 6681 and 6348 genes were expressed in androstenedione, cholesterol and glycerol supplemented media, and 5891 genes were expressed in all three conditions, with 237 specially expressed in cholesterol added medium. A total of 1852 and 454 genes were significantly up-regulated by cholesterol compared with the other two supplements. Only occasional changes were observed in basic carbon and nitrogen metabolism, while almost all of the genes involved in cholesterol catabolism and mammalian cell entry (MCE) were up-regulated by cholesterol, but not by androstenedione. Eleven and 16 gene clusters were induced by cholesterol when compared with glycerol or androstenedione, respectively. This study provides a comprehensive analysis of the cholesterol responsive transcriptome of M. smegmatis. Our results indicated that cholesterol induced many more genes and increased the expression of the majority of genes involved in cholesterol degradation and MCE in M. smegmatis, while androstenedione did not have the same effect.

  17. Genome-wide transcriptomic analysis of cotton under drought stress reveal significant down-regulation of genes and pathways involved in fibre elongation and up-regulation of defense responsive genes.

    Science.gov (United States)

    Padmalatha, Kethireddy Venkata; Dhandapani, Gurusamy; Kanakachari, Mogilicherla; Kumar, Saravanan; Dass, Abhishek; Patil, Deepak Prabhakar; Rajamani, Vijayalakshmi; Kumar, Krishan; Pathak, Ranjana; Rawat, Bhupendra; Leelavathi, Sadhu; Reddy, Palakolanu Sudhakar; Jain, Neha; Powar, Kasu N; Hiremath, Vamadevaiah; Katageri, Ishwarappa S; Reddy, Malireddy K; Solanke, Amolkumar U; Reddy, Vanga Siva; Kumar, Polumetla Ananda

    2012-02-01

    Cotton is an important source of natural fibre used in the textile industry and the productivity of the crop is adversely affected by drought stress. High throughput transcriptomic analyses were used to identify genes involved in fibre development. However, not much information is available on cotton genome response in developing fibres under drought stress. In the present study a genome wide transcriptome analysis was carried out to identify differentially expressed genes at various stages of fibre growth under drought stress. Our study identified a number of genes differentially expressed during fibre elongation as compared to other stages. High level up-regulation of genes encoding for enzymes involved in pectin modification and cytoskeleton proteins was observed at fibre initiation stage. While a large number of genes encoding transcription factors (AP2-EREBP, WRKY, NAC and C2H2), osmoprotectants, ion transporters and heat shock proteins and pathways involved in hormone (ABA, ethylene and JA) biosynthesis and signal transduction were up-regulated and genes involved in phenylpropanoid and flavonoid biosynthesis, pentose and glucuronate interconversions and starch and sucrose metabolism pathways were down-regulated during fibre elongation. This study showed that drought has relatively less impact on fibre initiation but has profound effect on fibre elongation by down-regulating important genes involved in cell wall loosening and expansion process. The comprehensive transcriptome analysis under drought stress has provided valuable information on differentially expressed genes and pathways during fibre development that will be useful in developing drought tolerant cotton cultivars without compromising fibre quality.

  18. No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects.

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    Jens Baumert

    Full Text Available Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI. Genome-wide association studies (GWAS have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8. This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.

  19. Genome-Wide Investigation Using sRNA-Seq, Degradome-Seq and Transcriptome-Seq Reveals Regulatory Networks of microRNAs and Their Target Genes in Soybean during Soybean mosaic virus Infection.

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    Hui Chen

    Full Text Available MicroRNAs (miRNAs play key roles in a variety of cellular processes through regulation of their target gene expression. Accumulated experimental evidence has demonstrated that infections by viruses are associated with the altered expression profile of miRNAs and their mRNA targets in the host. However, the regulatory network of miRNA-mRNA interactions during viral infection remains largely unknown. In this study, we performed small RNA (sRNA-seq, degradome-seq and as well as a genome-wide transcriptome analysis to profile the global gene and miRNA expression in soybean following infections by three different Soybean mosaic virus (SMV isolates, L (G2 strain, LRB (G2 strain and G7 (G7 strain. sRNA-seq analyses revealed a total of 253 soybean miRNAs with a two-fold or greater change in abundance compared with the mock-inoculated control. 125 transcripts were identified as the potential cleavage targets of 105 miRNAs and validated by degradome-seq analyses. Genome-wide transcriptome analysis showed that total 2679 genes are differentially expressed in response to SMV infection including 71 genes predicted as involved in defense response. Finally, complex miRNA-mRNA regulatory networks were derived using the RNAseq, small RNAseq and degradome data. This work represents a comprehensive, global approach to examining virus-host interactions. Genes responsive to SMV infection are identified as are their potential miRNA regulators. Additionally, regulatory changes of the miRNAs themselves are described and the regulatory relationships were supported with degradome data. Taken together these data provide new insights into molecular SMV-soybean interactions and offer candidate miRNAs and their targets for further elucidation of the SMV infection process.

  20. Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci.

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    Samuel E Jones

    2016-08-01

    Full Text Available Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8, including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10-12 and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10-10. The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants; thirteen of the chronotype signals remained associated at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10-8. For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10-16 and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10-9; and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10-9. Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05; undersleeping and BMI (rG = 0.147, P = 1x10-5 and oversleeping and BMI (rG = 0.097, P = 0.04, Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and

  1. An integrated transcriptomics-guided genome-wide promoter analysis and next-generation proteomics approach to mine factor(s) regulating cellular differentiation

    Science.gov (United States)

    Mandal, Kamal; Bader, Samuel L.; Kumar, Pankaj; Malakar, Dipankar; Campbell, David S.; Pradhan, Bhola Shankar; Sarkar, Rajesh K.; Wadhwa, Neerja; Sensharma, Souvik; Jain, Vaibhav; Moritz, Robert L.

    2017-01-01

    Abstract Differential next-generation-omics approaches aid in the visualization of biological processes and pave the way for divulging important events and/or interactions leading to a functional output at cellular or systems level. To this end, we undertook an integrated Nextgen transcriptomics and proteomics approach to divulge differential gene expression of infant and pubertal rat Sertoli cells (Sc).Unlike, pubertal Sc, infant Sc are immature and fail to support spermatogenesis. We found exclusive association of 14 and 19 transcription factor binding sites to infantile and pubertal states of Sc, respectively, using differential transcriptomics-guided genome-wide computational analysis of relevant promoters employing 220 Positional Weight Matrices from the TRANSFAC database. Proteomic SWATH-MS analysis provided extensive quantification of nuclear and cytoplasmic protein fractions revealing 1,670 proteins differentially located between the nucleus and cytoplasm of infant Sc and 890 proteins differentially located within those of pubertal Sc. Based on our multi-omics approach, the transcription factor YY1 was identified as one of the lead candidates regulating differentiation of Sc.YY1 was found to have abundant binding sites on promoters of genes upregulated during puberty. To determine its significance, we generated transgenic rats with Sc specific knockdown of YY1 that led to compromised spermatogenesis. PMID:28065881

  2. Genome-wide expression profiling of the transcriptomes of four Paulownia tomentosa accessions in response to drought.

    Science.gov (United States)

    Dong, Yanpeng; Fan, Guoqiang; Deng, Minjie; Xu, Enkai; Zhao, Zhenli

    2014-10-01

    Paulownia tomentosa is an important foundation forest tree species in semiarid areas. The lack of genetic information hinders research into the mechanisms involved in its response to abiotic stresses. Here, short-read sequencing technology (Illumina) was used to de novo assemble the transcriptome on P. tomentosa. A total of 99,218 unigenes with a mean length of 949 nucleotides were assembled. 68,295 unigenes were selected and the functions of their products were predicted using Clusters of Orthologous Groups, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes annotations. Afterwards, hundreds of genes involved in drought response were identified. Twelve putative drought response genes were analyzed by quantitative real-time polymerase chain reaction. This study provides a dataset of genes and inherent biochemical pathways, which will help in understanding the mechanisms of the water-deficit response in P. tomentosa. To our knowledge, this is the first study to highlight the genetic makeup of P. tomentosa.

  3. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics.

    Science.gov (United States)

    Fagerberg, Linn; Hallström, Björn M; Oksvold, Per; Kampf, Caroline; Djureinovic, Dijana; Odeberg, Jacob; Habuka, Masato; Tahmasebpoor, Simin; Danielsson, Angelika; Edlund, Karolina; Asplund, Anna; Sjöstedt, Evelina; Lundberg, Emma; Szigyarto, Cristina Al-Khalili; Skogs, Marie; Takanen, Jenny Ottosson; Berling, Holger; Tegel, Hanna; Mulder, Jan; Nilsson, Peter; Schwenk, Jochen M; Lindskog, Cecilia; Danielsson, Frida; Mardinoglu, Adil; Sivertsson, Asa; von Feilitzen, Kalle; Forsberg, Mattias; Zwahlen, Martin; Olsson, IngMarie; Navani, Sanjay; Huss, Mikael; Nielsen, Jens; Ponten, Fredrik; Uhlén, Mathias

    2014-02-01

    Global classification of the human proteins with regards to spatial expression patterns across organs and tissues is important for studies of human biology and disease. Here, we used a quantitative transcriptomics analysis (RNA-Seq) to classify the tissue-specific expression of genes across a representative set of all major human organs and tissues and combined this analysis with antibody-based profiling of the same tissues. To present the data, we launch a new version of the Human Protein Atlas that integrates RNA and protein expression data corresponding to ∼80% of the human protein-coding genes with access to the primary data for both the RNA and the protein analysis on an individual gene level. We present a classification of all human protein-coding genes with regards to tissue-specificity and spatial expression pattern. The integrative human expression map can be used as a starting point to explore the molecular constituents of the human body.

  4. Genome Wide Transcriptome Analysis reveals ABA mediated response in Arabidopsis during Gold (AuCl4- treatment

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    Devesh eShukla

    2014-11-01

    Full Text Available The unique physico-chemical properties of gold nanoparticles (AuNPs find manifold applications in diagnostics, medicine and catalysis. Chemical synthesis produces reactive AuNPs and generates hazardous by-products. Alternatively, plants can be utilized to produce AuNPs in an eco-friendly manner. To better control the biosynthesis of AuNPs, we need to first understand the detailed molecular response induced by AuCl4- In this study, we carried out global transcriptome analysis in root tissue of Arabidopsis grown for 12- hours in presence of gold solution (HAuCl4 using the novel unbiased Affymetrix exon array. Transcriptomics analysis revealed differential regulation of a total of 704 genes and 4900 exons. Of these, 492 and 212 genes were up- and downregulated, respectively. The validation of the expressed key genes, such as glutathione-S-transferases, auxin responsive genes, cytochrome P450 82C2, methyl transferases, transducin (G protein beta subunit, ERF transcription factor, ABC, and MATE transporters, was carried out through quantitative RT-PCR. These key genes demonstrated specific induction under AuCl4- treatment relative to other heavy metals, suggesting a unique plant-gold interaction. GO enrichment analysis reveals the upregulation of processes like oxidative stress, glutathione binding, metal binding, transport, and plant hormonal responses. Changes predicted in biochemical pathways indicated major modulation in glutathione mediated detoxification, flavones and derivatives, and plant hormone biosynthesis. Motif search analysis identified a highly significant enriched motif, ACGT, which is an abscisic acid responsive core element (ABRE, suggesting the possibility of ABA- mediated signaling. Identification of abscisic acid response element (ABRE points to the operation of a predominant signaling mechanism in response to AuCl4- exposure. Overall, this study presents a useful picture of plant-gold interaction with an identification of

  5. Multiplex and genome-wide analyses reveal distinctive properties of KIR+ and CD56+ T cells in human blood

    OpenAIRE

    Chan, Wing Keung; Rujkijyanont, Piya; Neale, Geoffrey; Jie YANG; Bari, Rafijul; Gupta, Neha Das; Holladay, Martha; Rooney, Barbara; Leung, Wing

    2013-01-01

    Killer-cell immunoglobulin-like receptors (KIRs) on natural killer (NK) cells have been linked to a wide spectrum of health conditions such as chronic infections, autoimmune diseases, pregnancy complications, cancers, and transplant failures. A small subset of effector memory T cells also expresses KIRs. Here, we use modern analytic tools including genome-wide and multiplex molecular, phenotypic, and functional assays to characterize the KIR+ T cells in human blood. We find that KIR+ T cells ...

  6. Systems genetics of obesity in an F2 pig model by genome-wide association, genetic network and pathway analyses

    DEFF Research Database (Denmark)

    Kogelman, Lisette; Pant, Sameer Dinkar; Fredholm, Merete;

    2014-01-01

    Obesity is a complex condition with world-wide exponentially rising prevalence rates, linked with severe diseases like Type 2 Diabetes. Economic and welfare consequences have led to a raised interest in a better understanding of the biological and genetic background. To date, whole genome...... of obesity-related phenotypes and genotyped using the 60K SNP chip. Firstly, Genome Wide Association (GWA) analysis was performed on the Obesity Index to locate candidate genomic regions that were further validated using combined Linkage Disequilibrium Linkage Analysis and investigated by evaluation...

  7. Systems genetics of obesity in an F2 pig model by genome-wide association, genetic network and pathway analyses

    DEFF Research Database (Denmark)

    Kogelman, Lisette; Pant, Sameer Dinkar; Fredholm, Merete

    2014-01-01

    Obesity is a complex condition with world-wide exponentially rising prevalence rates, linked with severe diseases like Type 2 Diabetes. Economic and welfare consequences have led to a raised interest in a better understanding of the biological and genetic background. To date, whole genome...... of obesity-related phenotypes and genotyped using the 60K SNP chip. Firstly, Genome Wide Association (GWA) analysis was performed on the Obesity Index to locate candidate genomic regions that were further validated using combined Linkage Disequilibrium Linkage Analysis and investigated by evaluation...

  8. Genome-Wide Analyses of the Soybean F-Box Gene Family in Response to Salt Stress.

    Science.gov (United States)

    Jia, Qi; Xiao, Zhi-Xia; Wong, Fuk-Ling; Sun, Song; Liang, Kang-Jing; Lam, Hon-Ming

    2017-04-12

    The F-box family is one of the largest gene families in plants that regulate diverse life processes, including salt responses. However, the knowledge of the soybean F-box genes and their roles in salt tolerance remains limited. Here, we conducted a genome-wide survey of the soybean F-box family, and their expression analysis in response to salinity via in silico analysis of online RNA-sequencing (RNA-seq) data and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) to predict their potential functions. A total of 725 potential F-box proteins encoded by 509 genes were identified and classified into 9 subfamilies. The gene structures, conserved domains and chromosomal distributions were characterized. There are 76 pairs of duplicate genes identified, including genome-wide segmental and tandem duplication events, which lead to the expansion of the number of F-box genes. The in silico expression analysis showed that these genes would be involved in diverse developmental functions and play an important role in salt response. Our qRT-PCR analysis confirmed 12 salt-responding F-box genes. Overall, our results provide useful information on soybean F-box genes, especially their potential roles in salt tolerance.

  9. Meta-analyses of genome-wide association studies identify multiple novel loci associated with pulmonary function

    Science.gov (United States)

    Hancock, Dana B.; Eijgelsheim, Mark; Wilk, Jemma B.; Gharib, Sina A.; Loehr, Laura R.; Marciante, Kristin D.; Franceschini, Nora; van Durme, Yannick M.T.A.; Chen, Ting-hsu; Barr, R. Graham; Schabath, Matthew B.; Couper, David J.; Brusselle, Guy G.; Psaty, Bruce M.; van Duijn, Cornelia M.; Rotter, Jerome I.; Uitterlinden, André G.; Hofman, Albert; Punjabi, Naresh M.; Rivadeneira, Fernando; Morrison, Alanna C.; Enright, Paul L.; North, Kari E.; Heckbert, Susan R.; Lumley, Thomas; Stricker, Bruno H.Ch.; O’Connor, George T.; London, Stephanie J.

    2010-01-01

    Measurements of lung function by spirometry are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important measures, forced expiratory volume in the first second (FEV1) and its ratio to forced vital capacity (FEV1/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE consortium studies: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), Framingham Heart Study (FHS), and Rotterdam Study (RS). We identified eight loci associated with FEV1/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1, and HTR4) and one locus associated with FEV1 (INTS12-GSTCD-NPNT) at or near genome-wide significance (PPID1) replicated with the SpiroMeta consortium. Our findings of novel loci influencing pulmonary function may offer insights into chronic lung disease pathogenesis. PMID:20010835

  10. Genome-Wide Identification and Validation of Reference Genes in Infected Tomato Leaves for Quantitative RT-PCR Analyses.

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    Oliver A Müller

    Full Text Available The Gram-negative bacterium Xanthomonas campestris pv. vesicatoria (Xcv causes bacterial spot disease of pepper and tomato by direct translocation of type III effector proteins into the plant cell cytosol. Once in the plant cell the effectors interfere with host cell processes and manipulate the plant transcriptome. Quantitative RT-PCR (qRT-PCR is usually the method of choice to analyze transcriptional changes of selected plant genes. Reliable results depend, however, on measuring stably expressed reference genes that serve as internal normalization controls. We identified the most stably expressed tomato genes based on microarray analyses of Xcv-infected tomato leaves and evaluated the reliability of 11 genes for qRT-PCR studies in comparison to four traditionally employed reference genes. Three different statistical algorithms, geNorm, NormFinder and BestKeeper, concordantly determined the superiority of the newly identified reference genes. The most suitable reference genes encode proteins with homology to PHD finger family proteins and the U6 snRNA-associated protein LSm7. In addition, we identified pepper orthologs and validated several genes as reliable normalization controls for qRT-PCR analysis of Xcv-infected pepper plants. The newly identified reference genes will be beneficial for future qRT-PCR studies of the Xcv-tomato and Xcv-pepper pathosystems, as well as for the identification of suitable normalization controls for qRT-PCR studies of other plant-pathogen interactions, especially, if related plant species are used in combination with bacterial pathogens.

  11. RGS2 expression predicts amyloid-β sensitivity, MCI and Alzheimer's disease: genome-wide transcriptomic profiling and bioinformatics data mining

    Science.gov (United States)

    Hadar, A; Milanesi, E; Squassina, A; Niola, P; Chillotti, C; Pasmanik-Chor, M; Yaron, O; Martásek, P; Rehavi, M; Weissglas-Volkov, D; Shomron, N; Gozes, I; Gurwitz, D

    2016-01-01

    Alzheimer's disease (AD) is the most frequent cause of dementia. Misfolded protein pathological hallmarks of AD are brain deposits of amyloid-β (Aβ) plaques and phosphorylated tau neurofibrillary tangles. However, doubts about the role of Aβ in AD pathology have been raised as Aβ is a common component of extracellular brain deposits found, also by in vivo imaging, in non-demented aged individuals. It has been suggested that some individuals are more prone to Aβ neurotoxicity and hence more likely to develop AD when aging brains start accumulating Aβ plaques. Here, we applied genome-wide transcriptomic profiling of lymphoblastoid cells lines (LCLs) from healthy individuals and AD patients for identifying genes that predict sensitivity to Aβ. Real-time PCR validation identified 3.78-fold lower expression of RGS2 (regulator of G-protein signaling 2; P=0.0085) in LCLs from healthy individuals exhibiting high vs low Aβ sensitivity. Furthermore, RGS2 showed 3.3-fold lower expression (P=0.0008) in AD LCLs compared with controls. Notably, RGS2 expression in AD LCLs correlated with the patients' cognitive function. Lower RGS2 expression levels were also discovered in published expression data sets from postmortem AD brain tissues as well as in mild cognitive impairment and AD blood samples compared with controls. In conclusion, Aβ sensitivity phenotyping followed by transcriptomic profiling and published patient data mining identified reduced peripheral and brain expression levels of RGS2, a key regulator of G-protein-coupled receptor signaling and neuronal plasticity. RGS2 is suggested as a novel AD biomarker (alongside other genes) toward early AD detection and future disease modifying therapeutics. PMID:27701409

  12. Unraveling the rat blood genome-wide transcriptome after oral administration of lavender oil by a two-color dye-swap DNA microarray approach

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    Motohide Hori

    2016-06-01

    Full Text Available Lavender oil (LO is a commonly used essential oil in aromatherapy as non-traditional medicine. With an aim to demonstrate LO effects on the body, we have recently established an animal model investigating the influence of orally administered LO in rat tissues, genome-wide. In this brief, we investigate the effect of LO ingestion in the blood of rat. Rats were administered LO at usual therapeutic dose (5 mg/kg in humans, and following collection of the venous blood from the heart and extraction of total RNA, the differentially expressed genes were screened using a 4 × 44-K whole-genome rat chip (Agilent microarray platform; Agilent Technologies, Palo Alto, CA, USA in conjunction with a two-color dye-swap approach. A total of 834 differentially expressed genes in the blood were identified: 362 up-regulated and 472 down-regulated. These genes were functionally categorized using bioinformatics tools. The gene expression inventory of rat blood transcriptome under LO, a first report, has been deposited into the Gene Expression Omnibus (GEO: GSE67499. The data will be a valuable resource in examining the effects of natural products, and which could also serve as a human model for further functional analysis and investigation.

  13. Powerful bivariate genome-wide association analyses suggest the SOX6 gene influencing both obesity and osteoporosis phenotypes in males.

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    Yao-Zhong Liu

    Full Text Available BACKGROUND: Current genome-wide association studies (GWAS are normally implemented in a univariate framework and analyze different phenotypes in isolation. This univariate approach ignores the potential genetic correlation between important disease traits. Hence this approach is difficult to detect pleiotropic genes, which may exist for obesity and osteoporosis, two common diseases of major public health importance that are closely correlated genetically. PRINCIPAL FINDINGS: To identify such pleiotropic genes and the key mechanistic links between the two diseases, we here performed the first bivariate GWAS of obesity and osteoporosis. We searched for genes underlying co-variation of the obesity phenotype, body mass index (BMI, with the osteoporosis risk phenotype, hip bone mineral density (BMD, scanning approximately 380,000 SNPs in 1,000 unrelated homogeneous Caucasians, including 499 males and 501 females. We identified in the male subjects two SNPs in intron 1 of the SOX6 (SRY-box 6 gene, rs297325 and rs4756846, which were bivariately associated with both BMI and hip BMD, achieving p values of 6.82x10(-7 and 1.47x10(-6, respectively. The two SNPs ranked at the top in significance for bivariate association with BMI and hip BMD in the male subjects among all the approximately 380,000 SNPs examined genome-wide. The two SNPs were replicated in a Framingham Heart Study (FHS cohort containing 3,355 Caucasians (1,370 males and 1,985 females from 975 families. In the FHS male subjects, the two SNPs achieved p values of 0.03 and 0.02, respectively, for bivariate association with BMI and femoral neck BMD. Interestingly, SOX6 was previously found to be essential to both cartilage formation/chondrogenesis and obesity-related insulin resistance, suggesting the gene's dual role in both bone and fat. CONCLUSIONS: Our findings, together with the prior biological evidence, suggest the SOX6 gene's importance in co-regulation of obesity and osteoporosis.

  14. Multigenic control of pod shattering resistance in Chinese rapeseed germplasm revealed by genome-wide association and linkage analyses

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    Jia Liu

    2016-07-01

    Full Text Available Majority of rapeseed cultivars shatter seeds upon maturity especially under hot-dry and windy conditions, reducing yield and gross margin return to growers. Here, we identified quantitative trait loci (QTL for resistance to pod shatter in unstructured diverse panel of 143 rapeseed accessions, and two structured populations derived from bi-parental doubled haploid (DH and inter-mated (IF2 crosses derived from R1 (resistant to pod shattering and R2 (prone to pod shattering accessions. Genome-wide association analysis identified six significant QTL for resistance to pod shatter located on chromosomes A01, A06, A07, A09, C02 and C05. Two of the QTL, qSRI.A09 delimited with the SNP marker Bn-A09-p30171993 (A09 and qSRI.A06 delimited with the SNP marker Bn-A06-p115948 (A06 could be repeatedly detected across environments in diversity panel, DH and IF2 populations, suggesting that at least two loci on chromosomes A06 and A09 were the main contributors to pod shatter resistance in Chinese germplasm. Significant SNP markers identified in this study especially those appeared repeatedly across environments provide a cost-effective and an efficient method for introgression and pyramiding of favorable alleles for pod shatter resistance via marker-assisted selection in rapeseed improvement programs.

  15. Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity

    Science.gov (United States)

    Yu, Yanqin; Zuo, Xianbo; He, Miao; Gao, Jinping; Fu, Yuchuan; Qin, Chuanqi; Meng, Liuyan; Wang, Wenjun; Song, Yaling; Cheng, Yong; Zhou, Fusheng; Chen, Gang; Zheng, Xiaodong; Wang, Xinhuan; Liang, Bo; Zhu, Zhengwei; Fu, Xiazhou; Sheng, Yujun; Hao, Jiebing; Liu, Zhongyin; Yan, Hansong; Mangold, Elisabeth; Ruczinski, Ingo; Liu, Jianjun; Marazita, Mary L.; Ludwig, Kerstin U.; Beaty, Terri H.; Zhang, Xuejun; Sun, Liangdan; Bian, Zhuan

    2017-01-01

    Non-syndromic cleft lip with palate (NSCLP) is the most serious sub-phenotype of non-syndromic orofacial clefts (NSOFC), which are the most common craniofacial birth defects in humans. Here we conduct a GWAS of NSCLP with multiple independent replications, totalling 7,404 NSOFC cases and 16,059 controls from several ethnicities, to identify new NSCLP risk loci, and explore the genetic heterogeneity between sub-phenotypes of NSOFC. We identify 41 SNPs within 26 loci that achieve genome-wide significance, 14 of which are novel (RAD54B, TMEM19, KRT18, WNT9B, GSC/DICER1, PTCH1, RPS26, OFCC1/TFAP2A, TAF1B, FGF10, MSX1, LINC00640, FGFR1 and SPRY1). These 26 loci collectively account for 10.94% of the heritability for NSCLP in Chinese population. We find evidence of genetic heterogeneity between the sub-phenotypes of NSOFC and among different populations. This study substantially increases the number of genetic susceptibility loci for NSCLP and provides important insights into the genetic aetiology of this common craniofacial malformation. PMID:28232668

  16. Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

    Directory of Open Access Journals (Sweden)

    Jingjing Liang

    2017-05-01

    Full Text Available Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8 for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4 and multiple-trait analyses identified one novel locus (FRMD3 for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

  17. Genome-wide QTL and bulked transcriptomic analysis reveals new candidate genes for the control of tuber carotenoid content in potato (Solanum tuberosum L.).

    Science.gov (United States)

    Campbell, Raymond; Pont, Simon D A; Morris, Jenny A; McKenzie, Gaynor; Sharma, Sanjeev Kumar; Hedley, Pete E; Ramsay, Gavin; Bryan, Glenn J; Taylor, Mark A

    2014-09-01

    Genome-wide QTL analysis of potato tuber carotenoid content was investigated in populations of Solanum tuberosum Group Phureja that segregate for flesh colour, revealing a novel major QTL on chromosome 9. The carotenoid content of edible plant storage organs is a key nutritional and quality trait. Although the structural genes that encode the biosynthetic enzymes are well characterised, much less is known about the factors that determine overall storage organ content. In this study, genome-wide QTL mapping, in concert with an efficient 'genetical genomics' analysis using bulked samples, has been employed to investigate the genetic architecture of potato tuber carotenoid content. Two diploid populations of Solanum tuberosum Group Phureja were genotyped (AFLP, SSR and DArT markers) and analysed for their tuber carotenoid content over two growing seasons. Common to both populations were QTL that explained relatively small proportions of the variation in constituent carotenoids and a major QTL on chromosome 3 explaining up to 71 % of the variation in carotenoid content. In one of the populations (01H15), a second major carotenoid QTL was identified on chromosome 9, explaining up to 20 % of the phenotypic variation. Whereas the major chromosome 3 QTL was likely to be due to an allele of a gene encoding β-carotene hydroxylase, no known carotenoid biosynthetic genes are located in the vicinity of the chromosome 9 QTL. A unique expression profiling strategy using phenotypically distinct bulks comprised individuals with similar carotenoid content provided further support for the QTL mapping to chromosome 9. This study shows the potential of using the potato genome sequence to link genetic maps to data arising from eQTL approaches to enhance the discovery of candidate genes underlying QTLs.

  18. Genome-Wide Transcriptome Analysis of Cotton (Gossypium hirsutum L.) Identifies Candidate Gene Signatures in Response to Aflatoxin Producing Fungus Aspergillus flavus.

    Science.gov (United States)

    Bedre, Renesh; Rajasekaran, Kanniah; Mangu, Venkata Ramanarao; Sanchez Timm, Luis Eduardo; Bhatnagar, Deepak; Baisakh, Niranjan

    2015-01-01

    Aflatoxins are toxic and potent carcinogenic metabolites produced from the fungi Aspergillus flavus and A. parasiticus. Aflatoxins can contaminate cottonseed under conducive preharvest and postharvest conditions. United States federal regulations restrict the use of aflatoxin contaminated cottonseed at >20 ppb for animal feed. Several strategies have been proposed for controlling aflatoxin contamination, and much success has been achieved by the application of an atoxigenic strain of A. flavus in cotton, peanut and maize fields. Development of cultivars resistant to aflatoxin through overexpression of resistance associated genes and/or knocking down aflatoxin biosynthesis of A. flavus will be an effective strategy for controlling aflatoxin contamination in cotton. In this study, genome-wide transcriptome profiling was performed to identify differentially expressed genes in response to infection with both toxigenic and atoxigenic strains of A. flavus on cotton (Gossypium hirsutum L.) pericarp and seed. The genes involved in antifungal response, oxidative burst, transcription factors, defense signaling pathways and stress response were highly differentially expressed in pericarp and seed tissues in response to A. flavus infection. The cell-wall modifying genes and genes involved in the production of antimicrobial substances were more active in pericarp as compared to seed. The genes involved in auxin and cytokinin signaling were also induced. Most of the genes involved in defense response in cotton were highly induced in pericarp than in seed. The global gene expression analysis in response to fungal invasion in cotton will serve as a source for identifying biomarkers for breeding, potential candidate genes for transgenic manipulation, and will help in understanding complex plant-fungal interaction for future downstream research.

  19. Cancer immunotherapy using novel tumor-associated antigenic peptides identified by genome-wide cDNA microarray analyses.

    Science.gov (United States)

    Nishimura, Yasuharu; Tomita, Yusuke; Yuno, Akira; Yoshitake, Yoshihiro; Shinohara, Masanori

    2015-05-01

    Recent genome-wide cDNA microarray analysis of gene expression profiles in comprehensive tumor types coupled with isolation of cancer tissues by laser-microbeam microdissection have revealed ideal tumor-associated antigens (TAAs) that are frequently overexpressed in various cancers including head and neck squamous cell cancer (HNSCC) and lung cancer, but not in most normal tissues except for testis, placenta, and fetal organs. Preclinical studies using HLA-transgenic mice and human T cells in vitro showed that TAA-derived CTL-epitope short peptides (SPs) are highly immunogenic and induce HLA-A2 or -A24-restricted CTLs. Based on the accumulated evidence, we carried out a phase II clinical trial of the TAA-SP vaccine in advanced 37 HNSCC patients. This study showed a significant induction of TAA-specific CTLs in the majority of patients without serious adverse effects. Importantly, clinical responses including a complete response were observed in this study. Another phase II clinical trial of therapeutic TAA-SP vaccine, designed to evaluate the ability of prevention of recurrence, is ongoing in HNSCC patients who have received curative operations. Further studies in human preclinical studies and in vivo studies using HLA class I transgenic mice showed TAA-derived long peptides (TAA-LPs) have the capacity to induce not only promiscuous HLA class II-restricted CD4(+) T helper type 1 cells but also tumor-specific CTLs through a cross-presentation mechanism. Moreover, we observed an augmentation of TAA-LP-specific T helper type 1 cell responses and tumor antigen-spreading in HNSCC patients vaccinated with TAA-SPs. This accumulated evidence suggests that therapeutic TAA-SPs and LPs vaccines may provide a promising cancer immunotherapy.

  20. Clear detection of ADIPOQ locus as the major gene for plasma adiponectin: results of genome-wide association analyses including 4659 European individuals

    Science.gov (United States)

    Heid, Iris M.; Henneman, Peter; Hicks, Andrew; Coassin, Stefan; Winkler, Thomas; Aulchenko, Yurii S.; Fuchsberger, Christian; Song, Kijoung; Hivert, Marie-France; Waterworth, Dawn M.; Timpson, Nicholas J.; Richards, J. Brent; Perry, John R.B.; Tanaka, Toshiko; Amin, Najaf; Kollerits, Barbara; Pichler, Irene; Oostra, Ben A.; Thorand, Barbara; Frants, Rune R.; Illig, Thomas; Dupuis, Josée; Glaser, Beate; Spector, Tim; Guralnik, Jack; Egan, Josephine M.; Florez, Jose C.; Evans, David M.; Soranzo, Nicole; Bandinelli, Stefania; Carlson, Olga D.; Frayling, Timothy M.; Burling, Keith; Smith, George Davey; Mooser, Vincent; Ferrucci, Luigi; Meigs, James B.; Vollenweider, Peter; van Dijk, Ko Willems; Pramstaller, Peter; Kronenberg, Florian; van Duijn, Cornelia M.

    2009-01-01

    Objective Plasma adiponectin is strongly associated with various components of metabolic syndrome, type 2 diabetes and cardiovascular outcomes. Concentrations are highly heritable and differ between men and women. We therefore aimed to investigate the genetics of plasma adiponectin in men and women. Methods We combined genome-wide association scans of three population-based studies including 4659 persons. For the replication stage in 13795 subjects, we selected the 20 top signals of the combined analysis, as well as the 10 top signals with p-values less than 1.0*10-4 for each the men- and the women-specific analyses. We further selected 73 SNPs that were consistently associated with metabolic syndrome parameters in previous genome-wide association studies to check for their association with plasma adiponectin. Results The ADIPOQ locus showed genome-wide significant p-values in the combined (p=4.3*10-24) as well as in both women- and men-specific analyses (p=8.7*10-17 and p=2.5*10-11, respectively). None of the other 39 top signal SNPs showed evidence for association in the replication analysis. None of 73 SNPs from metabolic syndrome loci exhibited association with plasma adiponectin (p>0.01). Conclusions We demonstrated the ADIPOQ gene as the only major gene for plasma adiponectin, which explains 6.7% of the phenotypic variance. We further found that neither this gene nor any of the metabolic syndrome loci explained the sex differences observed for plasma adiponectin. Larger studies are needed to identify more moderate genetic determinants of plasma adiponectin. PMID:20018283

  1. META-GSA: Combining Findings from Gene-Set Analyses across Several Genome-Wide Association Studies.

    Directory of Open Access Journals (Sweden)

    Albert Rosenberger

    Full Text Available Gene-set analysis (GSA methods are used as complementary approaches to genome-wide association studies (GWASs. The single marker association estimates of a predefined set of genes are either contrasted with those of all remaining genes or with a null non-associated background. To pool the p-values from several GSAs, it is important to take into account the concordance of the observed patterns resulting from single marker association point estimates across any given gene set. Here we propose an enhanced version of Fisher's inverse χ2-method META-GSA, however weighting each study to account for imperfect correlation between association patterns.We investigated the performance of META-GSA by simulating GWASs with 500 cases and 500 controls at 100 diallelic markers in 20 different scenarios, simulating different relative risks between 1 and 1.5 in gene sets of 10 genes. Wilcoxon's rank sum test was applied as GSA for each study. We found that META-GSA has greater power to discover truly associated gene sets than simple pooling of the p-values, by e.g. 59% versus 37%, when the true relative risk for 5 of 10 genes was assume to be 1.5. Under the null hypothesis of no difference in the true association pattern between the gene set of interest and the set of remaining genes, the results of both approaches are almost uncorrelated. We recommend not relying on p-values alone when combining the results of independent GSAs.We applied META-GSA to pool the results of four case-control GWASs of lung cancer risk (Central European Study and Toronto/Lunenfeld-Tanenbaum Research Institute Study; German Lung Cancer Study and MD Anderson Cancer Center Study, which had already been analyzed separately with four different GSA methods (EASE; SLAT, mSUMSTAT and GenGen. This application revealed the pathway GO0015291 "transmembrane transporter activity" as significantly enriched with associated genes (GSA-method: EASE, p = 0.0315 corrected for multiple testing. Similar

  2. Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study

    NARCIS (Netherlands)

    Luca, G. De; Haba-Rubio, J.; Dauvilliers, Y.; Lammers, G.J.; Overeem, S.; Donjacour, C.E.; Mayer, G.; Javidi, S.; Iranzo, A.; Santamaria, J.; Peraita-Adrados, R.; Hor, H.; Kutalik, Z.; Plazzi, G.; Poli, F.; Pizza, F.; Arnulf, I.; Lecendreux, M.; Bassetti, C.; Mathis, J.; Heinzer, R.; Jennum, P.; Knudsen, S.; Geisler, P.; Wierzbicka, A.; Feketeova, E.; Pfister, C.; Khatami, R.; Baumann, C.; Tafti, M.

    2013-01-01

    The aim of this study was to describe the clinical and PSG characteristics of narcolepsy with cataplexy and their genetic predisposition by using the retrospective patient database of the European Narcolepsy Network (EU-NN). We have analysed retrospective data of 1099 patients with narcolepsy diagno

  3. Genome-Wide Analyses of Individual Strongyloides stercoralis (Nematoda: Rhabditoidea) Provide Insights into Population Structure and Reproductive Life Cycles

    Science.gov (United States)

    Aung, Myo Pa Pa Thet Hnin Htwe; Afrin, Tanzila; Nagayasu, Eiji; Tanaka, Ryusei; Higashiarakawa, Miwa; Win, Kyu Kyu; Hirata, Tetsuo; Htike, Wah Win; Fujita, Jiro; Maruyama, Haruhiko

    2016-01-01

    The helminth Strongyloides stercoralis, which is transmitted through soil, infects 30–100 million people worldwide. S. stercoralis reproduces sexually outside the host as well as asexually within the host, which causes a life-long infection. To understand the population structure and transmission patterns of this parasite, we re-sequenced the genomes of 33 individual S. stercoralis nematodes collected in Myanmar (prevalent region) and Japan (non-prevalent region). We utilised a method combining whole genome amplification and next-generation sequencing techniques to detect 298,202 variant positions (0.6% of the genome) compared with the reference genome. Phylogenetic analyses of SNP data revealed an unambiguous geographical separation and sub-populations that correlated with the host geographical origin, particularly for the Myanmar samples. The relatively higher heterozygosity in the genomes of the Japanese samples can possibly be explained by the independent evolution of two haplotypes of diploid genomes through asexual reproduction during the auto-infection cycle, suggesting that analysing heterozygosity is useful and necessary to infer infection history and geographical prevalence. PMID:28033376

  4. Genome-wide classification and evolutionary and expression analyses of citrus MYB transcription factor families in sweet orange.

    Directory of Open Access Journals (Sweden)

    Xiao-Jin Hou

    Full Text Available MYB family genes are widely distributed in plants and comprise one of the largest transcription factors involved in various developmental processes and defense responses of plants. To date, few MYB genes and little expression profiling have been reported for citrus. Here, we describe and classify 177 members of the sweet orange MYB gene (CsMYB family in terms of their genomic gene structures and similarity to their putative Arabidopsis orthologs. According to these analyses, these CsMYBs were categorized into four groups (4R-MYB, 3R-MYB, 2R-MYB and 1R-MYB. Gene structure analysis revealed that 1R-MYB genes possess relatively more introns as compared with 2R-MYB genes. Investigation of their chromosomal localizations revealed that these CsMYBs are distributed across nine chromosomes. Sweet orange includes a relatively small number of MYB genes compared with the 198 members in Arabidopsis, presumably due to a paralog reduction related to repetitive sequence insertion into promoter and non-coding transcribed region of the genes. Comparative studies of CsMYBs and Arabidopsis showed that CsMYBs had fewer gene duplication events. Expression analysis revealed that the MYB gene family has a wide expression profile in sweet orange development and plays important roles in development and stress responses. In addition, 337 new putative microsatellites with flanking sequences sufficient for primer design were also identified from the 177 CsMYBs. These results provide a useful reference for the selection of candidate MYB genes for cloning and further functional analysis forcitrus.

  5. Genome-wide classification and evolutionary and expression analyses of citrus MYB transcription factor families in sweet orange.

    Science.gov (United States)

    Hou, Xiao-Jin; Li, Si-Bei; Liu, Sheng-Rui; Hu, Chun-Gen; Zhang, Jin-Zhi

    2014-01-01

    MYB family genes are widely distributed in plants and comprise one of the largest transcription factors involved in various developmental processes and defense responses of plants. To date, few MYB genes and little expression profiling have been reported for citrus. Here, we describe and classify 177 members of the sweet orange MYB gene (CsMYB) family in terms of their genomic gene structures and similarity to their putative Arabidopsis orthologs. According to these analyses, these CsMYBs were categorized into four groups (4R-MYB, 3R-MYB, 2R-MYB and 1R-MYB). Gene structure analysis revealed that 1R-MYB genes possess relatively more introns as compared with 2R-MYB genes. Investigation of their chromosomal localizations revealed that these CsMYBs are distributed across nine chromosomes. Sweet orange includes a relatively small number of MYB genes compared with the 198 members in Arabidopsis, presumably due to a paralog reduction related to repetitive sequence insertion into promoter and non-coding transcribed region of the genes. Comparative studies of CsMYBs and Arabidopsis showed that CsMYBs had fewer gene duplication events. Expression analysis revealed that the MYB gene family has a wide expression profile in sweet orange development and plays important roles in development and stress responses. In addition, 337 new putative microsatellites with flanking sequences sufficient for primer design were also identified from the 177 CsMYBs. These results provide a useful reference for the selection of candidate MYB genes for cloning and further functional analysis forcitrus.

  6. Genetic Influences on Political Ideologies: Twin Analyses of 19 Measures of Political Ideologies from Five Democracies and Genome-Wide Findings from Three Populations

    Science.gov (United States)

    Hatemi, Peter K.; Medland, Sarah E.; Klemmensen, Robert; Oskarrson, Sven; Littvay, Levente; Dawes, Chris; Verhulst, Brad; McDermott, Rose; Nørgaard, Asbjørn Sonne; Klofstad, Casey; Christensen, Kaare; Johannesson, Magnus; Magnusson, Patrik K.E.; Eaves, Lindon J.; Martin, Nicholas G.

    2014-01-01

    Almost forty years ago, evidence from large studies of adult twins and their relatives suggested that between 30-60% of the variance in social and political attitudes could be explained by genetic influences. However, these findings have not been widely accepted or incorporated into the dominant paradigms that explain the etiology of political ideology. This has been attributed in part to measurement and sample limitations, as well the relative absence of molecular genetic studies. Here we present results from original analyses of a combined sample of over 12,000 twins pairs, ascertained from nine different studies conducted in five democracies, sampled over the course of four decades. We provide evidence that genetic factors play a role in the formation of political ideology, regardless of how ideology is measured, the era, or the population sampled. The only exception is a question that explicitly uses the phrase “Left-Right”. We then present results from one of the first genome-wide association studies on political ideology using data from three samples: a 1990 Australian sample involving 6,894 individuals from 3,516 families; a 2008 Australian sample of 1,160 related individuals from 635 families and a 2010 Swedish sample involving 3,334 individuals from 2,607 families. No polymorphisms reached genome-wide significance in the meta-analysis. The combined evidence suggests that political ideology constitutes a fundamental aspect of one’s genetically informed psychological disposition, but as Fisher proposed long ago, genetic influences on complex traits will be composed of thousands of markers of very small effects and it will require extremely large samples to have enough power in order to identify specific polymorphisms related to complex social traits. PMID:24569950

  7. Genome-wide transcriptome analysis reveals that cadmium stress signaling controls the expression of genes in drought stress signal pathways in rice.

    Directory of Open Access Journals (Sweden)

    Youko Oono

    Full Text Available Plant growth is severely affected by toxic concentrations of the non-essential heavy metal cadmium (Cd. Comprehensive transcriptome analysis by RNA-Seq following cadmium exposure is required to further understand plant responses to Cd and facilitate future systems-based analyses of the underlying regulatory networks. In this study, rice plants were hydroponically treated with 50 µM Cd for 24 hours and ∼60,000 expressed transcripts, including transcripts that could not be characterized by microarray-based approaches, were evaluated. Upregulation of various ROS-scavenging enzymes, chelators and metal transporters demonstrated the appropriate expression profiles to Cd exposure. Gene Ontology enrichment analysis of the responsive transcripts indicated the upregulation of many drought stress-related genes under Cd exposure. Further investigation into the expression of drought stress marker genes such as DREB suggested that expression of genes in several drought stress signal pathways was activated under Cd exposure. Furthermore, qRT-PCR analyses of randomly selected Cd-responsive metal transporter transcripts under various metal ion stresses suggested that the expression of Cd-responsive transcripts might be easily affected by other ions. Our transcriptome analysis demonstrated a new transcriptional network linking Cd and drought stresses in rice. Considering our data and that Cd is a non-essential metal, the network underlying Cd stress responses and tolerance, which plants have developed to adapt to other stresses, could help to acclimate to Cd exposure. Our examination of this transcriptional network provides useful information for further studies of the molecular mechanisms of plant adaptation to Cd exposure and the improvement of tolerance in crop species.

  8. Genome-Wide Linkage and Positional Association Analyses Identify Associations of Novel AFF3 and NTM Genes with Triglycerides: The GenSalt Study

    Science.gov (United States)

    Li, Changwei; Bazzano, Lydia A.L.; Rao, Dabeeru C.; Hixson, James E.; He, Jiang; Gu, Dongfeng; Gu, Charles C.; Shimmin, Lawrence C.; Jaquish, Cashell E.; Schwander, Karen; Liu, De-Pei; Huang, Jianfeng; Lu, Fanghong; Cao, Jie; Chong, Shen; Lu, Xiangfeng; Kelly, Tanika N.

    2016-01-01

    We conducted a genome-wide linkage scan and positional association study to identify genes and variants influencing blood lipid levels among participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. The GenSalt study was conducted among 1906 participants from 633 Han Chinese families. Lipids were measured from overnight fasting blood samples using standard methods. Multipoint quantitative trait genome-wide linkage scans were performed on the high-density lipoprotein, low-density lipoprotein, and log-transformed triglyceride phenotypes. Using dense panels of single nucleotide polymorphisms (SNPs), single-marker and gene-based association analyses were conducted to follow-up on promising linkage signals. Additive associations between each SNP and lipid phenotypes were tested using mixed linear regression models. Gene-based analyses were performed by combining P-values from single-marker analyses within each gene using the truncated product method (TPM). Significant associations were assessed for replication among 777 Asian participants of the Multi-ethnic Study of Atherosclerosis (MESA). Bonferroni correction was used to adjust for multiple testing. In the GenSalt study, suggestive linkage signals were identified at 2p11.2–2q12.1 [maximum multipoint LOD score (MML) = 2.18 at 2q11.2] and 11q24.3–11q25 (MML = 2.29 at 11q25) for the log-transformed triglyceride phenotype. Follow-up analyses of these two regions revealed gene-based associations of charged multivesicular body protein 3 (CHMP3), ring finger protein 103 (RNF103), AF4/FMR2 family, member 3 (AFF3), and neurotrimin (NTM ) with triglycerides (P = 4 × 10−4, 1.00 × 10−5, 2.00 × 10−5, and 1.00 × 10−7, respectively). Both the AFF3 and NTM triglyceride associations were replicated among MESA study participants (P = 1.00 × 10−7 and 8.00 × 10−5, respectively). Furthermore, NTM explained the linkage signal on chromosome 11. In conclusion, we identified novel genes

  9. Differential gene expression in soybean leaf tissues at late developmental stages under drought stress revealed by genome-wide transcriptome analysis.

    Directory of Open Access Journals (Sweden)

    Dung Tien Le

    Full Text Available The availability of complete genome sequence of soybean has allowed research community to design the 66 K Affymetrix Soybean Array GeneChip for genome-wide expression profiling of soybean. In this study, we carried out microarray analysis of leaf tissues of soybean plants, which were subjected to drought stress from late vegetative V6 and from full bloom reproductive R2 stages. Our data analyses showed that out of 46,093 soybean genes, which were predicted with high confidence among approximately 66,000 putative genes, 41,059 genes could be assigned with a known function. Using the criteria of a ratio change > = 2 and a q-value<0.05, we identified 1458 and 1818 upregulated and 1582 and 1688 downregulated genes in drought-stressed V6 and R2 leaves, respectively. These datasets were classified into 19 most abundant biological categories with similar proportions. There were only 612 and 463 genes that were overlapped among the upregulated and downregulated genes, respectively, in both stages, suggesting that both conserved and unconserved pathways might be involved in regulation of drought response in different stages of plant development. A comparative expression analysis using our datasets and that of drought stressed Arabidopsis leaves revealed the existence of both conserved and species-specific mechanisms that regulate drought responses. Many upregulated genes encode either regulatory proteins, such as transcription factors, including those with high homology to Arabidopsis DREB, NAC, AREB and ZAT/STZ transcription factors, kinases and two-component system members, or functional proteins, e.g. late embryogenesis-abundant proteins, glycosyltransferases, glycoside hydrolases, defensins and glyoxalase I family proteins. A detailed analysis of the GmNAC family and the hormone-related gene category showed that expression of many GmNAC and hormone-related genes was altered by drought in V6 and/or R2 leaves. Additionally, the downregulation of

  10. Genome-wide Meta-analyses of Breast, Ovarian and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by At Least Two Cancer Types

    Science.gov (United States)

    Kar, Siddhartha P.; Beesley, Jonathan; Al Olama, Ali Amin; Michailidou, Kyriaki; Tyrer, Jonathan; Kote-Jarai, ZSofia; Lawrenson, Kate; Lindstrom, Sara; Ramus, Susan J.; Thompson, Deborah J.; Kibel, Adam S.; Dansonka-Mieszkowska, Agnieszka; Michael, Agnieszka; Dieffenbach, Aida K.; Gentry-Maharaj, Aleksandra; Whittemore, Alice S.; Wolk, Alicja; Monteiro, Alvaro; Peixoto, Ana; Kierzek, Andrzej; Cox, Angela; Rudolph, Anja; Gonzalez-Neira, Anna; Wu, Anna H.; Lindblom, Annika; Swerdlow, Anthony; Ziogas, Argyrios; Ekici, Arif B.; Burwinkel, Barbara; Karlan, Beth Y.; Nordestgaard, Børge G.; Blomqvist, Carl; Phelan, Catherine; McLean, Catriona; Pearce, Celeste Leigh; Vachon, Celine; Cybulski, Cezary; Slavov, Chavdar; Stegmaier, Christa; Maier, Christiane; Ambrosone, Christine B.; Høgdall, Claus K.; Teerlink, Craig C.; Kang, Daehee; Tessier, Daniel C.; Schaid, Daniel J.; Stram, Daniel O.; Cramer, Daniel W.; Neal, David E.; Eccles, Diana; Flesch-Janys, Dieter; Velez Edwards, Digna R.; Wokozorczyk, Dominika; Levine, Douglas A.; Yannoukakos, Drakoulis; Sawyer, Elinor J.; Bandera, Elisa V.; Poole, Elizabeth M.; Goode, Ellen L.; Khusnutdinova, Elza; Høgdall, Estrid; Song, Fengju; Bruinsma, Fiona; Heitz, Florian; Modugno, Francesmary; Hamdy, Freddie C.; Wiklund, Fredrik; Giles, Graham G.; Olsson, Håkan; Wildiers, Hans; Ulmer, Hans-Ulrich; Pandha, Hardev; Risch, Harvey A.; Darabi, Hatef; Salvesen, Helga B.; Nevanlinna, Heli; Gronberg, Henrik; Brenner, Hermann; Brauch, Hiltrud; Anton-Culver, Hoda; Song, Honglin; Lim, Hui-Yi; McNeish, Iain; Campbell, Ian; Vergote, Ignace; Gronwald, Jacek; Lubiński, Jan; Stanford, Janet L.; Benítez, Javier; Doherty, Jennifer A.; Permuth, Jennifer B.; Chang-Claude, Jenny; Donovan, Jenny L.; Dennis, Joe; Schildkraut, Joellen M.; Schleutker, Johanna; Hopper, John L.; Kupryjanczyk, Jolanta; Park, Jong Y.; Figueroa, Jonine; Clements, Judith A.; Knight, Julia A.; Peto, Julian; Cunningham, Julie M.; Pow-Sang, Julio; Batra, Jyotsna; Czene, Kamila; Lu, Karen H.; Herkommer, Kathleen; Khaw, Kay-Tee; Matsuo, Keitaro; Muir, Kenneth; Offitt, Kenneth; Chen, Kexin; Moysich, Kirsten B.; Aittomäki, Kristiina; Odunsi, Kunle; Kiemeney, Lambertus A.; Massuger, Leon F.A.G.; Fitzgerald, Liesel M.; Cook, Linda S.; Cannon-Albright, Lisa; Hooning, Maartje J.; Pike, Malcolm C.; Bolla, Manjeet K.; Luedeke, Manuel; Teixeira, Manuel R.; Goodman, Marc T.; Schmidt, Marjanka K.; Riggan, Marjorie; Aly, Markus; Rossing, Mary Anne; Beckmann, Matthias W.; Moisse, Matthieu; Sanderson, Maureen; Southey, Melissa C.; Jones, Michael; Lush, Michael; Hildebrandt, Michelle A. T.; Hou, Ming-Feng; Schoemaker, Minouk J.; Garcia-Closas, Montserrat; Bogdanova, Natalia; Rahman, Nazneen; Le, Nhu D.; Orr, Nick; Wentzensen, Nicolas; Pashayan, Nora; Peterlongo, Paolo; Guénel, Pascal; Brennan, Paul; Paulo, Paula; Webb, Penelope M.; Broberg, Per; Fasching, Peter A.; Devilee, Peter; Wang, Qin; Cai, Qiuyin; Li, Qiyuan; Kaneva, Radka; Butzow, Ralf; Kopperud, Reidun Kristin; Schmutzler, Rita K.; Stephenson, Robert A.; MacInnis, Robert J.; Hoover, Robert N.; Winqvist, Robert; Ness, Roberta; Milne, Roger L.; Travis, Ruth C.; Benlloch, Sara; Olson, Sara H.; McDonnell, Shannon K.; Tworoger, Shelley S.; Maia, Sofia; Berndt, Sonja; Lee, Soo Chin; Teo, Soo-Hwang; Thibodeau, Stephen N.; Bojesen, Stig E.; Gapstur, Susan M.; Kjær, Susanne Krüger; Pejovic, Tanja; Tammela, Teuvo L.J.; Dörk, Thilo; Brüning, Thomas; Wahlfors, Tiina; Key, Tim J.; Edwards, Todd L.; Menon, Usha; Hamann, Ute; Mitev, Vanio; Kosma, Veli-Matti; Setiawan, Veronica Wendy; Kristensen, Vessela; Arndt, Volker; Vogel, Walther; Zheng, Wei; Sieh, Weiva; Blot, William J.; Kluzniak, Wojciech; Shu, Xiao-Ou; Gao, Yu-Tang; Schumacher, Fredrick; Freedman, Matthew L.; Berchuck, Andrew; Dunning, Alison M.; Simard, Jacques; Haiman, Christopher A.; Spurdle, Amanda; Sellers, Thomas A.; Hunter, David J.; Henderson, Brian E.; Kraft, Peter; Chanock, Stephen J.; Couch, Fergus J.; Hall, Per; Gayther, Simon A.; Easton, Douglas F.; Chenevix-Trench, Georgia; Eeles, Rosalind; Pharoah, Paul D.P.; Lambrechts, Diether

    2016-01-01

    Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis. PMID:27432226

  11. Genome-wide association studies and epistasis analyses of candidate genes related to age at menarche and age at natural menopause in a Korean population.

    Science.gov (United States)

    Pyun, Jung-A; Kim, Sunshin; Cho, Nam H; Koh, InSong; Lee, Jong-Young; Shin, Chol; Kwack, KyuBum

    2014-05-01

    The aim of this study was to identify polymorphisms and gene-gene interactions that are significantly associated with age at menarche and age at menopause in a Korean population. A total of 3,452 and 1,827 women participated in studies of age at menarche and age at natural menopause, respectively. Linear regression analyses adjusted for residence area were used to perform genome-wide association studies (GWAS), candidate gene association studies, and interactions between the candidate genes for age at menarche and age at natural menopause. In GWAS, four single nucleotide polymorphisms (SNPs; rs7528241, rs1324329, rs11597068, and rs6495785) were strongly associated with age at natural menopause (lowest P = 9.66 × 10). However, GWAS of age at menarche did not reveal any strong associations. In candidate gene association studies, SNPs with P menopause, there was a significant interaction between intronic SNPs on ADAM metallopeptidase with thrombospondin type I motif 9 (ADAMTS9) and SMAD family member 3 (SMAD3) genes (P = 9.52 × 10). For age at menarche, there were three significant interactions between three intronic SNPs on follicle-stimulating hormone receptor (FSHR) gene and one SNP located at the 3' flanking region of insulin-like growth factor 2 receptor (IGF2R) gene (lowest P = 1.95 × 10). Novel SNPs and synergistic interactions between candidate genes are significantly associated with age at menarche and age at natural menopause in a Korean population.

  12. Genome-wide transcriptomic analysis of the effects of sub-ambient atmospheric oxygen and elevated atmospheric carbon dioxide levels on gametophytes of the moss, Physcomitrella patens.

    Science.gov (United States)

    Shinde, Suhas; Behpouri, Ali; McElwain, Jennifer C; Ng, Carl K-Y

    2015-07-01

    It is widely accepted that atmospheric O2 has played a key role in the development of life on Earth, as evident from the coincidence between the rise of atmospheric O2 concentrations in the Precambrian and biological evolution. Additionally, it has also been suggested that low atmospheric O2 is one of the major drivers for at least two of the five mass-extinction events in the Phanerozoic. At the molecular level, our understanding of the responses of plants to sub-ambient O2 concentrations is largely confined to studies of the responses of underground organs, e.g. roots to hypoxic conditions. Oxygen deprivation often results in elevated CO2 levels, particularly under waterlogged conditions, due to slower gas diffusion in water compared to air. In this study, changes in the transcriptome of gametophytes of the moss Physcomitrella patens arising from exposure to sub-ambient O2 of 13% (oxygen deprivation) and elevated CO2 (1500 ppmV) were examined to further our understanding of the responses of lower plants to changes in atmospheric gaseous composition. Microarray analyses revealed that the expression of a large number of genes was affected under elevated CO2 (814 genes) and sub-ambient O2 conditions (576 genes). Intriguingly, the expression of comparatively fewer numbers of genes (411 genes) was affected under a combination of both sub-ambient O2 and elevated CO2 condition (low O2-high CO2). Overall, the results point towards the effects of atmospheric changes in CO2 and O2 on transcriptional reprogramming, photosynthetic regulation, carbon metabolism, and stress responses. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  13. Genome-wide transcriptomic analysis of the effects of sub-ambient atmospheric oxygen and elevated atmospheric carbon dioxide levels on gametophytes of the moss, Physcomitrella patens

    Science.gov (United States)

    Shinde, Suhas; Behpouri, Ali; McElwain, Jennifer C.; Ng, Carl K.-Y.

    2015-01-01

    It is widely accepted that atmospheric O2 has played a key role in the development of life on Earth, as evident from the coincidence between the rise of atmospheric O2 concentrations in the Precambrian and biological evolution. Additionally, it has also been suggested that low atmospheric O2 is one of the major drivers for at least two of the five mass-extinction events in the Phanerozoic. At the molecular level, our understanding of the responses of plants to sub-ambient O2 concentrations is largely confined to studies of the responses of underground organs, e.g. roots to hypoxic conditions. Oxygen deprivation often results in elevated CO2 levels, particularly under waterlogged conditions, due to slower gas diffusion in water compared to air. In this study, changes in the transcriptome of gametophytes of the moss Physcomitrella patens arising from exposure to sub-ambient O2 of 13% (oxygen deprivation) and elevated CO2 (1500 ppmV) were examined to further our understanding of the responses of lower plants to changes in atmospheric gaseous composition. Microarray analyses revealed that the expression of a large number of genes was affected under elevated CO2 (814 genes) and sub-ambient O2 conditions (576 genes). Intriguingly, the expression of comparatively fewer numbers of genes (411 genes) was affected under a combination of both sub-ambient O2 and elevated CO2 condition (low O2–high CO2). Overall, the results point towards the effects of atmospheric changes in CO2 and O2 on transcriptional reprogramming, photosynthetic regulation, carbon metabolism, and stress responses. PMID:25948702

  14. Harvesting clues from genome wide transcriptome analysis for exploring thalidomide mediated anomalies in eye development of chick embryo: Nitric oxide rectifies the thalidomide mediated anomalies by swinging back the system to normal transcriptome pattern.

    Science.gov (United States)

    Kumar, Pavitra; Kasiviswanathan, Dharanibalan; Sundaresan, Lakshmikirupa; Kathirvel, Priyadarshan; Veeriah, Vimal; Dutta, Priya; Sankaranarayanan, Kavitha; Gupta, Ravi; Chatterjee, Suvro

    2016-02-01

    Thalidomide, the notorious teratogen is known to cause various developmental abnormalities, among which a range of eye deformations are very common. From the clinical point of view, it is necessary to pinpoint the mechanisms of teratogens that tune the gene expression. However, to our knowledge, the molecular basis of eye deformities under thalidomide treatmenthas not been reported so far. Present study focuses on the possible mechanism by which thalidomide affects eye development and the role of Nitric Oxide in recovering thalidomide-mediated anomalies of eye development using chick embryo and zebrafish models with transcriptome analysis. Transcriptome analysis showed that 403 genes were up-regulated and 223 genes were down-regulated significantly in thalidomide pre-treated embryos. 8% of the significantly modulated genes have been implicated in eye development including Pax6, OTX2, Dkk1 and Shh. A wide range of biological process and molecular function was affected by thalidomide exposure. Biological Processes including structural constituent of eye lens and Molecular functions such as visual perception and retinal metabolic process formed strong annotation clustersindicating the adverse effects of thalidomide on eye development and function. Here, we have discussed the whole embryo transcriptome with the expression of PAX6, SOX2, and CRYAAgenes from developing eyes. Our experimental data showing structural and functional aspects includingeye size, lens transparency and optic nerve activity and bioinformatics analyses of transcriptome suggest that NO could partially protect thalidomide treated embryos from its devastating effects on eye development and function.

  15. The molecular underpinning of lobular histological growth pattern: a genome-wide transcriptomic analysis of invasive lobular carcinomas and grade- and molecular subtype-matched invasive ductal carcinomas of no special type.

    Science.gov (United States)

    Weigelt, Britta; Geyer, Felipe C; Natrajan, Rachael; Lopez-Garcia, Maria A; Ahmad, Amar S; Savage, Kay; Kreike, Bas; Reis-Filho, Jorge S

    2010-01-01

    Invasive lobular carcinoma (ILC) is the most frequent special type of breast cancer. The majority of these tumours are of low histological grade, express hormone receptors, and lack HER2 expression. The pleomorphic variant of ILCs (PLCs) is characterized by atypical cells with pleomorphic nuclei and is reported to have an aggressive clinical behaviour. Expression profiling studies have demonstrated that classic ILCs preferentially display a luminal phenotype, whereas PLCs may be of luminal, HER2 or molecular apocrine subtypes. The aims of this study were two-fold: to determine the transcriptomic characteristics of lobular carcinomas and to define the genome-wide transcriptomic differences between classic ILCs and PLCs. To define the transcriptomic characteristics of ILCs, minimizing the impact of histological grade and molecular subtype on the analysis, we subjected a series of grade- and molecular subtype-matched ILCs and invasive ductal carcinomas (IDCs) to genome-wide gene expression profiling using oligonucleotide microarrays. Hierarchical clustering analysis demonstrated that ILCs formed a separate cluster and a supervised analysis revealed that 5.8% of the transcriptionally regulated genes were significantly differentially expressed in ILCs compared to grade- and molecular subtype-matched IDCs. ILCs displayed down-regulation of E-cadherin and of genes related to actin cytoskeleton remodelling, protein ubiquitin, DNA repair, cell adhesion, TGF-beta signalling; and up-regulation of transcription factors/immediate early genes, lipid/prostaglandin biosynthesis genes, and cell migration-associated genes. Supervised analysis of classic ILCs and PLCs demonstrated that less than 0.1% of genes were significantly differentially expressed between these tumour subtypes. Our results demonstrate that ILCs differ from grade- and molecular subtype-matched IDCs in the expression of genes related to cell adhesion, cell-to-cell signalling, and actin cytoskeleton signalling

  16. Determination of Genetic Structure and Signatures of Selection in Three Strains of Tanzania Shorthorn Zebu, Boran and Friesian Cattle by Genome-Wide SNP Analyses

    Science.gov (United States)

    Msalya, George; Kim, Eui-Soo; Laisser, Emmanuel L. K.; Kipanyula, Maulilio J.; Karimuribo, Esron D.; Kusiluka, Lughano J. M.; Chenyambuga, Sebastian W.; Rothschild, Max F.

    2017-01-01

    Background More than 90 percent of cattle in Tanzania belong to the indigenous Tanzania Short Horn Zebu (TSZ) population which has been classified into 12 strains based on historical evidence, morphological characteristics, and geographic distribution. However, specific genetic information of each TSZ population has been lacking and has caused difficulties in designing programs such as selection, crossbreeding, breed improvement or conservation. This study was designed to evaluate the genetic structure, assess genetic relationships, and to identify signatures of selection among cattle of Tanzania with the main goal of understanding genetic relationship, variation and uniqueness among them. Methodology/Principal findings The Illumina Bos indicus SNP 80K BeadChip was used to genotype genome wide SNPs in 168 DNA samples obtained from three strains of TSZ cattle namely Maasai, Tarime and Sukuma as well as two comparative breeds; Boran and Friesian. Population structure and signatures of selection were examined using principal component analysis (PCA), admixture analysis, pairwise distances (FST), integrated haplotype score (iHS), identical by state (IBS) and runs of homozygosity (ROH). There was a low level of inbreeding (F~0.01) in the TSZ population compared to the Boran and Friesian breeds. The analyses of FST, IBS and admixture identified no considerable differentiation between TSZ trains. Importantly, common ancestry in Boran and TSZ were revealed based on admixture and IBD, implying gene flow between two populations. In addition, Friesian ancestry was found in Boran. A few common significant iHS were detected, which may reflect influence of recent selection in each breed or strain. Conclusions Population admixture and selection signatures could be applied to develop conservation plan of TSZ cattle as well as future breeding programs in East African cattle. PMID:28129396

  17. Genome-wide analyses of chitin synthases identify horizontal gene transfers towards bacteria and allow a robust and unifying classification into fungi.

    Science.gov (United States)

    Gonçalves, Isabelle R; Brouillet, Sophie; Soulié, Marie-Christine; Gribaldo, Simonetta; Sirven, Catherine; Charron, Noémie; Boccara, Martine; Choquer, Mathias

    2016-11-24

    Chitin, the second most abundant biopolymer on earth after cellulose, is found in probably all fungi, many animals (mainly invertebrates), several protists and a few algae, playing an essential role in the development of many of them. This polysaccharide is produced by type 2 glycosyltransferases, called chitin synthases (CHS). There are several contradictory classifications of CHS isoenzymes and, as regards their evolutionary history, their origin and diversity is still a matter of debate. A genome-wide analysis resulted in the detection of more than eight hundred putative chitin synthases in proteomes associated with about 130 genomes. Phylogenetic analyses were performed with special care to avoid any pitfalls associated with the peculiarities of these sequences (e.g. highly variable regions, truncated or recombined sequences, long-branch attraction). This allowed us to revise and unify the fungal CHS classification and to study the evolutionary history of the CHS multigenic family. This update has the advantage of being user-friendly due to the development of a dedicated website ( http://wwwabi.snv.jussieu.fr/public/CHSdb ), and it includes any correspondences with previously published classifications and mutants. Concerning the evolutionary history of CHS, this family has mainly evolved via duplications and losses. However, it is likely that several horizontal gene transfers (HGT) also occurred in eukaryotic microorganisms and, even more surprisingly, in bacteria. This comprehensive multi-species analysis contributes to the classification of fungal CHS, in particular by optimizing its robustness, consensuality and accessibility. It also highlights the importance of HGT in the evolutionary history of CHS and describes bacterial chs genes for the first time. Many of the bacteria that have acquired a chitin synthase are plant pathogens (e.g. Dickeya spp; Pectobacterium spp; Brenneria spp; Agrobacterium vitis and Pseudomonas cichorii). Whether they are able to

  18. Integration of Genome-Wide Computation DRE Search, AhR ChIP-chip and Gene Expression Analyses of TCDD-Elicited Responses in the Mouse Liver

    Directory of Open Access Journals (Sweden)

    Matthews Jason

    2011-07-01

    Full Text Available Abstract Background The aryl hydrocarbon receptor (AhR is a ligand-activated transcription factor (TF that mediates responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD. Integration of TCDD-induced genome-wide AhR enrichment, differential gene expression and computational dioxin response element (DRE analyses further elucidate the hepatic AhR regulatory network. Results Global ChIP-chip and gene expression analyses were performed on hepatic tissue from immature ovariectomized mice orally gavaged with 30 μg/kg TCDD. ChIP-chip analysis identified 14,446 and 974 AhR enriched regions (1% false discovery rate at 2 and 24 hrs, respectively. Enrichment density was greatest in the proximal promoter, and more specifically, within ± 1.5 kb of a transcriptional start site (TSS. AhR enrichment also occurred distal to a TSS (e.g. intergenic DNA and 3' UTR, extending the potential gene expression regulatory roles of the AhR. Although TF binding site analyses identified over-represented DRE sequences within enriched regions, approximately 50% of all AhR enriched regions lacked a DRE core (5'-GCGTG-3'. Microarray analysis identified 1,896 number of TCDD-responsive genes (|fold change| ≥ 1.5, P1(t > 0.999. Integrating this gene expression data with our ChIP-chip and DRE analyses only identified 625 differentially expressed genes that involved an AhR interaction at a DRE. Functional annotation analysis of differentially regulated genes associated with AhR enrichment identified overrepresented processes related to fatty acid and lipid metabolism and transport, and xenobiotic metabolism, which are consistent with TCDD-elicited steatosis in the mouse liver. Conclusions Details of the AhR regulatory network have been expanded to include AhR-DNA interactions within intragenic and intergenic genomic regions. Moreover, the AhR can interact with DNA independent of a DRE core suggesting there are alternative mechanisms of AhR-mediated gene regulation.

  19. Pathway, in silico and tissue-specific expression quantitative analyses of oesophageal squamous cell carcinoma genome-wide association studies data.

    Science.gov (United States)

    Hyland, Paula L; Zhang, Han; Yang, Qi; Yang, Howard H; Hu, Nan; Lin, Shih-Wen; Su, Hua; Wang, Lemin; Wang, Chaoyu; Ding, Ti; Fan, Jin-Hu; Qiao, You-Lin; Sung, Hyuna; Wheeler, William; Giffen, Carol; Burdett, Laurie; Wang, Zhaoming; Lee, Maxwell P; Chanock, Stephen J; Dawsey, Sanford M; Freedman, Neal D; Abnet, Christian C; Goldstein, Alisa M; Yu, Kai; Taylor, Philip R

    2016-02-01

    Oesophageal cancer is the fourth leading cause of cancer death in China where essentially all cases are histologically oesophageal squamous cell carcinoma (ESCC). Agnostic pathway-based analyses of genome-wide association study (GWAS) data combined with tissue-specific expression quantitative trait loci (eQTL) analysis and publicly available functional data can identify biological pathways and/or genes enriched with functionally-relevant disease-associated variants. We used the adaptive multilocus joint test to analyse 1827 pathways containing 6060 genes using GWAS data from 1942 ESCC cases and 2111 controls with Chinese ancestry. We examined the function of risk alleles using in silico and eQTL analyses in oesophageal tissues. Associations with ESCC risk were observed for 36 pathways predominantly involved in apoptosis, cell cycle regulation and DNA repair and containing known GWAS-associated genes. After excluding genes with previous GWAS signals, candidate pathways (and genes) for ESCC risk included taste transduction (KEGG_hsa04742; TAS2R13, TAS2R42, TAS2R14, TAS2R46,TAS2R50), long-patch base excision repair (Reactome_pid; POLD2) and the metabolics pathway (KEGG_hsa01100; MTAP, GAPDH, DCTD, POLD2, AMDHD1). We identified and validated CASP8 rs13016963 and IDH2 rs11630814 as eQTLs, and CASP8 rs3769823 and IDH2 rs4561444 as the potential functional variants in high-linkage disequilibrium with these single nucleotide polymorphisms (SNPs), respectively. Further, IDH2 mRNA levels were down-regulated in ESCC (tumour:normal-fold change = 0.69, P =  .75E-14). Agnostic pathway-based analyses and integration of multiple types of functional data provide new evidence for the contribution of genes in taste transduction and metabolism to ESCC susceptibility, and for the functionality of both established and new ESCC risk-related SNPs. Published by Oxford University Press on behalf of the International Epidemiological Association 2015. This work is written by US Government

  20. A porcine gluteus medius muscle genome-wide transcriptome analysis: dietary effects of n-6 and n-3 fatty acids on biological mechanisms

    NARCIS (Netherlands)

    Ogłuszka, Magdalena; Szostak, Agnieszka; Pas, te M.F.W.; Poławska, Ewa; Urbański, Paweł; Juszczuk-Kubiak, Edyta; Blicharski, Tadeusz; Pareek, Chandra Shekhar; Dunkelberger, Jenelle R.; Horbańczuk, Jarosław O.; Pierzchała, Mariusz

    2017-01-01

    The level of n-6 and n-3 polyunsaturated fatty acids may affect many cellular systems and functions via nuclear receptors or the bioactive lipid regulation of gene expression. The objective of this study was to investigate the changes in the muscle transcriptome and the biological functions regulate

  1. A porcine gluteus medius muscle genome-wide transcriptome analysis: dietary effects of omega-6 and omega-3 fatty acids on biological mechanisms

    NARCIS (Netherlands)

    Ogłuszka, Magdalena; Szostak, Agnieszka; Pas, te Marinus F.W.; Poławska, Ewa; Urbański, Paweł; Blicharski, Tadeusz; Pareek, Chandra Shekhar; Juszczuk-Kubiak, Edyta; Dunkelberger, Jenelle R.; Horbańczuk, Jarosław O.; Pierzchała, Mariusz

    2017-01-01


    Background

    The level of omega-6 and omega-3 polyunsaturated fatty acids can affect many cellular systems and function via nuclear receptors or the bioactive lipid regulation of gene expression. The objective of this study was to investigate changes in the muscle transcriptome and the b

  2. Genome-wide analysis of the mouse lung transcriptome reveals novel molecular gene interaction networks and cell-specific expression signatures

    Directory of Open Access Journals (Sweden)

    Williams Robert W

    2011-05-01

    Full Text Available Abstract Background The lung is critical in surveillance and initial defense against pathogens. In humans, as in mice, individual genetic differences strongly modulate pulmonary responses to infectious agents, severity of lung disease, and potential allergic reactions. In a first step towards understanding genetic predisposition and pulmonary molecular networks that underlie individual differences in disease vulnerability, we performed a global analysis of normative lung gene expression levels in inbred mouse strains and a large family of BXD strains that are widely used for systems genetics. Our goal is to provide a key community resource on the genetics of the normative lung transcriptome that can serve as a foundation for experimental analysis and allow predicting genetic predisposition and response to pathogens, allergens, and xenobiotics. Methods Steady-state polyA+ mRNA levels were assayed across a diverse and fully genotyped panel of 57 isogenic strains using the Affymetrix M430 2.0 array. Correlations of expression levels between genes were determined. Global expression QTL (eQTL analysis and network covariance analysis was performed using tools and resources in GeneNetwork http://www.genenetwork.org. Results Expression values were highly variable across strains and in many cases exhibited a high heri-tability factor. Several genes which showed a restricted expression to lung tissue were identified. Using correlations between gene expression values across all strains, we defined and extended memberships of several important molecular networks in the lung. Furthermore, we were able to extract signatures of immune cell subpopulations and characterize co-variation and shared genetic modulation. Known QTL regions for respiratory infection susceptibility were investigated and several cis-eQTL genes were identified. Numerous cis- and trans-regulated transcripts and chromosomal intervals with strong regulatory activity were mapped. The Cyp1a1 P

  3. Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies

    NARCIS (Netherlands)

    T. Niu (Tianhua); N. Liu (Ning); M. Zhao (Ming); G. Xie (Guie); L. Zhang (Lei); J. Li (Jian); Y.-F. Pei (Yu-Fang); H. Shen (Hui); X. Fu (Xiaoying); H. He (Hao); S. Lu (Shan); X. Chen (Xiangding); L. Tan (Lijun); T.-L. Yang (Tie-Lin); Y. Guo (Yan); P.J. Leo (Paul); E.L. Duncan (Emma); J. Shen (Jie); Y.-F. Guo (Yan-fang); G.C. Nicholson (Geoffrey); R.L. Prince (Richard L.); J.A. Eisman (John); G. Jones (Graeme); P.N. Sambrook (Philip); X. Hu (Xiang); P.M. Das (Partha M.); Q. Tian (Qing); X.-Z. Zhu (Xue-Zhen); C.J. Papasian (Christopher J.); M.A. Brown (Matthew); A.G. Uitterlinden (André G.); Y.-P. Wang (Yu-Ping); S. Xiang (Shuanglin); H.-W. Deng

    2015-01-01

    textabstractMicroRNAs (miRNAs) are critical post-transcriptional regulators. Based on a previous genome-wide association (GWA) scan, we conducted a polymorphism in microRNAs' Target Sites (poly-miRTS)-centric multistage meta-analysis for lumbar spine (LS)-, total hip (HIP)-, and femoral neck (FN)-bo

  4. No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index : Results from meta-analyses of 80,607 subjects

    NARCIS (Netherlands)

    J. Baumert (Jens); J. Huang (Jian); B. McKnight (Barbara); M. Sabater-Lleal (Maria); M. Steri (Maristella); A.Y. Chu (Audrey); S. Trompet (Stella); Lopez, L.M. (Lorna M.); Fornage, M. (Myriam); A. Teumer (Alexander); W. Tang (Weihong); A.R. Rudnicka (Alicja); A. Mälarstig (Anders); J.J. Hottenga (Jouke Jan); M. Kavousi (Maryam); J. Lahti (Jari); T. Tanaka (Toshiko); C. Hayward (Caroline); J.E. Huffman (Jennifer); P.-E. Morange (P.); L.M. Rose (Lynda); S. Basu (Saonli); A. Rumley (Ann); D.J. Stott (David. J.); B.M. Buckley (Brendan M.); A.J. de Craen (Anton); S. Sanna (Serena); G. Masala (Giovanna); R. Biffar (Reiner); G. Homuth (Georg); A. Silveira (Angela); B. Sennblad (Bengt); A. Goel (Anuj); H. Watkins (Hugh); M. Müller-Nurasyid (Martina); Rückerl, R. (Regina); K.D. Taylor (Kent); Chen, M.-H. (Ming-Huei); E.J.C. de Geus (Eco); A. Hofman (Albert); J.C.M. Witteman (Jacqueline); M.P.M. de Maat (Moniek); A. Palotie (Aarno); G. Davies (Gail); D.S. Siscovick (David); I. Kolcic (Ivana); S.H. Wild (Sarah); Song, J. (Jaejoon); W.L. McArdle (Wendy); I. Ford (Ian); N. Sattar (Naveed); D. Schlessinger (David); A. Grotevendt (Anne); M. Franzosi; Illig, T. (Thomas); M. Waldenberger (Melanie); T. Lumley (Thomas); G.H. Tofler (Geoffrey); G.A.H.M. Willemsen (Gonneke); A.G. Uitterlinden (André); F. Rivadeneira Ramirez (Fernando); K. Räikkönen (Katri); D.I. Chasman (Daniel); A.R. Folsom (Aaron); G.D.O. Lowe (Gordon); R.G.J. Westendorp (Rudi); P.E. Slagboom (Eline); F. Cucca (Francesco); H. Wallaschofski (Henri); R.J. Strawbridge (Rona); U. Seedorf (Udo); W. Koenig (Wolfgang); J.C. Bis (Joshua); K. Mukamal (Kenneth); Van Dongen, J. (Jenny); E. Widen (Elisabeth); O.H. Franco (Oscar); J.M. Starr (John); K.Y. Liu; L. Ferrucci (Luigi); O. Polasek (Ozren); J.F. Wilson (James F); T. Oudot-Mellakh (Tiphaine); H. Campbell (Harry); P. Navarro (Pau); S. Bandinelli (Stefania); Eriksson, J. (Johan); D.I. Boomsma (Dorret); A. Dehghan (Abbas); R. Clarke (Robert); A. Hamsten (Anders); Boerwinkle, E. (Eric); J.W. Jukema (Jan Wouter); S. Naitza (Silvia); P.M. Ridker (Paul); H. Völzke (Henry); Deary, I.J. (Ian J.); A. Reiner (Alexander); D.-A. Tregouet (David-Alexandre); C.J. O'Donnell (Christopher); D.P. Strachan (David); A. Peters (Annette); Smith, N.L. (Nicholas L.)

    2014-01-01

    textabstractPlasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with

  5. Genome-wide association and systems genetic analyses of residual feed intake, daily feed consumption, backfat and weight gain in pigs.

    Science.gov (United States)

    Do, Duy Ngoc; Ostersen, Tage; Strathe, Anders Bjerring; Mark, Thomas; Jensen, Just; Kadarmideen, Haja N

    2014-02-17

    Feed efficiency is one of the major components determining costs of animal production. Residual feed intake (RFI) is defined as the difference between the observed and the expected feed intake given a certain production. Residual feed intake 1 (RFI1) was calculated based on regression of individual daily feed intake (DFI) on initial test weight and average daily gain. Residual feed intake 2 (RFI2) was as RFI1 except it was also regressed with respect to backfat (BF). It has been shown to be a sensitive and accurate measure for feed efficiency in livestock but knowledge of the genomic regions and mechanisms affecting RFI in pigs is lacking. The study aimed to identify genetic markers and candidate genes for RFI and its component traits as well as pathways associated with RFI in Danish Duroc boars by genome-wide associations and systems genetic analyses. Phenotypic and genotypic records (using the Illumina Porcine SNP60 BeadChip) were available on 1,272 boars. Fifteen and 12 loci were significantly associated (p < 1.52 × 10-6) with RFI1 and RFI2, respectively. Among them, 10 SNPs were significantly associated with both RFI1 and RFI2 implying the existence of common mechanisms controlling the two RFI measures. Significant QTL regions for component traits of RFI (DFI and BF) were detected on pig chromosome (SSC) 1 (for DFI) and 2 for (BF). The SNPs within MAP3K5 and PEX7 on SSC 1, ENSSSCG00000022338 on SSC 9, and DSCAM on SSC 13 might be interesting markers for both RFI measures. Functional annotation of genes in 0.5 Mb size flanking significant SNPs indicated regulation of protein and lipid metabolic process, gap junction, inositol phosphate metabolism and insulin signaling pathway are significant biological processes and pathways for RFI, respectively. The study detected novel genetic variants and QTLs on SSC 1, 8, 9, 13 and 18 for RFI and indicated significant biological processes and metabolic pathways involved in RFI. The study also detected novel QTLs for

  6. Genome-Wide Identification of Differentially Expressed Genes Associated with the High Yielding of Oleoresin in Secondary Xylem of Masson Pine (Pinus massoniana Lamb by Transcriptomic Analysis.

    Directory of Open Access Journals (Sweden)

    Qinghua Liu

    Full Text Available Masson pine is an important timber and resource for oleoresin in South China. Increasing yield of oleoresin in stems can raise economic benefits and enhance the resistance to bark beetles. However, the genetic mechanisms for regulating the yield of oleoresin were still unknown. Here, high-throughput sequencing technology was used to investigate the transcriptome and compare the gene expression profiles of high and low oleoresin-yielding genotypes. A total of 40,690,540 reads were obtained and assembled into 137,499 transcripts from the secondary xylem tissues. We identified 84,842 candidate unigenes based on sequence annotation using various databases and 96 unigenes were candidates for terpenoid backbone biosynthesis in pine. By comparing the expression profiles of high and low oleoresin-yielding genotypes, 649 differentially expressed genes (DEGs were identified. GO enrichment analysis of DEGs revealed that multiple pathways were related to high yield of oleoresin. Nine candidate genes were validated by QPCR analysis. Among them, the candidate genes encoding geranylgeranyl diphosphate synthase (GGPS and (--alpha/beta-pinene synthase were up-regulated in the high oleoresin-yielding genotype, while tricyclene synthase revealed lower expression level, which was in good agreement with the GC/MS result. In addition, DEG encoding ABC transporters, pathogenesis-related proteins (PR5 and PR9, phosphomethylpyrimidine synthase, non-specific lipid-transfer protein-like protein and ethylene responsive transcription factors (ERFs were also confirmed to be critical for the biosynthesis of oleoresin. The next-generation sequencing strategy used in this study has proven to be a powerful means for analyzing transcriptome variation related to the yield of oleoresin in masson pine. The candidate genes encoding GGPS, (--alpha/beta-pinene, tricyclene synthase, ABC transporters, non-specific lipid-transfer protein-like protein, phosphomethylpyrimidine synthase

  7. Genome-wide transcriptome profiling of black poplar (Populus nigra L.) under boron toxicity revealed candidate genes responsible in boron uptake, transport and detoxification.

    Science.gov (United States)

    Yıldırım, Kubilay; Uylaş, Senem

    2016-12-01

    Boron (B) is an essential nutrient for normal growth of plants. Despite its low abundance in soils, it could be highly toxic to plants in especially arid and semi-arid environments. Poplars are known to be tolerant species to B toxicity and accumulation. However, physiological and gene regulation responses of these trees to B toxicity have not been investigated yet. Here, B accumulation and tolerance level of black poplar clones were firstly tested in the current study. Rooted cutting of these clones were treated with elevated B toxicity to select the most B accumulator and tolerant genotype. Then we carried out a microarray based transcriptome experiment on the leaves and roots of this genotype to find out transcriptional networks, genes and molecular mechanisms behind B toxicity tolerance. The results of the study indicated that black poplar is quite suitable for phytoremediation of B pollution. It could resist 15 ppm soil B content and >1500 ppm B accumulation in leaves, which are highly toxic concentrations for almost all agricultural plants. Transcriptomics results of study revealed totally 1625 and 1419 altered probe sets under 15 ppm B toxicity in leaf and root tissues, respectively. The highest induction were recorded for the probes sets annotated to tyrosine aminotransferase, ATP binding cassette transporters, glutathione S transferases and metallochaperone proteins. Strong up regulation of these genes attributed to internal excretion of B into the cell vacuole and existence of B detoxification processes in black poplar. Many other candidate genes functional in signalling, gene regulation, antioxidation, B uptake and transport processes were also identified in this hyper B accumulator plant for the first time with the current study. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  8. Genome-Wide Identification and Transcriptome-Based Expression Profiling of the Sox Gene Family in the Nile Tilapia (Oreochromis niloticus).

    Science.gov (United States)

    Wei, Ling; Yang, Chao; Tao, Wenjing; Wang, Deshou

    2016-02-23

    The Sox transcription factor family is characterized with the presence of a Sry-related high-mobility group (HMG) box and plays important roles in various biological processes in animals, including sex determination and differentiation, and the development of multiple organs. In this study, 27 Sox genes were identified in the genome of the Nile tilapia (Oreochromis niloticus), and were classified into seven groups. The members of each group of the tilapia Sox genes exhibited a relatively conserved exon-intron structure. Comparative analysis showed that the Sox gene family has undergone an expansion in tilapia and other teleost fishes following their whole genome duplication, and group K only exists in teleosts. Transcriptome-based analysis demonstrated that most of the tilapia Sox genes presented stage-specific and/or sex-dimorphic expressions during gonadal development, and six of the group B Sox genes were specifically expressed in the adult brain. Our results provide a better understanding of gene structure and spatio-temporal expression of the Sox gene family in tilapia, and will be useful for further deciphering the roles of the Sox genes during sex determination and gonadal development in teleosts.

  9. Foxtail millet NF-Y families: genome-wide survey and evolution analyses identified two functional genes important in abiotic stresses

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    Zhi-Juan eFeng

    2015-12-01

    Full Text Available It was reported that Nuclear Factor Y (NF-Y genes were involved in abiotic stress in plants. Foxtail millet (Setaria italica, an elite stress tolerant crop, provided an impetus for the investigation of the NF-Y families in abiotic responses. In the present study, a total of 39 NF-Y genes were identified in foxtail millet. Synteny analyses suggested that foxtail millet NF-Y genes had experienced rapid expansion and strong purifying selection during the process of plant evolution. De novo transcriptome assembly of foxtail millet revealed 11 drought up-regulated NF-Y genes. SiNF-YA1 and SiNF-YB8 were highly activated in leaves and/or roots by drought and salt stresses. Abscisic acid (ABA and H2O2 played positive roles in the induction of SiNF-YA1 and SiNF-YB8 under stress treatments. Transient luciferase (LUC expression assays revealed that SiNF-YA1 and SiNF-YB8 could activate the LUC gene driven by the tobacco (Nicotiana tobacam NtERD10, NtLEA5, NtCAT, NtSOD or NtPOD promoter under normal or stress conditions. Overexpression of SiNF-YA1 enhanced drought and salt tolerance by activating stress-related genes NtERD10 and NtCAT1 and by maintaining relatively stable relative water content (RWC and contents of chlorophyll, superoxide dismutase (SOD, peroxidase (POD, catalase (CAT and malondialdehyde (MDA in transgenic lines under stresses. SiNF-YB8 regulated expression of NtSOD, NtPOD, NtLEA5 and NtERD10 and conferred relatively high RWC and chlorophyll contents and low MDA content, resulting in drought and osmotic tolerance in transgenic lines under stresses. Therefore, SiNF-YA1 and SiNF-YB8 could activate stress-related genes and improve physiological traits, resulting in tolerance to abiotic stresses in plants. All these results will facilitate functional characterization of foxtail millet NF-Ys in future studies.

  10. Foxtail Millet NF-Y Families: Genome-Wide Survey and Evolution Analyses Identified Two Functional Genes Important in Abiotic Stresses.

    Science.gov (United States)

    Feng, Zhi-Juan; He, Guan-Hua; Zheng, Wei-Jun; Lu, Pan-Pan; Chen, Ming; Gong, Ya-Ming; Ma, You-Zhi; Xu, Zhao-Shi

    2015-01-01

    It was reported that Nuclear Factor Y (NF-Y) genes were involved in abiotic stress in plants. Foxtail millet (Setaria italica), an elite stress tolerant crop, provided an impetus for the investigation of the NF-Y families in abiotic responses. In the present study, a total of 39 NF-Y genes were identified in foxtail millet. Synteny analyses suggested that foxtail millet NF-Y genes had experienced rapid expansion and strong purifying selection during the process of plant evolution. De novo transcriptome assembly of foxtail millet revealed 11 drought up-regulated NF-Y genes. SiNF-YA1 and SiNF-YB8 were highly activated in leaves and/or roots by drought and salt stresses. Abscisic acid (ABA) and H2O2 played positive roles in the induction of SiNF-YA1 and SiNF-YB8 under stress treatments. Transient luciferase (LUC) expression assays revealed that SiNF-YA1 and SiNF-YB8 could activate the LUC gene driven by the tobacco (Nicotiana tobacam) NtERD10, NtLEA5, NtCAT, NtSOD, or NtPOD promoter under normal or stress conditions. Overexpression of SiNF-YA1 enhanced drought and salt tolerance by activating stress-related genes NtERD10 and NtCAT1 and by maintaining relatively stable relative water content (RWC) and contents of chlorophyll, superoxide dismutase (SOD), peroxidase (POD), catalase (CAT) and malondialdehyde (MDA) in transgenic lines under stresses. SiNF-YB8 regulated expression of NtSOD, NtPOD, NtLEA5, and NtERD10 and conferred relatively high RWC and chlorophyll contents and low MDA content, resulting in drought and osmotic tolerance in transgenic lines under stresses. Therefore, SiNF-YA1 and SiNF-YB8 could activate stress-related genes and improve physiological traits, resulting in tolerance to abiotic stresses in plants. All these results will facilitate functional characterization of foxtail millet NF-Ys in future studies.

  11. Genome-wide DNA methylation analyses in the brain reveal four differentially methylated regions between humans and non-human primates

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    Wang Jinkai

    2012-08-01

    Full Text Available Abstract Background The highly improved cognitive function is the most significant change in human evolutionary history. Recently, several large-scale studies reported the evolutionary roles of DNA methylation; however, the role of DNA methylation on brain evolution is largely unknown. Results To test if DNA methylation has contributed to the evolution of human brain, with the use of MeDIP-Chip and SEQUENOM MassARRAY, we conducted a genome-wide analysis to identify differentially methylated regions (DMRs in the brain between humans and rhesus macaques. We first identified a total of 150 candidate DMRs by the MeDIP-Chip method, among which 4 DMRs were confirmed by the MassARRAY analysis. All 4 DMRs are within or close to the CpG islands, and a MIR3 repeat element was identified in one DMR, but no repeat sequence was observed in the other 3 DMRs. For the 4 DMR genes, their proteins tend to be conserved and two genes have neural related functions. Bisulfite sequencing and phylogenetic comparison among human, chimpanzee, rhesus macaque and rat suggested several regions of lineage specific DNA methylation, including a human specific hypomethylated region in the promoter of K6IRS2 gene. Conclusions Our study provides a new angle of studying human brain evolution and understanding the evolutionary role of DNA methylation in the central nervous system. The results suggest that the patterns of DNA methylation in the brain are in general similar between humans and non-human primates, and only a few DMRs were identified.

  12. Genome-Wide Approaches to Drosophila Heart Development

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    Manfred Frasch

    2016-05-01

    Full Text Available The development of the dorsal vessel in Drosophila is one of the first systems in which key mechanisms regulating cardiogenesis have been defined in great detail at the genetic and molecular level. Due to evolutionary conservation, these findings have also provided major inputs into studies of cardiogenesis in vertebrates. Many of the major components that control Drosophila cardiogenesis were discovered based on candidate gene approaches and their functions were defined by employing the outstanding genetic tools and molecular techniques available in this system. More recently, approaches have been taken that aim to interrogate the entire genome in order to identify novel components and describe genomic features that are pertinent to the regulation of heart development. Apart from classical forward genetic screens, the availability of the thoroughly annotated Drosophila genome sequence made new genome-wide approaches possible, which include the generation of massive numbers of RNA interference (RNAi reagents that were used in forward genetic screens, as well as studies of the transcriptomes and proteomes of the developing heart under normal and experimentally manipulated conditions. Moreover, genome-wide chromatin immunoprecipitation experiments have been performed with the aim to define the full set of genomic binding sites of the major cardiogenic transcription factors, their relevant target genes, and a more complete picture of the regulatory network that drives cardiogenesis. This review will give an overview on these genome-wide approaches to Drosophila heart development and on computational analyses of the obtained information that ultimately aim to provide a description of this process at the systems level.

  13. Lifestyle transitions in plant pathogenic Colletotrichum fungi deciphered by genome and transcriptome analyses.

    Science.gov (United States)

    O'Connell, Richard J; Thon, Michael R; Hacquard, Stéphane; Amyotte, Stefan G; Kleemann, Jochen; Torres, Maria F; Damm, Ulrike; Buiate, Ester A; Epstein, Lynn; Alkan, Noam; Altmüller, Janine; Alvarado-Balderrama, Lucia; Bauser, Christopher A; Becker, Christian; Birren, Bruce W; Chen, Zehua; Choi, Jaeyoung; Crouch, Jo Anne; Duvick, Jonathan P; Farman, Mark A; Gan, Pamela; Heiman, David; Henrissat, Bernard; Howard, Richard J; Kabbage, Mehdi; Koch, Christian; Kracher, Barbara; Kubo, Yasuyuki; Law, Audrey D; Lebrun, Marc-Henri; Lee, Yong-Hwan; Miyara, Itay; Moore, Neil; Neumann, Ulla; Nordström, Karl; Panaccione, Daniel G; Panstruga, Ralph; Place, Michael; Proctor, Robert H; Prusky, Dov; Rech, Gabriel; Reinhardt, Richard; Rollins, Jeffrey A; Rounsley, Steve; Schardl, Christopher L; Schwartz, David C; Shenoy, Narmada; Shirasu, Ken; Sikhakolli, Usha R; Stüber, Kurt; Sukno, Serenella A; Sweigard, James A; Takano, Yoshitaka; Takahara, Hiroyuki; Trail, Frances; van der Does, H Charlotte; Voll, Lars M; Will, Isa; Young, Sarah; Zeng, Qiandong; Zhang, Jingze; Zhou, Shiguo; Dickman, Martin B; Schulze-Lefert, Paul; Ver Loren van Themaat, Emiel; Ma, Li-Jun; Vaillancourt, Lisa J

    2012-09-01

    Colletotrichum species are fungal pathogens that devastate crop plants worldwide. Host infection involves the differentiation of specialized cell types that are associated with penetration, growth inside living host cells (biotrophy) and tissue destruction (necrotrophy). We report here genome and transcriptome analyses of Colletotrichum higginsianum infecting Arabidopsis thaliana and Colletotrichum graminicola infecting maize. Comparative genomics showed that both fungi have large sets of pathogenicity-related genes, but families of genes encoding secreted effectors, pectin-degrading enzymes, secondary metabolism enzymes, transporters and peptidases are expanded in C. higginsianum. Genome-wide expression profiling revealed that these genes are transcribed in successive waves that are linked to pathogenic transitions: effectors and secondary metabolism enzymes are induced before penetration and during biotrophy, whereas most hydrolases and transporters are upregulated later, at the switch to necrotrophy. Our findings show that preinvasion perception of plant-derived signals substantially reprograms fungal gene expression and indicate previously unknown functions for particular fungal cell types.

  14. Myelin basic protein as a novel genetic risk factor in rheumatoid arthritis--a genome-wide study combined with immunological analyses.

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    Chikashi Terao

    Full Text Available Rheumatoid arthritis (RA is a major cause of adult chronic inflammatory arthritis and a typical complex trait. Although several genetic determinants have been identified, they account for only a part of the genetic susceptibility. We conducted a genome-wide association study of RA in Japanese using 225,079 SNPs genotyped in 990 cases and 1,236 controls from two independent collections (658 cases and 934 controls in collection1; 332 cases and 302 controls in collection2, followed by replication studies in two additional collections (874 cases and 855 controls in collection3; 1,264 cases and 948 controls in collection4. SNPs showing p<0.005 in the first two collections and p<10(-4 by meta-analysis were further genotyped in the latter two collections. A novel risk variant, rs2000811, in intron2 of the myelin basic protein (MBP at chromosome 18q23 showed strong association with RA (p = 2.7×10(-8, OR 1.23, 95% CI: 1.14-1.32. The transcription of MBP was significantly elevated with the risk allele compared to the alternative allele (p<0.001. We also established by immunohistochemistry that MBP was expressed in the synovial lining layer of RA patients, the main target of inflammation in the disease. Circulating autoantibody against MBP derived from human brain was quantified by ELISA between patients with RA, other connective tissue diseases and healthy controls. As a result, the titer of anti-MBP antibody was markedly higher in plasma of RA patients compared to healthy controls (p<0.001 and patients with other connective tissue disorders (p<0.001. ELISA experiment using citrullinated recombinant MBP revealed that a large fraction of anti-MBP antibody in RA patients recognized citrullinated MBP. This is the first report of a genetic study in RA implicating MBP as a potential autoantigen and its involvement in pathogenesis of the disease.

  15. New insights into domestication of carrot from root transcriptome analyses

    NARCIS (Netherlands)

    Rong, J.; Lammers, Y.; Strasburg, J.L.; Schidlo, N.S.; Ariyurek, Y.; Jong, de T.J.; Klinkhamer, P.G.L.; Smulders, M.J.M.; Vrieling, K.

    2014-01-01

    Background - Understanding the molecular basis of domestication can provide insights into the processes of rapid evolution and crop improvement. Here we demonstrated the processes of carrot domestication and identified genes under selection based on transcriptome analyses. Results - The root transcr

  16. Genome-wide identification, classification and functional analyses of the bHLH transcription factor family in the pig, Sus scrofa.

    Science.gov (United States)

    Liu, Wuyi

    2015-08-01

    The basic helix-loop-helix (bHLH) transcription factors are one of the largest families of gene regulatory proteins and play crucial roles in genetic, developmental and physiological processes in eukaryotes. Here, we conducted a survey of the Sus scrofa genome and identified 109 putative bHLH transcription factor members belonging to super-groups A, B, C, D, E, and F, respectively, while four members were orphan genes. We identified 6 most significantly enriched KEGG pathways and 116 most significant GO annotation categories. Further comprehensive surveys in human genome and other 12 medical databases identified 72 significantly enriched biological pathways with these 113 pig bHLH transcription factors. From the functional protein association network analysis 93 hub proteins were identified and 55 hub proteins created a tight network or a functional module within their protein families. Especially, there were 20 hub proteins found highly connected in the functional interaction network. The present study deepens our understanding and provided insights into the evolution and functional aspects of animal bHLH proteins and should serve as a solid foundation for further for analyses of specific bHLH transcription factors in the pig and other mammals.

  17. Genome-wide analyses of radioresistance-associated miRNA expression profile in nasopharyngeal carcinoma using next generation deep sequencing.

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    Guo Li

    Full Text Available BACKGROUND: Rapidly growing evidence suggests that microRNAs (miRNAs are involved in a wide range of cancer malignant behaviours including radioresistance. Therefore, the present study was designed to investigate miRNA expression patterns associated with radioresistance in NPC. METHODS: The differential expression profiles of miRNAs and mRNAs associated with NPC radioresistance were constructed. The predicted target mRNAs of miRNAs and their enriched signaling pathways were analyzed via biological informatical algorithms. Finally, partial miRNAs and pathways-correlated target mRNAs were validated in two NPC radioreisitant cell models. RESULTS: 50 known and 9 novel miRNAs with significant difference were identified, and their target mRNAs were narrowed down to 53 nasopharyngeal-/NPC-specific mRNAs. Subsequent KEGG analyses demonstrated that the 53 mRNAs were enriched in 37 signaling pathways. Further qRT-PCR assays confirmed 3 down-regulated miRNAs (miR-324-3p, miR-93-3p and miR-4501, 3 up-regulated miRNAs (miR-371a-5p, miR-34c-5p and miR-1323 and 2 novel miRNAs. Additionally, corresponding alterations of pathways-correlated target mRNAs were observed including 5 up-regulated mRNAs (ICAM1, WNT2B, MYC, HLA-F and TGF-β1 and 3 down-regulated mRNAs (CDH1, PTENP1 and HSP90AA1. CONCLUSIONS: Our study provides an overview of miRNA expression profile and the interactions between miRNA and their target mRNAs, which will deepen our understanding of the important roles of miRNAs in NPC radioresistance.

  18. Genome-wide analyses and functional classification of proline repeat-rich proteins: potential role of eIF5A in eukaryotic evolution.

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    Ajeet Mandal

    Full Text Available The eukaryotic translation factor, eIF5A has been recently reported as a sequence-specific elongation factor that facilitates peptide bond formation at consecutive prolines in Saccharomyces cerevisiae, as its ortholog elongation factor P (EF-P does in bacteria. We have searched the genome databases of 35 representative organisms from six kingdoms of life for PPP (Pro-Pro-Pro and/or PPG (Pro-Pro-Gly-encoding genes whose expression is expected to depend on eIF5A. We have made detailed analyses of proteome data of 5 selected species, Escherichia coli, Saccharomyces cerevisiae, Drosophila melanogaster, Mus musculus and Homo sapiens. The PPP and PPG motifs are low in the prokaryotic proteomes. However, their frequencies markedly increase with the biological complexity of eukaryotic organisms, and are higher in newly derived proteins than in those orthologous proteins commonly shared in all species. Ontology classifications of S. cerevisiae and human genes encoding the highest level of polyprolines reveal their strong association with several specific biological processes, including actin/cytoskeletal associated functions, RNA splicing/turnover, DNA binding/transcription and cell signaling. Previously reported phenotypic defects in actin polarity and mRNA decay of eIF5A mutant strains are consistent with the proposed role for eIF5A in the translation of the polyproline-containing proteins. Of all the amino acid tandem repeats (≥3 amino acids, only the proline repeat frequency correlates with functional complexity of the five organisms examined. Taken together, these findings suggest the importance of proline repeat-rich proteins and a potential role for eIF5A and its hypusine modification pathway in the course of eukaryotic evolution.

  19. Placental invasion, preeclampsia risk and adaptive molecular evolution at the origin of the great apes: evidence from genome-wide analyses.

    Science.gov (United States)

    Crosley, E J; Elliot, M G; Christians, J K; Crespi, B J

    2013-02-01

    Recent evidence from chimpanzees and gorillas has raised doubts that preeclampsia is a uniquely human disease. The deep extravillous trophoblast (EVT) invasion and spiral artery remodeling that characterizes our placenta (and is abnormal in preeclampsia) is shared within great apes, setting Homininae apart from Hylobatidae and Old World Monkeys, which show much shallower trophoblast invasion and limited spiral artery remodeling. We hypothesize that the evolution of a more invasive placenta in the lineage ancestral to the great apes involved positive selection on genes crucial to EVT invasion and spiral artery remodeling. Furthermore, identification of placentally-expressed genes under selection in this lineage may identify novel genes involved in placental development. We tested for positive selection in approximately 18,000 genes using the ratio of non-synonymous to synonymous amino acid substitution for protein-coding DNA. DAVID Bioinformatics Resources identified biological processes enriched in positively selected genes, including processes related to EVT invasion and spiral artery remodeling. Analyses revealed 295 and 264 genes under significant positive selection on the branches ancestral to Hominidae (Human, Chimp, Gorilla, Orangutan) and Homininae (Human, Chimp, Gorilla), respectively. Gene ontology analysis of these gene sets demonstrated significant enrichments for several functional gene clusters relevant to preeclampsia risk, and sets of placentally-expressed genes that have been linked with preeclampsia and/or trophoblast invasion in other studies. Our study represents a novel approach to the identification of candidate genes and amino acid residues involved in placental pathologies by implicating them in the evolution of highly-invasive placenta. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Genomic and Transcriptomic Analyses of Foodborne Bacterial Pathogens

    Science.gov (United States)

    Zhang, Wei; Dudley, Edward G.; Wade, Joseph T.

    DNA microarrays (often interchangeably called DNA chips or DNA arrays) are among the most popular analytical tools for high-throughput comparative genomic and transcriptomic analyses of foodborne bacterial pathogens. A typical DNA microarray contains hundreds to millions of small DNA probes that are chemically attached (or "printed") onto the surface of a microscopic glass slide. Depending on the specific "printing" and probe synthesis technologies for different microarray platforms, such DNA probes can be PCR amplicons or in situ synthesized short oligonucleotides. DNA microarray technologies have revolutionized the way that we investigate the biology of foodborne bacterial pathogens. The major advantage of these technologies is that DNA microarrays allow comparison of subtle genomic or transcriptomic variations between two bacterial samples, such as genomic variations between two different bacterial strains or transcriptomic alterations of same bacterial strain under two different treatments. Some applications of comparative genomic hybridization microarrays and global gene expression microarrays have been covered in previous chapters of this book.

  1. Unraveling the Rat Intestine, Spleen and Liver Genome-Wide Transcriptome after the Oral Administration of Lavender Oil by a Two-Color Dye-Swap DNA Microarray Approach.

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    Hiroko Kubo

    Full Text Available The use of lavender oil (LO--a commonly, used oil in aromatherapy, with well-defined volatile components linalool and linalyl acetate--in non-traditional medicine is increasing globally. To understand and demonstrate the potential positive effects of LO on the body, we have established an animal model in this current study, investigating the orally administered LO effects genome wide in the rat small intestine, spleen, and liver. The rats were administered LO at 5 mg/kg (usual therapeutic dose in humans followed by the screening of differentially expressed genes in the tissues, using a 4×44-K whole-genome rat chip (Agilent microarray platform; Agilent Technologies, Palo Alto, CA, USA in conjunction with a dye-swap approach, a novelty of this study. Fourteen days after LO treatment and compared with a control group (sham, a total of 156 and 154 up (≧ 1.5-fold- and down (≦ 0.75-fold-regulated genes, 174 and 66 up- (≧ 1.5-fold- and down (≦ 0.75-fold-regulated genes, and 222 and 322 up- (≧ 1.5-fold- and down (≦ 0.75-fold-regulated genes showed differential expression at the mRNA level in the small intestine, spleen and liver, respectively. The reverse transcription-polymerase chain reaction (RT-PCR validation of highly up- and down-regulated genes confirmed the regulation of the Papd4, Lrp1b, Alb, Cyr61, Cyp2c, and Cxcl1 genes by LO as examples in these tissues. Using bioinformatics, including Ingenuity Pathway Analysis (IPA, differentially expressed genes were functionally categorized by their Gene Ontology (GO and biological function and network analysis, revealing their diverse functions and potential roles in LO-mediated effects in rat. Further IPA analysis in particular unraveled the presence of novel genes, such as Papd4, Or8k5, Gprc5b, Taar5, Trpc6, Pld2 and Onecut3 (up-regulated top molecules and Tnf, Slc45a4, Slc25a23 and Samt4 (down-regulated top molecules, to be influenced by LO treatment in the small intestine, spleen and

  2. Unraveling the Rat Intestine, Spleen and Liver Genome-Wide Transcriptome after the Oral Administration of Lavender Oil by a Two-Color Dye-Swap DNA Microarray Approach.

    Science.gov (United States)

    Kubo, Hiroko; Shibato, Junko; Saito, Tomomi; Ogawa, Tetsuo; Rakwal, Randeep; Shioda, Seiji

    2015-01-01

    The use of lavender oil (LO)--a commonly, used oil in aromatherapy, with well-defined volatile components linalool and linalyl acetate--in non-traditional medicine is increasing globally. To understand and demonstrate the potential positive effects of LO on the body, we have established an animal model in this current study, investigating the orally administered LO effects genome wide in the rat small intestine, spleen, and liver. The rats were administered LO at 5 mg/kg (usual therapeutic dose in humans) followed by the screening of differentially expressed genes in the tissues, using a 4×44-K whole-genome rat chip (Agilent microarray platform; Agilent Technologies, Palo Alto, CA, USA) in conjunction with a dye-swap approach, a novelty of this study. Fourteen days after LO treatment and compared with a control group (sham), a total of 156 and 154 up (≧ 1.5-fold)- and down (≦ 0.75-fold)-regulated genes, 174 and 66 up- (≧ 1.5-fold)- and down (≦ 0.75-fold)-regulated genes, and 222 and 322 up- (≧ 1.5-fold)- and down (≦ 0.75-fold)-regulated genes showed differential expression at the mRNA level in the small intestine, spleen and liver, respectively. The reverse transcription-polymerase chain reaction (RT-PCR) validation of highly up- and down-regulated genes confirmed the regulation of the Papd4, Lrp1b, Alb, Cyr61, Cyp2c, and Cxcl1 genes by LO as examples in these tissues. Using bioinformatics, including Ingenuity Pathway Analysis (IPA), differentially expressed genes were functionally categorized by their Gene Ontology (GO) and biological function and network analysis, revealing their diverse functions and potential roles in LO-mediated effects in rat. Further IPA analysis in particular unraveled the presence of novel genes, such as Papd4, Or8k5, Gprc5b, Taar5, Trpc6, Pld2 and Onecut3 (up-regulated top molecules) and Tnf, Slc45a4, Slc25a23 and Samt4 (down-regulated top molecules), to be influenced by LO treatment in the small intestine, spleen and liver

  3. Genome-wide DNA methylation profiling in cultured eutopic and ectopic endometrial stromal cells.

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    Yoshiaki Yamagata

    Full Text Available The objective of this study was to characterize the genome-wide DNA methylation profiles of isolated endometrial stromal cells obtained from eutopic endometria with (euESCa and without endometriosis (euESCb and ovarian endometrial cysts (choESC. Three samples were analyzed in each group. The infinium methylation array identified more hypermethylated and hypomethylated CpGs in choESC than in euESCa, and only a few genes were methylated differently in euESCa and euESCb. A functional analysis revealed that signal transduction, developmental processes, immunity, etc. were different in choESC and euESCa. A clustering analysis and a principal component analysis performed based on the methylation levels segregated choESC from euESC, while euESCa and euESCb were identical. A transcriptome analysis was then conducted and the results were compared with those of the DNA methylation analysis. Interestingly, the hierarchical clustering and principal component analyses showed that choESC were segregated from euESCa and euESCb in the DNA methylation analysis, while no segregation was recognized in the transcriptome analysis. The mRNA expression levels of the epigenetic modification enzymes, including DNA methyltransferases, obtained from the specimens were not significantly different between the groups. Some of the differentially methylated and/or expressed genes (NR5A1, STAR, STRA6 and HSD17B2, which are related with steroidogenesis, were validated by independent methods in a larger number of samples. Our findings indicate that different DNA methylation profiles exist in ectopic ESC, highlighting the benefits of genome wide DNA methylation analyses over transcriptome analyses in clarifying the development and characterization of endometriosis.

  4. Integration of high-resolution methylome and transcriptome analyses to dissect epigenomic changes in childhood acute lymphoblastic leukemia.

    Science.gov (United States)

    Busche, Stephan; Ge, Bing; Vidal, Ramon; Spinella, Jean-François; Saillour, Virginie; Richer, Chantal; Healy, Jasmine; Chen, Shu-Huang; Droit, Arnaud; Sinnett, Daniel; Pastinen, Tomi

    2013-07-15

    B-cell precursor acute lymphoblastic leukemia (pre-B ALL) is the most common pediatric cancer. Although the genetic determinants underlying disease onset remain unclear, epigenetic modifications including DNA methylation are suggested to contribute significantly to leukemogenesis. Using the Illumina 450K array, we assessed DNA methylation in matched tumor-normal samples of 46 childhood patients with pre-B ALL, extending single CpG-site resolution analysis of the pre-B ALL methylome beyond CpG-islands (CGI). Unsupervised hierarchical clustering of CpG-site neighborhood, gene, or microRNA (miRNA) gene-associated methylation levels separated the tumor cohort according to major pre-B ALL subtypes, and methylation in CGIs, CGI shores, and in regions around the transcription start site was found to significantly correlate with transcript expression. Focusing on samples carrying the t(12;21) ETV6-RUNX1 fusion, we identified 119 subtype-specific high-confidence marker CpG-loci. Pathway analyses linked the CpG-loci-associated genes with hematopoiesis and cancer. Further integration with whole-transcriptome data showed the effects of methylation on expression of 17 potential drivers of leukemogenesis. Independent validation of array methylation and sequencing-derived transcript expression with Sequenom Epityper technology and real-time quantitative reverse transcriptase PCR, respectively, indicates more than 80% empirical accuracy of our genome-wide findings. In summary, genome-wide DNA methylation profiling enabled us to separate pre-B ALL according to major subtypes, to map epigenetic biomarkers specific for the t(12;21) subtype, and through a combined methylome and transcriptome approach to identify downstream effects on candidate drivers of leukemogenesis.

  5. Genome-wide whole blood microRNAome and transcriptome analyses reveal miRNA-mRNA regulated host response to foodborne pathogen Salmonella infection in swine

    Science.gov (United States)

    MicroRNAs (miRNAs) are important regulators of gene expression and play key roles in several biological processes. However, little is known about the role of miRNAs in regulating genes involved in host response to bacterial infection. Here, we present a systematic study of miRNA and mRNA profiles fr...

  6. Genome-wide whole blood microRNAome and transcriptome analyses reveal miRNA-mRNA regulated host response to foodborne pathogen Salmonella infection in swine.

    Science.gov (United States)

    Bao, Hua; Kommadath, Arun; Liang, Guanxiang; Sun, Xu; Arantes, Adriano S; Tuggle, Christopher K; Bearson, Shawn M D; Plastow, Graham S; Stothard, Paul; Guan, Le Luo

    2015-07-31

    To understand the role of miRNAs in regulating genes involved in host response to bacterial infection and shedding of foodborne pathogens, a systematic profiling of miRNAs and mRNAs from the whole blood of pigs upon Salmonella challenge was performed. A total of 62 miRNAs were differentially expressed post infection (false discovery rate Salmonella infection. From these networks, miR-214 and miR-331-3p were identified as new candidates potentially associated with Salmonella infection. An miRNA seed sequence analysis suggested that these miRNAs regulate several critical immune-related genes including SLC11A1, PIGE-108A11.3 and VAV2. We showed that challenged pigs had reduced miR-214 expression and increased miR-331-3p expression in the whole blood. Furthermore, the expression of the proposed targets of miR-214 (SLC11A1 and PIGE-108A11.3) increased while that of the proposed target of miR-331-3p (VAV2) decreased following challenge (expression changes confirmed by in vitro assays). Based on these observations, we propose potential roles for miR-214 and miR-331-3p in regulation of immune responses to Salmonella infection.

  7. Transcriptome profiling and genome-wide DNA binding define the differential role of fenretinide and all-trans RA in regulating the death and survival of human hepatocellular carcinoma Huh7 cells.

    Science.gov (United States)

    Hu, Ying; Liu, Hui-Xin; He, Yuqi; Fang, Yaping; Fang, Jianwen; Wan, Yu-Jui Yvonne

    2013-04-01

    Fenretinide is significantly more effective in inducing apoptosis in cancer cells than all-trans retinoic acid (ATRA). The current study uses a genome-wide approach to understand the differential role fenretinide and ATRA have in inducing apoptosis in Huh7 cells. Fenretinide and ATRA-induced gene expressions and DNA bindings were profiled using microarray and chromatin immunoprecipitation with anti-RXRα antibody. The data showed that fenretinide was not a strong transcription regulator. Fenretinide only changed the expressions of 1 093 genes, approximately three times less than the number of genes regulated by ATRA (2 811). Biological function annotation demonstrated that both fenretinide and ATRA participated in pathways that determine cell fate and metabolic processes. However, fenretinide specifically induced Fas/TNFα-mediated apoptosis by increasing the expression of pro-apoptotic genes i.e., DEDD2, CASP8, CASP4, and HSPA1A/B; whereas, ATRA induced the expression of BIRC3 and TNFAIP3, which inhibit apoptosis by interacting with TRAF2. In addition, fenretinide inhibited the expression of the genes involved in RAS/RAF/ERK-mediated survival pathway. In contrast, ATRA increased the expression of SOSC2, BRAF, MEK, and ERK genes. Most genes regulated by fenretinide and ATRA were bound by RXRα, suggesting a direct effect. This study revealed that by regulating fewer genes, the effects of fenretinide become more specific and thus has fewer side effects than ATRA. The data also suggested that fenretinide induces apoptosis via death receptor effector and by inhibiting the RAS/RAF/ERK pathway. It provides insight on how retinoid efficacy can be improved and how side effects in cancer therapy can be reduced.

  8. Genome-wide measurement of RNA folding energies.

    Science.gov (United States)

    Wan, Yue; Qu, Kun; Ouyang, Zhengqing; Kertesz, Michael; Li, Jun; Tibshirani, Robert; Makino, Debora L; Nutter, Robert C; Segal, Eran; Chang, Howard Y

    2012-10-26

    RNA structural transitions are important in the function and regulation of RNAs. Here, we reveal a layer of transcriptome organization in the form of RNA folding energies. By probing yeast RNA structures at different temperatures, we obtained relative melting temperatures (Tm) for RNA structures in over 4000 transcripts. Specific signatures of RNA Tm demarcated the polarity of mRNA open reading frames and highlighted numerous candidate regulatory RNA motifs in 3' untranslated regions. RNA Tm distinguished noncoding versus coding RNAs and identified mRNAs with distinct cellular functions. We identified thousands of putative RNA thermometers, and their presence is predictive of the pattern of RNA decay in vivo during heat shock. The exosome complex recognizes unpaired bases during heat shock to degrade these RNAs, coupling intrinsic structural stabilities to gene regulation. Thus, genome-wide structural dynamics of RNA can parse functional elements of the transcriptome and reveal diverse biological insights.

  9. Genome-wide analysis of antiviral signature genes in porcine macrophages at different activation statuses.

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    Yongming Sang

    Full Text Available Macrophages (MФs can be polarized to various activation statuses, including classical (M1, alternative (M2, and antiviral states. To study the antiviral activation status of porcine MФs during porcine reproductive and respiratory syndrome virus (PRRSV infection, we used RNA Sequencing (RNA-Seq for transcriptomic analysis of differentially expressed genes (DEGs. Sequencing assessment and quality evaluation showed that our RNA-Seq data met the criteria for genome-wide transcriptomic analysis. Comparisons of any two activation statuses revealed more than 20,000 DEGs that were normalized to filter out 153-5,303 significant DEGs [false discovery rate (FDR ≤0.001, fold change ≥2] in each comparison. The highest 5,303 significant DEGs were found between lipopolysaccharide- (LPS and interferon (IFNγ-stimulated M1 cells, whereas only 153 significant DEGs were detected between interleukin (IL-10-polarized M2 cells and control mock-activated cells. To identify signature genes for antiviral regulation pertaining to each activation status, we identified a set of DEGs that showed significant up-regulation in only one activation state. In addition, pathway analyses defined the top 20-50 significantly regulated pathways at each activation status, and we further analyzed DEGs pertinent to pathways mediated by AMP kinase (AMPK and epigenetic mechanisms. For the first time in porcine macrophages, our transcriptomic analyses not only compared family-wide differential expression of most known immune genes at different activation statuses, but also revealed transcription evidence of multiple gene families. These findings show that using RNA-Seq transcriptomic analyses in virus-infected and status-synchronized macrophages effectively profiled signature genes and gene response pathways for antiviral regulation, which may provide a framework for optimizing antiviral immunity and immune homeostasis.

  10. Transcriptome analyses of Anguillicola crassus from native and novel hosts

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    Emanuel Heitlinger

    2014-11-01

    Full Text Available Anguillicola crassus is a swim bladder nematode of eels. The parasite is native to the Asian eel Anguilla japonica, but was introduced to Europe and the European eel Anguilla anguilla in the early 1980s. A Taiwanese source has been proposed for this introduction. In the new host in the recipient area, the parasite appears to be more pathogenic. As a reason for these differences, genetically fixed differences in infectivity and development between Taiwanese and European A.crassus have been described and disentangled from plasticity induced by different host environments. To explore whether transcriptional regulation is involved in these lifecycle differences, we have analysed a “common garden”, cross infection experiment, using deep-sequencing transcriptomics. Surprisingly, in the face of clear phenotypic differences in life history traits, we identified no significant differences in gene expression between parasite populations or between experimental host species. From 120,000 SNPs identified in the transcriptome data we found that European A. crassus were not a genetic subset of the Taiwanese nematodes sampled. The loci that have the major contribution to the European-Taiwanese population differentiation show an enrichment of synonymous and non-coding polymorphism. This argues against positive selection in population differentiation. However, genes involved in protein processing in the endoplasmatic reticulum membrane and genes bearing secretion signal sequences were enriched in the set of genes most differentiated between European and Taiwanese A. crassus. These genes could be a source for the phenotypically visible genetically fixed differences between European and Taiwanese A. crassus.

  11. Analyses of transcriptome sequences reveal multiple ancient large-scale duplication events in the ancestor of Sphagnopsida (Bryophyta).

    Science.gov (United States)

    Devos, Nicolas; Szövényi, Péter; Weston, David J; Rothfels, Carl J; Johnson, Matthew G; Shaw, A Jonathan

    2016-07-01

    The goal of this research was to investigate whether there has been a whole-genome duplication (WGD) in the ancestry of Sphagnum (peatmoss) or the class Sphagnopsida, and to determine if the timing of any such duplication(s) and patterns of paralog retention could help explain the rapid radiation and current ecological dominance of peatmosses. RNA sequencing (RNA-seq) data were generated for nine taxa in Sphagnopsida (Bryophyta). Analyses of frequency plots for synonymous substitutions per synonymous site (Ks ) between paralogous gene pairs and reconciliation of 578 gene trees were conducted to assess evidence of large-scale or genome-wide duplication events in each transcriptome. Both Ks frequency plots and gene tree-based analyses indicate multiple duplication events in the history of the Sphagnopsida. The most recent WGD event predates divergence of Sphagnum from the two other genera of Sphagnopsida. Duplicate retention is highly variable across species, which might be best explained by local adaptation. Our analyses indicate that the last WGD could have been an important factor underlying the diversification of peatmosses and facilitated their rise to ecological dominance in peatlands. The timing of the duplication events and their significance in the evolutionary history of peat mosses are discussed.

  12. Case-Control Genome-Wide Association Study of Attention-Deficit/Hyperactivity Disorder

    Science.gov (United States)

    Neale, Benjamin M.; Medland, Sarah; Ripke, Stephan; Anney, Richard J. L.; Asherson, Philip; Buitelaar, Jan; Franke, Barbara; Gill, Michael; Kent, Lindsey; Holmans, Peter; Middleton, Frank; Thapar, Anita; Lesch, Klaus-Peter; Faraone, Stephen V.; Daly, Mark; Nguyen, Thuy Trang; Schafer, Helmut; Steinhausen, Hans-Christoph; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Warnke, Andreas; Walitza, Susanne; Freitag, Christine; Meyer, Jobst; Palmason, Haukur; Rothenberger, Aribert; Hawi, Ziarih; Sergeant, Joseph; Roeyers, Herbert; Mick, Eric; Biederman, Joseph

    2010-01-01

    Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. Thus additional genome-wide association studies (GWAS) are needed. Method: We used case-control analyses of 896 cases…

  13. Anti-schistosomal Intervention Targets Identified by Lifecycle Transcriptomic Analyses

    Science.gov (United States)

    Fitzpatrick, Jennifer M.; Peak, Emily; Perally, Samirah; Chalmers, Iain W.; Barrett, John; Yoshino, Timothy P.; Ivens, Alasdair C.; Hoffmann, Karl F.

    2009-01-01

    Background Novel methods to identify anthelmintic drug and vaccine targets are urgently needed, especially for those parasite species currently being controlled by singular, often limited strategies. A clearer understanding of the transcriptional components underpinning helminth development will enable identification of exploitable molecules essential for successful parasite/host interactions. Towards this end, we present a combinatorial, bioinformatics-led approach, employing both statistical and network analyses of transcriptomic data, for identifying new immunoprophylactic and therapeutic lead targets to combat schistosomiasis. Methodology/Principal Findings Utilisation of a Schistosoma mansoni oligonucleotide DNA microarray consisting of 37,632 elements enabled gene expression profiling from 15 distinct parasite lifecycle stages, spanning three unique ecological niches. Statistical approaches of data analysis revealed differential expression of 973 gene products that minimally describe the three major characteristics of schistosome development: asexual processes within intermediate snail hosts, sexual maturation within definitive vertebrate hosts and sexual dimorphism amongst adult male and female worms. Furthermore, we identified a group of 338 constitutively expressed schistosome gene products (including 41 transcripts sharing no sequence similarity outside the Platyhelminthes), which are likely to be essential for schistosome lifecycle progression. While highly informative, statistics-led bioinformatics mining of the transcriptional dataset has limitations, including the inability to identify higher order relationships between differentially expressed transcripts and lifecycle stages. Network analysis, coupled to Gene Ontology enrichment investigations, facilitated a re-examination of the dataset and identified 387 clusters (containing 12,132 gene products) displaying novel examples of developmentally regulated classes (including 294 schistosomula and

  14. Inbreeding in genome-wide selection

    NARCIS (Netherlands)

    Daetwyler, H.D.; Villanueva, B.; Bijma, P.; Woolliams, J.A.

    2007-01-01

    Traditional selection methods, such as sib and best linear unbiased prediction (BLUP) selection, which increased genetic gain by increasing accuracy of evaluation have also led to an increased rate of inbreeding per generation (¿FG). This is not necessarily the case with genome-wide selection, which

  15. Genome-wide analysis of alternative transcripts in human breast cancer

    Science.gov (United States)

    Wen, Ji; Toomer, Kevin H.

    2016-01-01

    Transcript variants play a critical role in diversifying gene expression. Alternative splicing is a major mechanism for generating transcript variants. A number of genes have been implicated in breast cancer pathogenesis with their aberrant expression of alternative transcripts. In this study, we performed genome-wide analyses of transcript variant expression in breast cancer. With RNA-Seq data from 105 patients, we characterized the transcriptome of breast tumors, by pairwise comparison of gene expression in the breast tumor versus matched healthy tissue from each patient. We identified 2839 genes, ~10 % of protein-coding genes in the human genome, that had differential expression of transcript variants between tumors and healthy tissues. The validity of the computational analysis was confirmed by quantitative RT-PCR assessment of transcript variant expression from four top candidate genes. The alternative transcript profiling led to classification of breast cancer into two subgroups and yielded a novel molecular signature that could be prognostic of patients’ tumor burden and survival. We uncovered nine splicing factors (FOX2, MBNL1, QKI, PTBP1, ELAVL1, HNRNPC, KHDRBS1, SFRS2, and TIAR) that were involved in aberrant splicing in breast cancer. Network analyses for the coordinative patterns of transcript variant expression identified twelve “hub” genes that differentiated the cancerous and normal transcriptomes. Dysregulated expression of alternative transcripts may reveal novel biomarkers for tumor development. It may also suggest new therapeutic targets, such as the “hub” genes identified through the network analyses of transcript variant expression, or splicing factors implicated in the formation of the tumor transcriptome. PMID:25913416

  16. Progress in prokaryotic transcriptomics.

    Science.gov (United States)

    Filiatrault, Melanie J

    2011-10-01

    Genome-wide expression studies transformed the field of transcriptomics and made it feasible to study global gene expression in extraordinary detail. These new methods have revealed an enhanced view of the transcriptional landscape and have yielded many biological insights. It is increasingly clear that the prokaryotic transcriptome is much more complex than once thought. Recent advances in microbial transcriptome analyses are highlighted in this review. Areas of progress include the development of optimized techniques that minimize the abundance of ribosomal RNAs in RNA samples as well as the development of novel methods to create transcriptome libraries. Advances such as these have led to a new emphasis in areas such as metatranscriptomics and single cell gene expression studies. Published by Elsevier Ltd.

  17. Transcriptome landscape of Lactococcus lactis reveals many novel RNAs including a small regulatory RNA involved in carbon uptake and metabolism

    NARCIS (Netherlands)

    van der Meulen, Sjoerd B; de Jong, Anne; Kok, Jan

    2016-01-01

    RNA sequencing has revolutionized genome-wide transcriptome analyses, and the identification of non-coding regulatory RNAs in bacteria has thus increased concurrently. Here we reveal the transcriptome map of the lactic acid bacterial paradigm Lactococcus lactis MG1363 by employing differential RNA s

  18. Genome wide association and linkage analyses identified three loci -- 4q25, 17q23.2 and 10q11.21 -- associated with variation in leukocyte telomere length: The Long Life Family Study

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    Joseph H Lee

    2014-01-01

    Full Text Available Leukocyte telomere length is believed to measure cellular aging in humans, and short leukocyte telomere length is associated with increased risks of late onset diseases, including cardiovascular disease, dementia, etc. Many studies have shown that leukocyte telomere length is a heritable trait, and several candidate genes have been identified, including TERT, TERC, OBFC1, and CTC1. Unlike most studies that have focused on genetic causes of chronic diseases such as heart disease and diabetes in relation to leukocyte telomere length, the present study examined the genome to identify variants that may contribute to variation in leukocyte telomere length among families with exceptional longevity. From the genome wide association analysis in 4,289 LLFS participants, we identified a novel intergenic SNP rs7680468 located near PAPSS1 and DKK2 on 4q25 (p=4.7E-8. From our linkage analysis, we identified two additional loci with HLOD scores exceeding three, including 4.77 for 17q23.2 and 4.36 for 10q11.21. These two loci harbor a number of novel candidate genes with SNPs, and our gene-wise association analysis identified multiple genes, including DCAF7, POLG2, CEP95, and SMURF2 at 17q23.2; and RASGEF1A, HNRNPF, ANF487, CSTF2T, and PRKG1 at 10q11.21. Among these genes, multiple SNPs were associated with leukocyte telomere length, but the strongest association was observed with one contiguous haplotype in CEP95 and SMURF2. We also show that three previously reported genes – TERC, MYNN, and OBFC1 – were significantly associated with leukocyte telomere length at pempirical smaller than 0.05.

  19. Integrated analysis of copy number variation and genome-wide expression profiling in colorectal cancer tissues.

    Science.gov (United States)

    Ali Hassan, Nur Zarina; Mokhtar, Norfilza Mohd; Kok Sin, Teow; Mohamed Rose, Isa; Sagap, Ismail; Harun, Roslan; Jamal, Rahman

    2014-01-01

    Integrative analyses of multiple genomic datasets for selected samples can provide better insight into the overall data and can enhance our knowledge of cancer. The objective of this study was to elucidate the association between copy number variation (CNV) and gene expression in colorectal cancer (CRC) samples and their corresponding non-cancerous tissues. Sixty-four paired CRC samples from the same patients were subjected to CNV profiling using the Illumina HumanOmni1-Quad assay, and validation was performed using multiplex ligation probe amplification method. Genome-wide expression profiling was performed on 15 paired samples from the same group of patients using the Affymetrix Human Gene 1.0 ST array. Significant genes obtained from both array results were then overlapped. To identify molecular pathways, the data were mapped to the KEGG database. Whole genome CNV analysis that compared primary tumor and non-cancerous epithelium revealed gains in 1638 genes and losses in 36 genes. Significant gains were mostly found in chromosome 20 at position 20q12 with a frequency of 45.31% in tumor samples. Examples of genes that were associated at this cytoband were PTPRT, EMILIN3 and CHD6. The highest number of losses was detected at chromosome 8, position 8p23.2 with 17.19% occurrence in all tumor samples. Among the genes found at this cytoband were CSMD1 and DLC1. Genome-wide expression profiling showed 709 genes to be up-regulated and 699 genes to be down-regulated in CRC compared to non-cancerous samples. Integration of these two datasets identified 56 overlapping genes, which were located in chromosomes 8, 20 and 22. MLPA confirmed that the CRC samples had the highest gains in chromosome 20 compared to the reference samples. Interpretation of the CNV data in the context of the transcriptome via integrative analyses may provide more in-depth knowledge of the genomic landscape of CRC.

  20. Integrated analysis of copy number variation and genome-wide expression profiling in colorectal cancer tissues.

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    Nur Zarina Ali Hassan

    Full Text Available Integrative analyses of multiple genomic datasets for selected samples can provide better insight into the overall data and can enhance our knowledge of cancer. The objective of this study was to elucidate the association between copy number variation (CNV and gene expression in colorectal cancer (CRC samples and their corresponding non-cancerous tissues. Sixty-four paired CRC samples from the same patients were subjected to CNV profiling using the Illumina HumanOmni1-Quad assay, and validation was performed using multiplex ligation probe amplification method. Genome-wide expression profiling was performed on 15 paired samples from the same group of patients using the Affymetrix Human Gene 1.0 ST array. Significant genes obtained from both array results were then overlapped. To identify molecular pathways, the data were mapped to the KEGG database. Whole genome CNV analysis that compared primary tumor and non-cancerous epithelium revealed gains in 1638 genes and losses in 36 genes. Significant gains were mostly found in chromosome 20 at position 20q12 with a frequency of 45.31% in tumor samples. Examples of genes that were associated at this cytoband were PTPRT, EMILIN3 and CHD6. The highest number of losses was detected at chromosome 8, position 8p23.2 with 17.19% occurrence in all tumor samples. Among the genes found at this cytoband were CSMD1 and DLC1. Genome-wide expression profiling showed 709 genes to be up-regulated and 699 genes to be down-regulated in CRC compared to non-cancerous samples. Integration of these two datasets identified 56 overlapping genes, which were located in chromosomes 8, 20 and 22. MLPA confirmed that the CRC samples had the highest gains in chromosome 20 compared to the reference samples. Interpretation of the CNV data in the context of the transcriptome via integrative analyses may provide more in-depth knowledge of the genomic landscape of CRC.

  1. Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene.

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    Kerstin U Ludwig

    2016-03-01

    Full Text Available Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively. Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13 × 10(-14 for rs1258763; relative risk (RR: 1.46, 95% confidence interval (CI: 1.32-1.61 but not nsCLO (P = 0.27; RR: 1.09 (0.94-1.27. The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1, which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47-9.61, Pdiff<0.05. While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014. The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions.

  2. Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene

    Science.gov (United States)

    Ludwig, Kerstin U.; Ahmed, Syeda Tasnim; Böhmer, Anne C.; Sangani, Nasim Bahram; Varghese, Sheryil; Klamt, Johanna; Schuenke, Hannah; Gültepe, Pinar; Hofmann, Andrea; Rubini, Michele; Aldhorae, Khalid Ahmed; Steegers-Theunissen, Regine P.; Rojas-Martinez, Augusto; Reiter, Rudolf; Borck, Guntram; Knapp, Michael; Nakatomi, Mitsushiro; Graf, Daniel; Mangold, Elisabeth; Peters, Heiko

    2016-01-01

    Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13×10−14 for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32–1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94–1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47–9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions. PMID:26968009

  3. Genome-Wide Transcriptome Analysis of Cadmium Stress in Rice

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    Youko Oono

    2016-01-01

    Full Text Available Rice growth is severely affected by toxic concentrations of the nonessential heavy metal cadmium (Cd. To elucidate the molecular basis of the response to Cd stress, we performed mRNA sequencing of rice following our previous study on exposure to high concentrations of Cd (Oono et al., 2014. In this study, rice plants were hydroponically treated with low concentrations of Cd and approximately 211 million sequence reads were mapped onto the IRGSP-1.0 reference rice genome sequence. Many genes, including some identified under high Cd concentration exposure in our previous study, were found to be responsive to low Cd exposure, with an average of about 11,000 transcripts from each condition. However, genes expressed constitutively across the developmental course responded only slightly to low Cd concentrations, in contrast to their clear response to high Cd concentration, which causes fatal damage to rice seedlings according to phenotypic changes. The expression of metal ion transporter genes tended to correlate with Cd concentration, suggesting the potential of the RNA-Seq strategy to reveal novel Cd-responsive transporters by analyzing gene expression under different Cd concentrations. This study could help to develop novel strategies for improving tolerance to Cd exposure in rice and other cereal crops.

  4. Profiling genome-wide DNA methylation.

    Science.gov (United States)

    Yong, Wai-Shin; Hsu, Fei-Man; Chen, Pao-Yang

    2016-01-01

    DNA methylation is an epigenetic modification that plays an important role in regulating gene expression and therefore a broad range of biological processes and diseases. DNA methylation is tissue-specific, dynamic, sequence-context-dependent and trans-generationally heritable, and these complex patterns of methylation highlight the significance of profiling DNA methylation to answer biological questions. In this review, we surveyed major methylation assays, along with comparisons and biological examples, to provide an overview of DNA methylation profiling techniques. The advances in microarray and sequencing technologies make genome-wide profiling possible at a single-nucleotide or even a single-cell resolution. These profiling approaches vary in many aspects, such as DNA input, resolution, genomic region coverage, and bioinformatics analysis, and selecting a feasible method requires knowledge of these methods. We first introduce the biological background of DNA methylation and its pattern in plants, animals and fungi. We present an overview of major experimental approaches to profiling genome-wide DNA methylation and hydroxymethylation and then extend to the single-cell methylome. To evaluate these methods, we outline their strengths and weaknesses and perform comparisons across the different platforms. Due to the increasing need to compute high-throughput epigenomic data, we interrogate the computational pipeline for bisulfite sequencing data and also discuss the concept of identifying differentially methylated regions (DMRs). This review summarizes the experimental and computational concepts for profiling genome-wide DNA methylation, followed by biological examples. Overall, this review provides researchers useful guidance for the selection of a profiling method suited to specific research questions.

  5. Genome-wide approaches to understanding human ageing

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    Kaeberlein Matt

    2006-06-01

    Full Text Available Abstract The use of genomic technologies in biogerontology has the potential to greatly enhance our understanding of human ageing. High-throughput screens for alleles correlated with survival in long-lived people have uncovered novel genes involved in age-associated disease. Genome-wide longevity studies in simple eukaryotes are identifying evolutionarily conserved pathways that determine longevity. It is hoped that validation of these 'public' aspects of ageing in mice, along with analyses of variation in candidate human ageing genes, will provide targets for future interventions to slow the ageing process and retard the onset of age-associated pathologies.

  6. Genome-wide identification of enhancer elements.

    Science.gov (United States)

    Tulin, Sarah; Barsi, Julius C; Bocconcelli, Carlo; Smith, Joel

    2016-01-01

    We present a prospective genome-wide regulatory element database for the sea urchin embryo and the modified chromosome capture-related methodology used to create it. The method we developed is termed GRIP-seq for genome-wide regulatory element immunoprecipitation and combines features of chromosome conformation capture, chromatin immunoprecipitation, and paired-end next-generation sequencing with molecular steps that enrich for active cis-regulatory elements associated with basal transcriptional machinery. The first GRIP-seq database, available to the community, comes from S. purpuratus 24 hpf embryos and takes advantage of the extremely well-characterized cis-regulatory elements in this system for validation. In addition, using the GRIP-seq database, we identify and experimentally validate a novel, intronic cis-regulatory element at the onecut locus. We find GRIP-seq signal sensitively identifies active cis-regulatory elements with a high signal-to-noise ratio for both distal and intronic elements. This promising GRIP-seq protocol has the potential to address a rate-limiting step in resolving comprehensive, predictive network models in all systems.

  7. Genome-wide inference of regulatory networks in Streptomyces coelicolor

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    Takano Eriko

    2010-10-01

    Full Text Available Abstract Background The onset of antibiotics production in Streptomyces species is co-ordinated with differentiation events. An understanding of the genetic circuits that regulate these coupled biological phenomena is essential to discover and engineer the pharmacologically important natural products made by these species. The availability of genomic tools and access to a large warehouse of transcriptome data for the model organism, Streptomyces coelicolor, provides incentive to decipher the intricacies of the regulatory cascades and develop biologically meaningful hypotheses. Results In this study, more than 500 samples of genome-wide temporal transcriptome data, comprising wild-type and more than 25 regulatory gene mutants of Streptomyces coelicolor probed across multiple stress and medium conditions, were investigated. Information based on transcript and functional similarity was used to update a previously-predicted whole-genome operon map and further applied to predict transcriptional networks constituting modules enriched in diverse functions such as secondary metabolism, and sigma factor. The predicted network displays a scale-free architecture with a small-world property observed in many biological networks. The networks were further investigated to identify functionally-relevant modules that exhibit functional coherence and a consensus motif in the promoter elements indicative of DNA-binding elements. Conclusions Despite the enormous experimental as well as computational challenges, a systems approach for integrating diverse genome-scale datasets to elucidate complex regulatory networks is beginning to emerge. We present an integrated analysis of transcriptome data and genomic features to refine a whole-genome operon map and to construct regulatory networks at the cistron level in Streptomyces coelicolor. The functionally-relevant modules identified in this study pose as potential targets for further studies and verification.

  8. Genome-wide Association Study of Obsessive-Compulsive Disorder

    Science.gov (United States)

    Stewart, S Evelyn; Yu, Dongmei; Scharf, Jeremiah M; Neale, Benjamin M; Fagerness, Jesen A; Mathews, Carol A; Arnold, Paul D; Evans, Patrick D; Gamazon, Eric R; Osiecki, Lisa; McGrath, Lauren; Haddad, Stephen; Crane, Jacquelyn; Hezel, Dianne; Illman, Cornelia; Mayerfeld, Catherine; Konkashbaev, Anuar; Liu, Chunyu; Pluzhnikov, Anna; Tikhomirov, Anna; Edlund, Christopher K; Rauch, Scott L; Moessner, Rainald; Falkai, Peter; Maier, Wolfgang; Ruhrmann, Stephan; Grabe, Hans-Jörgen; Lennertz, Leonard; Wagner, Michael; Bellodi, Laura; Cavallini, Maria Cristina; Richter, Margaret A; Cook, Edwin H; Kennedy, James L; Rosenberg, David; Stein, Dan J; Hemmings, Sian MJ; Lochner, Christine; Azzam, Amin; Chavira, Denise A; Fournier, Eduardo; Garrido, Helena; Sheppard, Brooke; Umaña, Paul; Murphy, Dennis L; Wendland, Jens R; Veenstra-VanderWeele, Jeremy; Denys, Damiaan; Blom, Rianne; Deforce, Dieter; Van Nieuwerburgh, Filip; Westenberg, Herman GM; Walitza, Susanne; Egberts, Karin; Renner, Tobias; Miguel, Euripedes Constantino; Cappi, Carolina; Hounie, Ana G; Conceição do Rosário, Maria; Sampaio, Aline S; Vallada, Homero; Nicolini, Humberto; Lanzagorta, Nuria; Camarena, Beatriz; Delorme, Richard; Leboyer, Marion; Pato, Carlos N; Pato, Michele T; Voyiaziakis, Emanuel; Heutink, Peter; Cath, Danielle C; Posthuma, Danielle; Smit, Jan H; Samuels, Jack; Bienvenu, O Joseph; Cullen, Bernadette; Fyer, Abby J; Grados, Marco A; Greenberg, Benjamin D; McCracken, James T; Riddle, Mark A; Wang, Ying; Coric, Vladimir; Leckman, James F; Bloch, Michael; Pittenger, Christopher; Eapen, Valsamma; Black, Donald W; Ophoff, Roel A; Strengman, Eric; Cusi, Daniele; Turiel, Maurizio; Frau, Francesca; Macciardi, Fabio; Gibbs, J Raphael; Cookson, Mark R; Singleton, Andrew; Hardy, John; Crenshaw, Andrew T; Parkin, Melissa A; Mirel, Daniel B; Conti, David V; Purcell, Shaun; Nestadt, Gerald; Hanna, Gregory L; Jenike, Michael A; Knowles, James A; Cox, Nancy; Pauls, David L

    2014-01-01

    Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1,465 cases, 5,557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9,657 X-chromosome SNPs. Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two p-values were located within DLGAP1 (p=2.49×10-6 and p=3.44×10-6), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a p-value=3.84 × 10-8. However, when trios were meta-analyzed with the combined case-control samples, the p-value for this variant was 3.62×10-5, losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation-QTLs (p<0.001) and frontal lobe eQTLs (p=0.001) was observed within the top-ranked SNPs (p<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD. PMID:22889921

  9. Genome-wide association study of smoking initiation and current smoking

    DEFF Research Database (Denmark)

    Vink, Jacqueline M; Smit, August B; de Geus, Eco J C;

    2009-01-01

    For the identification of genes associated with smoking initiation and current smoking, genome-wide association analyses were carried out in 3497 subjects. Significant genes that replicated in three independent samples (n = 405, 5810, and 1648) were visualized into a biologically meaningful network......) and cell-adhesion molecules (e.g., CDH23). We conclude that a network-based genome-wide association approach can identify genes influencing smoking behavior....

  10. Genome-wide Analysis of Gene Regulation

    DEFF Research Database (Denmark)

    Chen, Yun

    cells are capable of regulating their gene expression, so that each cell can only express a particular set of genes yielding limited numbers of proteins with specialized functions. Therefore a rigid control of differential gene expression is necessary for cellular diversity. On the other hand, aberrant...... gene regulation will disrupt the cell’s fundamental processes, which in turn can cause disease. Hence, understanding gene regulation is essential for deciphering the code of life. Along with the development of high throughput sequencing (HTS) technology and the subsequent large-scale data analysis......, genome-wide assays have increased our understanding of gene regulation significantly. This thesis describes the integration and analysis of HTS data across different important aspects of gene regulation. Gene expression can be regulated at different stages when the genetic information is passed from gene...

  11. Comprehensive analyses of genomes, transcriptomes and metabolites of neem tree

    Directory of Open Access Journals (Sweden)

    Nagesh A. Kuravadi

    2015-08-01

    Full Text Available Neem (Azadirachta indica A. Juss is one of the most versatile tropical evergreen tree species known in India since the Vedic period (1500 BC–600 BC. Neem tree is a rich source of limonoids, having a wide spectrum of activity against insect pests and microbial pathogens. Complex tetranortriterpenoids such as azadirachtin, salanin and nimbin are the major active principles isolated from neem seed. Absolutely nothing is known about the biochemical pathways of these metabolites in neem tree. To identify genes and pathways in neem, we sequenced neem genomes and transcriptomes using next generation sequencing technologies. Assembly of Illumina and 454 sequencing reads resulted in 267 Mb, which accounts for 70% of estimated size of neem genome. We predicted 44,495 genes in the neem genome, of which 32,278 genes were expressed in neem tissues. Neem genome consists about 32.5% (87 Mb of repetitive DNA elements. Neem tree is phylogenetically related to citrus, Citrus sinensis. Comparative analysis anchored 62% (161 Mb of assembled neem genomic contigs onto citrus chromomes. Ultrahigh performance liquid chromatography-mass spectrometry-selected reaction monitoring (UHPLC-MS/SRM method was used to quantify azadirachtin, nimbin, and salanin from neem tissues. Weighted Correlation Network Analysis (WCGNA of expressed genes and metabolites resulted in identification of possible candidate genes involved in azadirachtin biosynthesis pathway. This study provides genomic, transcriptomic and quantity of top three neem metabolites resource, which will accelerate basic research in neem to understand biochemical pathways.

  12. Comprehensive analyses of genomes, transcriptomes and metabolites of neem tree.

    Science.gov (United States)

    Kuravadi, Nagesh A; Yenagi, Vijay; Rangiah, Kannan; Mahesh, H B; Rajamani, Anantharamanan; Shirke, Meghana D; Russiachand, Heikham; Loganathan, Ramya Malarini; Shankara Lingu, Chandana; Siddappa, Shilpa; Ramamurthy, Aishwarya; Sathyanarayana, B N; Gowda, Malali

    2015-01-01

    Neem (Azadirachta indica A. Juss) is one of the most versatile tropical evergreen tree species known in India since the Vedic period (1500 BC-600 BC). Neem tree is a rich source of limonoids, having a wide spectrum of activity against insect pests and microbial pathogens. Complex tetranortriterpenoids such as azadirachtin, salanin and nimbin are the major active principles isolated from neem seed. Absolutely nothing is known about the biochemical pathways of these metabolites in neem tree. To identify genes and pathways in neem, we sequenced neem genomes and transcriptomes using next generation sequencing technologies. Assembly of Illumina and 454 sequencing reads resulted in 267 Mb, which accounts for 70% of estimated size of neem genome. We predicted 44,495 genes in the neem genome, of which 32,278 genes were expressed in neem tissues. Neem genome consists about 32.5% (87 Mb) of repetitive DNA elements. Neem tree is phylogenetically related to citrus, Citrus sinensis. Comparative analysis anchored 62% (161 Mb) of assembled neem genomic contigs onto citrus chromomes. Ultrahigh performance liquid chromatography-mass spectrometry-selected reaction monitoring (UHPLC-MS/SRM) method was used to quantify azadirachtin, nimbin, and salanin from neem tissues. Weighted Correlation Network Analysis (WCGNA) of expressed genes and metabolites resulted in identification of possible candidate genes involved in azadirachtin biosynthesis pathway. This study provides genomic, transcriptomic and quantity of top three neem metabolites resource, which will accelerate basic research in neem to understand biochemical pathways.

  13. Examination of Triacylglycerol Biosynthetic Pathways via De Novo Transcriptomic and Proteomic Analyses in an Unsequenced Microalga

    Science.gov (United States)

    2011-10-17

    Examination of Triacylglycerol Biosynthetic Pathways via De Novo Transcriptomic and Proteomic Analyses in an Unsequenced Microalga Michael T...dependent upon available genomic sequence data, and the lack of these data has hindered the pursuit of such analyses for many oleaginous microalgae . In order...to examine the triacylglycerol biosynthetic pathway in the unsequenced oleaginous microalga , Chlorella vulgaris, we have established a strategy with

  14. Transcriptomics and proteomics analyses of the PACAP38 influenced ischemic brain in permanent middle cerebral artery occlusion model mice

    Directory of Open Access Journals (Sweden)

    Hori Motohide

    2012-11-01

    Full Text Available Abstract Introduction The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP is considered to be a potential therapeutic agent for prevention of cerebral ischemia. Ischemia is a most common cause of death after heart attack and cancer causing major negative social and economic consequences. This study was designed to investigate the effect of PACAP38 injection intracerebroventrically in a mouse model of permanent middle cerebral artery occlusion (PMCAO along with corresponding SHAM control that used 0.9% saline injection. Methods Ischemic and non-ischemic brain tissues were sampled at 6 and 24 hours post-treatment. Following behavioral analyses to confirm whether the ischemia has occurred, we investigated the genome-wide changes in gene and protein expression using DNA microarray chip (4x44K, Agilent and two-dimensional gel electrophoresis (2-DGE coupled with matrix assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS, respectively. Western blotting and immunofluorescent staining were also used to further examine the identified protein factor. Results Our results revealed numerous changes in the transcriptome of ischemic hemisphere (ipsilateral treated with PACAP38 compared to the saline-injected SHAM control hemisphere (contralateral. Previously known (such as the interleukin family and novel (Gabra6, Crtam genes were identified under PACAP influence. In parallel, 2-DGE analysis revealed a highly expressed protein spot in the ischemic hemisphere that was identified as dihydropyrimidinase-related protein 2 (DPYL2. The DPYL2, also known as Crmp2, is a marker for the axonal growth and nerve development. Interestingly, PACAP treatment slightly increased its abundance (by 2-DGE and immunostaining at 6 h but not at 24 h in the ischemic hemisphere, suggesting PACAP activates neuronal defense mechanism early on. Conclusions This study provides a detailed inventory of PACAP influenced gene expressions

  15. Genome-wide analysis correlates Ayurveda Prakriti.

    Science.gov (United States)

    Govindaraj, Periyasamy; Nizamuddin, Sheikh; Sharath, Anugula; Jyothi, Vuskamalla; Rotti, Harish; Raval, Ritu; Nayak, Jayakrishna; Bhat, Balakrishna K; Prasanna, B V; Shintre, Pooja; Sule, Mayura; Joshi, Kalpana S; Dedge, Amrish P; Bharadwaj, Ramachandra; Gangadharan, G G; Nair, Sreekumaran; Gopinath, Puthiya M; Patwardhan, Bhushan; Kondaiah, Paturu; Satyamoorthy, Kapaettu; Valiathan, Marthanda Varma Sankaran; Thangaraj, Kumarasamy

    2015-10-29

    The practice of Ayurveda, the traditional medicine of India, is based on the concept of three major constitutional types (Vata, Pitta and Kapha) defined as "Prakriti". To the best of our knowledge, no study has convincingly correlated genomic variations with the classification of Prakriti. In the present study, we performed genome-wide SNP (single nucleotide polymorphism) analysis (Affymetrix, 6.0) of 262 well-classified male individuals (after screening 3416 subjects) belonging to three Prakritis. We found 52 SNPs (p ≤ 1 × 10(-5)) were significantly different between Prakritis, without any confounding effect of stratification, after 10(6) permutations. Principal component analysis (PCA) of these SNPs classified 262 individuals into their respective groups (Vata, Pitta and Kapha) irrespective of their ancestry, which represent its power in categorization. We further validated our finding with 297 Indian population samples with known ancestry. Subsequently, we found that PGM1 correlates with phenotype of Pitta as described in the ancient text of Caraka Samhita, suggesting that the phenotypic classification of India's traditional medicine has a genetic basis; and its Prakriti-based practice in vogue for many centuries resonates with personalized medicine.

  16. Transcriptomic and Proteomic Analyses of Rice Pistils during Pollination

    Institute of Scientific and Technical Information of China (English)

    Kun Wang; Ming Li; Pingfang Yang

    2012-01-01

    Pollination is a critical step that can determine the rate of seed set.Compared with those of the self-incompatibility (SI),the mechanisms of compatible pollination are still largely unknown.previous studies mainly focused on the gene expression profile of stigma or pistil rather than its dynamic changes during the pollen-pistil interaction.In this study,we used deep sequencing based transcriptomic technique,iTRAQ and two-dimensional gel electrophoresis based quantitative proteomic techniques were combined to analyze the dynamic changes of gene expression profile in rice pistil during the pollination.After bioinformatics analysis,RNA-Seq results yielded a total 963 genes that exhibited significant (FDR <0.001) and differential (ratio value >2 or <0.5) expression.iTRAQ and 2D-MS seperately yielded 145 and 41 differentially expressed proteins.Among those,we found that fine-tuning of the biochemical and physiological cellular environment is crucial for reproductive success.Our study provides a temporal and spatial gene expression profile of pollen-pistil interactions,which will help us to obtain a more comprehensive view into the gene expression networks and biochemical pathways during the plant sexual reproductive process.

  17. Genome-wide association analysis of imputed rare variants: application to seven common complex diseases.

    Science.gov (United States)

    Mägi, Reedik; Asimit, Jennifer L; Day-Williams, Aaron G; Zeggini, Eleftheria; Morris, Andrew P

    2012-12-01

    Genome-wide association studies have been successful in identifying loci contributing effects to a range of complex human traits. The majority of reproducible associations within these loci are with common variants, each of modest effect, which together explain only a small proportion of heritability. It has been suggested that much of the unexplained genetic component of complex traits can thus be attributed to rare variation. However, genome-wide association study genotyping chips have been designed primarily to capture common variation, and thus are underpowered to detect the effects of rare variants. Nevertheless, we demonstrate here, by simulation, that imputation from an existing scaffold of genome-wide genotype data up to high-density reference panels has the potential to identify rare variant associations with complex traits, without the need for costly re-sequencing experiments. By application of this approach to genome-wide association studies of seven common complex diseases, imputed up to publicly available reference panels, we identify genome-wide significant evidence of rare variant association in PRDM10 with coronary artery disease and multiple genes in the major histocompatibility complex (MHC) with type 1 diabetes. The results of our analyses highlight that genome-wide association studies have the potential to offer an exciting opportunity for gene discovery through association with rare variants, conceivably leading to substantial advancements in our understanding of the genetic architecture underlying complex human traits.

  18. Genome wide selection in Citrus breeding.

    Science.gov (United States)

    Gois, I B; Borém, A; Cristofani-Yaly, M; de Resende, M D V; Azevedo, C F; Bastianel, M; Novelli, V M; Machado, M A

    2016-10-17

    Genome wide selection (GWS) is essential for the genetic improvement of perennial species such as Citrus because of its ability to increase gain per unit time and to enable the efficient selection of characteristics with low heritability. This study assessed GWS efficiency in a population of Citrus and compared it with selection based on phenotypic data. A total of 180 individual trees from a cross between Pera sweet orange (Citrus sinensis Osbeck) and Murcott tangor (Citrus sinensis Osbeck x Citrus reticulata Blanco) were evaluated for 10 characteristics related to fruit quality. The hybrids were genotyped using 5287 DArT_seq(TM) (diversity arrays technology) molecular markers and their effects on phenotypes were predicted using the random regression - best linear unbiased predictor (rr-BLUP) method. The predictive ability, prediction bias, and accuracy of GWS were estimated to verify its effectiveness for phenotype prediction. The proportion of genetic variance explained by the markers was also computed. The heritability of the traits, as determined by markers, was 16-28%. The predictive ability of these markers ranged from 0.53 to 0.64, and the regression coefficients between predicted and observed phenotypes were close to unity. Over 35% of the genetic variance was accounted for by the markers. Accuracy estimates with GWS were lower than those obtained by phenotypic analysis; however, GWS was superior in terms of genetic gain per unit time. Thus, GWS may be useful for Citrus breeding as it can predict phenotypes early and accurately, and reduce the length of the selection cycle. This study demonstrates the feasibility of genomic selection in Citrus.

  19. Genome-wide DNA methylation maps in follicular lymphoma cells determined by methylation-enriched bisulfite sequencing.

    Directory of Open Access Journals (Sweden)

    Jeong-Hyeon Choi

    Full Text Available BACKGROUND: Follicular lymphoma (FL is a form of non-Hodgkin's lymphoma (NHL that arises from germinal center (GC B-cells. Despite the significant advances in immunotherapy, FL is still not curable. Beyond transcriptional profiling and genomics datasets, there currently is no epigenome-scale dataset or integrative biology approach that can adequately model this disease and therefore identify novel mechanisms and targets for successful prevention and treatment of FL. METHODOLOGY/PRINCIPAL FINDINGS: We performed methylation-enriched genome-wide bisulfite sequencing of FL cells and normal CD19(+ B-cells using 454 sequencing technology. The methylated DNA fragments were enriched with methyl-binding proteins, treated with bisulfite, and sequenced using the Roche-454 GS FLX sequencer. The total number of bases covered in the human genome was 18.2 and 49.3 million including 726,003 and 1.3 million CpGs in FL and CD19(+ B-cells, respectively. 11,971 and 7,882 methylated regions of interest (MRIs were identified respectively. The genome-wide distribution of these MRIs displayed significant differences between FL and normal B-cells. A reverse trend in the distribution of MRIs between the promoter and the gene body was observed in FL and CD19(+ B-cells. The MRIs identified in FL cells also correlated well with transcriptomic data and ChIP-on-Chip analyses of genome-wide histone modifications such as tri-methyl-H3K27, and tri-methyl-H3K4, indicating a concerted epigenetic alteration in FL cells. CONCLUSIONS/SIGNIFICANCE: This study is the first to provide a large scale and comprehensive analysis of the DNA methylation sequence composition and distribution in the FL epigenome. These integrated approaches have led to the discovery of novel and frequent targets of aberrant epigenetic alterations. The genome-wide bisulfite sequencing approach developed here can be a useful tool for profiling DNA methylation in clinical samples.

  20. Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases.

    Science.gov (United States)

    Witoelar, Aree; Jansen, Iris E; Wang, Yunpeng; Desikan, Rahul S; Gibbs, J Raphael; Blauwendraat, Cornelis; Thompson, Wesley K; Hernandez, Dena G; Djurovic, Srdjan; Schork, Andrew J; Bettella, Francesco; Ellinghaus, David; Franke, Andre; Lie, Benedicte A; McEvoy, Linda K; Karlsen, Tom H; Lesage, Suzanne; Morris, Huw R; Brice, Alexis; Wood, Nicholas W; Heutink, Peter; Hardy, John; Singleton, Andrew B; Dale, Anders M; Gasser, Thomas; Andreassen, Ole A; Sharma, Manu

    2017-07-01

    Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. The primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases. Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes. The study findings provide novel mechanistic

  1. Comparative transcriptome analyses and genome assembly of Fusarium oxysporum f. sp. cubense

    NARCIS (Netherlands)

    Dita, M.A.; Herai, R.; Waalwijk, C.; Yamagishi, M.; Giachetto, P.; Ferreira, G.; Souza, de M.; Kema, G.H.J.

    2013-01-01

    Fusarium oxysporum f. sp. cubense (Foc), the causal agent of Fusarium wilt of banana, is a highly destructive and genetically diverse pathogen. Despite its economic importance, genomic information about Foc is limited and no transcriptomic analyses have been reported so far. By using 454 sequencing

  2. Genome-wide chromatin accessibility, DNA methylation and gene expression analysis of histone deacetylase inhibition in triple-negative breast cancer.

    Science.gov (United States)

    Bustos, Matias A; Salomon, Matthew P; Nelson, Nellie; Hsu, Sandy C; DiNome, Maggie L; Hoon, Dave S B; Marzese, Diego M

    2017-06-01

    Triple-negative breast cancer (TNBC), especially the subset with a basal phenotype, represents the most aggressive subtype of breast cancer. Unlike other solid tumors, TNBCs harbor a low number of driver mutations. Conversely, we and others have demonstrated a significant impact of epigenetic alterations, including DNA methylation and histone post-translational modifications, affecting TNBCs. Due to the promising results in pre-clinical studies, histone deacetylase inhibitors (HDACi) are currently being tested in several clinical trials for breast cancer and other solid tumors. However, the genome-wide epigenetic and transcriptomic implications of HDAC inhibition are still poorly understood. Here, we provide detailed information about the design of a multi-platform dataset that describes the epigenomic and transcriptomic effects of HDACi. This dataset includes genome-wide chromatin accessibility (assessed by ATAC-Sequencing), DNA methylation (assessed by Illumina HM450K BeadChip) and gene expression (assessed by RNA-Sequencing) analyses before and after HDACi treatment of HCC1806 and MDA-MB-231, two human TNBC cell lines with basal-like phenotype.

  3. Genome-wide transcription analyses in rice using tiling microarrays

    DEFF Research Database (Denmark)

    Li, Lei; Wang, Xiangfeng; Stolc, Viktor;

    2006-01-01

    Sequencing and computational annotation revealed several features, including high gene numbers, unusual composition of the predicted genes and a large number of genes lacking homology to known genes, that distinguish the rice (Oryza sativa) genome from that of other fully sequenced model species....... We report here a full-genome transcription analysis of the indica rice subspecies using high-density oligonucleotide tiling microarrays. Our results provided expression data support for the existence of 35,970 (81.9%) annotated gene models and identified 5,464 unique transcribed intergenic regions...... activity between duplicated segments of the genome. Collectively, our results provide the first whole-genome transcription map useful for further understanding the rice genome. Udgivelsesdato: 2006-Jan...

  4. A genome-wide association study of anorexia nervosa

    Science.gov (United States)

    Boraska, Vesna; Franklin, Christopher S; Floyd, James AB; Thornton, Laura M; Huckins, Laura M; Southam, Lorraine; Rayner, N William; Tachmazidou, Ioanna; Klump, Kelly L; Treasure, Janet; Lewis, Cathryn M; Schmidt, Ulrike; Tozzi, Federica; Kiezebrink, Kirsty; Hebebrand, Johannes; Gorwood, Philip; Adan, Roger AH; Kas, Martien JH; Favaro, Angela; Santonastaso, Paolo; Fernández-Aranda, Fernando; Gratacos, Monica; Rybakowski, Filip; Dmitrzak-Weglarz, Monika; Kaprio, Jaakko; Keski-Rahkonen, Anna; Raevuori, Anu; Van Furth, Eric F; Landt, Margarita CT Slof-Op t; Hudson, James I; Reichborn-Kjennerud, Ted; Knudsen, Gun Peggy S; Monteleone, Palmiero; Kaplan, Allan S; Karwautz, Andreas; Hakonarson, Hakon; Berrettini, Wade H; Guo, Yiran; Li, Dong; Schork, Nicholas J.; Komaki, Gen; Ando, Tetsuya; Inoko, Hidetoshi; Esko, Tõnu; Fischer, Krista; Männik, Katrin; Metspalu, Andres; Baker, Jessica H; Cone, Roger D; Dackor, Jennifer; DeSocio, Janiece E; Hilliard, Christopher E; O'Toole, Julie K; Pantel, Jacques; Szatkiewicz, Jin P; Taico, Chrysecolla; Zerwas, Stephanie; Trace, Sara E; Davis, Oliver SP; Helder, Sietske; Bühren, Katharina; Burghardt, Roland; de Zwaan, Martina; Egberts, Karin; Ehrlich, Stefan; Herpertz-Dahlmann, Beate; Herzog, Wolfgang; Imgart, Hartmut; Scherag, André; Scherag, Susann; Zipfel, Stephan; Boni, Claudette; Ramoz, Nicolas; Versini, Audrey; Brandys, Marek K; Danner, Unna N; de Kovel, Carolien; Hendriks, Judith; Koeleman, Bobby PC; Ophoff, Roel A; Strengman, Eric; van Elburg, Annemarie A; Bruson, Alice; Clementi, Maurizio; Degortes, Daniela; Forzan, Monica; Tenconi, Elena; Docampo, Elisa; Escaramís, Geòrgia; Jiménez-Murcia, Susana; Lissowska, Jolanta; Rajewski, Andrzej; Szeszenia-Dabrowska, Neonila; Slopien, Agnieszka; Hauser, Joanna; Karhunen, Leila; Meulenbelt, Ingrid; Slagboom, P Eline; Tortorella, Alfonso; Maj, Mario; Dedoussis, George; Dikeos, Dimitris; Gonidakis, Fragiskos; Tziouvas, Konstantinos; Tsitsika, Artemis; Papezova, Hana; Slachtova, Lenka; Martaskova, Debora; Kennedy, James L.; Levitan, Robert D.; Yilmaz, Zeynep; Huemer, Julia; Koubek, Doris; Merl, Elisabeth; Wagner, Gudrun; Lichtenstein, Paul; Breen, Gerome; Cohen-Woods, Sarah; Farmer, Anne; McGuffin, Peter; Cichon, Sven; Giegling, Ina; Herms, Stefan; Rujescu, Dan; Schreiber, Stefan; Wichmann, H-Erich; Dina, Christian; Sladek, Rob; Gambaro, Giovanni; Soranzo, Nicole; Julia, Antonio; Marsal, Sara; Rabionet, Raquel; Gaborieau, Valerie; Dick, Danielle M; Palotie, Aarno; Ripatti, Samuli; Widén, Elisabeth; Andreassen, Ole A; Espeseth, Thomas; Lundervold, Astri; Reinvang, Ivar; Steen, Vidar M; Le Hellard, Stephanie; Mattingsdal, Morten; Ntalla, Ioanna; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Navratilova, Marie; Gallinger, Steven; Pinto, Dalila; Scherer, Stephen; Aschauer, Harald; Carlberg, Laura; Schosser, Alexandra; Alfredsson, Lars; Ding, Bo; Klareskog, Lars; Padyukov, Leonid; Finan, Chris; Kalsi, Gursharan; Roberts, Marion; Logan, Darren W; Peltonen, Leena; Ritchie, Graham RS; Barrett, Jeffrey C; Estivill, Xavier; Hinney, Anke; Sullivan, Patrick F; Collier, David A; Zeggini, Eleftheria; Bulik, Cynthia M

    2015-01-01

    Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10-7) in SOX2OT and rs17030795 (P=5.84×10-6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10-6) between CUL3 and FAM124B and rs1886797 (P=8.05×10-6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4×10-6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field. PMID:24514567

  5. A genome-wide association study of anorexia nervosa.

    Science.gov (United States)

    Boraska, V; Franklin, C S; Floyd, J A B; Thornton, L M; Huckins, L M; Southam, L; Rayner, N W; Tachmazidou, I; Klump, K L; Treasure, J; Lewis, C M; Schmidt, U; Tozzi, F; Kiezebrink, K; Hebebrand, J; Gorwood, P; Adan, R A H; Kas, M J H; Favaro, A; Santonastaso, P; Fernández-Aranda, F; Gratacos, M; Rybakowski, F; Dmitrzak-Weglarz, M; Kaprio, J; Keski-Rahkonen, A; Raevuori, A; Van Furth, E F; Slof-Op 't Landt, M C T; Hudson, J I; Reichborn-Kjennerud, T; Knudsen, G P S; Monteleone, P; Kaplan, A S; Karwautz, A; Hakonarson, H; Berrettini, W H; Guo, Y; Li, D; Schork, N J; Komaki, G; Ando, T; Inoko, H; Esko, T; Fischer, K; Männik, K; Metspalu, A; Baker, J H; Cone, R D; Dackor, J; DeSocio, J E; Hilliard, C E; O'Toole, J K; Pantel, J; Szatkiewicz, J P; Taico, C; Zerwas, S; Trace, S E; Davis, O S P; Helder, S; Bühren, K; Burghardt, R; de Zwaan, M; Egberts, K; Ehrlich, S; Herpertz-Dahlmann, B; Herzog, W; Imgart, H; Scherag, A; Scherag, S; Zipfel, S; Boni, C; Ramoz, N; Versini, A; Brandys, M K; Danner, U N; de Kovel, C; Hendriks, J; Koeleman, B P C; Ophoff, R A; Strengman, E; van Elburg, A A; Bruson, A; Clementi, M; Degortes, D; Forzan, M; Tenconi, E; Docampo, E; Escaramís, G; Jiménez-Murcia, S; Lissowska, J; Rajewski, A; Szeszenia-Dabrowska, N; Slopien, A; Hauser, J; Karhunen, L; Meulenbelt, I; Slagboom, P E; Tortorella, A; Maj, M; Dedoussis, G; Dikeos, D; Gonidakis, F; Tziouvas, K; Tsitsika, A; Papezova, H; Slachtova, L; Martaskova, D; Kennedy, J L; Levitan, R D; Yilmaz, Z; Huemer, J; Koubek, D; Merl, E; Wagner, G; Lichtenstein, P; Breen, G; Cohen-Woods, S; Farmer, A; McGuffin, P; Cichon, S; Giegling, I; Herms, S; Rujescu, D; Schreiber, S; Wichmann, H-E; Dina, C; Sladek, R; Gambaro, G; Soranzo, N; Julia, A; Marsal, S; Rabionet, R; Gaborieau, V; Dick, D M; Palotie, A; Ripatti, S; Widén, E; Andreassen, O A; Espeseth, T; Lundervold, A; Reinvang, I; Steen, V M; Le Hellard, S; Mattingsdal, M; Ntalla, I; Bencko, V; Foretova, L; Janout, V; Navratilova, M; Gallinger, S; Pinto, D; Scherer, S W; Aschauer, H; Carlberg, L; Schosser, A; Alfredsson, L; Ding, B; Klareskog, L; Padyukov, L; Courtet, P; Guillaume, S; Jaussent, I; Finan, C; Kalsi, G; Roberts, M; Logan, D W; Peltonen, L; Ritchie, G R S; Barrett, J C; Estivill, X; Hinney, A; Sullivan, P F; Collier, D A; Zeggini, E; Bulik, C M

    2014-10-01

    Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

  6. Transcriptomic and metabolite analyses of Cabernet Sauvignon grape berry development

    Directory of Open Access Journals (Sweden)

    Schlauch Karen A

    2007-11-01

    development (28% of transcripts, 4,151 Unigenes, had pronounced (≥2 fold differences in mRNA expression illustrating the dynamic nature of the developmental process. The subset of 4,151 Unigenes was split into twenty well-correlated expression profiles. Expression profile patterns included those with declining or increasing mRNA expression over the course of berry development as well as transient peak or trough patterns across various developmental stages as defined by the modified E-L system. These detailed surveys revealed the expression patterns for genes that play key functional roles in phytohormone biosynthesis and response, calcium sequestration, transport and signaling, cell wall metabolism mediating expansion, ripening, and softening, flavonoid metabolism and transport, organic and amino acid metabolism, hexose sugar and triose phosphate metabolism and transport, starch metabolism, photosynthesis, circadian cycles and pathogen resistance. In particular, mRNA expression patterns of transcription factors, abscisic acid (ABA biosynthesis, and calcium signaling genes identified candidate factors likely to participate in the progression of key developmental events such as véraison and potential candidate genes associated with such processes as auxin partitioning within berry cells, aroma compound production, and pathway regulation and sequestration of flavonoid compounds. Finally, analysis of sugar metabolism gene expression patterns indicated the existence of an alternative pathway for glucose and triose phosphate production that is invoked from véraison to mature berries. Conclusion These results reveal the first high-resolution picture of the transcriptome dynamics that occur during seven stages of grape berry development. This work also establishes an extensive catalog of gene expression patterns for future investigations aimed at the dissection of the transcriptional regulatory hierarchies that govern berry development in a widely grown cultivar of wine grape

  7. Genome-wide analytical approaches for reverse metabolic engineering of industrially relevant phenotypes in yeast

    Science.gov (United States)

    Oud, Bart; Maris, Antonius J A; Daran, Jean-Marc; Pronk, Jack T

    2012-01-01

    Successful reverse engineering of mutants that have been obtained by nontargeted strain improvement has long presented a major challenge in yeast biotechnology. This paper reviews the use of genome-wide approaches for analysis of Saccharomyces cerevisiae strains originating from evolutionary engineering or random mutagenesis. On the basis of an evaluation of the strengths and weaknesses of different methods, we conclude that for the initial identification of relevant genetic changes, whole genome sequencing is superior to other analytical techniques, such as transcriptome, metabolome, proteome, or array-based genome analysis. Key advantages of this technique over gene expression analysis include the independency of genome sequences on experimental context and the possibility to directly and precisely reproduce the identified changes in naive strains. The predictive value of genome-wide analysis of strains with industrially relevant characteristics can be further improved by classical genetics or simultaneous analysis of strains derived from parallel, independent strain improvement lineages. PMID:22152095

  8. Genome-wide analytical approaches for reverse metabolic engineering of industrially relevant phenotypes in yeast.

    Science.gov (United States)

    Oud, Bart; van Maris, Antonius J A; Daran, Jean-Marc; Pronk, Jack T

    2012-03-01

    Successful reverse engineering of mutants that have been obtained by nontargeted strain improvement has long presented a major challenge in yeast biotechnology. This paper reviews the use of genome-wide approaches for analysis of Saccharomyces cerevisiae strains originating from evolutionary engineering or random mutagenesis. On the basis of an evaluation of the strengths and weaknesses of different methods, we conclude that for the initial identification of relevant genetic changes, whole genome sequencing is superior to other analytical techniques, such as transcriptome, metabolome, proteome, or array-based genome analysis. Key advantages of this technique over gene expression analysis include the independency of genome sequences on experimental context and the possibility to directly and precisely reproduce the identified changes in naive strains. The predictive value of genome-wide analysis of strains with industrially relevant characteristics can be further improved by classical genetics or simultaneous analysis of strains derived from parallel, independent strain improvement lineages.

  9. Genome-Wide Association Study of Meiotic Recombination Phenotypes

    Science.gov (United States)

    Begum, Ferdouse; Chowdhury, Reshmi; Cheung, Vivian G.; Sherman, Stephanie L.; Feingold, Eleanor

    2016-01-01

    Meiotic recombination is an essential step in gametogenesis, and is one that also generates genetic diversity. Genome-wide association studies (GWAS) and molecular studies have identified genes that influence of human meiotic recombination. RNF212 is associated with total or average number of recombination events, and PRDM9 is associated with the locations of hotspots, or sequences where crossing over appears to cluster. In addition, a common inversion on chromosome 17 is strongly associated with recombination. Other genes have been identified by GWAS, but those results have not been replicated. In this study, using new datasets, we characterized additional recombination phenotypes to uncover novel candidates and further dissect the role of already known loci. We used three datasets totaling 1562 two-generation families, including 3108 parents with 4304 children. We estimated five different recombination phenotypes including two novel phenotypes (average recombination counts within recombination hotspots and outside of hotspots) using dense SNP array genotype data. We then performed gender-specific and combined-sex genome-wide association studies (GWAS) meta-analyses. We replicated associations for several previously reported recombination genes, including RNF212 and PRDM9. By looking specifically at recombination events outside of hotspots, we showed for the first time that PRDM9 has different effects in males and females. We identified several new candidate loci, particularly for recombination events outside of hotspots. These include regions near the genes SPINK6, EVC2, ARHGAP25, and DLGAP2. This study expands our understanding of human meiotic recombination by characterizing additional features that vary across individuals, and identifying regulatory variants influencing the numbers and locations of recombination events. PMID:27733454

  10. Genome-wide significant loci for addiction and anxiety

    Science.gov (United States)

    Hodgson, K.; Almasy, L.; Knowles, E.E.M.; Kent, J.W.; Curran, J.E.; Dyer, T.D.; Göring, H.H.H.; Olvera, R.L.; Fox, P.T.; Pearlson, G.D.; Krystal, J.H.; Duggirala, R.; Blangero, J.; Glahn, D.C.

    2017-01-01

    Background Psychiatric comorbidity is common among individuals with addictive disorders, with patients frequently suffering from anxiety disorders. While the genetic architecture of comorbid addictive and anxiety disorders remains unclear, elucidating the genes involved could provide important insights into the underlying etiology. Methods Here we examine a sample of 1284 Mexican-Americans from randomly selected extended pedigrees. Variance decomposition methods were used to examine the role of genetics in addiction phenotypes (lifetime history of alcohol dependence, drug dependence or chronic smoking) and various forms of clinically relevant anxiety. Genome-wide univariate and bivariate linkage scans were conducted to localize the chromosomal regions influencing these traits. Results Addiction phenotypes and anxiety were shown to be heritable and univariate genome-wide linkage scans revealed significant quantitative trait loci for drug dependence (14q13.2–q21.2, LOD = 3.322) and a broad anxiety phenotype (12q24.32–q24.33, LOD = 2.918). Significant positive genetic correlations were observed between anxiety and each of the addiction subtypes (ρg = 0.550–0.655) and further investigation with bivariate linkage analyses identified significant pleiotropic signals for alcohol dependence-anxiety (9q33.1–q33.2, LOD = 3.054) and drug dependence-anxiety (18p11.23–p11.22, LOD = 3.425). Conclusions This study confirms the shared genetic underpinnings of addiction and anxiety and identifies genomic loci involved in the etiology of these comorbid disorders. The linkage signal for anxiety on 12q24 spans the location of TMEM132D, an emerging gene of interest from previous GWAS of anxiety traits, whilst the bivariate linkage signal identified for anxiety-alcohol on 9q33 peak coincides with a region where rare CNVs have been associated with psychiatric disorders. Other signals identified implicate novel regions of the genome in addiction genetics. PMID:27318301

  11. Genome-wide prediction and validation of sigma70 promoters in Lactobacillus plantarum WCFS1.

    Directory of Open Access Journals (Sweden)

    Tilman J Todt

    Full Text Available BACKGROUND: In prokaryotes, sigma factors are essential for directing the transcription machinery towards promoters. Various sigma factors have been described that recognize, and bind to specific DNA sequence motifs in promoter sequences. The canonical sigma factor σ(70 is commonly involved in transcription of the cell's housekeeping genes, which is mediated by the conserved σ(70 promoter sequence motifs. In this study the σ(70-promoter sequences in Lactobacillus plantarum WCFS1 were predicted using a genome-wide analysis. The accuracy of the transcriptionally-active part of this promoter prediction was subsequently evaluated by correlating locations of predicted promoters with transcription start sites inferred from the 5'-ends of transcripts detected by high-resolution tiling array transcriptome datasets. RESULTS: To identify σ(70-related promoter sequences, we performed a genome-wide sequence motif scan of the L. plantarum WCFS1 genome focussing on the regions upstream of protein-encoding genes. We obtained several highly conserved motifs including those resembling the conserved σ(70-promoter consensus. Position weight matrices-based models of the recovered σ(70-promoter sequence motif were employed to identify 3874 motifs with significant similarity (p-value<10(-4 to the model-motif in the L. plantarum genome. Genome-wide transcript information deduced from whole genome tiling-array transcriptome datasets, was used to infer transcription start sites (TSSs from the 5'-end of transcripts. By this procedure, 1167 putative TSSs were identified that were used to corroborate the transcriptionally active fraction of these predicted promoters. In total, 568 predicted promoters were found in proximity (≤ 40 nucleotides of the putative TSSs, showing a highly significant co-occurrence of predicted promoter and TSS (p-value<10(-263. CONCLUSIONS: High-resolution tiling arrays provide a suitable source to infer TSSs at a genome-wide level, and

  12. Every cell is special : genome-wide studies add a new dimension to single-cell biology

    NARCIS (Netherlands)

    Junker, Jan Philipp; van Oudenaarden, Alexander

    2014-01-01

    Single-cell analyses have provided invaluable insights into studying heterogenity, signaling, and stochastic gene expression. Recent technological advances now open the door to genome-wide single-cell studies.

  13. Genome-wide microarray analysis of tomato roots showed defined responses to iron deficiency

    Directory of Open Access Journals (Sweden)

    Zamboni Anita

    2012-03-01

    Full Text Available Abstract Background Plants react to iron deficiency stress adopting different kind of adaptive responses. Tomato, a Strategy I plant, improves iron uptake through acidification of rhizosphere, reduction of Fe3+ to Fe2+ and transport of Fe2+ into the cells. Large-scale transcriptional analyses of roots under iron deficiency are only available for a very limited number of plant species with particular emphasis for Arabidopsis thaliana. Regarding tomato, an interesting model species for Strategy I plants and an economically important crop, physiological responses to Fe-deficiency have been thoroughly described and molecular analyses have provided evidence for genes involved in iron uptake mechanisms and their regulation. However, no detailed transcriptome analysis has been described so far. Results A genome-wide transcriptional analysis, performed with a chip that allows to monitor the expression of more than 25,000 tomato transcripts, identified 97 differentially expressed transcripts by comparing roots of Fe-deficient and Fe-sufficient tomato plants. These transcripts are related to the physiological responses of tomato roots to the nutrient stress resulting in an improved iron uptake, including regulatory aspects, translocation, root morphological modification and adaptation in primary metabolic pathways, such as glycolysis and TCA cycle. Other genes play a role in flavonoid biosynthesis and hormonal metabolism. Conclusions The transcriptional characterization confirmed the presence of the previously described mechanisms to adapt to iron starvation in tomato, but also allowed to identify other genes potentially playing a role in this process, thus opening new research perspectives to improve the knowledge on the tomato root response to the nutrient deficiency.

  14. Meta-Analysis in Genome-Wide Association Datasets: Strategies and Application in Parkinson Disease

    Science.gov (United States)

    Evangelou, Evangelos; Maraganore, Demetrius M.; Ioannidis, John P.A.

    2007-01-01

    Background Genome-wide association studies hold substantial promise for identifying common genetic variants that regulate susceptibility to complex diseases. However, for the detection of small genetic effects, single studies may be underpowered. Power may be improved by combining genome-wide datasets with meta-analytic techniques. Methodology/Principal Findings Both single and two-stage genome-wide data may be combined and there are several possible strategies. In the two-stage framework, we considered the options of (1) enhancement of replication data and (2) enhancement of first-stage data, and then, we also considered (3) joint meta-analyses including all first-stage and second-stage data. These strategies were examined empirically using data from two genome-wide association studies (three datasets) on Parkinson disease. In the three strategies, we derived 12, 5, and 49 single nucleotide polymorphisms that show significant associations at conventional levels of statistical significance. None of these remained significant after conservative adjustment for the number of performed analyses in each strategy. However, some may warrant further consideration: 6 SNPs were identified with at least 2 of the 3 strategies and 3 SNPs [rs1000291 on chromosome 3, rs2241743 on chromosome 4 and rs3018626 on chromosome 11] were identified with all 3 strategies and had no or minimal between-dataset heterogeneity (I2 = 0, 0 and 15%, respectively). Analyses were primarily limited by the suboptimal overlap of tested polymorphisms across different datasets (e.g., only 31,192 shared polymorphisms between the two tier 1 datasets). Conclusions/Significance Meta-analysis may be used to improve the power and examine the between-dataset heterogeneity of genome-wide association studies. Prospective designs may be most efficient, if they try to maximize the overlap of genotyping platforms and anticipate the combination of data across many genome-wide association studies. PMID:17332845

  15. Meta-analysis in genome-wide association datasets: strategies and application in Parkinson disease.

    Science.gov (United States)

    Evangelou, Evangelos; Maraganore, Demetrius M; Ioannidis, John P A

    2007-02-07

    Genome-wide association studies hold substantial promise for identifying common genetic variants that regulate susceptibility to complex diseases. However, for the detection of small genetic effects, single studies may be underpowered. Power may be improved by combining genome-wide datasets with meta-analytic techniques. Both single and two-stage genome-wide data may be combined and there are several possible strategies. In the two-stage framework, we considered the options of (1) enhancement of replication data and (2) enhancement of first-stage data, and then, we also considered (3) joint meta-analyses including all first-stage and second-stage data. These strategies were examined empirically using data from two genome-wide association studies (three datasets) on Parkinson disease. In the three strategies, we derived 12, 5, and 49 single nucleotide polymorphisms that show significant associations at conventional levels of statistical significance. None of these remained significant after conservative adjustment for the number of performed analyses in each strategy. However, some may warrant further consideration: 6 SNPs were identified with at least 2 of the 3 strategies and 3 SNPs [rs1000291 on chromosome 3, rs2241743 on chromosome 4 and rs3018626 on chromosome 11] were identified with all 3 strategies and had no or minimal between-dataset heterogeneity (I(2) = 0, 0 and 15%, respectively). Analyses were primarily limited by the suboptimal overlap of tested polymorphisms across different datasets (e.g., only 31,192 shared polymorphisms between the two tier 1 datasets). Meta-analysis may be used to improve the power and examine the between-dataset heterogeneity of genome-wide association studies. Prospective designs may be most efficient, if they try to maximize the overlap of genotyping platforms and anticipate the combination of data across many genome-wide association studies.

  16. Genome-wide ancestry of 17th-century enslaved Africans from the Caribbean

    DEFF Research Database (Denmark)

    Schroeder, Hannes; Avila-Arcos, Maria C.; Malaspinas, Anna-Sapfo

    2015-01-01

    Between 1500 and 1850, more than 12 million enslaved Africans were transported to the New World. The vast majority were shipped from West and West-Central Africa, but their precise origins are largely unknown. We used genome-wide ancient DNA analyses to investigate the genetic origins of three...

  17. Coupled electrophysiological recording and single cell transcriptome analyses revealed molecular mechanisms underlying neuronal maturation

    Directory of Open Access Journals (Sweden)

    Xiaoying Chen

    2016-02-01

    Full Text Available ABSTRACT The mammalian brain is heterogeneous, containing billions of neurons and trillions of synapses forming various neural circuitries, through which sense, movement, thought, and emotion arise. The cellular heterogeneity of the brain has made it difficult to study the molecular logic of neural circuitry wiring, pruning, activation, and plasticity, until recently, transcriptome analyses with single cell resolution makes decoding of gene regulatory networks underlying aforementioned circuitry properties possible. Here we report success in performing both electrophysiological and whole-genome transcriptome analyses on single human neurons in culture. Using Weighted Gene Coexpression Network Analyses (WGCNA, we identified gene clusters highly correlated with neuronal maturation judged by electrophysiological characteristics. A tight link between neuronal maturation and genes involved in ubiquitination and mitochondrial function was revealed. Moreover, we identified a list of candidate genes, which could potentially serve as biomarkers for neuronal maturation. Coupled electrophysiological recording and single cell transcriptome analysis will serve as powerful tools in the future to unveil molecular logics for neural circuitry functions.

  18. Time-Series Analyses of Transcriptomes and Proteomes Reveal Molecular Networks Underlying Oil Accumulation in Canola

    Science.gov (United States)

    Wan, Huafang; Cui, Yixin; Ding, Yijuan; Mei, Jiaqin; Dong, Hongli; Zhang, Wenxin; Wu, Shiqi; Liang, Ying; Zhang, Chunyu; Li, Jiana; Xiong, Qing; Qian, Wei

    2017-01-01

    Understanding the regulation of lipid metabolism is vital for genetic engineering of canola (Brassica napus L.) to increase oil yield or modify oil composition. We conducted time-series analyses of transcriptomes and proteomes to uncover the molecular networks associated with oil accumulation and dynamic changes in these networks in canola. The expression levels of genes and proteins were measured at 2, 4, 6, and 8 weeks after pollination (WAP). Our results show that the biosynthesis of fatty acids is a dominant cellular process from 2 to 6 WAP, while the degradation mainly happens after 6 WAP. We found that genes in almost every node of fatty acid synthesis pathway were significantly up-regulated during oil accumulation. Moreover, significant expression changes of two genes, acetyl-CoA carboxylase and acyl-ACP desaturase, were detected on both transcriptomic and proteomic levels. We confirmed the temporal expression patterns revealed by the transcriptomic analyses using quantitative real-time PCR experiments. The gene set association analysis show that the biosynthesis of fatty acids and unsaturated fatty acids are the most significant biological processes from 2-4 WAP and 4-6 WAP, respectively, which is consistent with the results of time-series analyses. These results not only provide insight into the mechanisms underlying lipid metabolism, but also reveal novel candidate genes that are worth further investigation for their values in the genetic engineering of canola. PMID:28119706

  19. Escherichia coli genome-wide promoter analysis: Identification of additional AtoC binding target elements

    Directory of Open Access Journals (Sweden)

    Kolisis Fragiskos N

    2011-05-01

    Full Text Available Abstract Background Studies on bacterial signal transduction systems have revealed complex networks of functional interactions, where the response regulators play a pivotal role. The AtoSC system of E. coli activates the expression of atoDAEB operon genes, and the subsequent catabolism of short-chain fatty acids, upon acetoacetate induction. Transcriptome and phenotypic analyses suggested that atoSC is also involved in several other cellular activities, although we have recently reported a palindromic repeat within the atoDAEB promoter as the single, cis-regulatory binding site of the AtoC response regulator. In this work, we used a computational approach to explore the presence of yet unidentified AtoC binding sites within other parts of the E. coli genome. Results Through the implementation of a computational de novo motif detection workflow, a set of candidate motifs was generated, representing putative AtoC binding targets within the E. coli genome. In order to assess the biological relevance of the motifs and to select for experimental validation of those sequences related robustly with distinct cellular functions, we implemented a novel approach that applies Gene Ontology Term Analysis to the motif hits and selected those that were qualified through this procedure. The computational results were validated using Chromatin Immunoprecipitation assays to assess the in vivo binding of AtoC to the predicted sites. This process verified twenty-two additional AtoC binding sites, located not only within intergenic regions, but also within gene-encoding sequences. Conclusions This study, by tracing a number of putative AtoC binding sites, has indicated an AtoC-related cross-regulatory function. This highlights the significance of computational genome-wide approaches in elucidating complex patterns of bacterial cell regulation.

  20. Genome-wide association study of clinical dimensions of schizophrenia

    DEFF Research Database (Denmark)

    Fanous, Ayman H; Zhou, Baiyu; Aggen, Steven H;

    2012-01-01

    Multiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia....

  1. Cancer genetic association studies in the genome-wide age

    OpenAIRE

    Savage, Sharon A

    2008-01-01

    Genome-wide association studies of hundreds of thousands of SNPs have led to a deluge of studies of genetic variation in cancer and other common diseases. Large case–control and cohort studies have identified novel SNPs as markers of cancer risk. Genome-wide association study SNP data have also advanced understanding of population-specific genetic variation. While studies of risk profiles, combinations of SNPs that may increase cancer risk, are not yet clinically applicable, future, large-sca...

  2. Genome-wide polymorphisms show unexpected targets of natural selection

    OpenAIRE

    Pespeni, Melissa H.; Garfield, David A.; Manier, Mollie K; Palumbi, Stephen R.

    2011-01-01

    Natural selection can act on all the expressed genes of an individual, leaving signatures of genetic differentiation or diversity at many loci across the genome. New power to assay these genome-wide effects of selection comes from associating multi-locus patterns of polymorphism with gene expression and function. Here, we performed one of the first genome-wide surveys in a marine species, comparing purple sea urchins, Strongylocentrotus purpuratus, from two distant locations along the species...

  3. Genome-wide association study of multiplex schizophrenia pedigrees

    DEFF Research Database (Denmark)

    Levinson, Douglas F; Shi, Jianxin; Wang, Kai

    2012-01-01

    The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs).......The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs)....

  4. Data for transcriptomic and proteomic analyses of leaves from Clematis terniflora DC. under binary stress

    Directory of Open Access Journals (Sweden)

    Bingxian Yang

    2017-06-01

    Full Text Available High level of UV-B irradiation followed by dark treatment accumulates secondary metabolites in Clematis terniflora DC. To investigate the response mechanism under high level of UV-B irradiation followed by dark treatment, transcriptomic and proteomic analyses were performed in leaves of Clematis terniflora DC. The experimental design for the transcriptomic and proteomic analyses in leaves of C. terniflora under stresses was organized into a picture. For transcriptomics, mRNA-sequencing technology was used. Genes identified in leaves of C. terniflora at starting point, high level of UV-B irradiation, and high level of UV-B irradiation followed by dark treatment were listed; genes with different expression levels at starting point, high level of UV-B irradiation, and high level of UV-B irradiation followed by dark treatment were also presented in this DiB article. For proteomics, a gel-free/label-free proteomic technique was used. Proteins with different abundances in leaves at starting point, high level of UV-B irradiation, and high level of UV-B irradiation followed by dark treatment were presented in this DiB article. In order to monitor the expression levels of genes under the stress, quantitative reverse transcription polymerase chain reaction was performed. The primer sequences of genes selected for quantitative reverse transcription polymerase chain reaction was presented in this DiB article.

  5. Transcriptome analyses of Bactericera cockerelli adults in response to "Candidatus Liberibacter solanacearum" infection.

    Science.gov (United States)

    Nachappa, Punya; Levy, Julien; Tamborindeguy, Cecilia

    2012-10-01

    The potato/tomato psyllid, Bactericera cockerelli (Šulc) is an economically important crop pest that not only causes damage through its feeding but also transmits the bacterium, "Candidatus Liberibacter solanacearum" (CLs), which causes zebra chip disease in potato. There is some information about the phenotypic effects of phytopathogenic bacteria on their insect vectors; however, there are no published reports of the molecular mechanisms underlying phytopathogenic bacteria-insect vector interaction. In order to investigate the effects of CLs infection on B. cockerelli, transcriptomic analyses of CLs-infected and uninfected adult psyllids that were reared on potato were performed. De novo assembly of cDNA sequences generated 136,518 and 109,983 contigs for infected and uninfected insect libraries with an average contig length of 514 bp. BlastX analysis against the NCBI-nr database revealed that 33.33 % had significant matches. Gene ontology data illustrated that the majority of the expressed psyllid genes are involved in metabolic process, biological regulation, binding and catalytic activity. The psyllid transcriptome had an abundance of genes such as vitellogenin, heat shock protein, ejaculatory bulb-specific protein, ferritin, and cytochrome oxidase. Notably absent in the psyllid transcriptome were innate immunity genes induced in response to Gram-negative bacteria (IMD pathway). Several functionally diverse contigs related to symbiotic bacteria including the primary endosymbiont Carsonella ruddii, Wolbachia, and CLs in the psyllid transcriptome were identified. A total of 247 contigs showed differential expression in response to CLs infection including immune and stress-related genes and vitellogenins. Expression analyses of selected psyllid genes were performed on psyllids that were exclusively reared on potato (host of the insects used for RNAseq) and psyllids exclusively reared on tomato (alternative host of psyllids). These genes showed similar expression

  6. Identification of differential translation in genome wide studies.

    Science.gov (United States)

    Larsson, Ola; Sonenberg, Nahum; Nadon, Robert

    2010-12-14

    Regulation of gene expression through translational control is a fundamental mechanism implicated in many biological processes ranging from memory formation to innate immunity and whose dysregulation contributes to human diseases. Genome wide analyses of translational control strive to identify differential translation independent of cytosolic mRNA levels. For this reason, most studies measure genes' translation levels as log ratios (translation levels divided by corresponding cytosolic mRNA levels obtained in parallel). Counterintuitively, arising from a mathematical necessity, these log ratios tend to be highly correlated with the cytosolic mRNA levels. Accordingly, they do not effectively correct for cytosolic mRNA level and generate substantial numbers of biological false positives and false negatives. We show that analysis of partial variance, which produces estimates of translational activity that are independent of cytosolic mRNA levels, is a superior alternative. When combined with a variance shrinkage method for estimating error variance, analysis of partial variance has the additional benefit of having greater statistical power and identifying fewer genes as translationally regulated resulting merely from unrealistically low variance estimates rather than from large changes in translational activity. In contrast to log ratios, this formal analytical approach estimates translation effects in a statistically rigorous manner, eliminates the need for inefficient and error-prone heuristics, and produces results that agree with biological function. The method is applicable to datasets obtained from both the commonly used polysome microarray method and the sequencing-based ribosome profiling method.

  7. Meta-analysis of genome-wide expression patterns associated with behavioral maturation in honey bees

    Directory of Open Access Journals (Sweden)

    Southey Bruce R

    2008-10-01

    confirmed previously reported genes and helped identify genes (e.g. Tomosyn, Chitinase 5, Adar, Innexin 2, Transferrin 1, Sick, Oatp26F and Gene Ontology categories (e.g. purine nucleotide binding not previously associated with maturation in honey bees. Conclusion This study demonstrated that a combination of meta-analytical approaches best addresses the highly dimensional nature of genome-wide microarray studies. As expected, the integration of gene expression information from microarray studies using meta-analysis enhanced the characterization of the transcriptome of complex biological processes.

  8. RSIADB, a collective resource for genome and transcriptome analyses in Rhizoctonia solani AG1 IA.

    Science.gov (United States)

    Chen, Lei; Ai, Peng; Zhang, Jinfeng; Deng, Qiming; Wang, Shiquan; Li, Shuangcheng; Zhu, Jun; Li, Ping; Zheng, Aiping

    2016-01-01

    Rice [Oryza sativa (L.)] feeds more than half of the world's population. Rhizoctonia solaniis a major fungal pathogen of rice causing extreme crop losses in all rice-growing regions of the world. R. solani AG1 IA is a major cause of sheath blight in rice. In this study, we constructed a comprehensive and user-friendly web-based database, RSIADB, to analyse its draft genome and transcriptome. The database was built using the genome sequence (10,489 genes) and annotation information for R. solani AG1 IA. A total of six RNAseq samples of R. solani AG1 IA were also analysed, corresponding to 10, 18, 24, 32, 48 and 72 h after infection of rice leaves. The RSIADB database enables users to search, browse, and download gene sequences for R. solani AG1 IA, and mine the data using BLAST, Sequence Extractor, Browse and Construction Diagram tools that were integrated into the database. RSIADB is an important genomic resource for scientists working with R. solani AG1 IA and will assist researchers in analysing the annotated genome and transcriptome of this pathogen. This resource will facilitate studies on gene function, pathogenesis factors and secreted proteins, as well as provide an avenue for comparative analyses of genes expressed during different stages of infection. Database URL:http://genedenovoweb.ticp.net:81/rsia/index.php.

  9. A novel statistic for genome-wide interaction analysis.

    Science.gov (United States)

    Wu, Xuesen; Dong, Hua; Luo, Li; Zhu, Yun; Peng, Gang; Reveille, John D; Xiong, Momiao

    2010-09-23

    Although great progress in genome-wide association studies (GWAS) has been made, the significant SNP associations identified by GWAS account for only a few percent of the genetic variance, leading many to question where and how we can find the missing heritability. There is increasing interest in genome-wide interaction analysis as a possible source of finding heritability unexplained by current GWAS. However, the existing statistics for testing interaction have low power for genome-wide interaction analysis. To meet challenges raised by genome-wide interactional analysis, we have developed a novel statistic for testing interaction between two loci (either linked or unlinked). The null distribution and the type I error rates of the new statistic for testing interaction are validated using simulations. Extensive power studies show that the developed statistic has much higher power to detect interaction than classical logistic regression. The results identified 44 and 211 pairs of SNPs showing significant evidence of interactions with FDRanalysis is a valuable tool for finding remaining missing heritability unexplained by the current GWAS, and the developed novel statistic is able to search significant interaction between SNPs across the genome. Real data analysis showed that the results of genome-wide interaction analysis can be replicated in two independent studies.

  10. A Genome-Wide Scan for Breast Cancer Risk Haplotypes among African American Women

    Science.gov (United States)

    Song, Chi; Chen, Gary K.; Millikan, Robert C.; Ambrosone, Christine B.; John, Esther M.; Bernstein, Leslie; Zheng, Wei; Hu, Jennifer J.; Ziegler, Regina G.; Nyante, Sarah; Bandera, Elisa V.; Ingles, Sue A.; Press, Michael F.; Deming, Sandra L.; Rodriguez-Gil, Jorge L.; Chanock, Stephen J.; Wan, Peggy; Sheng, Xin; Pooler, Loreall C.; Van Den Berg, David J.; Le Marchand, Loic; Kolonel, Laurence N.; Henderson, Brian E.; Haiman, Chris A.; Stram, Daniel O.

    2013-01-01

    Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls) using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density. PMID:23468962

  11. Genome-wide signatures of convergent evolution in echolocating mammals.

    Science.gov (United States)

    Parker, Joe; Tsagkogeorga, Georgia; Cotton, James A; Liu, Yuan; Provero, Paolo; Stupka, Elia; Rossiter, Stephen J

    2013-10-10

    Evolution is typically thought to proceed through divergence of genes, proteins and ultimately phenotypes. However, similar traits might also evolve convergently in unrelated taxa owing to similar selection pressures. Adaptive phenotypic convergence is widespread in nature, and recent results from several genes have suggested that this phenomenon is powerful enough to also drive recurrent evolution at the sequence level. Where homoplasious substitutions do occur these have long been considered the result of neutral processes. However, recent studies have demonstrated that adaptive convergent sequence evolution can be detected in vertebrates using statistical methods that model parallel evolution, although the extent to which sequence convergence between genera occurs across genomes is unknown. Here we analyse genomic sequence data in mammals that have independently evolved echolocation and show that convergence is not a rare process restricted to several loci but is instead widespread, continuously distributed and commonly driven by natural selection acting on a small number of sites per locus. Systematic analyses of convergent sequence evolution in 805,053 amino acids within 2,326 orthologous coding gene sequences compared across 22 mammals (including four newly sequenced bat genomes) revealed signatures consistent with convergence in nearly 200 loci. Strong and significant support for convergence among bats and the bottlenose dolphin was seen in numerous genes linked to hearing or deafness, consistent with an involvement in echolocation. Unexpectedly, we also found convergence in many genes linked to vision: the convergent signal of many sensory genes was robustly correlated with the strength of natural selection. This first attempt to detect genome-wide convergent sequence evolution across divergent taxa reveals the phenomenon to be much more pervasive than previously recognized.

  12. Power analysis for genome-wide association studies

    Directory of Open Access Journals (Sweden)

    Klein Robert J

    2007-08-01

    Full Text Available Abstract Background Genome-wide association studies are a promising new tool for deciphering the genetics of complex diseases. To choose the proper sample size and genotyping platform for such studies, power calculations that take into account genetic model, tag SNP selection, and the population of interest are required. Results The power of genome-wide association studies can be computed using a set of tag SNPs and a large number of genotyped SNPs in a representative population, such as available through the HapMap project. As expected, power increases with increasing sample size and effect size. Power also depends on the tag SNPs selected. In some cases, more power is obtained by genotyping more individuals at fewer SNPs than fewer individuals at more SNPs. Conclusion Genome-wide association studies should be designed thoughtfully, with the choice of genotyping platform and sample size being determined from careful power calculations.

  13. A novel statistic for genome-wide interaction analysis.

    Directory of Open Access Journals (Sweden)

    Xuesen Wu

    2010-09-01

    Full Text Available Although great progress in genome-wide association studies (GWAS has been made, the significant SNP associations identified by GWAS account for only a few percent of the genetic variance, leading many to question where and how we can find the missing heritability. There is increasing interest in genome-wide interaction analysis as a possible source of finding heritability unexplained by current GWAS. However, the existing statistics for testing interaction have low power for genome-wide interaction analysis. To meet challenges raised by genome-wide interactional analysis, we have developed a novel statistic for testing interaction between two loci (either linked or unlinked. The null distribution and the type I error rates of the new statistic for testing interaction are validated using simulations. Extensive power studies show that the developed statistic has much higher power to detect interaction than classical logistic regression. The results identified 44 and 211 pairs of SNPs showing significant evidence of interactions with FDR<0.001 and 0.001genome-wide interaction analysis is a valuable tool for finding remaining missing heritability unexplained by the current GWAS, and the developed novel statistic is able to search significant interaction between SNPs across the genome. Real data analysis showed that the results of genome-wide interaction analysis can be replicated in two independent studies.

  14. Comparative transcriptome analyses of flower development in four species of Achimenes (Gesneriaceae).

    Science.gov (United States)

    Roberts, Wade R; Roalson, Eric H

    2017-03-20

    Flowers have an amazingly diverse display of colors and shapes, and these characteristics often vary significantly among closely related species. The evolution of diverse floral form can be thought of as an adaptive response to pollination and reproduction, but it can also be seen through the lens of morphological and developmental constraints. To explore these interactions, we use RNA-seq across species and development to investigate gene expression and sequence evolution as they relate to the evolution of the diverse flowers in a group of Neotropical plants native to Mexico-magic flowers (Achimenes, Gesneriaceae). The assembled transcriptomes contain between 29,000 and 42,000 genes expressed during development. We combine sequence orthology and coexpression clustering with analyses of protein evolution to identify candidate genes for roles in floral form evolution. Over 25% of transcripts captured were distinctive to Achimenes and overrepresented by genes involved in transcription factor activity. Using a model-based clustering approach we find dynamic, temporal patterns of gene expression among species. Selection tests provide evidence of positive selection in several genes with roles in pigment production, flowering time, and morphology. Combining these approaches to explore genes related to flower color and flower shape, we find distinct patterns that correspond to transitions of floral form among Achimenes species. The floral transcriptomes developed from four species of Achimenes provide insight into the mechanisms involved in the evolution of diverse floral form among closely related species with different pollinators. We identified several candidate genes that will serve as an important and useful resource for future research. High conservation of sequence structure, patterns of gene coexpression, and detection of positive selection acting on few genes suggests that large phenotypic differences in floral form may be caused by genetic differences in a small

  15. The genetic aetiology of cannabis use initiation: A meta-analysis of genome-wide association studies and a SNP-based heritability estimation

    NARCIS (Netherlands)

    Verweij, C.J.H.; Vinkhuyzen, A.A.E.; Benyamin, B.; Lynskey, M.T.; Quaye, L.; Agrawal, A.; Gordon, S.D.; Montgomery, G.W.; Madden, P.A.F.; Heath, A.C.; Spector, T.D.; Martin, N.G.; Medland, S.E.

    2013-01-01

    While initiation of cannabis use is around 40% heritable, not much is known about the underlying genetic aetiology. Here, we meta-analysed two genome-wide association studies of initiation of cannabis use with >10000 individuals. None of the genetic variants reached genome-wide significance. We a

  16. ReplicationDomain: a visualization tool and comparative database for genome-wide replication timing data

    Directory of Open Access Journals (Sweden)

    Yokochi Tomoki

    2008-12-01

    Full Text Available Abstract Background Eukaryotic DNA replication is regulated at the level of large chromosomal domains (0.5–5 megabases in mammals within which replicons are activated relatively synchronously. These domains replicate in a specific temporal order during S-phase and our genome-wide analyses of replication timing have demonstrated that this temporal order of domain replication is a stable property of specific cell types. Results We have developed ReplicationDomain http://www.replicationdomain.org as a web-based database for analysis of genome-wide replication timing maps (replication profiles from various cell lines and species. This database also provides comparative information of transcriptional expression and is configured to display any genome-wide property (for instance, ChIP-Chip or ChIP-Seq data via an interactive web interface. Our published microarray data sets are publicly available. Users may graphically display these data sets for a selected genomic region and download the data displayed as text files, or alternatively, download complete genome-wide data sets. Furthermore, we have implemented a user registration system that allows registered users to upload their own data sets. Upon uploading, registered users may choose to: (1 view their data sets privately without sharing; (2 share with other registered users; or (3 make their published or "in press" data sets publicly available, which can fulfill journal and funding agencies' requirements for data sharing. Conclusion ReplicationDomain is a novel and powerful tool to facilitate the comparative visualization of replication timing in various cell types as well as other genome-wide chromatin features and is considerably faster and more convenient than existing browsers when viewing multi-megabase segments of chromosomes. Furthermore, the data upload function with the option of private viewing or sharing of data sets between registered users should be a valuable resource for the

  17. Genome-Wide Architecture of Disease Resistance Genes in Lettuce.

    Science.gov (United States)

    Christopoulou, Marilena; Wo, Sebastian Reyes-Chin; Kozik, Alex; McHale, Leah K; Truco, Maria-Jose; Wroblewski, Tadeusz; Michelmore, Richard W

    2015-10-08

    Genome-wide motif searches identified 1134 genes in the lettuce reference genome of cv. Salinas that are potentially involved in pathogen recognition, of which 385 were predicted to encode nucleotide binding-leucine rich repeat receptor (NLR) proteins. Using a maximum-likelihood approach, we grouped the NLRs into 25 multigene families and 17 singletons. Forty-one percent of these NLR-encoding genes belong to three families, the largest being RGC16 with 62 genes in cv. Salinas. The majority of NLR-encoding genes are located in five major resistance clusters (MRCs) on chromosomes 1, 2, 3, 4, and 8 and cosegregate with multiple disease resistance phenotypes. Most MRCs contain primarily members of a single NLR gene family but a few are more complex. MRC2 spans 73 Mb and contains 61 NLRs of six different gene families that cosegregate with nine disease resistance phenotypes. MRC3, which is 25 Mb, contains 22 RGC21 genes and colocates with Dm13. A library of 33 transgenic RNA interference tester stocks was generated for functional analysis of NLR-encoding genes that cosegregated with disease resistance phenotypes in each of the MRCs. Members of four NLR-encoding families, RGC1, RGC2, RGC21, and RGC12 were shown to be required for 16 disease resistance phenotypes in lettuce. The general composition of MRCs is conserved across different genotypes; however, the specific repertoire of NLR-encoding genes varied particularly of the rapidly evolving Type I genes. These tester stocks are valuable resources for future analyses of additional resistance phenotypes. Copyright © 2015 Christopoulou et al.

  18. Genome-wide identification of direct HBx genomic targets

    KAUST Repository

    Guerrieri, Francesca

    2017-02-17

    Background The Hepatitis B Virus (HBV) HBx regulatory protein is required for HBV replication and involved in HBV-related carcinogenesis. HBx interacts with chromatin modifying enzymes and transcription factors to modulate histone post-translational modifications and to regulate viral cccDNA transcription and cellular gene expression. Aiming to identify genes and non-coding RNAs (ncRNAs) directly targeted by HBx, we performed a chromatin immunoprecipitation sequencing (ChIP-Seq) to analyse HBV recruitment on host cell chromatin in cells replicating HBV. Results ChIP-Seq high throughput sequencing of HBx-bound fragments was used to obtain a high-resolution, unbiased, mapping of HBx binding sites across the genome in HBV replicating cells. Protein-coding genes and ncRNAs involved in cell metabolism, chromatin dynamics and cancer were enriched among HBx targets together with genes/ncRNAs known to modulate HBV replication. The direct transcriptional activation of genes/miRNAs that potentiate endocytosis (Ras-related in brain (RAB) GTPase family) and autophagy (autophagy related (ATG) genes, beclin-1, miR-33a) and the transcriptional repression of microRNAs (miR-138, miR-224, miR-576, miR-596) that directly target the HBV pgRNA and would inhibit HBV replication, contribute to HBx-mediated increase of HBV replication. Conclusions Our ChIP-Seq analysis of HBx genome wide chromatin recruitment defined the repertoire of genes and ncRNAs directly targeted by HBx and led to the identification of new mechanisms by which HBx positively regulates cccDNA transcription and HBV replication.

  19. Genome-Wide Associations of Gene Expression Variation in Humans.

    Directory of Open Access Journals (Sweden)

    2005-12-01

    Full Text Available The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12-13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis- to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level.

  20. Genome-wide associations of gene expression variation in humans.

    Directory of Open Access Journals (Sweden)

    Barbara E Stranger

    2005-12-01

    Full Text Available The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12-13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis- to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level.

  1. A method for obtaining RNA from Hemileia vastatrix appressoria produced in planta, suitable for transcriptomic analyses.

    Science.gov (United States)

    Loureiro, Andreia; Gil Azinheira, Helena; do Céu Silva, Maria; Talhinhas, Pedro

    2015-11-01

    Appressoria are the first infection structures developed by rust fungi and require specific topographic signals from the host for their differentiation. The ease in obtaining appressoria in vitro for these biotrophic fungi led to studies concerning gene expression and gene discovery at appressorial level, avoiding the need to distinguish plant and fungal transcripts. However, in some pathosystems, it was observed that gene expression in appressoria seems to be influenced by host-derived signals, suggesting that transcriptomic analyses performed from in planta differentiated appressoria would be potentially more informative than those from in vitro differentiated appressoria. Nevertheless analysing appressorial RNA obtained from in planta samples is often hampered by an excessive dilution of fungal RNA within plant RNA, besides uncertainty regarding the fungal or plant origin of RNA from highly conserved genes. To circumvent these difficulties, we have recovered Hemileia vastatrix appressoria from Arabica coffee leaf surface using a film of nitrocellulose dissolved in butyl and ethyl acetates (nail polish), and extracted fungal RNA from the polish peel. RNA thus obtained is of good quality and usable for cDNA synthesis and transcriptomic (quantitative PCR) studies. This method could provide the means to investigate specific host-induced appressoria-related fungal pathogenicity factors.

  2. Transcriptomic Analyses on the Role of Nitric Oxide in Plant Disease Resistance.

    Science.gov (United States)

    Mata-Pérez, Capilla; Begara-Morales, Juan C; Luque, Francisco; Padilla, María N; Jiménez-Ruiz, Jaime; Sánchez-Calvo, Beatriz; Fierro-Risco, Jesús; Barroso, Juan B

    2016-01-01

    Nitric oxide (NO) is a gaseous molecule having key roles in many physiological processes such as germination, growth, development and senescence. It has been also shown the important role of NO as a signaling molecule in the response to a wide variety of stress situations, including both biotic and abiotic stress conditions. In the last few years, a growing number of studies have focused on NO-cell targets by several approaches such as transcriptomic and proteomic analyses. This review is centered on offering an update about the principal medium- and large-scale transcriptomic analyses performed with several NO donors including microarray, cDNA-amplification fragment length polymorphism (AFLP) and high throughput sequencing (RNA-seq technology) approaches mainly focused on the role of this reactive nitrogen species in relation to plant disease resistance. Different putative NO-responsive genes have been identified in different plant tissues and plant species by application of several NO donors suggesting the implication of NO-responsive genes with plant adaptive responses to biotic stress processes. Finally, it is also provided an overview about common transcription factor-binding sites of NO-responsive genes and the need to further analyze the different NO-targets by other omics studies.

  3. Genome-wide Differences in DNA Methylation Changes in Two Contrasting Rice Genotypes in Response to Drought Conditions

    Directory of Open Access Journals (Sweden)

    Wensheng Wang

    2016-11-01

    Full Text Available Differences in drought stress tolerance within diverse rice genotypes have been attributed to genetic diversity and epigenetic alterations. DNA methylation is an important epigenetic modification that influences diverse biological processes, but its effects on rice drought stress tolerance are poorly understood. In this study, methylated DNA immunoprecipitation sequencing and an Affymetrix GeneChip rice genome array were used to profile the DNA methylation patterns and transcriptomes of the drought-tolerant introgression line DK151 and its drought-sensitive recurrent parent IR64 under drought and control conditions. The introgression of donor genomic DNA induced genome-wide DNA methylation changes in DK151 plants. A total of 1190 differentially methylated regions (DMRs were detected between the two genotypes under normal growth conditions, and the DMR-associated genes in DK151 plants were mainly related to stress response, programmed cell death, and nutrient reservoir activity, which are implicated to constitutive drought stress tolerance. A comparison of the DNA methylation changes in the two genotypes under drought conditions indicated that DK151 plants have a more stable methylome, with only 92 drought-induced DMRs, than IR64 plants with 506 DMRs. Gene ontology analyses of the DMR-associated genes in drought-stressed plants revealed that changes to the DNA methylation status of genotype-specific genes are associated with the epigenetic regulation of drought stress responses. Transcriptome analysis further helped to identify a set of 12 and 23 DMR-associated genes that were differentially expressed in DK151 and IR64, respectively, under drought stress compared with respective controls. Correlation analysis indicated that DNA methylation has various effects on gene expression, implying that it affects gene expression directly or indirectly through diverse regulatory pathways. Our results indicate that drought-induced alterations to DNA

  4. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma

    OpenAIRE

    Chambers, John C.; Zhang, Weihua; Sehmi, Joban; Li, Xinzhong; Wass, Mark N; Harst, Pim; Holm, Hilma; Sanna, Serena; Kavousi, Maryam; Baumeister, Sebastian E.; Coin, Lachlan J.; Deng, Guohong; Gieger, Christian; Heard-Costa, Nancy L.; Hottenga, Jouke-Jan

    2011-01-01

    Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, includi...

  5. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma

    OpenAIRE

    Chambers, John C.; Zhang, Weihua; Sehmi, Joban; Li, Xinzhong; Wass, Mark N; Harst, Pim; Holm, Hilma; Sanna, Serena; Kavousi, Maryam; Baumeister, Sebastian E.; Coin, Lachlan J.; Deng, Guohong; Gieger, Christian; Heard-Costa, Nancy L.; Hottenga, Jouke-Jan

    2011-01-01

    Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10−8 to P = 10−190). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including g...

  6. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.

    OpenAIRE

    Chambers, John C.; Zhang, Weihua; Sehmi, Joban; Li, Xinzhong; Wass, Mark N; Harst, Pim; Holm, Hilma; Sanna, Serena; Kavousi, Maryam; Baumeister, Sebastian E.; Coin, Lachlan J.; Abecasis, Goncalo R.; Ahmadi, Kourosh R; Boomsma, Dorret I; Caulfield, Mark

    2011-01-01

    Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, includi...

  7. Mapping the sensory perception of apple using descriptive sensory evaluation in a genome wide association study

    OpenAIRE

    Amyotte, Beatrice; Bowen, Amy J.; Banks, Travis; Rajcan, Istvan; Somers, Daryl J.

    2017-01-01

    Breeding apples is a long-term endeavour and it is imperative that new cultivars are selected to have outstanding consumer appeal. This study has taken the approach of merging sensory science with genome wide association analyses in order to map the human perception of apple flavour and texture onto the apple genome. The goal was to identify genomic associations that could be used in breeding apples for improved fruit quality. A collection of 85 apple cultivars was examined over two years thr...

  8. Genome wide association study identifies KCNMA1 contributing to human obesity

    DEFF Research Database (Denmark)

    Jiao, Hong; Arner, Peter; Hoffstedt, Johan;

    2011-01-01

    Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population....... Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity....

  9. Genome-wide gene expression analysis of anguillid herpesvirus 1

    NARCIS (Netherlands)

    Beurden, van S.J.; Peeters, B.P.H.; Rottier, P.J.M.; Davison, A.A.; Engelsma, M.Y.

    2013-01-01

    Background Whereas temporal gene expression in mammalian herpesviruses has been studied extensively, little is known about gene expression in fish herpesviruses. Here we report a genome-wide transcription analysis of a fish herpesvirus, anguillid herpesvirus 1, in cell culture, studied during the

  10. Genome-Wide Scan Reveals Mutation Associated with Melanoma

    Science.gov (United States)

    ... Q R S T U V W X Y Z We want to hear from you You are here: News & Events 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 Spotlight on Research 2012 July 2012 (historical) Genome-Wide Scan Reveals Mutation Associated with Melanoma A team of ...

  11. A genome-wide scan for preeclampsia in the Netherlands

    NARCIS (Netherlands)

    Lachmeijer, AMA; Arngrimsson, R; Bastiaans, EJ; Frigge, ML; Pals, G; Sigurdardottir, S; Stefansson, H; Palsson, B; Nicolae, D; Kong, A; Aarnoudse, JG; Gulcher, [No Value; Dekker, GA; ten Kate, LP; Stefansson, K

    2001-01-01

    Preeclampsia, hallmarked by de novo hypertension and proteinuria in pregnancy, has a familial tendency. Recently, a large Icelandic genome-wide scan provided evidence for a maternal susceptibility locus for preeclampsia on chromosome 2p13 which was confirmed by a genome scan from Australia and New

  12. Genome-wide RNA Tomography in the Zebrafish Embryo

    NARCIS (Netherlands)

    Junker, Jan Philipp; Noël, Emily S; Guryev, Victor; Peterson, Kevin A; Shah, Gopi; Huisken, Jan; McMahon, Andrew P; Berezikov, Eugene; Bakkers, Jeroen; van Oudenaarden, Alexander

    2014-01-01

    Advancing our understanding of embryonic development is heavily dependent on identification of novel pathways or regulators. Although genome-wide techniques such as RNA sequencing are ideally suited for discovering novel candidate genes, they are unable to yield spatially resolved information in

  13. Genome-wide RNA Tomography in the zebrafish embryo

    NARCIS (Netherlands)

    Junker, Jan Philipp; Noël, Emily S; Guryev, Victor; Peterson, Kevin A; Shah, Gopi; Huisken, Jan; McMahon, Andrew P; Berezikov, Eugene; Bakkers, Jeroen; van Oudenaarden, Alexander

    2014-01-01

    Advancing our understanding of embryonic development is heavily dependent on identification of novel pathways or regulators. Although genome-wide techniques such as RNA sequencing are ideally suited for discovering novel candidate genes, they are unable to yield spatially resolved information in

  14. Genome-wide association study identifies five new schizophrenia loci

    NARCIS (Netherlands)

    Ripke, Stephan; Sanders, Alan R.; Kendler, Kenneth S.; Levinson, Douglas F.; Sklar, Pamela; Holmans, Peter A.; Lin, Dan-Yu; Duan, Jubao; Ophoff, Roel A.; Andreassen, Ole A.; Scolnick, Edward; Cichon, Sven; Clair, David St.; Corvin, Aiden; Gurling, Hugh; Werge, Thomas; Rujescu, Dan; Blackwood, Douglas H. R.; Pato, Carlos N.; Malhotra, Anil K.; Purcell, Shaun; Dudbridge, Frank; Neale, Benjamin M.; Rossin, Lizzy; Visscher, Peter M.; Posthuma, Danielle; Ruderfer, Douglas M.; Fanous, Ayman; Stefansson, Hreinn; Steinberg, Stacy; Mowry, Bryan J.; Golimbet, Vera; De Hert, Marc; Jonsson, Erik G.; Bitter, Istvan; Pietilainen, Olli P. H.; Collier, David A.; Tosato, Sarah; Agartz, Ingrid; Albus, Margot; Alexander, Madeline; Amdur, Richard L.; Amin, Farooq; Bass, Nicholas; Bergen, Sarah E.; Black, Donald W.; Borglum, Anders D.; Brown, Matthew A.; Bruggeman, Richard; Buccola, Nancy G.; Byerley, William F.; Cahn, Wiepke; Cantor, Rita M.; Carr, Vaughan J.; Catts, Stanley V.; Choudhury, Khalid; Cloninger, C. Robert; Cormican, Paul; Craddock, Nicholas; Danoy, Patrick A.; Datta, Susmita; De Haan, Lieuwe; Demontis, Ditte; Dikeos, Dimitris; Djurovic, Srdjan; Donnelly, Peter; Donohoe, Gary; Duong, Linh; Dwyer, Sarah; Fink-Jensen, Anders; Freedman, Robert; Freimer, Nelson B.; Friedl, Marion; Georgieva, Lyudmila; Giegling, Ina; Gill, Michael; Glenthoj, Birte; Godard, Stephanie; Hamshere, Marian; Hansen, Mark; Hansen, Thomas; Hartmann, Annette M.; Henskens, Frans A.; Hougaard, David M.; Hultman, Christina M.; Ingason, Andres; Jablensky, Assen V.; Jakobsen, Klaus D.; Jay, Maurice; Juergens, Gesche; Kahn, Renes; Keller, Matthew C.; Kenis, Gunter; Kenny, Elaine; Kim, Yunjung; Kirov, George K.; Konnerth, Heike; Konte, Bettina; Krabbendam, Lydia; Krasucki, Robert; Lasseter, Virginia K.; Laurent, Claudine; Lawrence, Jacob; Lencz, Todd; Lerer, F. Bernard; Liang, Kung-Yee; Lichtenstein, Paul; Lieberman, Jeffrey A.; Linszen, Don H.; Lonnqvist, Jouko; Loughland, Carmel M.; Maclean, Alan W.; Maher, Brion S.; Maier, Wolfgang; Mallet, Jacques; Malloy, Pat; Mattheisen, Manuel; Mattingsdal, Morten; McGhee, Kevin A.; McGrath, John J.; McIntosh, Andrew; McLean, Duncan E.; McQuillin, Andrew; Melle, Ingrid; Michie, Patricia T.; Milanova, Vihra; Morris, Derek W.; Mors, Ole; Mortensen, Preben B.; Moskvina, Valentina; Muglia, Pierandrea; Myin-Germeys, Inez; Nertney, Deborah A.; Nestadt, Gerald; Nielsen, Jimmi; Nikolov, Ivan; Nordentoft, Merete; Norton, Nadine; Noethen, Markus M.; O'Dushlaine, Colm T.; Olincy, Ann; Olsen, Line; O'Neill, F. Anthony; Orntoft, Torben F.; Owen, Michael J.; Pantelis, Christos; Papadimitriou, George; Pato, Michele T.; Peltonen, Leena; Petursson, Hannes; Pickard, Ben; Pimm, Jonathan; Pulver, Ann E.; Puri, Vinay; Quested, Digby; Quinn, Emma M.; Rasmussen, Henrik B.; Rethelyi, Janos M.; Ribble, Robert; Rietschel, Marcella; Riley, Brien P.; Ruggeri, Mirella; Schall, Ulrich; Schulze, Thomas G.; Schwab, Sibylle G.; Scott, Rodney J.; Shi, Jianxin; Sigurdsson, Engilbert; Silverman, Jeremy M.; Spencer, Chris C. A.; Stefansson, Kari; Strange, Amy; Strengman, Eric; Stroup, T. Scott; Suvisaari, Jaana; Terenius, Lars; Thirumalai, Srinivasa; Thygesen, Johan H.; Timm, Sally; Toncheva, Draga; van den Oord, Edwin; van Os, Jim; van Winkel, Ruud; Veldink, Jan; Walsh, Dermot; Wang, August G.; Wiersma, Durk; Wildenauer, Dieter B.; Williams, Hywel J.; Williams, Nigel M.; Wormley, Brandon; Zammit, Stan; Sullivan, Patrick F.; O'Donovan, Michael C.; Daly, Mark J.; Gejman, Pablo V.

    2011-01-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded

  15. A genome-wide association study of anorexia nervosa

    NARCIS (Netherlands)

    Boraska, V; Franklin, C S; Floyd, J A B; Thornton, L M; Huckins, L M; Southam, L; Rayner, N W; Tachmazidou, I; Klump, K L; Treasure, J; Lewis, C M; Schmidt, U; Tozzi, F; Kiezebrink, K; Hebebrand, J; Gorwood, P; Adan, R A H; Kas, M J H; Favaro, A; Santonastaso, P; Fernández-Aranda, F; Gratacos, M; Rybakowski, F; Dmitrzak-Weglarz, M; Kaprio, J; Keski-Rahkonen, A; Raevuori, A; Van Furth, E F; Slof-Op 't Landt, M C T; Hudson, J I; Reichborn-Kjennerud, T; Knudsen, G P S; Monteleone, P; Kaplan, A S; Karwautz, A; Hakonarson, H; Berrettini, W H; Guo, Y; Li, D; Schork, N J; Komaki, G; Ando, T; Inoko, H; Esko, T; Fischer, K; Männik, K; Metspalu, A; Baker, J H; Cone, R D; Dackor, J; DeSocio, J E; Hilliard, C E; O'Toole, J K; Pantel, J; Szatkiewicz, J P; Taico, C; Zerwas, S; Trace, S E; Davis, O S P; Helder, S; Bühren, K; Burghardt, R; de Zwaan, M; Egberts, K; Ehrlich, S; Herpertz-Dahlmann, B; Herzog, W; Imgart, H; Scherag, A; Scherag, S; Zipfel, S; Boni, C; Ramoz, N; Versini, A; Brandys, M K; Danner, U N; de Kovel, C; Hendriks, J; Koeleman, B P C; Ophoff, R A; Strengman, E; van Elburg, Annemarie; Bruson, A; Clementi, M; Degortes, D; Forzan, M; Tenconi, E; Docampo, E; Escaramís, G; Jiménez-Murcia, S; Lissowska, J; Rajewski, A; Szeszenia-Dabrowska, N; Slopien, A; Hauser, J; Karhunen, L; Meulenbelt, I; Slagboom, P E; Tortorella, A; Maj, M; Dedoussis, G; Dikeos, D; Gonidakis, F; Tziouvas, K; Tsitsika, A; Papezova, H; Slachtova, L; Martaskova, D; Kennedy, J L; Levitan, R D; Yilmaz, Z; Huemer, J; Koubek, D; Merl, E; Wagner, G; Lichtenstein, P; Breen, G; Cohen-Woods, S; Farmer, A; McGuffin, P; Cichon, S; Giegling, I; Herms, S; Rujescu, D; Schreiber, S; Wichmann, H-E; Dina, C; Sladek, R; Gambaro, G; Soranzo, N; Julia, A; Marsal, S; Rabionet, R; Gaborieau, V; Dick, D M; Palotie, A; Ripatti, S; Widén, E; Andreassen, O A; Espeseth, T; Lundervold, A; Reinvang, I; Steen, V M; Le Hellard, S; Mattingsdal, M; Ntalla, I; Bencko, V; Foretova, L; Janout, V; Navratilova, M; Gallinger, S; Pinto, D; Scherer, S W; Aschauer, H; Carlberg, L; Schosser, A; Alfredsson, L; Ding, B; Klareskog, L; Padyukov, L; Courtet, P; Guillaume, S; Jaussent, I; Finan, C; Kalsi, G; Roberts, M; Logan, D W; Peltonen, L; Ritchie, G R S; Barrett, J C; Estivill, X; Hinney, A; Sullivan, P F; Collier, D A; Zeggini, E; Bulik, C M

    2014-01-01

    Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countri

  16. Genome-Wide Association Analysis in Primary Sclerosing Cholangitis

    NARCIS (Netherlands)

    T.H. Karlsen; A. Franke; E. Melum; A.. Kaser; J.R. Hov; T. Balschun; B.A. Lie; A. Bergquist; C. Schramm; T.J. Weismüller; D. Gotthardt; C. Rust; E.E.R. Philipp; T. Fritz; L. Henckaerts; R. Weersma; P. Stokkers; C.Y. Ponsioen; C. Wijmenga; M. Sterneck; M. Nothnagel; J. Hampe; A. Teufel; H. Runz; P. Rosenstiel; A. Stiehl; S. Vermeire; U. Beuers; M. Manns; E. Schrumpf; K.M. Boberg; S. Schreiber

    2010-01-01

    BACKGROUND & AIMS: We aimed to characterize the genetic susceptibility to primary sclerosing cholangitis (PSC) by means of a genome-wide association analysis of single nucleotide polymorphism (SNP) markers. METHODS: A total of 443,816 SNPs on the Affymetrix SNP Array 5.0 (Affymetrix, Santa Clara, CA

  17. Genome-wide association study of Tourette's syndrome

    NARCIS (Netherlands)

    Scharf, J. M.; Yu, D.; Mathews, C. A.; Neale, B. M.; Stewart, S. E.; Fagerness, J. A.; Evans, P.; Gamazon, E.; Edlund, C. K.; Service, S. K.; Tikhomirov, A.; Osiecki, L.; Illmann, C.; Pluzhnikov, A.; Konkashbaev, A.; Davis, L. K.; Han, B.; Crane, J.; Moorjani, P.; Crenshaw, A. T.; Parkin, M. A.; Reus, V. I.; Lowe, T. L.; Rangel-Lugo, M.; Chouinard, S.; Dion, Y.; Girard, S.; Cath, D. C.; Smit, J. H.; King, R. A.; Fernandez, T. V.; Leckman, J. F.; Kidd, K. K.; Kidd, J. R.; Pakstis, A. J.; State, M. W.; Herrera, L. D.; Romero, R.; Fournier, E.; Sandor, P.; Barr, C. L.; Phan, N.; Gross-Tsur, V.; Benarroch, F.; Pollak, Y.; Budman, C. L.; Bruun, R. D.; Erenberg, G.; Naarden, A. L.; Lee, P. C.; Weiss, N.; Kremeyer, B.; Berrio, G. B.; Campbell, D. D.; Cardona Silgado, J. C.; Ochoa, W. C.; Mesa Restrepo, S. C.; Muller, H.; Valencia Duarte, A. V.; Lyon, G. J.; Leppert, M.; Morgan, J.; Weiss, R.; Grados, M. A.; Anderson, K.; Davarya, S.; Singer, H.; Walkup, J.; Jankovic, J.; Tischfield, J. A.; Heiman, G. A.; Gilbert, D. L.; Hoekstra, P. J.; Robertson, M. M.; Kurlan, R.; Liu, C.; Gibbs, J. R.; Singleton, A.; Hardy, J.; Strengman, E.; Ophoff, R. A.; Wagner, M.; Moessner, R.; Mirel, D. B.; Posthuma, D.; Sabatti, C.; Eskin, E.; Conti, D. V.; Knowles, J. A.; Ruiz-Linares, A.; Rouleau, G. A.; Purcell, S.; Heutink, P.; Oostra, B. A.; McMahon, W. M.; Freimer, N. B.; Cox, N. J.; Pauls, D. L.

    2013-01-01

    Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association

  18. Genome-wide association study identifies five new schizophrenia loci

    NARCIS (Netherlands)

    Ripke, Stephan; Sanders, Alan R.; Kendler, Kenneth S.; Levinson, Douglas F.; Sklar, Pamela; Holmans, Peter A.; Lin, Dan-Yu; Duan, Jubao; Ophoff, Roel A.; Andreassen, Ole A.; Scolnick, Edward; Cichon, Sven; Clair, David St.; Corvin, Aiden; Gurling, Hugh; Werge, Thomas; Rujescu, Dan; Blackwood, Douglas H. R.; Pato, Carlos N.; Malhotra, Anil K.; Purcell, Shaun; Dudbridge, Frank; Neale, Benjamin M.; Rossin, Lizzy; Visscher, Peter M.; Posthuma, Danielle; Ruderfer, Douglas M.; Fanous, Ayman; Stefansson, Hreinn; Steinberg, Stacy; Mowry, Bryan J.; Golimbet, Vera; De Hert, Marc; Jonsson, Erik G.; Bitter, Istvan; Pietilainen, Olli P. H.; Collier, David A.; Tosato, Sarah; Agartz, Ingrid; Albus, Margot; Alexander, Madeline; Amdur, Richard L.; Amin, Farooq; Bass, Nicholas; Bergen, Sarah E.; Black, Donald W.; Borglum, Anders D.; Brown, Matthew A.; Bruggeman, Richard; Buccola, Nancy G.; Byerley, William F.; Cahn, Wiepke; Cantor, Rita M.; Carr, Vaughan J.; Catts, Stanley V.; Choudhury, Khalid; Cloninger, C. Robert; Cormican, Paul; Craddock, Nicholas; Danoy, Patrick A.; Datta, Susmita; De Haan, Lieuwe; Demontis, Ditte; Dikeos, Dimitris; Djurovic, Srdjan; Donnelly, Peter; Donohoe, Gary; Duong, Linh; Dwyer, Sarah; Fink-Jensen, Anders; Freedman, Robert; Freimer, Nelson B.; Friedl, Marion; Georgieva, Lyudmila; Giegling, Ina; Gill, Michael; Glenthoj, Birte; Godard, Stephanie; Hamshere, Marian; Hansen, Mark; Hansen, Thomas; Hartmann, Annette M.; Henskens, Frans A.; Hougaard, David M.; Hultman, Christina M.; Ingason, Andres; Jablensky, Assen V.; Jakobsen, Klaus D.; Jay, Maurice; Juergens, Gesche; Kahn, Renes; Keller, Matthew C.; Kenis, Gunter; Kenny, Elaine; Kim, Yunjung; Kirov, George K.; Konnerth, Heike; Konte, Bettina; Krabbendam, Lydia; Krasucki, Robert; Lasseter, Virginia K.; Laurent, Claudine; Lawrence, Jacob; Lencz, Todd; Lerer, F. Bernard; Liang, Kung-Yee; Lichtenstein, Paul; Lieberman, Jeffrey A.; Linszen, Don H.; Lonnqvist, Jouko; Loughland, Carmel M.; Maclean, Alan W.; Maher, Brion S.; Maier, Wolfgang; Mallet, Jacques; Malloy, Pat; Mattheisen, Manuel; Mattingsdal, Morten; McGhee, Kevin A.; McGrath, John J.; McIntosh, Andrew; McLean, Duncan E.; McQuillin, Andrew; Melle, Ingrid; Michie, Patricia T.; Milanova, Vihra; Morris, Derek W.; Mors, Ole; Mortensen, Preben B.; Moskvina, Valentina; Muglia, Pierandrea; Myin-Germeys, Inez; Nertney, Deborah A.; Nestadt, Gerald; Nielsen, Jimmi; Nikolov, Ivan; Nordentoft, Merete; Norton, Nadine; Noethen, Markus M.; O'Dushlaine, Colm T.; Olincy, Ann; Olsen, Line; O'Neill, F. Anthony; Orntoft, Torben F.; Owen, Michael J.; Pantelis, Christos; Papadimitriou, George; Pato, Michele T.; Peltonen, Leena; Petursson, Hannes; Pickard, Ben; Pimm, Jonathan; Pulver, Ann E.; Puri, Vinay; Quested, Digby; Quinn, Emma M.; Rasmussen, Henrik B.; Rethelyi, Janos M.; Ribble, Robert; Rietschel, Marcella; Riley, Brien P.; Ruggeri, Mirella; Schall, Ulrich; Schulze, Thomas G.; Schwab, Sibylle G.; Scott, Rodney J.; Shi, Jianxin; Sigurdsson, Engilbert; Silverman, Jeremy M.; Spencer, Chris C. A.; Stefansson, Kari; Strange, Amy; Strengman, Eric; Stroup, T. Scott; Suvisaari, Jaana; Terenius, Lars; Thirumalai, Srinivasa; Thygesen, Johan H.; Timm, Sally; Toncheva, Draga; van den Oord, Edwin; van Os, Jim; van Winkel, Ruud; Veldink, Jan; Walsh, Dermot; Wang, August G.; Wiersma, Durk; Wildenauer, Dieter B.; Williams, Hywel J.; Williams, Nigel M.; Wormley, Brandon; Zammit, Stan; Sullivan, Patrick F.; O'Donovan, Michael C.; Daly, Mark J.; Gejman, Pablo V.

    2011-01-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded

  19. Genome-wide association study identifies five new schizophrenia loci.

    LENUS (Irish Health Repository)

    Ripke, Stephan

    2011-10-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)).

  20. Genome-wide association study identifies five new schizophrenia loci

    DEFF Research Database (Denmark)

    Ripke, Stephan; Sanders, Alan R; Kendler, Kenneth S

    2011-01-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yiel...

  1. Genome-wide significant risk associations for mucinous ovarian carcinoma

    DEFF Research Database (Denmark)

    Kelemen, Linda E; Lawrenson, Kate; Tyrer, Jonathan;

    2015-01-01

    Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at...

  2. Whole transcriptome analyses of six thoroughbred horses before and after exercise using RNA-Seq

    Directory of Open Access Journals (Sweden)

    Park Kyung-Do

    2012-09-01

    Full Text Available Abstract Background Thoroughbred horses are the most expensive domestic animals, and their running ability and knowledge about their muscle-related diseases are important in animal genetics. While the horse reference genome is available, there has been no large-scale functional annotation of the genome using expressed genes derived from transcriptomes. Results We present a large-scale analysis of whole transcriptome data. We sequenced the whole mRNA from the blood and muscle tissues of six thoroughbred horses before and after exercise. By comparing current genome annotations, we identified 32,361 unigene clusters spanning 51.83 Mb that contained 11,933 (36.87% annotated genes. More than 60% (20,428 of the unigene clusters did not match any current equine gene model. We also identified 189,973 single nucleotide variations (SNVs from the sequences aligned against the horse reference genome. Most SNVs (171,558 SNVs; 90.31% were novel when compared with over 1.1 million equine SNPs from two SNP databases. Using differential expression analysis, we further identified a number of exercise-regulated genes: 62 up-regulated and 80 down-regulated genes in the blood, and 878 up-regulated and 285 down-regulated genes in the muscle. Six of 28 previously-known exercise-related genes were over-expressed in the muscle after exercise. Among the differentially expressed genes, there were 91 transcription factor-encoding genes, which included 56 functionally unknown transcription factor candidates that are probably associated with an early regulatory exercise mechanism. In addition, we found interesting RNA expression patterns where different alternative splicing forms of the same gene showed reversed expressions before and after exercising. Conclusion The first sequencing-based horse transcriptome data, extensive analyses results, deferentially expressed genes before and after exercise, and candidate genes that are related to the exercise are provided in this

  3. p53 regulates the cardiac transcriptome

    Science.gov (United States)

    Mak, Tak W.; Hauck, Ludger; Grothe, Daniela; Billia, Filio

    2017-01-01

    The tumor suppressor Trp53 (p53) inhibits cell growth after acute stress by regulating gene transcription. The mammalian genome contains hundreds of p53-binding sites. However, whether p53 participates in the regulation of cardiac tissue homeostasis under normal conditions is not known. To examine the physiologic role of p53 in adult cardiomyocytes in vivo, Cre-loxP–mediated conditional gene targeting in adult mice was used. Genome-wide transcriptome analyses of conditional heart-specific p53 knockout mice were performed. Genome-wide annotation and pathway analyses of >5,000 differentially expressed transcripts identified many p53-regulated gene clusters. Correlative analyses identified >20 gene sets containing more than 1,000 genes relevant to cardiac architecture and function. These transcriptomic changes orchestrate cardiac architecture, excitation-contraction coupling, mitochondrial biogenesis, and oxidative phosphorylation capacity. Interestingly, the gene expression signature in p53-deficient hearts confers resistance to acute biomechanical stress. The data presented here demonstrate a role for p53, a previously unrecognized master regulator of the cardiac transcriptome. The complex contributions of p53 define a biological paradigm for the p53 regulator network in the heart under physiological conditions. PMID:28193895

  4. Garlic (Allium sativum L. fertility: transcriptome and proteome analyses provide insight into flower and pollen development

    Directory of Open Access Journals (Sweden)

    Einat eShemesh Mayer

    2015-04-01

    Full Text Available Commercial cultivars of garlic, a popular condiment, are sterile, making genetic studies and breeding of this plant challenging. However, recent fertility restoration has enabled advanced physiological and genetic research and hybridization in this important crop. Morphophysiological studies, combined with transcriptome and proteome analyses and quantitative PCR validation, enabled the identification of genes and specific processes involved in gametogenesis in fertile and male-sterile garlic genotypes. Both genotypes exhibit normal meiosis at early stages of anther development, but in the male-sterile plants, tapetal hypertrophy after microspore release leads to pollen degeneration. Transcriptome analysis and global gene-expression profiling showed that >16,000 genes are differentially expressed in the fertile vs. male-sterile developing flowers. Proteome analysis and quantitative comparison of 2D-gel protein maps revealed 36 significantly different protein spots, 9 of which were present only in the male-sterile genotype. Bioinformatic and quantitative PCR validation of 10 candidate genes exhibited significant expression differences between male-sterile and fertile flowers. A comparison of morphophysiological and molecular traits of fertile and male-sterile garlic flowers suggests that respiratory restrictions and/or nonregulated programmed cell death of the tapetum can lead to energy deficiency and consequent pollen abortion. Potential molecular markers for male fertility and sterility in garlic are proposed.

  5. Dissecting the nascent human transcriptome by analysing the RNA content of transcription factories

    Science.gov (United States)

    Caudron-Herger, Maïwen; Cook, Peter R.; Rippe, Karsten; Papantonis, Argyris

    2015-01-01

    While mapping total and poly-adenylated human transcriptomes has now become routine, characterizing nascent transcripts remains challenging, largely because nascent RNAs have such short half-lives. Here, we describe a simple, fast and cost-effective method to isolate RNA associated with transcription factories, the sites responsible for the majority of nuclear transcription. Following stimulation of human endothelial cells with the pro-inflammatory cytokine TNFα, we isolate and analyse the RNA content of factories by sequencing. Comparison with total, poly(A)+ and chromatin RNA fractions reveals that sequencing of purified factory RNA maps the complete nascent transcriptome; it is rich in intronic unprocessed transcript, as well as long intergenic non-coding (lincRNAs) and enhancer-associated RNAs (eRNAs), micro-RNA precursors and repeat-derived RNAs. Hence, we verify that transcription factories produce most nascent RNA and confer a regulatory role via their association with a set of specifically-retained non-coding transcripts. PMID:25897132

  6. Garlic (Allium sativum L.) fertility: transcriptome and proteome analyses provide insight into flower and pollen development

    Science.gov (United States)

    Shemesh-Mayer, Einat; Ben-Michael, Tomer; Rotem, Neta; Rabinowitch, Haim D.; Doron-Faigenboim, Adi; Kosmala, Arkadiusz; Perlikowski, Dawid; Sherman, Amir; Kamenetsky, Rina

    2015-01-01

    Commercial cultivars of garlic, a popular condiment, are sterile, making genetic studies and breeding of this plant challenging. However, recent fertility restoration has enabled advanced physiological and genetic research and hybridization in this important crop. Morphophysiological studies, combined with transcriptome and proteome analyses and quantitative PCR validation, enabled the identification of genes and specific processes involved in gametogenesis in fertile and male-sterile garlic genotypes. Both genotypes exhibit normal meiosis at early stages of anther development, but in the male-sterile plants, tapetal hypertrophy after microspore release leads to pollen degeneration. Transcriptome analysis and global gene-expression profiling showed that >16,000 genes are differentially expressed in the fertile vs. male-sterile developing flowers. Proteome analysis and quantitative comparison of 2D-gel protein maps revealed 36 significantly different protein spots, 9 of which were present only in the male-sterile genotype. Bioinformatic and quantitative PCR validation of 10 candidate genes exhibited significant expression differences between male-sterile and fertile flowers. A comparison of morphophysiological and molecular traits of fertile and male-sterile garlic flowers suggests that respiratory restrictions and/or non-regulated programmed cell death of the tapetum can lead to energy deficiency and consequent pollen abortion. Potential molecular markers for male fertility and sterility in garlic are proposed. PMID:25972879

  7. Genome-wide transcriptional profiling reveals molecular signatures of secondary xylem differentiation in Populus tomentosa.

    Science.gov (United States)

    Yang, X H; Li, X G; Li, B L; Zhang, D Q

    2014-11-11

    Wood formation occurs via cell division, primary cell wall and secondary wall formation, and programmed cell death in the vascular cambium. Transcriptional profiling of secondary xylem differentiation is essential for understanding the molecular mechanisms underlying wood formation. Differential gene expression in secondary xylem differentiation of Populus has been previously investigated using cDNA microarray analysis. However, little is known about the molecular mechanisms from a genome-wide perspective. In this study, the Affymetrix poplar genome chips containing 61,413 probes were used to investigate the changes in the transcriptome during secondary xylem differentiation in Chinese white poplar (Populus tomentosa). Two xylem tissues (newly formed and lignified) were sampled for genome-wide transcriptional profiling. In total, 6843 genes (~11%) were identified with differential expression in the two xylem tissues. Many genes involved in cell division, primary wall modification, and cellulose synthesis were preferentially expressed in the newly formed xylem. In contrast, many genes, including 4-coumarate:cinnamate-4-hydroxylase (C4H), 4-coumarate:CoA ligase (4CL), cinnamyl alcohol dehydrogenase (CAD), and caffeoyl CoA 3-O-methyltransferase (CCoAOMT), associated with lignin biosynthesis were more transcribed in the lignified xylem. The two xylem tissues also showed differential expression of genes related to various hormones; thus, the secondary xylem differentiation could be regulated by hormone signaling. Furthermore, many transcription factor genes were preferentially expressed in the lignified xylem, suggesting that wood lignification involves extensive transcription regulation. The genome-wide transcriptional profiling of secondary xylem differentiation could provide additional insights into the molecular basis of wood formation in poplar species.

  8. PPARgamma in adipocyte differentiation and metabolism--novel insights from genome-wide studies.

    Science.gov (United States)

    Siersbaek, Rasmus; Nielsen, Ronni; Mandrup, Susanne

    2010-08-04

    Adipocyte differentiation is controlled by a tightly regulated transcriptional cascade in which PPARgamma and members of the C/EBP family are key players. Here we review the roles of PPARgamma and C/EBPs in adipocyte differentiation with emphasis on the recently published genome-wide binding profiles for PPARgamma and C/EBPalpha. Interestingly, these analyses show that PPARgamma and C/EBPalpha binding sites are associated with most genes that are induced during adipogenesis suggesting direct activation of many more adipocyte genes than previously anticipated. Furthermore, an extensive overlap between the C/EBPalpha and PPARgamma cistromes indicate a hitherto unrecognized direct crosstalk between these transcription factors. As more genome-wide data emerge in the future, this crosstalk will likely be found to include several other adipogenic transcription factors. Copyright (c) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  9. Novel R tools for analysis of genome-wide population genetic data with emphasis on clonality

    Directory of Open Access Journals (Sweden)

    Zhian N Kamvar

    2015-06-01

    Full Text Available To gain a detailed understanding of how plant microbes evolve and adapt to hosts, pesticides, and other factors, knowledge of the population dynamics and evolutionary history of populations is crucial. Plant pathogen populations are often clonal or partially clonal which requires different analytical tools. With the advent of high throughput sequencing technologies, obtaining genome-wide population genetic data has become easier than ever before. We previously contributed the R package poppr specifically addressing issues with analysis of clonal populations. In this paper we provide several significant extensions to poppr with a focus on large, genome-wide SNP data. Specifically, we provide several new functionalities including the new function mlg.filter to define clone boundaries allowing for inspection and definition of what is a clonal lineage, minimum spanning networks with reticulation, a sliding-window analysis of the index of association, modular bootstrapping of any genetic distance, and analyses across any level of hierarchies.

  10. Cooperative genome-wide analysis shows increased homozygosity in early onset Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Javier Simón-Sánchez

    Full Text Available Parkinson's disease (PD occurs in both familial and sporadic forms, and both monogenic and complex genetic factors have been identified. Early onset PD (EOPD is particularly associated with autosomal recessive (AR mutations, and three genes, PARK2, PARK7 and PINK1, have been found to carry mutations leading to AR disease. Since mutations in these genes account for less than 10% of EOPD patients, we hypothesized that further recessive genetic factors are involved in this disorder, which may appear in extended runs of homozygosity.We carried out genome wide SNP genotyping to look for extended runs of homozygosity (ROHs in 1,445 EOPD cases and 6,987 controls. Logistic regression analyses showed an increased level of genomic homozygosity in EOPD cases compared to controls. These differences are larger for ROH of 9 Mb and above, where there is a more than three-fold increase in the proportion of cases carrying a ROH. These differences are not explained by occult recessive mutations at existing loci. Controlling for genome wide homozygosity in logistic regression analyses increased the differences between cases and controls, indicating that in EOPD cases ROHs do not simply relate to genome wide measures of inbreeding. Homozygosity at a locus on chromosome19p13.3 was identified as being more common in EOPD cases as compared to controls. Sequencing analysis of genes and predicted transcripts within this locus failed to identify a novel mutation causing EOPD in our cohort.There is an increased rate of genome wide homozygosity in EOPD, as measured by an increase in ROHs. These ROHs are a signature of inbreeding and do not necessarily harbour disease-causing genetic variants. Although there might be other regions of interest apart from chromosome 19p13.3, we lack the power to detect them with this analysis.

  11. Simultaneous analysis of all SNPs in genome-wide and re-sequencing association studies.

    Directory of Open Access Journals (Sweden)

    Clive J Hoggart

    2008-07-01

    Full Text Available Testing one SNP at a time does not fully realise the potential of genome-wide association studies to identify multiple causal variants, which is a plausible scenario for many complex diseases. We show that simultaneous analysis of the entire set of SNPs from a genome-wide study to identify the subset that best predicts disease outcome is now feasible, thanks to developments in stochastic search methods. We used a Bayesian-inspired penalised maximum likelihood approach in which every SNP can be considered for additive, dominant, and recessive contributions to disease risk. Posterior mode estimates were obtained for regression coefficients that were each assigned a prior with a sharp mode at zero. A non-zero coefficient estimate was interpreted as corresponding to a significant SNP. We investigated two prior distributions and show that the normal-exponential-gamma prior leads to improved SNP selection in comparison with single-SNP tests. We also derived an explicit approximation for type-I error that avoids the need to use permutation procedures. As well as genome-wide analyses, our method is well-suited to fine mapping with very dense SNP sets obtained from re-sequencing and/or imputation. It can accommodate quantitative as well as case-control phenotypes, covariate adjustment, and can be extended to search for interactions. Here, we demonstrate the power and empirical type-I error of our approach using simulated case-control data sets of up to 500 K SNPs, a real genome-wide data set of 300 K SNPs, and a sequence-based dataset, each of which can be analysed in a few hours on a desktop workstation.

  12. Genome-wide identification of novel small RNAs in Pseudomonas aeruginosa

    DEFF Research Database (Denmark)

    Gómez Lozano, María

    and RNA sequencing (RNAseq) technologies. The latter approach, in particular, has revolutionized sRNA discovery by enabling interrogation of the transcriptome at unprecedented depths. The size and complexity of the P. aeruginosa genome suggests that it encodes many hitherto undetected sRNAs. In this study...... of regulatory sRNAs in P. aeruginosa and the approach described here may be applied to identify sRNAs in any bacterium under different growth and stress conditions. In addition the role of sRNA OsiS was investigated. OsiS was identified in our genome-wide search of sRNAs in P. aeruginosa. OsiS is highly...... to know the exact nature of the interaction between these two sRNAs. Notably, OsiS is, to the best of our knowledge, the first sRNA whose main function seems to be regulating the cellular levels of another sRNA....

  13. Genome-wide differential gene expression in children exposed to air pollution in the Czech Republic

    DEFF Research Database (Denmark)

    van Leeuwen, D M; van Herwijnen, M H M; Pedersen, Marie

    2006-01-01

    The Teplice area in the Czech Republic is a mining district where elevated levels of air pollution including airborne carcinogens, have been demonstrated, especially during winter time. This environmental exposure can impact human health; in particular children may be more vulnerable. To study....... This suggests an effect of air pollution on the primary structural unit of the condensed DNA. In addition, several other pathways were modulated. Based on the results of this study, we suggest that transcriptomic analysis represents a promising biomarker for environmental carcinogenesis....... the impact of air pollution in children at the transcriptional level, peripheral blood cells were subjected to whole genome response analysis, in order to identify significantly modulated biological pathways and processes as a result of exposure. Using genome-wide oligonucleotide microarrays, we investigated...

  14. SOAPsplice: genome-wide ab initio detection of splice junctions from RNA-Seq data

    Directory of Open Access Journals (Sweden)

    Songbo eHuang

    2011-07-01

    Full Text Available RNA-Seq, a method using next generation sequencing technologies to sequence the transcriptome, facilitates genome-wide analysis of splice junction sites. In this paper, we introduce SOAPsplice, a robust tool to detect splice junctions using RNA-Seq data without using any information of known splice junctions. SOAPsplice uses a novel two-step approach consisting of first identifying as many reasonable splice junction candidates as possible, and then, filtering the false positives with two effective filtering strategies. In both simulated and real datasets, SOAPsplice is able to detect many reliable splice junctions with low false positive rate. The improvement gained by SOAPsplice, when compared to other existing tools, becomes more obvious when the depth of sequencing is low. SOAPsplice is freely available at http://soap.genomics.org.cn/soapsplice.html.

  15. Genome-wide association studies and resting heart rate

    DEFF Research Database (Denmark)

    Oskari Kilpeläinen, Tuomas

    2016-01-01

    Genome-wide association studies (GWASs) have revolutionized the search for genetic variants regulating resting heart rate. In the last 10 years, GWASs have led to the identification of at least 21 novel heart rate loci. These discoveries have provided valuable insights into the mechanisms...... and pathways that regulate heart rate and link heart rate to cardiovascular morbidity and mortality. GWASs capture majority of genetic variation in a population sample by utilizing high-throughput genotyping chips measuring genotypes for up to several millions of SNPs across the genome in thousands...... of individuals. This allows the identification of the strongest heart rate associated signals at genome-wide level. While GWASs provide robust statistical evidence of the association of a given genetic locus with heart rate, they are only the starting point for detailed follow-up studies to locate the causal...

  16. Genome-wide patterns of selection in 230 ancient Eurasians

    Science.gov (United States)

    Mathieson, Iain; Lazaridis, Iosif; Rohland, Nadin; Mallick, Swapan; Patterson, Nick; Roodenberg, Songül Alpaslan; Harney, Eadaoin; Stewardson, Kristin; Fernandes, Daniel; Novak, Mario; Sirak, Kendra; Gamba, Cristina; Jones, Eppie R.; Llamas, Bastien; Dryomov, Stanislav; Pickrel, Joseph; Arsuaga, Juan Luís; de Castro, José María Bermúdez; Carbonell, Eudald; Gerritsen, Fokke; Khokhlov, Aleksandr; Kuznetsov, Pavel; Lozano, Marina; Meller, Harald; Mochalov, Oleg; Moiseyev, Vayacheslav; Rojo Guerra, Manuel A.; Roodenberg, Jacob; Vergès, Josep Maria; Krause, Johannes; Cooper, Alan; Alt, Kurt W.; Brown, Dorcas; Anthony, David; Lalueza-Fox, Carles; Haak, Wolfgang; Pinhasi, Ron; Reich, David

    2016-01-01

    Ancient DNA makes it possible to directly witness natural selection by analyzing samples from populations before, during and after adaptation events. Here we report the first scan for selection using ancient DNA, capitalizing on the largest genome-wide dataset yet assembled: 230 West Eurasians dating to between 6500 and 1000 BCE, including 163 with newly reported data. The new samples include the first genome-wide data from the Anatolian Neolithic culture whose genetic material we extracted from the DNA-rich petrous bone and who we show were members of the population that was the source of Europe’s first farmers. We also report a complete transect of the steppe region in Samara between 5500 and 1200 BCE that allows us to recognize admixture from at least two external sources into steppe populations during this period. We detect selection at loci associated with diet, pigmentation and immunity, and two independent episodes of selection on height. PMID:26595274

  17. Genome wide copy number analysis of single cells

    Science.gov (United States)

    Baslan, Timour; Kendall, Jude; Rodgers, Linda; Cox, Hilary; Riggs, Mike; Stepansky, Asya; Troge, Jennifer; Ravi, Kandasamy; Esposito, Diane; Lakshmi, B.; Wigler, Michael; Navin, Nicholas; Hicks, James

    2016-01-01

    Summary Copy number variation (CNV) is increasingly recognized as an important contributor to phenotypic variation in health and disease. Most methods for determining CNV rely on admixtures of cells, where information regarding genetic heterogeneity is lost. Here, we present a protocol that allows for the genome wide copy number analysis of single nuclei isolated from mixed populations of cells. Single nucleus sequencing (SNS), combines flow sorting of single nuclei based on DNA content, whole genome amplification (WGA), followed by next generation sequencing to quantize genomic intervals in a genome wide manner. Multiplexing of single cells is discussed. Additionally, we outline informatic approaches that correct for biases inherent in the WGA procedure and allow for accurate determination of copy number profiles. All together, the protocol takes ~3 days from flow cytometry to sequence-ready DNA libraries. PMID:22555242

  18. Genome-wide patterns of nucleotide polymorphism in domesticated rice

    DEFF Research Database (Denmark)

    Caicedo, Ana L; Williamson, Scott H; Hernandez, Ryan D

    2007-01-01

    Domesticated Asian rice (Oryza sativa) is one of the oldest domesticated crop species in the world, having fed more people than any other plant in human history. We report the patterns of DNA sequence variation in rice and its wild ancestor, O. rufipogon, across 111 randomly chosen gene fragments......, and use these to infer the evolutionary dynamics that led to the origins of rice. There is a genome-wide excess of high-frequency derived single nucleotide polymorphisms (SNPs) in O. sativa varieties, a pattern that has not been reported for other crop species. We developed several alternative models...... explanations for patterns of variation in domesticated rice varieties. If selective sweeps are indeed the explanation for the observed nucleotide data of domesticated rice, it suggests that strong selection can leave its imprint on genome-wide polymorphism patterns, contrary to expectations that selection...

  19. Genome-Wide Association Study of Polymorphisms Predisposing to Bronchiolitis

    Science.gov (United States)

    Pasanen, Anu; Karjalainen, Minna K.; Bont, Louis; Piippo-Savolainen, Eija; Ruotsalainen, Marja; Goksör, Emma; Kumawat, Kuldeep; Hodemaekers, Hennie; Nuolivirta, Kirsi; Jartti, Tuomas; Wennergren, Göran; Hallman, Mikko; Rämet, Mika; Korppi, Matti

    2017-01-01

    Bronchiolitis is a major cause of hospitalization among infants. Severe bronchiolitis is associated with later asthma, suggesting a common genetic predisposition. Genetic background of bronchiolitis is not well characterized. To identify polymorphisms associated with bronchiolitis, we conducted a genome-wide association study (GWAS) in which 5,300,000 single nucleotide polymorphisms (SNPs) were tested for association in a Finnish–Swedish population of 217 children hospitalized for bronchiolitis and 778 controls. The most promising SNPs (n = 77) were genotyped in a Dutch replication population of 416 cases and 432 controls. Finally, we used a set of 202 Finnish bronchiolitis cases to further investigate candidate SNPs. We did not detect genome-wide significant associations, but several suggestive association signals (p bronchiolitis. These preliminary findings require further validation in a larger sample size. PMID:28139761

  20. Genome-Wide Prediction of C. elegans Genetic Interactions

    OpenAIRE

    Zhong, Weiwei; Sternberg, Paul W.

    2006-01-01

    To obtain a global view of functional interactions among genes in a metazoan genome, we computationally integrated interactome data, gene expression data, phenotype data, and functional annotation data from three model organisms—Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster—and predicted genome-wide genetic interactions in C. elegans. The resulting genetic interaction network (consisting of 18,183 interactions) provides a framework for system-level understandin...

  1. Genome-wide association study of relative telomere length.

    Science.gov (United States)

    Prescott, Jennifer; Kraft, Peter; Chasman, Daniel I; Savage, Sharon A; Mirabello, Lisa; Berndt, Sonja I; Weissfeld, Joel L; Han, Jiali; Hayes, Richard B; Chanock, Stephen J; Hunter, David J; De Vivo, Immaculata

    2011-05-10

    Telomere function is essential to maintaining the physical integrity of linear chromosomes and healthy human aging. The probability of forming proper telomere structures depends on the length of the telomeric DNA tract. We attempted to identify common genetic variants associated with log relative telomere length using genome-wide genotyping data on 3,554 individuals from the Nurses' Health Study and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial that took part in the National Cancer Institute Cancer Genetic Markers of Susceptibility initiative for breast and prostate cancer. After genotyping 64 independent SNPs selected for replication in additional Nurses' Health Study and Women's Genome Health Study participants, we did not identify genome-wide significant loci; however, we replicated the inverse association of log relative telomere length with the minor allele variant [C] of rs16847897 at the TERC locus (per allele β = -0.03, P = 0.003) identified by a previous genome-wide association study. We did not find evidence for an association with variants at the OBFC1 locus or other loci reported to be associated with telomere length. With this sample size we had >80% power to detect β estimates as small as ±0.10 for SNPs with minor allele frequencies of ≥0.15 at genome-wide significance. However, power is greatly reduced for β estimates smaller than ±0.10, such as those for variants at the TERC locus. In general, common genetic variants associated with telomere length homeostasis have been difficult to detect. Potential biological and technical issues are discussed.

  2. Genome-wide association study of relative telomere length.

    Directory of Open Access Journals (Sweden)

    Jennifer Prescott

    Full Text Available Telomere function is essential to maintaining the physical integrity of linear chromosomes and healthy human aging. The probability of forming proper telomere structures depends on the length of the telomeric DNA tract. We attempted to identify common genetic variants associated with log relative telomere length using genome-wide genotyping data on 3,554 individuals from the Nurses' Health Study and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial that took part in the National Cancer Institute Cancer Genetic Markers of Susceptibility initiative for breast and prostate cancer. After genotyping 64 independent SNPs selected for replication in additional Nurses' Health Study and Women's Genome Health Study participants, we did not identify genome-wide significant loci; however, we replicated the inverse association of log relative telomere length with the minor allele variant [C] of rs16847897 at the TERC locus (per allele β = -0.03, P = 0.003 identified by a previous genome-wide association study. We did not find evidence for an association with variants at the OBFC1 locus or other loci reported to be associated with telomere length. With this sample size we had >80% power to detect β estimates as small as ±0.10 for SNPs with minor allele frequencies of ≥0.15 at genome-wide significance. However, power is greatly reduced for β estimates smaller than ±0.10, such as those for variants at the TERC locus. In general, common genetic variants associated with telomere length homeostasis have been difficult to detect. Potential biological and technical issues are discussed.

  3. Genome-wide association studies in pediatric endocrinology.

    Science.gov (United States)

    Dauber, Andrew; Hirschhorn, Joel N

    2011-01-01

    Genome-wide association (GWA) studies are a powerful tool for understanding the genetic underpinnings of human disease. In this article, we briefly review the role and findings of GWA studies in type 1 diabetes, stature, pubertal timing, obesity, and vitamin D deficiency. We then discuss the present and future implications of these findings with regards to disease prediction, uncovering basic biology, and the development of novel therapeutic agents.

  4. Statistical Approaches in Genome-Wide Association Studies

    OpenAIRE

    Yazdani, Akram

    2014-01-01

    Genome-wide association studies, GWAS, typically contain hundreds of thousands single nucleotide polymorphisms, SNPs, genotyped for few numbers of samples. The aim of these studies is to identify regions harboring SNPs or to predict the outcomes of interest. Since the number of predictors in the GWAS far exceeds the number of samples, it is impossible to analyze the data with classical statistical methods. In the current GWAS, the widely applied methods are based on single marker analysis th...

  5. Integrative genome-wide approaches in embryonic stem cell research.

    Science.gov (United States)

    Zhang, Xinyue; Huang, Jing

    2010-10-01

    Embryonic stem (ES) cells are derived from blastocysts. They can differentiate into the three embryonic germ layers and essentially any type of somatic cells. They therefore hold great potential in tissue regeneration therapy. The ethical issues associated with the use of human embryonic stem cells are resolved by the technical break-through of generating induced pluripotent stem (iPS) cells from various types of somatic cells. However, how ES and iPS cells self-renew and maintain their pluripotency is still largely unknown in spite of the great progress that has been made in the last two decades. Integrative genome-wide approaches, such as the gene expression microarray, chromatin immunoprecipitation based microarray (ChIP-chip) and chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) offer unprecedented opportunities to elucidate the mechanism of the pluripotency, reprogramming and DNA damage response of ES and iPS cells. This frontier article summarizes the fundamental biological questions about ES and iPS cells and reviews the recent advances in ES and iPS cell research using genome-wide technologies. To this end, we offer our perspectives on the future of genome-wide studies on stem cells.

  6. Genome-Wide Detection and Analysis of Multifunctional Genes

    Science.gov (United States)

    Pritykin, Yuri; Ghersi, Dario; Singh, Mona

    2015-01-01

    Many genes can play a role in multiple biological processes or molecular functions. Identifying multifunctional genes at the genome-wide level and studying their properties can shed light upon the complexity of molecular events that underpin cellular functioning, thereby leading to a better understanding of the functional landscape of the cell. However, to date, genome-wide analysis of multifunctional genes (and the proteins they encode) has been limited. Here we introduce a computational approach that uses known functional annotations to extract genes playing a role in at least two distinct biological processes. We leverage functional genomics data sets for three organisms—H. sapiens, D. melanogaster, and S. cerevisiae—and show that, as compared to other annotated genes, genes involved in multiple biological processes possess distinct physicochemical properties, are more broadly expressed, tend to be more central in protein interaction networks, tend to be more evolutionarily conserved, and are more likely to be essential. We also find that multifunctional genes are significantly more likely to be involved in human disorders. These same features also hold when multifunctionality is defined with respect to molecular functions instead of biological processes. Our analysis uncovers key features about multifunctional genes, and is a step towards a better genome-wide understanding of gene multifunctionality. PMID:26436655

  7. Identification of cellular targets for the human papillomavirus E6 and E7 oncogenes by RNA interference and transcriptome analyses.

    Science.gov (United States)

    Kuner, Ruprecht; Vogt, Markus; Sultmann, Holger; Buness, Andreas; Dymalla, Susanne; Bulkescher, Julia; Fellmann, Mark; Butz, Karin; Poustka, Annemarie; Hoppe-Seyler, Felix

    2007-11-01

    Specific types of human papillomaviruses (HPVs) cause cervical cancer, the second most common tumor in women worldwide. Both cellular transformation and the maintenance of the oncogenic phenotype of HPV-positive tumor cells are linked to the expression of the viral E6 and E7 oncogenes. To identify downstream cellular target genes for the viral oncogenes, we silenced endogenous E6 and E7 expression in HPV-positive HeLa cells by RNA interference (RNAi). Subsequently, we assessed changes of the cellular transcriptome by genome-wide microarray analysis. We identified 648 genes, which were either downregulated (360 genes) or upregulated (288 genes), upon inhibition of E6/E7 expression. A large fraction of these genes is involved in tumor-relevant processes, such as apoptosis control, cell cycle regulation, or spindle formation. Others may represent novel cellular targets for the HPV oncogenes, such as a large group of C-MYC-associated genes involved in RNA processing and splicing. Comparison with published microarray data revealed a substantial concordance between the genes repressed by RNAi-mediated E6/E7 silencing in HeLa cells and genes reported to be upregulated in HPV-positive cervical cancer biopsies.

  8. Genome-wide association between DNA methylation and alternative splicing in an invertebrate

    Directory of Open Access Journals (Sweden)

    Flores Kevin

    2012-09-01

    Full Text Available Abstract Background Gene bodies are the most evolutionarily conserved targets of DNA methylation in eukaryotes. However, the regulatory functions of gene body DNA methylation remain largely unknown. DNA methylation in insects appears to be primarily confined to exons. Two recent studies in Apis mellifera (honeybee and Nasonia vitripennis (jewel wasp analyzed transcription and DNA methylation data for one gene in each species to demonstrate that exon-specific DNA methylation may be associated with alternative splicing events. In this study we investigated the relationship between DNA methylation, alternative splicing, and cross-species gene conservation on a genome-wide scale using genome-wide transcription and DNA methylation data. Results We generated RNA deep sequencing data (RNA-seq to measure genome-wide mRNA expression at the exon- and gene-level. We produced a de novo transcriptome from this RNA-seq data and computationally predicted splice variants for the honeybee genome. We found that exons that are included in transcription are higher methylated than exons that are skipped during transcription. We detected enrichment for alternative splicing among methylated genes compared to unmethylated genes using fisher’s exact test. We performed a statistical analysis to reveal that the presence of DNA methylation or alternative splicing are both factors associated with a longer gene length and a greater number of exons in genes. In concordance with this observation, a conservation analysis using BLAST revealed that each of these factors is also associated with higher cross-species gene conservation. Conclusions This study constitutes the first genome-wide analysis exhibiting a positive relationship between exon-level DNA methylation and mRNA expression in the honeybee. Our finding that methylated genes are enriched for alternative splicing suggests that, in invertebrates, exon-level DNA methylation may play a role in the construction of splice

  9. Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis

    Science.gov (United States)

    Smolonska, Joanna; Koppelman, Gerard H.; Wijmenga, Cisca; Vonk, Judith M.; Zanen, Pieter; Bruinenberg, Marcel; Curjuric, Ivan; Imboden, Medea; Thun, Gian-Andri; Franke, Lude; Probst-Hensch, Nicole M.; Nürnberg, Peter; Riemersma, Roland A.; van Schayck, Onno; Loth, Daan W.; Bruselle, Guy G.; Stricker, Bruno H; Hofman, Albert; Uitterlinden, André G.; Lahousse, Lies; London, Stephanie J.; Loehr, Laura R.; Manichaikul, Ani; Barr, R. Graham; Donohue, Kathleen M.; Rich, Stephen S.; Pare, Peter; Bossé, Yohan; Hao, Ke; van den Berge, Maarten; Groen, Harry J.M.; Lammers, Jan-Willem J.; Mali, Willem; Boezen, H. Marike; Postma, Dirkje S.

    2014-01-01

    Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background (“Dutch hypothesis”). We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses. Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the NFκβ pathway) and GNG5P5, respectively. SNP rs9534578 in GNG5P5 reached genome-wide significance after first stage replication (p=9.96·*10−9). The second stage replication in seven independent cohorts provided no significant replication. eQTL analysis in blood and lung on the top 20 associated SNPs identified two SNPs in COMMD10 influencing gene expression. Inflammatory processes differ in asthma and COPD and are mediated by NFκβ, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role of two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings either suggest that there is no common genetic component in asthma and COPD or, alternatively, different environmental factors, like lifestyle and occupation in different countries and continents may have obscured the genetic common contribution. PMID:24993907

  10. Histone deacetylase inhibition modulates histone acetylation at gene promoter regions and affects genome-wide gene transcription in Schistosoma mansoni

    Science.gov (United States)

    Anderson, Letícia; Gomes, Monete Rajão; daSilva, Lucas Ferreira; Pereira, Adriana da Silva Andrade; Mourão, Marina M.; Romier, Christophe; Pierce, Raymond

    2017-01-01

    Background Schistosomiasis is a parasitic disease infecting hundreds of millions of people worldwide. Treatment depends on a single drug, praziquantel, which kills the Schistosoma spp. parasite only at the adult stage. HDAC inhibitors (HDACi) such as Trichostatin A (TSA) induce parasite mortality in vitro (schistosomula and adult worms), however the downstream effects of histone hyperacetylation on the parasite are not known. Methodology/Principal findings TSA treatment of adult worms in vitro increased histone acetylation at H3K9ac and H3K14ac, which are transcription activation marks, not affecting the unrelated transcription repression mark H3K27me3. We investigated the effect of TSA HDACi on schistosomula gene expression at three different time points, finding a marked genome-wide change in the transcriptome profile. Gene transcription activity was correlated with changes on the chromatin acetylation mark at gene promoter regions. Moreover, combining expression data with ChIP-Seq public data for schistosomula, we found that differentially expressed genes having the H3K4me3 mark at their promoter region in general showed transcription activation upon HDACi treatment, compared with those without the mark, which showed transcription down-regulation. Affected genes are enriched for DNA replication processes, most of them being up-regulated. Twenty out of 22 genes encoding proteins involved in reducing reactive oxygen species accumulation were down-regulated. Dozens of genes encoding proteins with histone reader motifs were changed, including SmEED from the PRC2 complex. We targeted SmEZH2 methyltransferase PRC2 component with a new EZH2 inhibitor (GSK343) and showed a synergistic effect with TSA, significantly increasing schistosomula mortality. Conclusions/Significance Genome-wide gene expression analyses have identified important pathways and cellular functions that were affected and may explain the schistosomicidal effect of TSA HDACi. The change in expression

  11. Direct targets of the tomato-ripening regulator RIN identified by transcriptome and chromatin immunoprecipitation analyses.

    Science.gov (United States)

    Fujisawa, Masaki; Shima, Yoko; Higuchi, Naoki; Nakano, Toshitsugu; Koyama, Yoshiyuki; Kasumi, Takafumi; Ito, Yasuhiro

    2012-06-01

    The physiological and biochemical changes in fruit ripening produce key attributes of fruit quality including color, taste, aroma and texture. These changes are driven by the highly regulated and synchronized activation of a huge number of ripening-associated genes. In tomato (Solanum lycopersicum), a typical climacteric fruit, the MADS-box transcription factor RIN is one of the earliest-acting ripening regulators, required for both ethylene-dependent and ethylene-independent pathways. Although we previously identified several direct RIN targets, many additional targets remain unidentified, likely including key ripening-associated genes. Here, we report the identification of novel RIN targets by transcriptome and chromatin immunoprecipitation (ChIP) analyses. Transcriptome comparisons by microarray of wild-type and rin mutant tomatoes identified 342 positively regulated genes and 473 negatively regulated genes by RIN during ripening. Most of the positively regulated genes contained possible RIN-binding (CArG-box) sequences in their promoters. Subsequently, we selected six genes from the positively regulated genes and a ripening regulator gene, CNR, and assayed their promoters by quantitative ChIP-PCR to examine RIN binding. All of the seven genes, which are involved in cell wall modification, aroma and flavor development, pathogen defense and transcriptional regulation during ripening, are targets of RIN, suggesting that RIN may control multiple diverse ripening processes. In particular, RIN directly regulates the expression of the ripening-associated transcription factors, CNR, TDR4 and a GRAS family gene, providing an important clue to elucidate the complicated transcriptional cascade for fruit ripening.

  12. Transcriptomic and metabolic analyses reveal salvage pathways in creatine-deficient AGAT(-/-) mice.

    Science.gov (United States)

    Stockebrand, Malte; Nejad, Ali Sasani; Neu, Axel; Kharbanda, Kusum K; Sauter, Kathrin; Schillemeit, Stefan; Isbrandt, Dirk; Choe, Chi-Un

    2016-08-01

    Skeletal muscles require energy either at constant low (e.g., standing and posture) or immediate high rates (e.g., exercise). To fulfill these requirements, myocytes utilize the phosphocreatine (PCr)/creatine (Cr) system as a fast energy buffer and shuttle. We have generated mice lacking L-arginine:glycine amidino transferase (AGAT), the first enzyme of creatine biosynthesis. These AGAT(-/-) (d/d) mice are devoid of the PCr/Cr system and reveal severely altered oxidative phosphorylation. In addition, they exhibit complete resistance to diet-induced obesity, which is associated with a chronic activation of AMP-activated protein kinase in muscle and white adipose tissue. The underlying metabolic rearrangements have not yet been further analyzed. Here, we performed gene expression analysis in skeletal muscle and a serum amino acid profile of d/d mice revealing transcriptomic and metabolic alterations in pyruvate and glucose pathways. Differential pyruvate tolerance tests demonstrated preferential conversion of pyruvate to alanine, which was supported by increased protein levels of enzymes involved in pyruvate and alanine metabolism. Pyruvate tolerance tests suggested severely impaired hepatic gluconeogenesis despite increased availability of pyruvate and alanine. Furthermore, enzymes of serine production and one-carbon metabolism were significantly up-regulated in d/d mice, indicating increased de novo formation of one-carbon units from carbohydrate metabolism linked to NAD(P)H production. Besides the well-established function of the PCr/Cr system in energy metabolism, our transcriptomic and metabolic analyses suggest that it plays a pivotal role in systemic one-carbon metabolism, oxidation/reduction, and biosynthetic processes. Therefore, the PCr/Cr system is not only an energy buffer and shuttle, but also a crucial component involved in numerous systemic metabolic processes.

  13. From human monocytes to genome-wide binding sites--a protocol for small amounts of blood: monocyte isolation/ChIP-protocol/library amplification/genome wide computational data analysis.

    Directory of Open Access Journals (Sweden)

    Sebastian Weiterer

    Full Text Available Chromatin immunoprecipitation in combination with a genome-wide analysis via high-throughput sequencing is the state of the art method to gain genome-wide representation of histone modification or transcription factor binding profiles. However, chromatin immunoprecipitation analysis in the context of human experimental samples is limited, especially in the case of blood cells. The typically extremely low yields of precipitated DNA are usually not compatible with library amplification for next generation sequencing. We developed a highly reproducible protocol to present a guideline from the first step of isolating monocytes from a blood sample to analyse the distribution of histone modifications in a genome-wide manner.The protocol describes the whole work flow from isolating monocytes from human blood samples followed by a high-sensitivity and small-scale chromatin immunoprecipitation assay with guidance for generating libraries compatible with next generation sequencing from small amounts of immunoprecipitated DNA.

  14. A comparison in association and linkage genome-wide scans for alcoholism susceptibility genes using single-nucleotide polymorphisms.

    Science.gov (United States)

    Chiu, Yen-Feng; Liu, Su-Yun; Tsai, Ya-Yu

    2005-12-30

    We conducted genome-wide linkage scans using both microsatellite and single-nucleotide polymorphism (SNP) markers. Regions showing the strongest evidence of linkage to alcoholism susceptibility genes were identified. Haplotype analyses using a sliding-window approach for SNPs in these regions were performed. In addition, we performed a genome-wide association scan using SNP data. SNPs in these regions with evidence of association (P alcoholism (the most significant SNP had a p-value of 0.030) as those identified from association genomic screening (the most significant SNP had a p-value of 2.0 x 10(-8)).

  15. Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes

    DEFF Research Database (Denmark)

    Imamura, Minako; Takahashi, Atsushi; Yamauchi, Toshimasa;

    2016-01-01

    and subsequent validation analyses (23,399 T2D cases and 31,722 controls) identify 7 new loci with genome-wide significance (PCCDC85A, rs147538848 in FAM60A, rs1575972 near DMRTA1, rs9309245 near ASB3, rs67156297 near ATP8B2, rs7107784 near MIR4686 and rs67839313 near INAFM2...

  16. Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults

    DEFF Research Database (Denmark)

    Graff, Mariaelisa; Scott, Robert A; Justice, Anne E

    2017-01-01

    Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adu...

  17. Genome-wide physical activity interactions in adiposity ― A meta-analysis of 200,452 adults

    NARCIS (Netherlands)

    M.J. Graff (Maud J.L.); R.A. Scott (Robert); A.E. Justice (Anne); Young, K.L. (Kristin L.); M.F. Feitosa (Mary Furlan); Barata, L. (Llilda); T.W. Winkler (Thomas W.); A.Y. Chu (Audrey); A. Mahajan (Anubha); Hadley, D. (David); L. Xue (Luting); T. Workalemahu (Tsegaselassie); N.L. Heard-Costa (Nancy); M. den Hoed (Marcel); T.S. Ahluwalia (Tarunveer Singh); Q. Qi; J.S. Ngwa; F. Renström (Frida); L. Quaye (Lydia); Eicher, J.D. (John D.); Hayes, J.E. (James E.); M. Cornelis (Marilyn); Z. Kutalik (Zoltán); Lim, E. (Elise); J. Luan (Jian'An); J.E. Huffman (Jennifer); Zhang, W. (Weihua); W. Zhao (Wei); Griffin, P.J. (Paula J.); T. Haller (Toomas); S. Ahmad (Shafqat); P. Marques-Vidal (Pedro); Bien, S. (Stephanie); L. Yengo (Loic); A. Teumer (Alexander); A.V. Smith (Albert Vernon); M. Kumari (Meena); Harder, M.N. (Marie Neergaard); J.M. Justesen (Johanne M.); M.E. Kleber (Marcus); Hollensted, M. (Mette); Lohman, K. (Kurt); N.V. Rivera (Natalia); J.B. Whitfield (John B.); Zhao, J.H. (Jing Hua); H.M. Stringham (Heather); L.-P. Lyytikäinen (Leo-Pekka); Huppertz, C. (Charlotte); G.A.H.M. Willemsen (Gonneke); W.J. Peyrot (Wouter ); Y. Wu (Ying); K. Kristiansson (Kati); A. Demirkan (Ayşe); M. Fornage (Myriam); Hassinen, M. (Maija); L.F. Bielak (Lawrence F.); G. Cadby (Gemma); T. Tanaka (Toshiko); R. Mägi (Reedik); P.J. van der Most (Peter); A.U. Jackson (Anne); Bragg-Gresham, J.L. (Jennifer L.); Vitart, V. (Veronique); J. Marten (Jonathan); P. Navarro (Pau); C. Bellis (Claire); D. Pasko (Dorota); Johansson, Å. (Åsa); S. Snitker (Soren); Cheng, Y.-C. (Yu-Ching); J. Eriksson (Joel); Lim, U. (Unhee); Aadahl, M. (Mette); L.S. Adair (Linda); N. Amin (Najaf); B. Balkau (Beverley); Auvinen, J. (Juha); J.P. Beilby (John); Bergman, R.N. (Richard N.); S.M. Bergmann (Sven); Bertoni, A.G. (Alain G.); J. Blangero (John); A. Bonnefond (Amélie); L.L. Bonnycastle (Lori); J.B. Borja (Judith); S. Brage (Soren); F. Busonero; S. Buyske (Steven); H. Campbell (Harry); P.S. Chines (Peter); F.S. Collins (Francis); T. Corre (Tanguy); Smith, G.D. (George Davey); G. Delgado; N. Dueker (Nicole); M. Dörr (Marcus); T. Ebeling (Tapani); G. Eiriksdottir (Gudny); T. Esko (Tõnu); J.D. Faul (Jessica D.); M. Fu (Mao); Færch, K. (Kristine); C. Gieger (Christian); S. Gläser; Gong, J. (Jian); P. Gordon-Larsen (Penny); H. Grallert (Harald); T.B. Grammer (Tanja B); N. Grarup (Niels); G. van Grootheest (Gerard); K. Harald (Kennet); N. Hastie (Nick); A.S. Havulinna (Aki); D.G. Hernandez (Dena); L.A. Hindorff (Lucia A); L.J. Hocking (Lynne); Holmens, O.L. (Oddgeir L.); C. Holzapfel (Christina); J.J. Hottenga (Jouke Jan); J. Huang (Jian); Huang, T. (Tao); J. Hui (Jennie); C. Huth (Cornelia); Hutri-Kähönen, N. (Nina); A. James (Alan); Jansson, J.-O. (John-Olov); M.A. Jhun (Min A.); Juonala, M. (Markus); L. Kinnunen (Leena); H. Koistinen (Heikki); I. Kolcic (Ivana); P. Komulainen (Pirjo); J. Kuusisto (Johanna); K. Kvaløy (Kirsti); M. Kähönen (Mika); T.A. Lakka (Timo); L.J. Launer (Lenore); Lehne, B. (Benjamin); C.M. Lindgren (Cecilia M.); M. Lorentzon (Mattias); R.N. Luben (Robert); M. Marre (Michel); Milaneschi, Y. (Yuri); K.L. Monda (Keri); Montgomery, G.W. (Grant W.); M.H.M. de Moor; Mulas, A. (Antonella); M. Müller-Nurasyid (Martina); Musk, A.W.; Männikkö, R. (Reija); S. Männistö (Satu); N. Narisu (Narisu); M. Nauck (Matthias); J.A. Nettleton (Jennifer ); I.M. Nolte (Ilja M.); A.J. Oldehinkel (Albertine); M. Olden (Matthias); Ong, K.K. (Ken K.); S. Padmanabhan (Sandosh); L. Paternoster (Lavinia); Perez, J. (Jeremiah); M. Perola (Markus); A. Peters (Annette); U. Peters (Ulrike); P.A. Peyser (Patricia A.); I. Prokopenko (Inga); Puolijoki, H. (Hannu); Raitakari, O.T. (Olli T.); T. Rankinen (Tuomo); Rasmussen-Torvik, L.J. (Laura J.); R. Rawal (R.); P.M. Ridker (Paul); L.M. Rose (Lynda); I. Rudan (Igor); Sarti, C. (Cinzia); M.A. Sarzynski (Mark A.); K. Savonen (Kai); W.R. Scott (William R.); S. Sanna (Serena); A.R. Shuldiner (Alan); Sidney, S. (Steve); G. Silbernagel (Günther); B.H. Smith; J.A. Smith (Jennifer A); H. Snieder (Harold); A. Stancáková (Alena); Sternfeld, B. (Barbara); A.J. Swift (Amy); Tammelin, T. (Tuija); S.-T. Tan (Sian-Tsung); B. Thorand (Barbara); D. Thuillier (Dorothee); L. Vandenput (Liesbeth); Vestergaard, H. (Henrik); J.V. van Vliet-Ostaptchouk (Jana); M.-C. Vohl (Marie-Claude); U. Völker (Uwe); G. Waeber (Gérard); Walker, M. (Mark); Wild, S. (Sarah); A. Wong (Andrew); A.F. Wright (Alan); M.C. Zillikens (Carola); Zubair, N. (Niha); C.A. Haiman (Christopher); L. LeMarchand (Loic); U. Gyllensten (Ulf); C. Ohlsson (Claes); A. Hofman (Albert); F. Rivadeneira Ramirez (Fernando); A.G. Uitterlinden (André); L. Perusse (Louis); J.F. Wilson (James); C. Hayward (Caroline); O. Polasek (Ozren); F. Cucca (Francesco); K. Hveem (Kristian); C.A. Hartman (Catharina A.); A. Tönjes (Anke); S. Bandinelli (Stefania); Palmer, L.J. (Lyle J.); Kardia, S.L.R. (Sharon L. R.); R. Rauramaa (Rainer); T.I.A. Sørensen (Thorkild); J. Tuomilehto (Jaakko); V. Salomaa (Veikko); B.W.J.H. Penninx (Brenda); E.J.C. de Geus (Eco); D.I. Boomsma (Dorret); T. Lehtimäki (Terho); M. Mangino (Massimo); Laakso, M. (Markku); C. Bouchard (Claude); N.G. Martin (Nicholas); D. Kuh (Diana); Y. Liu (Yongmei); A. Linneberg (Allan); W. März (Winfried); K. Strauch (Konstantin); M. Kivimaki (Mika); T.B. Harris (Tamara); V. Gudnason (Vilmundur); H. Völzke (Henry); Qi, L. (Lu); M.-R. Jarvelin (Marjo-Riitta); J.C. Chambers (John); J.S. Kooner (Jaspal S.); P. Froguel (Philippe); C. Kooperberg (Charles); P. Vollenweider (Peter); G. Hallmans (Göran); T. Hansen (T.); O. Pedersen (Oluf); A. Metspalu (Andres); N.J. Wareham (Nick); C. Langenberg (Claudia); D.R. Weir (David); D.J. Porteous (David J.); E.A. Boerwinkle (Eric); D.I. Chasman (Daniel); Abecasis, G.R. (Gonçalo R.); I. Barroso (Inês); McCarthy, M.I. (Mark I.); T.M. Frayling (Timothy); O’Connell, J.R. (Jeffrey R.); C.M. van Duijn (Cock); M. Boehnke (Michael); I.M. Heid (Iris); K.L. Mohlke (Karen); D.P. Strachan (David); C.S. Fox (Caroline); Liu, C.-T. (Ching-Ti); J.N. Hirschhorn (Joel); Klein, R.J. (Robert J.); A.D. Johnson (Andrew); I.B. Borecki (Ingrid); P.W. Franks (Paul); K.E. North (Kari); L.A. Cupples (Adrienne); R.J.F. Loos (Ruth); T.O. Kilpeläinen (Tuomas)

    2017-01-01

    textabstractPhysical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 20

  18. Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults

    NARCIS (Netherlands)

    Graff, Mariaelisa; Scott, Robert A.; Justice, Anne E.; Young, Kristin L.; Feitosa, Mary F.; Barata, Llilda; Winkler, Thomas W.; Chu, Audrey Y.; Mahajan, Anubha; Hadley, David; Xue, Luting; Workalemahu, Tsegaselassie; Heard-Costa, Nancy L.; den Hoed, Marcel; Ahluwalia, Tarunveer S.; Qi, Qibin; Ngwa, Julius S.; Renstrom, Frida; Quaye, Lydia; Eicher, John D.; Hayes, James E.; Cornelis, Marilyn; Kutalik, Zoltan; Lim, Elise; Luan, Jian'an; Huffman, Jennifer E.; Zhang, Weihua; Zhao, Wei; Griffin, Paula J.; Haller, Toomas; Ahmad, Shafqat; Marques-Vidal, Pedro M.; Bien, Stephanie; Yengo, Loic; Teumer, Alexander; Smith, Albert Vernon; Kumari, Meena; Harder, Marie Neergaard; Justesen, Johanne Marie; Kleber, Marcus E.; Hollensted, Mette; Lohman, Kurt; Rivera, Natalia V.; Whitfield, John B.; Zhao, Jing Hua; Stringham, Heather M.; Lyytikainen, Leo-Pekka; Huppertz, Charlotte; Willemsen, Gonneke; Peyrot, Wouter J.; Wu, Ying; Kristiansson, Kati; Demirkan, Ayse; Fornage, Myriam; Hassinen, Maija; Bielak, Lawrence F.; Cadby, Gemma; Tanaka, Toshiko; Magl, Reedlk; Van der Most, Peter J.; Jackson, Anne U.; Bragg-Gresham, Jennifer L.; Vitart, Veronique; Marten, Jonathan; Navarro, Pau; Bellis, Claire; Pasko, Dorota; Johansson, Asa; Snitker, Soren; Cheng, Yu-Ching; Eriksson, Joel; Lim, Unhee; Aadahl, Mette; Adair, Linda S.; Amin, Najaf; Balkau, Beverley; Auvinen, Juha; Beilby, John; Bergman, Richard N.; Bergmann, Sven; Bertoni, Alain G.; Blangero, John; Bonnefond, Amelle; Bonnycastle, Lori L.; Borja, Judith B.; Brage, Soren; Busonero, Fabio; Buyske, Steve; Campbell, Harry; Chines, Peter S.; Collins, Francis S.; Corre, Tanguy; Smith, George Davey; Delgado, Graciela E.; Dueker, Nicole; Doerr, Marcus; Ebeling, Tapani; Eiriksdottir, Gudny; Esko, Tonu; Faul, Jessica D.; Fu, Mao; Faerch, Kristine; Gieger, Christian; Glaeser, Sven; Gong, Jian; Gordon-Larsen, Penny; Grallert, Harald; Grammer, Tanja B.; Grarup, Niels; van Grootheest, Gerard; Harald, Kennet; Hastie, Nicholas D.; Havulinna, Aki S.; Hernandez, Dena; Hindorff, Lucia; Hocking, Lynne J.; Holmens, Oddgeir L.; Holzapfel, Christina; Hottenga, Jouke Jan; Huang, Jie; Huang, Tao; Hui, Jennie; Huth, Cornelia; Hutri-Kahonen, Nina; James, Alan L.; Jansson, John-Olov; Jhun, Min A.; Juonala, Markus; Kinnunen, Leena; Koistinen, Heikki A.; Kolcic, Ivana; Komulainen, Pirjo; Kuusisto, Johanna; Kvaloy, Kirsti; Kahonen, Mika; Lakka, Timo A.; Launer, Lenore J.; Lehne, Benjamin; Lindgren, Cecilia M.; Lorentzon, Mattias; Luben, Robert; Marre, Michel; Milaneschi, Yuri; Monda, Keri L.; Montgomery, Grant W.; De Moor, Marleen H. M.; Mulas, Antonella; Mueller-Nurasyid, Martina; Musk, A. W.; Mannikko, Reija; Mannisto, Satu; Narisu, Narisu; Nauck, Matthias; Nettleton, Jennifer A.; Nolte, Ilja M.; Oldehinkel, Albertine J.; Olden, Matthias; Ong, Ken K.; Padmanabhan, Sandosh; Paternoster, Lavinia; Perez, Jeremiah; Perola, Markus; Peters, Annette; Peters, Ulrike; Peyser, Patricia A.; Prokopenko, Inga; Puolijoki, Hannu; Raitakari, Olli T.; Rankinen, Tuomo; Rasmussen-Torvik, Laura J.; Rawal, Rajesh; Ridker, Paul M.; Rose, Lynda M.; Rudan, Igor; Sarti, Cinzia; Sarzynski, Mark A.; Savonen, Kai; Scott, William R.; Sanna, Serena; Shuldiner, Alan R.; Sidney, Steve; Silbernagel, Guenther; Smith, Blair H.; Smith, Jennifer A.; Snieder, Harold; Stancakova, Alena; Sternfeld, Barbara; Swift, Amy J.; Tammelin, Tuija; Tan, Sian-Tsung; Thorand, Barbara; Thuillier, Dorothee; Vandenput, Liesbeth; Vestergaard, Henrik; van Vliet-Ostaptchouk, Jana V.; Vohl, Marie-Claude; Voelker, Uwe; Waeber, Gerard; Walker, Mark; Wild, Sarah; Wong, Andrew; Wright, Alan F.; Zillikens, M. Carola; Zubair, Niha; Haiman, Christopher A.; Lemarchand, Loic; Gyllensten, Ulf; Ohlsson, Claes; Ohlsson, Claes; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; Perusse, Louis; Wilson, James F.; Hayward, Caroline; Polasek, Ozren; Cucca, Francesco; Hveem, Kristian; Hartman, Catharina A.; Toenjes, Anke; Bandinelli, Stefania; Palmer, Lyle J.; Kardia, Sharon L. R.; Rauramaa, Rainer; Sorensen, Thorkild I. A.; Tuomilehto, Jaakko; Salomaa, Veikko; Penninx, Brenda W. J. H.; de Geus, Eco J. C.; Boomsma, Dorret I.; Lehtimaki, Terho; Mangino, Massimo; Laakso, Markku; Bouchard, Claude; Martin, Nicholas G.; Kuh, Diana; Liu, Yongmei; Linneberg, Allan; Maerz, Winfried; Strauch, Konstantin; Kivimaki, Mika; Harris, Tamara B.; Gudnason, Vilmundur; Voelzke, Henry; Qi, Lu; Jarvelin, Marjo-Riitta; Chambers, John C.; Kooner, Jaspal S.; Froguel, Philippe; Kooperberg, Charles; Vollenweider, Peter; Hallmans, Goran; Hansen, Torben; Pedersen, Oluf; Metspalu, Andres; Wareham, Nicholas J.; Langenberg, Claudia; Weir, David R.; Porteous, David J.; Boerwinkle, Eric; Chasman, Daniel I.; Abecasis, Goncalo R.; Barroso, Ines; McCarthy, Mark I.; Frayling, Timothy M.; O'Connell, Jeffrey R.; van Duijn, Cornelia M.; Boehnke, Michael; Heid, Iris M.; Mohlke, Karen L.; Strachan, David P.; Fox, Caroline S.; Liu, Ching-Ti; Hirschhorn, Joel N.; Klein, Robert J.; Johnson, Andrew D.; Borecki, Ingrid B.; Franks, Paul W.; North, Kari E.; Cupples, L. Adrienne; Loos, Ruth J. F.; Kilpelainen, Tuomas O.

    2017-01-01

    Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults

  19. Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction

    NARCIS (Netherlands)

    Wilk, Jemma B; Shrine, Nick R G; Loehr, Laura R; Zhao, Jing Hua; Manichaikul, Ani; Lopez, Lorna M; Smith, Albert Vernon; Heckbert, Susan R; Smolonska, Joanna; Tang, Wenbo; Loth, Daan W; Curjuric, Ivan; Hui, Jennie; Cho, Michael H; Latourelle, Jeanne C; Henry, Amanda P; Aldrich, Melinda; Bakke, Per; Beaty, Terri H; Bentley, Amy R; Borecki, Ingrid B; Brusselle, Guy G; Burkart, Kristin M; Chen, Ting-hsu; Couper, David; Crapo, James D; Davies, Gail; Dupuis, Josée; Franceschini, Nora; Gulsvik, Amund; Hancock, Dana B; Harris, Tamara B; Hofman, Albert; Imboden, Medea; James, Alan L; Khaw, Kay-Tee; Lahousse, Lies; Launer, Lenore J; Litonjua, Augusto; Liu, Yongmei; Lohman, Kurt K; Lomas, David A; Lumley, Thomas; Marciante, Kristin D; McArdle, Wendy L; Meibohm, Bernd; Morrison, Alanna C; Musk, Arthur W; Myers, Richard H; North, Kari E; Postma, Dirkje S; Psaty, Bruce M; Rich, Stephen S; Rivadeneira, Fernando; Rochat, Thierry; Rotter, Jerome I; Artigas, María Soler; Starr, John M; Uitterlinden, André G; Wareham, Nicholas J; Wijmenga, Cisca; Zanen, Pieter; Province, Michael A; Silverman, Edwin K; Deary, Ian J; Palmer, Lyle J; Cassano, Patricia A; Gudnason, Vilmundur; Barr, R Graham; Loos, Ruth J F; Strachan, David P; London, Stephanie J; Boezen, Hendrika; Probst-Hensch, Nicole; Gharib, Sina A; Hall, Ian P; O'Connor, George T; Tobin, Martin D; Stricker, Bruno H

    2012-01-01

    RATIONALE: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known. OBJECTIVES: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD asses

  20. Genome-wide landscapes of human local adaptation in Asia.

    Directory of Open Access Journals (Sweden)

    Wei Qian

    Full Text Available Genetic studies of human local adaptation have been facilitated greatly by recent advances in high-throughput genotyping and sequencing technologies. However, few studies have investigated local adaptation in Asian populations on a genome-wide scale and with a high geographic resolution. In this study, taking advantage of the dense population coverage in Southeast Asia, which is the part of the world least studied in term of natural selection, we depicted genome-wide landscapes of local adaptations in 63 Asian populations representing the majority of linguistic and ethnic groups in Asia. Using genome-wide data analysis, we discovered many genes showing signs of local adaptation or natural selection. Notable examples, such as FOXQ1, MAST2, and CDH4, were found to play a role in hair follicle development and human cancer, signal transduction, and tumor repression, respectively. These showed strong indications of natural selection in Philippine Negritos, a group of aboriginal hunter-gatherers living in the Philippines. MTTP, which has associations with metabolic syndrome, body mass index, and insulin regulation, showed a strong signature of selection in Southeast Asians, including Indonesians. Functional annotation analysis revealed that genes and genetic variants underlying natural selections were generally enriched in the functional category of alternative splicing. Specifically, many genes showing significant difference with respect to allele frequency between northern and southern Asian populations were found to be associated with human height and growth and various immune pathways. In summary, this study contributes to the overall understanding of human local adaptation in Asia and has identified both known and novel signatures of natural selection in the human genome.

  1. Genome-wide prediction of C. elegans genetic interactions.

    Science.gov (United States)

    Zhong, Weiwei; Sternberg, Paul W

    2006-03-10

    To obtain a global view of functional interactions among genes in a metazoan genome, we computationally integrated interactome data, gene expression data, phenotype data, and functional annotation data from three model organisms-Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster-and predicted genome-wide genetic interactions in C. elegans. The resulting genetic interaction network (consisting of 18,183 interactions) provides a framework for system-level understanding of gene functions. We experimentally tested the predicted interactions for two human disease-related genes and identified 14 new modifiers.

  2. Genome-wide association studies and contribution to cardiovascular physiology.

    Science.gov (United States)

    Munroe, Patricia B; Tinker, Andrew

    2015-09-01

    The study of family pedigrees with rare monogenic cardiovascular disorders has revealed new molecular players in physiological processes. Genome-wide association studies of complex traits with a heritable component may afford a similar and potentially intellectually richer opportunity. In this review we focus on the interpretation of genetic associations and the issue of causality in relation to known and potentially new physiology. We mainly discuss cardiometabolic traits as it reflects our personal interests, but the issues pertain broadly in many other disciplines. We also describe some of the resources that are now available that may expedite follow up of genetic association signals into observations on causal mechanisms and pathophysiology.

  3. [Genome-wide association study for adolescent idiopathic scoliosis].

    Science.gov (United States)

    Ogura, Yoji; Kou, Ikuyo; Scoliosis, Japan; Matsumoto, Morio; Watanabe, Kota; Ikegawa, Shiro

    2016-04-01

    Adolescent idiopathic scoliosis(AIS)is a polygenic disease. Genome-wide association studies(GWASs)have been performed for a lot of polygenic diseases. For AIS, we conducted GWAS and identified the first AIS locus near LBX1. After the discovery, we have extended our study by increasing the numbers of subjects and SNPs. In total, our Japanese GWAS has identified four susceptibility genes. GWASs for AIS have also been performed in the USA and China, which identified one and three susceptibility genes, respectively. Here we review GWASs in Japan and abroad and functional analysis to clarify the pathomechanism of AIS.

  4. Genome-wide approaches to understanding behaviour in Drosophila melanogaster.

    Science.gov (United States)

    Neville, Megan; Goodwin, Stephen F

    2012-09-01

    Understanding how an organism exhibits specific behaviours remains a major and important biological question. Studying behaviour in a simple model organism like the fruit fly Drosophila melanogaster has the advantages of advanced molecular genetics approaches along with well-defined anatomy and physiology. With advancements in functional genomic technologies, researchers are now attempting to uncover genes and pathways involved in complex behaviours on a genome-wide scale. A systems-level network approach, which will include genomic approaches, to study behaviour will be key to understanding the regulation and modulation of behaviours and the importance of context in regulating them.

  5. Arabidopsis transcription factors: genome-wide comparative analysis among eukaryotes.

    Science.gov (United States)

    Riechmann, J L; Heard, J; Martin, G; Reuber, L; Jiang, C; Keddie, J; Adam, L; Pineda, O; Ratcliffe, O J; Samaha, R R; Creelman, R; Pilgrim, M; Broun, P; Zhang, J Z; Ghandehari, D; Sherman, B K; Yu, G

    2000-12-15

    The completion of the Arabidopsis thaliana genome sequence allows a comparative analysis of transcriptional regulators across the three eukaryotic kingdoms. Arabidopsis dedicates over 5% of its genome to code for more than 1500 transcription factors, about 45% of which are from families specific to plants. Arabidopsis transcription factors that belong to families common to all eukaryotes do not share significant similarity with those of the other kingdoms beyond the conserved DNA binding domains, many of which have been arranged in combinations specific to each lineage. The genome-wide comparison reveals the evolutionary generation of diversity in the regulation of transcription.

  6. Genome-wide association study of sepsis in extremely premature infants.

    Science.gov (United States)

    Srinivasan, Lakshmi; Page, Grier; Kirpalani, Haresh; Murray, Jeffrey C; Das, Abhik; Higgins, Rosemary D; Carlo, Waldemar A; Bell, Edward F; Goldberg, Ronald N; Schibler, Kurt; Sood, Beena G; Stevenson, David K; Stoll, Barbara J; Van Meurs, Krisa P; Johnson, Karen J; Levy, Joshua; McDonald, Scott A; Zaterka-Baxter, Kristin M; Kennedy, Kathleen A; Sánchez, Pablo J; Duara, Shahnaz; Walsh, Michele C; Shankaran, Seetha; Wynn, James L; Cotten, C Michael

    2017-09-01

    To identify genetic variants associated with sepsis (early-onset and late-onset) using a genome-wide association (GWA) analysis in a cohort of extremely premature infants. Previously generated GWA data from the Neonatal Research Network's anonymised genomic database biorepository of extremely premature infants were used for this study. Sepsis was defined as culture-positive early-onset or late-onset sepsis or culture-proven meningitis. Genomic and whole-genome-amplified DNA was genotyped for 1.2 million single-nucleotide polymorphisms (SNPs); 91% of SNPs were successfully genotyped. We imputed 7.2 million additional SNPs. p Values and false discovery rates (FDRs) were calculated from multivariate logistic regression analysis adjusting for gender, gestational age and ancestry. Target statistical value was p<10(-5). Secondary analyses assessed associations of SNPs with pathogen type. Pathway analyses were also run on primary and secondary end points. Data from 757 extremely premature infants were included: 351 infants with sepsis and 406 infants without sepsis. No SNPs reached genome-wide significance levels (5×10(-8)); two SNPs in proximity to FOXC2 and FOXL1 genes achieved target levels of significance. In secondary analyses, SNPs for ELMO1, IRAK2 (Gram-positive sepsis), RALA, IMMP2L (Gram-negative sepsis) and PIEZO2 (fungal sepsis) met target significance levels. Pathways associated with sepsis and Gram-negative sepsis included gap junctions, fibroblast growth factor receptors, regulators of cell division and interleukin-1-associated receptor kinase 2 (p values<0.001 and FDR<20%). No SNPs met genome-wide significance in this cohort of extremely low birthweight infants; however, areas of potential association and pathways meriting further study were identified. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  7. Physiological and transcriptomic analyses reveal a response mechanism to cold stress in Santalum album L. leaves

    Science.gov (United States)

    Zhang, Xinhua; Teixeira da Silva, Jaime A.; Niu, Meiyun; Li, Mingzhi; He, Chunmei; Zhao, Jinhui; Zeng, Songjun; Duan, Jun; Ma, Guohua

    2017-01-01

    Santalum album L. (Indian sandalwood) is an economically important plant species because of its ability to produce highly valued perfume oils. Little is known about the mechanisms by which S. album adapts to low temperatures. In this study, we obtained 100,445,724 raw reads by paired-end sequencing from S. album leaves. Physiological and transcriptomic changes in sandalwood seedlings exposed to 4 °C for 0–48 h were characterized. Cold stress induced the accumulation of malondialdehyde, proline and soluble carbohydrates, and increased the levels of antioxidants. A total of 4,424 differentially expressed genes were responsive to cold, including 3,075 cold-induced and 1,349 cold-repressed genes. When cold stress was prolonged, there was an increase in the expression of cold-responsive genes coding for transporters, responses to stimuli and stress, regulation of defense response, as well as genes related to signal transduction of all phytohormones. Candidate genes in the terpenoid biosynthetic pathway were identified, eight of which were significantly involved in the cold stress response. Gene expression analyses using qRT-PCR showed a peak in the accumulation of SaCBF2 to 4, 50-fold more than control leaves and roots following 12 h and 24 h of cold stress, respectively. The CBF-dependent pathway may play a crucial role in increasing cold tolerance. PMID:28169358

  8. Inhalation toxicity of indoor air pollutants in Drosophila melanogaster using integrated transcriptomics and computational behavior analyses

    Science.gov (United States)

    Eom, Hyun-Jeong; Liu, Yuedan; Kwak, Gyu-Suk; Heo, Muyoung; Song, Kyung Seuk; Chung, Yun Doo; Chon, Tae-Soo; Choi, Jinhee

    2017-06-01

    We conducted an inhalation toxicity test on the alternative animal model, Drosophila melanogaster, to investigate potential hazards of indoor air pollution. The inhalation toxicity of toluene and formaldehyde was investigated using comprehensive transcriptomics and computational behavior analyses. The ingenuity pathway analysis (IPA) based on microarray data suggests the involvement of pathways related to immune response, stress response, and metabolism in formaldehyde and toluene exposure based on hub molecules. We conducted a toxicity test using mutants of the representative genes in these pathways to explore the toxicological consequences of alterations of these pathways. Furthermore, extensive computational behavior analysis showed that exposure to either toluene or formaldehyde reduced most of the behavioral parameters of both wild-type and mutants. Interestingly, behavioral alteration caused by toluene or formaldehyde exposure was most severe in the p38b mutant, suggesting that the defects in the p38 pathway underlie behavioral alteration. Overall, the results indicate that exposure to toluene and formaldehyde via inhalation causes severe toxicity in Drosophila, by inducing significant alterations in gene expression and behavior, suggesting that Drosophila can be used as a potential alternative model in inhalation toxicity screening.

  9. Extraction of venom and venom gland microdissections from spiders for proteomic and transcriptomic analyses.

    Science.gov (United States)

    Garb, Jessica E

    2014-11-03

    Venoms are chemically complex secretions typically comprising numerous proteins and peptides with varied physiological activities. Functional characterization of venom proteins has important biomedical applications, including the identification of drug leads or probes for cellular receptors. Spiders are the most species rich clade of venomous organisms, but the venoms of only a few species are well-understood, in part due to the difficulty associated with collecting minute quantities of venom from small animals. This paper presents a protocol for the collection of venom from spiders using electrical stimulation, demonstrating the procedure on the Western black widow (Latrodectus hesperus). The collected venom is useful for varied downstream analyses including direct protein identification via mass spectrometry, functional assays, and stimulation of venom gene expression for transcriptomic studies. This technique has the advantage over protocols that isolate venom from whole gland homogenates, which do not separate genuine venom components from cellular proteins that are not secreted as part of the venom. Representative results demonstrate the detection of known venom peptides from the collected sample using mass spectrometry. The venom collection procedure is followed by a protocol for dissecting spider venom glands, with results demonstrating that this leads to the characterization of venom-expressed proteins and peptides at the sequence level.

  10. A survey of the venom of the spider Lycosa vittata by biochemical, pharmacological and transcriptomic analyses.

    Science.gov (United States)

    Zhang, Fan; Liu, Changjun; Tan, Huaxin; Wang, Hengyun; Jiang, Yinjie; Liang, Songping; Zhang, Fuping; Liu, Zhonghua

    2015-12-01

    Lycosa vittata, mainly distributed in the southwest of China, is a medium-sized and venomous spider, whose venom remains unexplored so far. This study aims to present an overview of the venom. It mainly consisted of diverse peptides and exhibited inhibitory effects on voltage-gated ion channels in rat dorsal root ganglia neurons, with a strongest inhibition on tetrodotoxin-sensitive and tetrodotoxin-resistant voltage-gated Na(+) channels. Interestingly, it exerted cytotoxicity to cancer cells, with approximately 10-fold selectivity on PC-3 over others, implying the existence of selective anti-PC-3 agents in the venom. Moreover, 51 toxin-like peptides were deduced from the venom gland transcriptome. Bioinformatic analyses suggested their structures might have some distinguished properties and their predicted functions were consistent with the venom activities. This study suggests that the venom is an attractive source of neurotoxins with therapeutic significance, and provides references for the structure and function investigation of specific toxins in the future.

  11. De novo transcriptome analyses of host-fungal interactions in oil palm (Elaeis guineensis Jacq.).

    Science.gov (United States)

    Ho, Chai-Ling; Tan, Yung-Chie; Yeoh, Keat-Ai; Ghazali, Ahmad-Kamal; Yee, Wai-Yan; Hoh, Chee-Choong

    2016-01-19

    Basal stem rot (BSR) is a fungal disease in oil palm (Elaeis guineensis Jacq.) which is caused by hemibiotrophic white rot fungi belonging to the Ganoderma genus. Molecular responses of oil palm to these pathogens are not well known although this information is crucial to strategize effective measures to eradicate BSR. In order to elucidate the molecular interactions between oil palm and G. boninense and its biocontrol fungus Trichoderma harzianum, we compared the root transcriptomes of untreated oil palm seedlings with those inoculated with G. boninense and T. harzianum, respectively. Differential gene expression analyses revealed that jasmonate (JA) and salicylate (SA) may act in an antagonistic manner in affecting the hormone biosynthesis, signaling, and downstream defense responses in G. boninense-treated oil palm roots. In addition, G. boninense may compete with the host to control disease symptom through the transcriptional regulation of ethylene (ET) biosynthesis, reactive oxygen species (ROS) production and scavenging. The strengthening of host cell walls and production of pathogenesis-related proteins as well as antifungal secondary metabolites in host plants, are among the important defense mechanisms deployed by oil palm against G. boninense. Meanwhile, endophytic T. harzianum was shown to improve the of nutrition status and nutrient transportation in host plants. The findings of this analysis have enhanced our understanding on the molecular interactions of G. boninense and oil palm, and also the biocontrol mechanisms involving T. harzianum, thus contributing to future formulations of better strategies for prevention and treatment of BSR.

  12. Genome-Wide Identification and Evolutionary Analysis of the Animal Specific ETS Transcription Factor Family

    OpenAIRE

    Wang, Zhipeng; Zhang, Qin

    2009-01-01

    The ETS proteins are a family of transcription factors (TFs) that regulate a variety of biological processes. We made genome-wide analyses to explore the classification of the ETS gene family. We identified 207 ETS genes which encode 321 ETS TFs from ten animal species. Of the 321 ETS TFs, 155 contain only an ETS domain, about 50% contain a ETS_PEA3_N or a SAM_PNT domain in addition to an ETS domain, the rest (only four) contain a second ETS domain or a second ETS_PEA3_N domain or an another ...

  13. BlueSNP: R package for highly scalable genome-wide association studies using Hadoop clusters.

    Science.gov (United States)

    Huang, Hailiang; Tata, Sandeep; Prill, Robert J

    2013-01-01

    Computational workloads for genome-wide association studies (GWAS) are growing in scale and complexity outpacing the capabilities of single-threaded software designed for personal computers. The BlueSNP R package implements GWAS statistical tests in the R programming language and executes the calculations across computer clusters configured with Apache Hadoop, a de facto standard framework for distributed data processing using the MapReduce formalism. BlueSNP makes computationally intensive analyses, such as estimating empirical p-values via data permutation, and searching for expression quantitative trait loci over thousands of genes, feasible for large genotype-phenotype datasets. http://github.com/ibm-bioinformatics/bluesnp

  14. A genome-wide association study of female sexual dysfunction.

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    Andrea Burri

    Full Text Available BACKGROUND: Female sexual dysfunction (FSD is an important but controversial problem with serious negative impact on women's quality of life. Data from twin studies have shown a genetic contribution to the development and maintenance of FSD. METHODOLOGY/PRINCIPAL FINDINGS: We performed a genome-wide association study (GWAS on 2.5 million single-nucleotide polymorphisms (SNPs in 1,104 female twins (25-81 years of age in a population-based register and phenotypic data on lifelong sexual functioning. Although none reached conventional genome-wide level of significance (10 × -8, we found strongly suggestive associations with the phenotypic dimension of arousal (rs13202860, P = 1.2 × 10(-7; rs1876525, P = 1.2 × 10(-7; and rs13209281 P = 8.3 × 10(-7 on chromosome 6, around 500 kb upstream of the locus HTR1E (5-hydroxytryptamine receptor 1E locus, related to the serotonin brain pathways. We could not replicate previously reported candidate SNPs associated with FSD in the DRD4, 5HT2A and IL-1B loci. CONCLUSIONS/SIGNIFICANCE: We report the first GWAS of FSD symptoms in humans. This has pointed to several "risk alleles" and the implication of the serotonin and GABA pathways. Ultimately, understanding key mechanisms via this research may lead to new FSD treatments and inform clinical practice and developments in psychiatric nosology.

  15. A genome-wide association study of aging.

    Science.gov (United States)

    Walter, Stefan; Atzmon, Gil; Demerath, Ellen W; Garcia, Melissa E; Kaplan, Robert C; Kumari, Meena; Lunetta, Kathryn L; Milaneschi, Yuri; Tanaka, Toshiko; Tranah, Gregory J; Völker, Uwe; Yu, Lei; Arnold, Alice; Benjamin, Emelia J; Biffar, Reiner; Buchman, Aron S; Boerwinkle, Eric; Couper, David; De Jager, Philip L; Evans, Denis A; Harris, Tamara B; Hoffmann, Wolfgang; Hofman, Albert; Karasik, David; Kiel, Douglas P; Kocher, Thomas; Kuningas, Maris; Launer, Lenore J; Lohman, Kurt K; Lutsey, Pamela L; Mackenbach, Johan; Marciante, Kristin; Psaty, Bruce M; Reiman, Eric M; Rotter, Jerome I; Seshadri, Sudha; Shardell, Michelle D; Smith, Albert V; van Duijn, Cornelia; Walston, Jeremy; Zillikens, M Carola; Bandinelli, Stefania; Baumeister, Sebastian E; Bennett, David A; Ferrucci, Luigi; Gudnason, Vilmundur; Kivimaki, Mika; Liu, Yongmei; Murabito, Joanne M; Newman, Anne B; Tiemeier, Henning; Franceschini, Nora

    2011-11-01

    Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.

  16. A Pooled Genome-Wide Association Study of Asperger Syndrome.

    Directory of Open Access Journals (Sweden)

    Varun Warrier

    Full Text Available Asperger Syndrome (AS is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC, which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448 were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448 lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision.

  17. Genome-wide association studies of obesity and metabolic syndrome.

    Science.gov (United States)

    Fall, Tove; Ingelsson, Erik

    2014-01-25

    Until just a few years ago, the genetic determinants of obesity and metabolic syndrome were largely unknown, with the exception of a few forms of monogenic extreme obesity. Since genome-wide association studies (GWAS) became available, large advances have been made. The first single nucleotide polymorphism robustly associated with increased body mass index (BMI) was in 2007 mapped to a gene with for the time unknown function. This gene, now known as fat mass and obesity associated (FTO) has been repeatedly replicated in several ethnicities and is affecting obesity by regulating appetite. Since the first report from a GWAS of obesity, an increasing number of markers have been shown to be associated with BMI, other measures of obesity or fat distribution and metabolic syndrome. This systematic review of obesity GWAS will summarize genome-wide significant findings for obesity and metabolic syndrome and briefly give a few suggestions of what is to be expected in the next few years. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  18. Genome-wide mapping of DNA strand breaks.

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    Frédéric Leduc

    Full Text Available Determination of cellular DNA damage has so far been limited to global assessment of genome integrity whereas nucleotide-level mapping has been restricted to specific loci by the use of specific primers. Therefore, only limited DNA sequences can be studied and novel regions of genomic instability can hardly be discovered. Using a well-characterized yeast model, we describe a straightforward strategy to map genome-wide DNA strand breaks without compromising nucleotide-level resolution. This technique, termed "damaged DNA immunoprecipitation" (dDIP, uses immunoprecipitation and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin end-labeling (TUNEL to capture DNA at break sites. When used in combination with microarray or next-generation sequencing technologies, dDIP will allow researchers to map genome-wide DNA strand breaks as well as other types of DNA damage and to establish a clear profiling of altered genes and/or intergenic sequences in various experimental conditions. This mapping technique could find several applications for instance in the study of aging, genotoxic drug screening, cancer, meiosis, radiation and oxidative DNA damage.

  19. A Pooled Genome-Wide Association Study of Asperger Syndrome.

    Science.gov (United States)

    Warrier, Varun; Chakrabarti, Bhismadev; Murphy, Laura; Chan, Allen; Craig, Ian; Mallya, Uma; Lakatošová, Silvia; Rehnstrom, Karola; Peltonen, Leena; Wheelwright, Sally; Allison, Carrie; Fisher, Simon E; Baron-Cohen, Simon

    2015-01-01

    Asperger Syndrome (AS) is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC), which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls) of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448) were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448) lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision.

  20. Genome-wide patterns of Arabidopsis gene expression in nature.

    Directory of Open Access Journals (Sweden)

    Christina L Richards

    Full Text Available Organisms in the wild are subject to multiple, fluctuating environmental factors, and it is in complex natural environments that genetic regulatory networks actually function and evolve. We assessed genome-wide gene expression patterns in the wild in two natural accessions of the model plant Arabidopsis thaliana and examined the nature of transcriptional variation throughout its life cycle and gene expression correlations with natural environmental fluctuations. We grew plants in a natural field environment and measured genome-wide time-series gene expression from the plant shoot every three days, spanning the seedling to reproductive stages. We find that 15,352 genes were expressed in the A. thaliana shoot in the field, and accession and flowering status (vegetative versus flowering were strong components of transcriptional variation in this plant. We identified between ∼110 and 190 time-varying gene expression clusters in the field, many of which were significantly overrepresented by genes regulated by abiotic and biotic environmental stresses. The two main principal components of vegetative shoot gene expression (PC(veg correlate to temperature and precipitation occurrence in the field. The largest PC(veg axes included thermoregulatory genes while the second major PC(veg was associated with precipitation and contained drought-responsive genes. By exposing A. thaliana to natural environments in an open field, we provide a framework for further understanding the genetic networks that are deployed in natural environments, and we connect plant molecular genetics in the laboratory to plant organismal ecology in the wild.

  1. Planning and executing a genome wide association study (GWAS).

    Science.gov (United States)

    Sale, Michèle M; Mychaleckyj, Josyf C; Chen, Wei-Min

    2009-01-01

    In recent years, genome-wide association approaches have proven a powerful and successful strategy to identify genetic contributors to complex traits, including a number of endocrine disorders. Their success has meant that genome wide association studies (GWAS) are fast becoming the default study design for discovery of new genetic variants that influence a clinical trait or phenotype. This chapter focuses on a number of key elements that require consideration for the successful conduct of a GWAS. Although many of the considerations are common to any genetic study, the greater cost, extreme multiple testing, and greater openness to data sharing require specific awareness and planning by investigators. In the section on designing a GWAS, we reflect on ethical considerations, study design, selection of phenotype/s, power considerations, sample tracking and storage issues, and genotyping product selection. During execution, important considerations include DNA quantity and preparation, genotyping methods, quality control checks of genotype data, in silico genotyping (imputation), tests of association, and replication of association signals. Although the field of human genetics is rapidly evolving, recent experiences can help guide an investigator in making practical and methodological choices that will eventually determine the overall quality of GWAS results. Given the investment to recruit patient populations or cohorts that are powered for a GWAS, and the still substantial costs associated with genotyping, it is helpful to be aware of these aspects to maximize the likelihood of success, especially where there is an opportunity for implementing them prospectively.

  2. Genome-wide patterns of nucleotide polymorphism in domesticated rice.

    Directory of Open Access Journals (Sweden)

    Ana L Caicedo

    2007-09-01

    Full Text Available Domesticated Asian rice (Oryza sativa is one of the oldest domesticated crop species in the world, having fed more people than any other plant in human history. We report the patterns of DNA sequence variation in rice and its wild ancestor, O. rufipogon, across 111 randomly chosen gene fragments, and use these to infer the evolutionary dynamics that led to the origins of rice. There is a genome-wide excess of high-frequency derived single nucleotide polymorphisms (SNPs in O. sativa varieties, a pattern that has not been reported for other crop species. We developed several alternative models to explain contemporary patterns of polymorphisms in rice, including a (i selectively neutral population bottleneck model, (ii bottleneck plus migration model, (iii multiple selective sweeps model, and (iv bottleneck plus selective sweeps model. We find that a simple bottleneck model, which has been the dominant demographic model for domesticated species, cannot explain the derived nucleotide polymorphism site frequency spectrum in rice. Instead, a bottleneck model that incorporates selective sweeps, or a more complex demographic model that includes subdivision and gene flow, are more plausible explanations for patterns of variation in domesticated rice varieties. If selective sweeps are indeed the explanation for the observed nucleotide data of domesticated rice, it suggests that strong selection can leave its imprint on genome-wide polymorphism patterns, contrary to expectations that selection results only in a local signature of variation.

  3. Genome-wide mapping of DNA methylation in chicken.

    Directory of Open Access Journals (Sweden)

    Qinghe Li

    Full Text Available Cytosine DNA methylation is an important epigenetic modification termed as the fifth base that functions in diverse processes. Till now, the genome-wide DNA methylation maps of many organisms has been reported, such as human, Arabidopsis, rice and silkworm, but the methylation pattern of bird remains rarely studied. Here we show the genome-wide DNA methylation map of bird, using the chicken as a model organism and an immunocapturing approach followed by high-throughput sequencing. In both of the red jungle fowl and the avian broiler, DNA methylation was described separately for the liver and muscle tissue. Generally, chicken displays analogous methylation pattern with that of animals and plants. DNA methylation is enriched in the gene body regions and the repetitive sequences, and depleted in the transcription start site (TSS and the transcription termination site (TTS. Most of the CpG islands in the chicken genome are kept in unmethylated state. Promoter methylation is negatively correlated with the gene expression level, indicating its suppressive role in regulating gene transcription. This work contributes to our understanding of epigenetics in birds.

  4. Genome-Wide Scan for Methylation Profiles in Keloids

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    Lamont R. Jones

    2015-01-01

    Full Text Available Keloids are benign fibroproliferative tumors of the skin which commonly occur after injury mainly in darker skinned patients. Medical treatment is fraught with high recurrence rates mainly because of an incomplete understanding of the biological mechanisms that lead to keloids. The purpose of this project was to examine keloid pathogenesis from the epigenome perspective of DNA methylation. Genome-wide profiling used the Infinium HumanMethylation450 BeadChip to interrogate DNA from 6 fresh keloid and 6 normal skin samples from 12 anonymous donors. A 3-tiered approach was used to call out genes most differentially methylated between keloid and normal. When compared to normal, of the 685 differentially methylated CpGs at Tier 3, 510 were hypomethylated and 175 were hypermethylated with 190 CpGs in promoter and 495 in nonpromoter regions. The 190 promoter region CpGs corresponded to 152 genes: 96 (63% were hypomethylated and 56 (37% hypermethylated. This exploratory genome-wide scan of the keloid methylome highlights a predominance of hypomethylated genomic landscapes, favoring nonpromoter regions. DNA methylation, as an additional mechanism for gene regulation in keloid pathogenesis, holds potential for novel treatments that reverse deleterious epigenetic changes. As an alternative mechanism for regulating genes, epigenetics may explain why gene mutations alone do not provide definitive mechanisms for keloid formation.

  5. Genome-wide association study in German patients with attention deficit/hyperactivity disorder.

    Science.gov (United States)

    Hinney, Anke; Scherag, André; Jarick, Ivonne; Albayrak, Özgür; Pütter, Carolin; Pechlivanis, Sonali; Dauvermann, Maria R; Beck, Sebastian; Weber, Heike; Scherag, Susann; Nguyen, Trang T; Volckmar, Anna-Lena; Knoll, Nadja; Faraone, Stephen V; Neale, Benjamin M; Franke, Barbara; Cichon, Sven; Hoffmann, Per; Nöthen, Markus M; Schreiber, Stefan; Jöckel, Karl-Heinz; Wichmann, H-Erich; Freitag, Christine; Lempp, Thomas; Meyer, Jobst; Gilsbach, Susanne; Herpertz-Dahlmann, Beate; Sinzig, Judith; Lehmkuhl, Gerd; Renner, Tobias J; Warnke, Andreas; Romanos, Marcel; Lesch, Klaus-Peter; Reif, Andreas; Schimmelmann, Benno G; Hebebrand, Johannes

    2011-12-01

    The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome-wide association studies (GWAS) have not led to the identification of significant results. We performed a GWAS based on 495 German young patients with ADHD (according to DSM-IV criteria; Human660W-Quadv1; Illumina, San Diego, CA) and on 1,300 population-based adult controls (HumanHap550v3; Illumina). Some genes neighboring the single nucleotide polymorphisms (SNPs) with the lowest P-values (best P-value: 8.38 × 10(-7)) have potential relevance for ADHD (e.g., glutamate receptor, metabotropic 5 gene, GRM5). After quality control, the 30 independent SNPs with the lowest P-values (P-values ≤ 7.57 × 10(-5) ) were chosen for confirmation. Genotyping of these SNPs in up to 320 independent German families comprising at least one child with ADHD revealed directionally consistent effect-size point estimates for 19 (10 not consistent) of the SNPs. In silico analyses of the 30 SNPs in the largest meta-analysis so far (2,064 trios, 896 cases, and 2,455 controls) revealed directionally consistent effect-size point estimates for 16 SNPs (11 not consistent). None of the combined analyses revealed a genome-wide significant result. SNPs in previously described autosomal candidate genes did not show significantly lower P-values compared to SNPs within random sets of genes of the same size. We did not find genome-wide significant results in a GWAS of German children with ADHD compared to controls. The second best SNP is located in an intron of GRM5, a gene located within a recently described region with an infrequent copy number variation in patients with ADHD.

  6. Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology.

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    John R Shaffer

    2016-08-01

    Full Text Available Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array imputed to the 1000 Genomes reference panel (Phase 3. We observed genome-wide significant associations (p < 5 x 10-8 for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: MAFB, PAX9, MIPOL1, ALX3, HDAC8, and PAX1. We also tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features. Improved understanding of the genes associated with facial morphology in healthy individuals can provide insights into the pathways and mechanisms controlling normal and abnormal facial morphogenesis.

  7. Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis.

    Science.gov (United States)

    Yildiz, Gokhan; Arslan-Ergul, Ayca; Bagislar, Sevgi; Konu, Ozlen; Yuzugullu, Haluk; Gursoy-Yuzugullu, Ozge; Ozturk, Nuri; Ozen, Cigdem; Ozdag, Hilal; Erdal, Esra; Karademir, Sedat; Sagol, Ozgul; Mizrak, Dilsa; Bozkaya, Hakan; Ilk, Hakki Gokhan; Ilk, Ozlem; Bilen, Biter; Cetin-Atalay, Rengul; Akar, Nejat; Ozturk, Mehmet

    2013-01-01

    Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become "immortal") by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during hepatocellular carcinoma (HCC) development in patients with liver cirrhosis, however, the accompanying transcriptional changes are virtually unknown. We investigated genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Initially, we performed transcriptome analysis of senescent and immortal clones of Huh7 HCC cell line, and identified genes with significant differential expression to establish a senescence-related gene list. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Based on these distinctive gene expression features we developed a 15-gene

  8. Genome-wide analysis of the MYB transcription factor superfamily in soybean

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    Du Hai

    2012-07-01

    Full Text Available Abstract Background The MYB superfamily constitutes one of the most abundant groups of transcription factors described in plants. Nevertheless, their functions appear to be highly diverse and remain rather unclear. To date, no genome-wide characterization of this gene family has been conducted in a legume species. Here we report the first genome-wide analysis of the whole MYB superfamily in a legume species, soybean (Glycine max, including the gene structures, phylogeny, chromosome locations, conserved motifs, and expression patterns, as well as a comparative genomic analysis with Arabidopsis. Results A total of 244 R2R3-MYB genes were identified and further classified into 48 subfamilies based on a phylogenetic comparative analysis with their putative orthologs, showed both gene loss and duplication events. The phylogenetic analysis showed that most characterized MYB genes with similar functions are clustered in the same subfamily, together with the identification of orthologs by synteny analysis, functional conservation among subgroups of MYB genes was strongly indicated. The phylogenetic relationships of each subgroup of MYB genes were well supported by the highly conserved intron/exon structures and motifs outside the MYB domain. Synonymous nucleotide substitution (dN/dS analysis showed that the soybean MYB DNA-binding domain is under strong negative selection. The chromosome distribution pattern strongly indicated that genome-wide segmental and tandem duplication contribute to the expansion of soybean MYB genes. In addition, we found that ~ 4% of soybean R2R3-MYB genes had undergone alternative splicing events, producing a variety of transcripts from a single gene, which illustrated the extremely high complexity of transcriptome regulation. Comparative expression profile analysis of R2R3-MYB genes in soybean and Arabidopsis revealed that MYB genes play conserved and various roles in plants, which is indicative of a divergence in

  9. Layers of epistasis: genome-wide regulatory networks and network approaches to genome-wide association studies

    Science.gov (United States)

    Cowper-Sal·lari, Richard; Cole, Michael D.; Karagas, Margaret R.; Lupien, Mathieu; Moore, Jason H.

    2010-01-01

    The conceptual foundation of the genome-wide association study (GWAS) has advanced unchecked since its conception. A revision might seem premature as the potential of GWAS has not been fully realized. Multiple technical and practical limitations need to be overcome before GWAS can be fairly criticized. But with the completion of hundreds of studies and a deeper understanding of the genetic architecture of disease, warnings are being raised. The results compiled to date indicate that risk-associated variants lie predominantly in non-coding regions of the genome. Additionally, alternative methodologies are uncovering large and heterogeneous sets of rare variants underlying disease. The fear is that, even in its fulfilment, the current GWAS paradigm might be incapable of dissecting all kinds of phenotypes. In the following text we review several initiatives that aim to overcome these limitations. The overarching theme of these studies is the inclusion of biological knowledge to both the analysis and interpretation of genotyping data. GWAS is uninformed of biology by design and although there is some virtue in its simplicity it is also its most conspicuous deficiency. We propose a framework in which to integrate these novel approaches, both empirical and theoretical, in the form of a genome-wide regulatory network (GWRN). By processing experimental data into networks, emerging data types based on chromatin-immunoprecipitation are made computationally tractable. This will give GWAS re-analysis efforts the most current and relevant substrates, and root them firmly on our knowledge of human disease. PMID:21197657

  10. A genome-wide association study of optic disc parameters.

    Directory of Open Access Journals (Sweden)

    Wishal D Ramdas

    2010-06-01

    Full Text Available The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR. Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72x10(-19 within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67x10(-33 within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15x10(-11 in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93x10(-10 within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612, and the TwinsUK cohort (N = 843. Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant, and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin.

  11. Genome-wide association study of antisocial personality disorder

    Science.gov (United States)

    Rautiainen, M-R; Paunio, T; Repo-Tiihonen, E; Virkkunen, M; Ollila, H M; Sulkava, S; Jolanki, O; Palotie, A; Tiihonen, J

    2016-01-01

    The pathophysiology of antisocial personality disorder (ASPD) remains unclear. Although the most consistent biological finding is reduced grey matter volume in the frontal cortex, about 50% of the total liability to developing ASPD has been attributed to genetic factors. The contributing genes remain largely unknown. Therefore, we sought to study the genetic background of ASPD. We conducted a genome-wide association study (GWAS) and a replication analysis of Finnish criminal offenders fulfilling DSM-IV criteria for ASPD (N=370, N=5850 for controls, GWAS; N=173, N=3766 for controls and replication sample). The GWAS resulted in suggestive associations of two clusters of single-nucleotide polymorphisms at 6p21.2 and at 6p21.32 at the human leukocyte antigen (HLA) region. Imputation of HLA alleles revealed an independent association with DRB1*01:01 (odds ratio (OR)=2.19 (1.53–3.14), P=1.9 × 10-5). Two polymorphisms at 6p21.2 LINC00951–LRFN2 gene region were replicated in a separate data set, and rs4714329 reached genome-wide significance (OR=1.59 (1.37–1.85), P=1.6 × 10−9) in the meta-analysis. The risk allele also associated with antisocial features in the general population conditioned for severe problems in childhood family (β=0.68, P=0.012). Functional analysis in brain tissue in open access GTEx and Braineac databases revealed eQTL associations of rs4714329 with LINC00951 and LRFN2 in cerebellum. In humans, LINC00951 and LRFN2 are both expressed in the brain, especially in the frontal cortex, which is intriguing considering the role of the frontal cortex in behavior and the neuroanatomical findings of reduced gray matter volume in ASPD. To our knowledge, this is the first study showing genome-wide significant and replicable findings on genetic variants associated with any personality disorder. PMID:27598967

  12. High-resolution genome-wide mapping of histone modifications.

    Science.gov (United States)

    Roh, Tae-young; Ngau, Wing Chi; Cui, Kairong; Landsman, David; Zhao, Keji

    2004-08-01

    The expression patterns of eukaryotic genomes are controlled by their chromatin structure, consisting of nucleosome subunits in which DNA of approximately 146 bp is wrapped around a core of 8 histone molecules. Post-translational histone modifications play an essential role in modifying chromatin structure. Here we apply a combination of SAGE and chromatin immunoprecipitation (ChIP) protocols to determine the distribution of hyperacetylated histones H3 and H4 in the Saccharomyces cerevisiae genome. We call this approach genome-wide mapping technique (GMAT). Using GMAT, we find that the highest acetylation levels are detected in the 5' end of a gene's coding region, but not in the promoter. Furthermore, we show that the histone acetyltransferase, GCN5p, regulates H3 acetylation in the promoter and 5' end of the coding regions. These findings indicate that GMAT should find valuable applications in mapping target sites of chromatin-modifying enzymes.

  13. Genome-wide association studies in pharmacogenomics of antidepressants.

    Science.gov (United States)

    Lin, Eugene; Lane, Hsien-Yuan

    2015-01-01

    Major depressive disorder (MDD) is one of the most common psychiatric disorders worldwide. Doctors must prescribe antidepressants based on educated guesses due to the fact that it is unmanageable to predict the effectiveness of any particular antidepressant in an individual patient. With the recent advent of scientific research, the genome-wide association study (GWAS) is extensively employed to analyze hundreds of thousands of single nucleotide polymorphisms by high-throughput genotyping technologies. In addition to the candidate-gene approach, the GWAS approach has recently been utilized to investigate the determinants of antidepressant response to therapy. In this study, we reviewed GWAS studies, their limitations and future directions with respect to the pharmacogenomics of antidepressants in MDD.

  14. Genome-wide association studies in pediatric chronic kidney disease.

    Science.gov (United States)

    Gupta, Jayanta; Kanetsky, Peter A; Wuttke, Matthias; Köttgen, Anna; Schaefer, Franz; Wong, Craig S

    2016-08-01

    The genome-wide association study (GWAS) has become an established scientific method that provides an unbiased screen for genetic loci potentially associated with phenotypes of clinical interest, such as chronic kidney disease (CKD). Thus, GWAS provides opportunities to gain new perspectives regarding the genetic architecture of CKD progression by identifying new candidate genes and targets for intervention. As such, it has become an important arm of translational science providing a complementary line of investigation to identify novel therapeutics to treat CKD. In this review, we describe the method and the challenges of performing GWAS in the pediatric CKD population. We also provide an overview of successful GWAS for kidney disease, and we discuss the established pediatric CKD cohorts in North America and Europe that are poised to identify genetic risk variants associated with CKD progression.

  15. Chapter 10: Mining genome-wide genetic markers.

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    Xiang Zhang

    Full Text Available Genome-wide association study (GWAS aims to discover genetic factors underlying phenotypic traits. The large number of genetic factors poses both computational and statistical challenges. Various computational approaches have been developed for large scale GWAS. In this chapter, we will discuss several widely used computational approaches in GWAS. The following topics will be covered: (1 An introduction to the background of GWAS. (2 The existing computational approaches that are widely used in GWAS. This will cover single-locus, epistasis detection, and machine learning methods that have been recently developed in biology, statistic, and computer science communities. This part will be the main focus of this chapter. (3 The limitations of current approaches and future directions.

  16. Genome-wide genetic changes during modern breeding of maize.

    Science.gov (United States)

    Jiao, Yinping; Zhao, Hainan; Ren, Longhui; Song, Weibin; Zeng, Biao; Guo, Jinjie; Wang, Baobao; Liu, Zhipeng; Chen, Jing; Li, Wei; Zhang, Mei; Xie, Shaojun; Lai, Jinsheng

    2012-06-03

    The success of modern maize breeding has been demonstrated by remarkable increases in productivity over the last four decades. However, the underlying genetic changes correlated with these gains remain largely unknown. We report here the sequencing of 278 temperate maize inbred lines from different stages of breeding history, including deep resequencing of 4 lines with known pedigree information. The results show that modern breeding has introduced highly dynamic genetic changes into the maize genome. Artificial selection has affected thousands of targets, including genes and non-genic regions, leading to a reduction in nucleotide diversity and an increase in the proportion of rare alleles. Genetic changes during breeding happen rapidly, with extensive variation (SNPs, indels and copy-number variants (CNVs)) occurring, even within identity-by-descent regions. Our genome-wide assessment of genetic changes during modern maize breeding provides new strategies as well as practical targets for future crop breeding and biotechnology.

  17. AID/APOBEC cytosine deaminase induces genome-wide kataegis

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    Lada Artem G

    2012-12-01

    Full Text Available Abstract Clusters of localized hypermutation in human breast cancer genomes, named “kataegis” (from the Greek for thunderstorm, are hypothesized to result from multiple cytosine deaminations catalyzed by AID/APOBEC proteins. However, a direct link between APOBECs and kataegis is still lacking. We have sequenced the genomes of yeast mutants induced in diploids by expression of the gene for PmCDA1, a hypermutagenic deaminase from sea lamprey. Analysis of the distribution of 5,138 induced mutations revealed localized clusters very similar to those found in tumors. Our data provide evidence that unleashed cytosine deaminase activity is an evolutionary conserved, prominent source of genome-wide kataegis events. Reviewers This article was reviewed by: Professor Sandor Pongor, Professor Shamil R. Sunyaev, and Dr Vladimir Kuznetsov.

  18. DNA Break Mapping Reveals Topoisomerase II Activity Genome-Wide

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    Laura Baranello

    2014-07-01

    Full Text Available Genomic DNA is under constant assault by endogenous and exogenous DNA damaging agents. DNA breakage can represent a major threat to genome integrity but can also be necessary for genome function. Here we present approaches to map DNA double-strand breaks (DSBs and single-strand breaks (SSBs at the genome-wide scale by two methods called DSB- and SSB-Seq, respectively. We tested these methods in human colon cancer cells and validated the results using the Topoisomerase II (Top2-poisoning agent etoposide (ETO. Our results show that the combination of ETO treatment with break-mapping techniques is a powerful method to elaborate the pattern of Top2 enzymatic activity across the genome.

  19. Genome-wide association study of serum selenium concentrations

    DEFF Research Database (Denmark)

    Gong, Jian; Hsu, Li; Harrison, Tabitha

    2013-01-01

    Selenium is an essential trace element and circulating selenium concentrations have been associated with a wide range of diseases. Candidate gene studies suggest that circulating selenium concentrations may be impacted by genetic variation; however, no study has comprehensively investigated...... this hypothesis. Therefore, we conducted a two-stage genome-wide association study to identify genetic variants associated with serum selenium concentrations in 1203 European descents from two cohorts: the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening and the Women’s Health Initiative (WHI). We...... tested association between 2,474,333 single nucleotide polymorphisms (SNPs) and serum selenium concentrations using linear regression models. In the first stage (PLCO) 41 SNPs clustered in 15 regions had p

  20. Genome-wide transcriptional reprogramming under drought stress

    KAUST Repository

    Chen, Hao

    2012-01-01

    Soil water deficit is one of the major factors limiting plant productivity. Plants cope with this adverse environmental condition by coordinating the up- or downregulation of an array of stress responsive genes. Reprogramming the expression of these genes leads to rebalanced development and growth that are in concert with the reduced water availability and that ultimately confer enhanced stress tolerance. Currently, several techniques have been employed to monitor genome-wide transcriptional reprogramming under drought stress. The results from these high throughput studies indicate that drought stress-induced transcriptional reprogramming is dynamic, has temporal and spatial specificity, and is coupled with the circadian clock and phytohormone signaling pathways. © 2012 Springer-Verlag Berlin Heidelberg. All rights are reserved.

  1. Genome-Wide Association Study of Coronary Artery Disease

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    Naomi Ogawa

    2010-01-01

    Full Text Available Coronary artery disease (CAD is a multifactorial disease with environmental and genetic determinants. The genetic determinants of CAD have previously been explored by the candidate gene approach. Recently, the data from the International HapMap Project and the development of dense genotyping chips have enabled us to perform genome-wide association studies (GWAS on a large number of subjects without bias towards any particular candidate genes. In 2007, three chip-based GWAS simultaneously revealed the significant association between common variants on chromosome 9p21 and CAD. This association was replicated among other ethnic groups and also in a meta-analysis. Further investigations have detected several other candidate loci associated with CAD. The chip-based GWAS approach has identified novel and unbiased genetic determinants of CAD and these insights provide the important direction to better understand the pathogenesis of CAD and to develop new and improved preventive measures and treatments for CAD.

  2. A comparison of multivariate genome-wide association methods

    DEFF Research Database (Denmark)

    Galesloot, Tessel E; Van Steen, Kristel; Kiemeney, Lambertus A L M

    2014-01-01

    Joint association analysis of multiple traits in a genome-wide association study (GWAS), i.e. a multivariate GWAS, offers several advantages over analyzing each trait in a separate GWAS. In this study we directly compared a number of multivariate GWAS methods using simulated data. We focused on six...... methods that are implemented in the software packages PLINK, SNPTEST, MultiPhen, BIMBAM, PCHAT and TATES, and also compared them to standard univariate GWAS, analysis of the first principal component of the traits, and meta-analysis of univariate results. We simulated data (N = 1000) for three...... correlation. We compared the power of the methods using empirically fixed significance thresholds (α = 0.05). Our results showed that the multivariate methods implemented in PLINK, SNPTEST, MultiPhen and BIMBAM performed best for the majority of the tested scenarios, with a notable increase in power...

  3. Comparative transcriptomic analyses of vegetable and grain pea (Pisum sativum L. seed development

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    Na eLiu

    2015-11-01

    Full Text Available Understanding the molecular mechanisms regulating pea seed developmental process is extremely important for pea breeding. In this study, we used high-throughput RNA-Seq and bioinformatics analyses to examine the changes in gene expression during seed development in vegetable pea and grain pea, and compare the gene expression profiles of these two pea types. RNA-Seq generated 18.7 G of raw data, which were then de novo assembled into 77,273 unigenes with a mean length of 930 bp. Our results illustrate that transcriptional control during pea seed development is a highly coordinated process. There were 459 and 801 genes differentially expressed at early and late seed maturation stages between vegetable pea and grain pea, respectively. Soluble sugar and starch metabolism related genes were significantly activated during the development of pea seeds coinciding with the onset of accumulation of sugar and starch in the seeds. A comparative analysis of genes involved in sugar and starch biosynthesis in vegetable pea (high seed soluble sugar and low starch and grain pea (high seed starch and low soluble sugar revealed that differential expression of related genes at late development stages results in a negative correlation between soluble sugar and starch biosynthetic flux in vegetable and grain pea seeds. RNA-Seq data was validated by using real-time quantitative RT-PCR analysis for 30 randomly selected genes. To our knowledge, this work represents the first report of seed development transcriptomics in pea. The obtained results provide a foundation to support future efforts to unravel the underlying mechanisms that control the developmental biology of pea seeds, and serve as a valuable resource for improving pea breeding.

  4. Impact of delay to cryopreservation on RNA integrity and genome-wide expression profiles in resected tumor samples.

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    Elodie Caboux

    Full Text Available The quality of tissue samples and extracted mRNA is a major source of variability in tumor transcriptome analysis using genome-wide expression microarrays. During and immediately after surgical tumor resection, tissues are exposed to metabolic, biochemical and physical stresses characterized as "warm ischemia". Current practice advocates cryopreservation of biosamples within 30 minutes of resection, but this recommendation has not been systematically validated by measurements of mRNA decay over time. Using Illumina HumanHT-12 v3 Expression BeadChips, providing a genome-wide coverage of over 24,000 genes, we have analyzed gene expression variation in samples of 3 hepatocellular carcinomas (HCC and 3 lung carcinomas (LC cryopreserved at times up to 2 hours after resection. RNA Integrity Numbers (RIN revealed no significant deterioration of mRNA up to 2 hours after resection. Genome-wide transcriptome analysis detected non-significant gene expression variations of -3.5%/hr (95% CI: -7.0%/hr to 0.1%/hr; p = 0.054. In LC, no consistent gene expression pattern was detected in relation with warm ischemia. In HCC, a signature of 6 up-regulated genes (CYP2E1, IGLL1, CABYR, CLDN2, NQO1, SCL13A5 and 6 down-regulated genes (MT1G, MT1H, MT1E, MT1F, HABP2, SPINK1 was identified (FDR <0.05. Overall, our observations support current recommendation of time to cryopreservation of up to 30 minutes and emphasize the need for identifying tissue-specific genes deregulated following resection to avoid misinterpreting expression changes induced by warm ischemia as pathologically significant changes.

  5. Impact of delay to cryopreservation on RNA integrity and genome-wide expression profiles in resected tumor samples.

    Science.gov (United States)

    Caboux, Elodie; Paciencia, Maria; Durand, Geoffroy; Robinot, Nivonirina; Wozniak, Magdalena B; Galateau-Salle, Françoise; Byrnes, Graham; Hainaut, Pierre; Le Calvez-Kelm, Florence

    2013-01-01

    The quality of tissue samples and extracted mRNA is a major source of variability in tumor transcriptome analysis using genome-wide expression microarrays. During and immediately after surgical tumor resection, tissues are exposed to metabolic, biochemical and physical stresses characterized as "warm ischemia". Current practice advocates cryopreservation of biosamples within 30 minutes of resection, but this recommendation has not been systematically validated by measurements of mRNA decay over time. Using Illumina HumanHT-12 v3 Expression BeadChips, providing a genome-wide coverage of over 24,000 genes, we have analyzed gene expression variation in samples of 3 hepatocellular carcinomas (HCC) and 3 lung carcinomas (LC) cryopreserved at times up to 2 hours after resection. RNA Integrity Numbers (RIN) revealed no significant deterioration of mRNA up to 2 hours after resection. Genome-wide transcriptome analysis detected non-significant gene expression variations of -3.5%/hr (95% CI: -7.0%/hr to 0.1%/hr; p = 0.054). In LC, no consistent gene expression pattern was detected in relation with warm ischemia. In HCC, a signature of 6 up-regulated genes (CYP2E1, IGLL1, CABYR, CLDN2, NQO1, SCL13A5) and 6 down-regulated genes (MT1G, MT1H, MT1E, MT1F, HABP2, SPINK1) was identified (FDR <0.05). Overall, our observations support current recommendation of time to cryopreservation of up to 30 minutes and emphasize the need for identifying tissue-specific genes deregulated following resection to avoid misinterpreting expression changes induced by warm ischemia as pathologically significant changes.

  6. Genome-wide association and genomic selection in animal breeding.

    Science.gov (United States)

    Hayes, Ben; Goddard, Mike

    2010-11-01

    Results from genome-wide association studies in livestock, and humans, has lead to the conclusion that the effect of individual quantitative trait loci (QTL) on complex traits, such as yield, are likely to be small; therefore, a large number of QTL are necessary to explain genetic variation in these traits. Given this genetic architecture, gains from marker-assisted selection (MAS) programs using only a small number of DNA markers to trace a limited number of QTL is likely to be small. This has lead to the development of alternative technology for using the available dense single nucleotide polymorphism (SNP) information, called genomic selection. Genomic selection uses a genome-wide panel of dense markers so that all QTL are likely to be in linkage disequilibrium with at least one SNP. The genomic breeding values are predicted to be the sum of the effect of these SNPs across the entire genome. In dairy cattle breeding, the accuracy of genomic estimated breeding values (GEBV) that can be achieved and the fact that these are available early in life have lead to rapid adoption of the technology. Here, we discuss the design of experiments necessary to achieve accurate prediction of GEBV in future generations in terms of the number of markers necessary and the size of the reference population where marker effects are estimated. We also present a simple method for implementing genomic selection using a genomic relationship matrix. Future challenges discussed include using whole genome sequence data to improve the accuracy of genomic selection and management of inbreeding through genomic relationships.

  7. A genome-wide methylation study on obesity

    Science.gov (United States)

    Xu, Xiaojing; Su, Shaoyong; Barnes, Vernon A.; De Miguel, Carmen; Pollock, Jennifer; Ownby, Dennis; Shi, Huidong; Zhu, Haidong; Snieder, Harold; Wang, Xiaoling

    2013-01-01

    Besides differential methylation, DNA methylation variation has recently been proposed and demonstrated to be a potential contributing factor to cancer risk. Here we aim to examine whether differential variability in methylation is also an important feature of obesity, a typical non-malignant common complex disease. We analyzed genome-wide methylation profiles of over 470,000 CpGs in peripheral blood samples from 48 obese and 48 lean African-American youth aged 14–20 y old. A substantial number of differentially variable CpG sites (DVCs), using statistics based on variances, as well as a substantial number of differentially methylated CpG sites (DMCs), using statistics based on means, were identified. Similar to the findings in cancers, DVCs generally exhibited an outlier structure and were more variable in cases than in controls. By randomly splitting the current sample into a discovery and validation set, we observed that both the DVCs and DMCs identified from the first set could independently predict obesity status in the second set. Furthermore, both the genes harboring DMCs and the genes harboring DVCs showed significant enrichment of genes identified by genome-wide association studies on obesity and related diseases, such as hypertension, dyslipidemia, type 2 diabetes and certain types of cancers, supporting their roles in the etiology and pathogenesis of obesity. We generalized the recent finding on methylation variability in cancer research to obesity and demonstrated that differential variability is also an important feature of obesity-related methylation changes. Future studies on the epigenetics of obesity will benefit from both statistics based on means and statistics based on variances. PMID:23644594

  8. Genome-wide association studies in asthma: progress and pitfalls

    Directory of Open Access Journals (Sweden)

    March ME

    2015-01-01

    Full Text Available Michael E March,1 Patrick MA Sleiman,1,2 Hakon Hakonarson1,2 1Center for Applied Genomics, Children's Hospital of Philadelphia Research Institute, 2Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Abstract: Genetic studies of asthma have revealed that there is considerable heritability to the phenotype. An extensive history of candidate-gene studies has identified a long list of genes associated with immune function that are potentially involved in asthma pathogenesis. However, many of the results of candidate-gene studies have failed to be replicated, leaving in question the true impact of the implicated biological pathways on asthma. With the advent of genome-wide association studies, geneticists are able to examine the association of hundreds of thousands of genetic markers with a phenotype, allowing the hypothesis-free identification of variants associated with disease. Many such studies examining asthma or related phenotypes have been published, and several themes have begun to emerge regarding the biological pathways underpinning asthma. The results of many genome-wide association studies have currently not been replicated, and the large sample sizes required for this experimental strategy invoke difficulties with sample stratification and phenotypic heterogeneity. Recently, large collaborative groups of researchers have formed consortia focused on asthma, with the goals of sharing material and data and standardizing diagnosis and experimental methods. Additionally, research has begun to focus on genetic variants that affect the response to asthma medications and on the biology that generates the heterogeneity in the asthma phenotype. As this work progresses, it will move asthma patients closer to more specific, personalized medicine. Keywords: asthma, genetics, GWAS, pharmacogenetics, biomarkers

  9. Genome-wide expression profiling of complex regional pain syndrome.

    Directory of Open Access Journals (Sweden)

    Eun-Heui Jin

    Full Text Available Complex regional pain syndrome (CRPS is a chronic, progressive, and devastating pain syndrome characterized by spontaneous pain, hyperalgesia, allodynia, altered skin temperature, and motor dysfunction. Although previous gene expression profiling studies have been conducted in animal pain models, there genome-wide expression profiling in the whole blood of CRPS patients has not been reported yet. Here, we successfully identified certain pain-related genes through genome-wide expression profiling in the blood from CRPS patients. We found that 80 genes were differentially expressed between 4 CRPS patients (2 CRPS I and 2 CRPS II and 5 controls (cut-off value: 1.5-fold change and p<0.05. Most of those genes were associated with signal transduction, developmental processes, cell structure and motility, and immunity and defense. The expression levels of major histocompatibility complex class I A subtype (HLA-A29.1, matrix metalloproteinase 9 (MMP9, alanine aminopeptidase N (ANPEP, l-histidine decarboxylase (HDC, granulocyte colony-stimulating factor 3 receptor (G-CSF3R, and signal transducer and activator of transcription 3 (STAT3 genes selected from the microarray were confirmed in 24 CRPS patients and 18 controls by quantitative reverse transcription-polymerase chain reaction (qRT-PCR. We focused on the MMP9 gene that, by qRT-PCR, showed a statistically significant difference in expression in CRPS patients compared to controls with the highest relative fold change (4.0±1.23 times and p = 1.4×10(-4. The up-regulation of MMP9 gene in the blood may be related to the pain progression in CRPS patients. Our findings, which offer a valuable contribution to the understanding of the differential gene expression in CRPS may help in the understanding of the pathophysiology of CRPS pain progression.

  10. Genome-Wide Analysis of Protein and mRNA Copy Numbers in Single Escherichia coli Cells with Single-Molecule Sensitivity.

    Science.gov (United States)

    Taniguchi, Yuichi

    2015-01-01

    Single-cell proteomic and transcriptomic analysis is an emerging approach for providing quantitative and comprehensive characterization of gene functions in individual cells. This analysis, however, is often hampered by insufficient sensitivity for detecting low copy gene expression products such as transcription factors and regulators. Here I describe a method for the quantitative genome-wide analysis of single-cell protein and mRNA copy numbers with single molecule sensitivity for the model organism Escherichia coli.

  11. Genome-wide association study of a quantitative disordered gambling trait.

    Science.gov (United States)

    Lind, Penelope A; Zhu, Gu; Montgomery, Grant W; Madden, Pamela A F; Heath, Andrew C; Martin, Nicholas G; Slutske, Wendy S

    2013-05-01

    Disordered gambling is a moderately heritable trait, but the underlying genetic basis is largely unknown. We performed a genome-wide association study (GWAS) for disordered gambling using a quantitative factor score in 1312 twins from 894 Australian families. Association was conducted for 2 381 914 single-nucleotide polymorphisms (SNPs) using the family-based association test in Merlin followed by gene and pathway enrichment analyses. Although no SNP reached genome-wide significance, six achieved P-values Secondary case-control analyses found two SNPs on chromosome 9 (rs1106076 and rs12305135 near VLDLR) and rs10812227 near FZD10 on chromosome 12 to be significantly associated with lifetime Diagnostic and Statistical Manual of Mental Disorders, fourth edition pathological gambling and South Oaks Gambling Screen classified probable pathological gambling status. Furthermore, several addiction-related pathways were enriched for SNPs associated with disordered gambling. Finally, gene-based analysis of 24 candidate genes for dopamine agonist-induced gambling in individuals with Parkinson's disease suggested an enrichment of SNPs associated with disordered gambling. We report the first GWAS of disordered gambling. While further replication is required, the identification of susceptibility loci and biological pathways will be important in characterizing the biological mechanisms that underpin disordered gambling.

  12. A genome-wide analysis of putative functional and exonic variation associated with extremely high intelligence.

    Science.gov (United States)

    Spain, S L; Pedroso, I; Kadeva, N; Miller, M B; Iacono, W G; McGue, M; Stergiakouli, E; Smith, G D; Putallaz, M; Lubinski, D; Meaburn, E L; Plomin, R; Simpson, M A

    2016-08-01

    Although individual differences in intelligence (general cognitive ability) are highly heritable, molecular genetic analyses to date have had limited success in identifying specific loci responsible for its heritability. This study is the first to investigate exome variation in individuals of extremely high intelligence. Under the quantitative genetic model, sampling from the high extreme of the distribution should provide increased power to detect associations. We therefore performed a case-control association analysis with 1409 individuals drawn from the top 0.0003 (IQ >170) of the population distribution of intelligence and 3253 unselected population-based controls. Our analysis focused on putative functional exonic variants assayed on the Illumina HumanExome BeadChip. We did not observe any individual protein-altering variants that are reproducibly associated with extremely high intelligence and within the entire distribution of intelligence. Moreover, no significant associations were found for multiple rare alleles within individual genes. However, analyses using genome-wide similarity between unrelated individuals (genome-wide complex trait analysis) indicate that the genotyped functional protein-altering variation yields a heritability estimate of 17.4% (s.e. 1.7%) based on a liability model. In addition, investigation of nominally significant associations revealed fewer rare alleles associated with extremely high intelligence than would be expected under the null hypothesis. This observation is consistent with the hypothesis that rare functional alleles are more frequently detrimental than beneficial to intelligence.

  13. Genome-wide association study identified CNP12587 region underlying height variation in Chinese females.

    Directory of Open Access Journals (Sweden)

    Yin-Ping Zhang

    Full Text Available INTRODUCTION: Human height is a highly heritable trait considered as an important factor for health. There has been limited success in identifying the genetic factors underlying height variation. We aim to identify sequence variants associated with adult height by a genome-wide association study of copy number variants (CNVs in Chinese. METHODS: Genome-wide CNV association analyses were conducted in 1,625 unrelated Chinese adults and sex specific subgroup for height variation, respectively. Height was measured with a stadiometer. Affymetrix SNP6.0 genotyping platform was used to identify copy number polymorphisms (CNPs. We constructed a genomic map containing 1,009 CNPs in Chinese individuals and performed a genome-wide association study of CNPs with height. RESULTS: We detected 10 significant association signals for height (p<0.05 in the whole population, 9 and 11 association signals for Chinese female and male population, respectively. A copy number polymorphism (CNP12587, chr18:54081842-54086942, p = 2.41 × 10(-4 was found to be significantly associated with height variation in Chinese females even after strict Bonferroni correction (p = 0.048. Confirmatory real time PCR experiments lent further support for CNV validation. Compared to female subjects with two copies of the CNP, carriers of three copies had an average of 8.1% decrease in height. An important candidate gene, ubiquitin-protein ligase NEDD4-like (NEDD4L, was detected at this region, which plays important roles in bone metabolism by binding to bone formation regulators. CONCLUSIONS: Our findings suggest the important genetic variants underlying height variation in Chinese.

  14. Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster.

    Science.gov (United States)

    Frank, Josef; Cichon, Sven; Treutlein, Jens; Ridinger, Monika; Mattheisen, Manuel; Hoffmann, Per; Herms, Stefan; Wodarz, Norbert; Soyka, Michael; Zill, Peter; Maier, Wolfgang; Mössner, Rainald; Gaebel, Wolfgang; Dahmen, Norbert; Scherbaum, Norbert; Schmäl, Christine; Steffens, Michael; Lucae, Susanne; Ising, Marcus; Müller-Myhsok, Bertram; Nöthen, Markus M; Mann, Karl; Kiefer, Falk; Rietschel, Marcella

    2012-01-01

    Alcohol dependence (AD) is an important contributory factor to the global burden of disease. The etiology of AD involves both environmental and genetic factors, and the disorder has a heritability of around 50%. The aim of the present study was to identify susceptibility genes for AD by performing a genome-wide association study (GWAS). The sample comprised 1333 male in-patients with severe AD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and 2168 controls. These included 487 patients and 1358 controls from a previous GWAS study by our group. All individuals were of German descent. Single-marker tests and a polygenic score-based analysis to assess the combined contribution of multiple markers with small effects were performed. The single nucleotide polymorphism (SNP) rs1789891, which is located between the ADH1B and ADH1C genes, achieved genome-wide significance [P = 1.27E-8, odds ratio (OR) = 1.46]. Other markers from this region were also associated with AD, and conditional analyses indicated that these made a partially independent contribution. The SNP rs1789891 is in complete linkage disequilibrium with the functional Arg272Gln variant (P = 1.24E-7, OR = 1.31) of the ADH1C gene, which has been reported to modify the rate of ethanol oxidation to acetaldehyde in vitro. A polygenic score-based approach produced a significant result (P = 9.66E-9). This is the first GWAS of AD to provide genome-wide significant support for the role of the ADH gene cluster and to suggest a polygenic component to the etiology of AD. The latter result may indicate that many more AD susceptibility genes still await identification.

  15. Meta-analysis of genome-wide association studies of anxiety disorders

    Science.gov (United States)

    Otowa, Takeshi; Hek, Karin; Lee, Minyoung; Byrne, Enda M.; Mirza, Saira S.; Nivard, Michel G.; Bigdeli, Timothy; Aggen, Steven H.; Adkins, Daniel; Wolen, Aaron; Fanous, Ayman; Keller, Matthew C.; Castelao, Enrique; Kutalik, Zoltan; Van der Auwera, Sandra; Homuth, Georg; Nauck, Matthias; Teumer, Alexander; Milaneschi, Yuri; Hottenga, Jouke-Jan; Direk, Nese; Hofman, Albert; Uitterlinden, Andre; Mulder, Cornelis L.; Henders, Anjali K.; Medland, Sarah E.; Gordon, Scott; Heath, Andrew C.; Madden, Pamela A.F.; Pergadia, Michelle; van der Most, Peter J.; Nolte, Ilja M.; van Oort, Floor V.A.; Hartman, Catharina A.; Oldehinkel, Albertine J.; Preisig, Martin; Grabe, Hans Jörgen; Middeldorp, Christel M.; Penninx, Brenda WJH; Boomsma, Dorret; Martin, Nicholas G.; Montgomery, Grant; Maher, Brion S.; van den Oord, Edwin J.; Wray, Naomi R.; Tiemeier, Henning; Hettema, John M.

    2015-01-01

    Anxiety disorders, namely generalized anxiety disorder, panic disorder, and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based upon clinical presentation, anxiety disorders likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based anxiety disorders, we applied two phenotypic approaches: (1) comparisons between categorical anxiety disorder cases and super-normal controls, and (2) quantitative phenotypic factor scores derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65×10−8); for factor scores, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86×10−9). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of anxiety disorders. PMID:26754954

  16. Comparative analysis of genome-wide divergence, domestication footprints and genome-wide association study of root traits for Gossypium hirsutum and Gossypium barbadense

    Science.gov (United States)

    Use of 10,129 singleton SNPs of known genomic location in tetraploid cotton provided unique opportunities to characterize genome-wide diversity among 440 Gossypium hirsutum and 219 G. barbadense cultivars and landrace accessions of widespread origin. Using genome-wide distributed SNPs, we examined ...

  17. Genome-wide characterization of the routes to pluripotency

    NARCIS (Netherlands)

    Hussein, Samer M I; Puri, Mira C; Tonge, Peter D; Benevento, Marco; Corso, Andrew J; Clancy, Jennifer L; Mosbergen, Rowland; Li, Mira; Lee, Dong-Sung; Cloonan, Nicole; Wood, David L A; Munoz, Javier; Middleton, Robert; Korn, Othmar; Patel, Hardip R; White, Carl A; Shin, Jong-Yeon; Gauthier, Maely E; Lê Cao, Kim-Anh; Kim, Jong-Il; Mar, Jessica C; Shakiba, Nika; Ritchie, William; Rasko, John E J; Grimmond, Sean M; Zandstra, Peter W; Wells, Christine A; Preiss, Thomas; Seo, Jeong-Sun; Heck, Albert J R; Rogers, Ian M; Nagy, Andras

    2014-01-01

    Somatic cell reprogramming to a pluripotent state continues to challenge many of our assumptions about cellular specification, and despite major efforts, we lack a complete molecular characterization of the reprograming process. To address this gap in knowledge, we generated extensive transcriptomic

  18. Non-replication study of a genome-wide association study for hypertension and blood pressure in African Americans

    Directory of Open Access Journals (Sweden)

    Kidambi Srividya

    2012-04-01

    Full Text Available Abstract Background A recent genome wide association study in 1017 African Americans identified several single nucleotide polymorphisms that reached genome-wide significance for systolic blood pressure. We attempted to replicate these findings in an independent sample of 2474 unrelated African Americans in the Milwaukee metropolitan area; 53% were women and 47% were hypertensives. Methods We evaluated sixteen top associated SNPs from the above genome wide association study for hypertension as a binary trait or blood pressure as a continuous trait. In addition, we evaluated eight single nucleotide polymorphisms located in two genes (STK-39 and CDH-13 found to be associated with systolic and diastolic blood pressures by other genome wide association studies in European and Amish populations. TaqMan MGB-based chemistry with fluorescent probes was used for genotyping. We had an adequate sample size (80% power to detect an effect size of 1.2-2.0 for all the single nucleotide polymorphisms for hypertension as a binary trait, and 1% variance in blood pressure as a continuous trait. Quantitative trait analyses were performed both by excluding and also by including subjects on anti-hypertensive therapy (after adjustments were made for anti-hypertensive medications. Results For all 24 SNPs, no statistically significant differences were noted in the minor allele frequencies between cases and controls. One SNP (rs2146204 showed borderline association (p = 0.006 with hypertension status using recessive model and systolic blood pressure (p = 0.02, but was not significant after adjusting for multiple comparisons. In quantitative trait analyses, among normotensives only, rs12748299 was associated with SBP (p = 0.002. In addition, several nominally significant associations were noted with SBP and DBP among normotensives but none were statistically significant. Conclusions This study highlights the importance of replication to confirm the validity of genome wide

  19. Comparative analyses of lipidomes and transcriptomes reveal a concerted action of multiple defensive systems against photooxidative stress in Haematococcus pluvialis.

    Science.gov (United States)

    Gwak, Yunho; Hwang, Yong-sic; Wang, Baobei; Kim, Minju; Jeong, Jooyeon; Lee, Choul-Gyun; Hu, Qiang; Han, Danxiang; Jin, EonSeon

    2014-08-01

    Haematococcus pluvialis cells predominantly remain in the macrozooid stage under favourable environmental conditions but are rapidly differentiated into haematocysts upon exposure to various environmental stresses. Haematocysts are characterized by massive accumulations of astaxanthin sequestered in cytosolic oil globules. Lipidomic analyses revealed that synthesis of the storage lipid triacylglycerol (TAG) was substantially stimulated under high irradiance. Simultaneously, remodelling of membrane glycerolipids occurred as a result of dramatic reductions in chloroplast membrane glycolipids but remained unchanged or declined slightly in extraplastidic membrane glycerolipids. De novo assembly of transcriptomes revealed the genomic and metabolic features of this unsequenced microalga. Comparative transcriptomic analysis showed that so-called resting cells (haematocysts) may be more active than fast-growing vegetative cells (macrozooids) regarding metabolic pathways and functions. Comparative transcriptomic analyses of astaxanthin biosynthesis suggested that the non-mevalonate pathway mediated the synthesis of isopentenyl diphosphate, as the majority of genes involved in subsequent astaxanthin biosynthesis were substantially up-regulated under high irradiance, with the genes encoding phytoene synthase, phytoene desaturase, and β-carotene hydroxylase identified as the most prominent regulatory components. Accumulation of TAG under high irradiance was attributed to moderate up-regulation of de novo fatty acid biosynthesis at the gene level as well as to moderate elevation of the TAG assembly pathways. Additionally, inferred from transcriptomic differentiation, an increase in reactive oxygen species (ROS) scavenging activity, a decrease in ROS production, and the relaxation of over-reduction of the photosynthetic electron transport chain will work together to protect against photooxidative stress in H. pluvialis under high irradiance. © The Author 2014. Published by

  20. Semantically enabling a genome-wide association study database

    Directory of Open Access Journals (Sweden)

    Beck Tim

    2012-12-01

    Full Text Available Abstract Background The amount of data generated from genome-wide association studies (GWAS has grown rapidly, but considerations for GWAS phenotype data reuse and interchange have not kept pace. This impacts on the work of GWAS Central – a free and open access resource for the advanced querying and comparison of summary-level genetic association data. The benefits of employing ontologies for standardising and structuring data are widely accepted. The complex spectrum of observed human phenotypes (and traits, and the requirement for cross-species phenotype comparisons, calls for reflection on the most appropriate solution for the organisation of human phenotype data. The Semantic Web provides standards for the possibility of further integration of GWAS data and the ability to contribute to the web of Linked Data. Results A pragmatic consideration when applying phenotype ontologies to GWAS data is the ability to retrieve all data, at the most granular level possible, from querying a single ontology graph. We found the Medical Subject Headings (MeSH terminology suitable for describing all traits (diseases and medical signs and symptoms at various levels of granularity and the Human Phenotype Ontology (HPO most suitable for describing phenotypic abnormalities (medical signs and symptoms at the most granular level. Diseases within MeSH are mapped to HPO to infer the phenotypic abnormalities associated with diseases. Building on the rich semantic phenotype annotation layer, we are able to make cross-species phenotype comparisons and publish a core subset of GWAS data as RDF nanopublications. Conclusions We present a methodology for applying phenotype annotations to a comprehensive genome-wide association dataset and for ensuring compatibility with the Semantic Web. The annotations are used to assist with cross-species genotype and phenotype comparisons. However, further processing and deconstructions of terms may be required to facilitate automatic

  1. Integration of transcriptomics and metabonomics

    DEFF Research Database (Denmark)

    Bjerrum, Jacob Tveiten; Rantalainen, Mattias; Wang, Yulan

    2014-01-01

    the possibilities of a molecular phenotyping of ulcerative colitis (UC) patients. Biopsies were obtained from the descending colon of 43 UC patients (22 active UC and 21 quiescent UC) and 15 controls. Genome-wide gene expression analyses were performed using Affymetrix GeneChip Human Genome U133 Plus 2.0. Metabolic...... profiles were generated using (1)H Nuclear magnetic resonance spectroscopy (Bruker 600 MHz, Bruker BioSpin, Rheinstetten, Germany). Data were analyzed with the use of orthogonal-projection to latent structure-discriminant analysis and a multivariate logistic regression model fitted by lasso. Prediction...... with or without steroid dependency, as well as between early or late disease onset. Consequently, this study demonstrates that the novel approach of integrating metabonomics and transcriptomics combines the better of the two worlds, and provides us with clinical applicable candidate biomarker panels...

  2. Transcriptomic analyses reveal novel genes with sexually dimorphic expression in the zebrafish gonad and brain.

    Directory of Open Access Journals (Sweden)

    Rajini Sreenivasan

    Full Text Available BACKGROUND: Our knowledge on zebrafish reproduction is very limited. We generated a gonad-derived cDNA microarray from zebrafish and used it to analyze large-scale gene expression profiles in adult gonads and other organs. METHODOLOGY/PRINCIPAL FINDINGS: We have identified 116638 gonad-derived zebrafish expressed sequence tags (ESTs, 21% of which were isolated in our lab. Following in silico normalization, we constructed a gonad-derived microarray comprising 6370 unique, full-length cDNAs from differentiating and adult gonads. Labeled targets from adult gonad, brain, kidney and 'rest-of-body' from both sexes were hybridized onto the microarray. Our analyses revealed 1366, 881 and 656 differentially expressed transcripts (34.7% novel that showed highest expression in ovary, testis and both gonads respectively. Hierarchical clustering showed correlation of the two gonadal transcriptomes and their similarities to those of the brains. In addition, we have identified 276 genes showing sexually dimorphic expression both between the brains and between the gonads. By in situ hybridization, we showed that the gonadal transcripts with the strongest array signal intensities were germline-expressed. We found that five members of the GTP-binding septin gene family, from which only one member (septin 4 has previously been implicated in reproduction in mice, were all strongly expressed in the gonads. CONCLUSIONS/SIGNIFICANCE: We have generated a gonad-derived zebrafish cDNA microarray and demonstrated its usefulness in identifying genes with sexually dimorphic co-expression in both the gonads and the brains. We have also provided the first evidence of large-scale differential gene expression between female and male brains of a teleost. Our microarray would be useful for studying gonad development, differentiation and function not only in zebrafish but also in related teleosts via cross-species hybridizations. Since several genes have been shown to play similar

  3. Chronic Periodontitis Genome-wide Association Study in the Hispanic Community Health Study / Study of Latinos.

    Science.gov (United States)

    Sanders, A E; Sofer, T; Wong, Q; Kerr, K F; Agler, C; Shaffer, J R; Beck, J D; Offenbacher, S; Salazar, C R; North, K E; Marazita, M L; Laurie, C C; Singer, R H; Cai, J; Finlayson, T L; Divaris, K

    2017-01-01

    Chronic periodontitis (CP) has a genetic component, particularly its severe forms. Evidence from genome-wide association studies (GWASs) has highlighted several potential novel loci. Here, the authors report the first GWAS of CP among a large community-based sample of Hispanics/Latinos. The authors interrogated a quantitative trait of CP (mean interproximal clinical attachment level determined by full-mouth periodontal examinations) among 10,935 adult participants (mean age: 45 y, range: 18 to 76 y) from the Hispanic Community Health Study / Study of Latinos. Genotyping was done with a custom Illumina Omni2.5M array, and imputation to approximately 20 million single-nucleotide polymorphisms was based on the 1000 Genomes Project phase 1 reference panel. Analyses were based on linear mixed models adjusting for sex, age, study design features, ancestry, and kinship and employed a conventional P evidence of association ( P based sample of Hispanic/Latinos. It identified a genome-wide significant locus that was independently replicated in an African-American population. Identifying this genetic marker offers direction for interrogation in subsequent genomic and experimental studies of CP.

  4. Genome-wide microsatellite characterization and marker development in the sequenced Brassica crop species.

    Science.gov (United States)

    Shi, Jiaqin; Huang, Shunmou; Zhan, Jiepeng; Yu, Jingyin; Wang, Xinfa; Hua, Wei; Liu, Shengyi; Liu, Guihua; Wang, Hanzhong

    2014-02-01

    Although much research has been conducted, the pattern of microsatellite distribution has remained ambiguous, and the development/utilization of microsatellite markers has still been limited/inefficient in Brassica, due to the lack of genome sequences. In view of this, we conducted genome-wide microsatellite characterization and marker development in three recently sequenced Brassica crops: Brassica rapa, Brassica oleracea and Brassica napus. The analysed microsatellite characteristics of these Brassica species were highly similar or almost identical, which suggests that the pattern of microsatellite distribution is likely conservative in Brassica. The genomic distribution of microsatellites was highly non-uniform and positively or negatively correlated with genes or transposable elements, respectively. Of the total of 115 869, 185 662 and 356 522 simple sequence repeat (SSR) markers developed with high frequencies (408.2, 343.8 and 356.2 per Mb or one every 2.45, 2.91 and 2.81 kb, respectively), most represented new SSR markers, the majority had determined physical positions, and a large number were genic or putative single-locus SSR markers. We also constructed a comprehensive database for the newly developed SSR markers, which was integrated with public Brassica SSR markers and annotated genome components. The genome-wide SSR markers developed in this study provide a useful tool to extend the annotated genome resources of sequenced Brassica species to genetic study/breeding in different Brassica species.

  5. Mapping the sensory perception of apple using descriptive sensory evaluation in a genome wide association study.

    Science.gov (United States)

    Amyotte, Beatrice; Bowen, Amy J; Banks, Travis; Rajcan, Istvan; Somers, Daryl J

    2017-01-01

    Breeding apples is a long-term endeavour and it is imperative that new cultivars are selected to have outstanding consumer appeal. This study has taken the approach of merging sensory science with genome wide association analyses in order to map the human perception of apple flavour and texture onto the apple genome. The goal was to identify genomic associations that could be used in breeding apples for improved fruit quality. A collection of 85 apple cultivars was examined over two years through descriptive sensory evaluation by a trained sensory panel. The trained sensory panel scored randomized sliced samples of each apple cultivar for seventeen taste, flavour and texture attributes using controlled sensory evaluation practices. In addition, the apple collection was subjected to genotyping by sequencing for marker discovery. A genome wide association analysis suggested significant genomic associations for several sensory traits including juiciness, crispness, mealiness and fresh green apple flavour. The findings include previously unreported genomic regions that could be used in apple breeding and suggest that similar sensory association mapping methods could be applied in other plants.

  6. Genome-wide investigation of schizophrenia associated plasma Ndel1 enzyme activity.

    Science.gov (United States)

    Gadelha, Ary; Coleman, Jonathan; Breen, Gerome; Mazzoti, Diego Robles; Yonamine, Camila M; Pellegrino, Renata; Ota, Vanessa Kiyomi; Belangero, Sintia Iole; Glessner, Joseph; Sleiman, Patrick; Hakonarson, Hakon; Hayashi, Mirian A F; Bressan, Rodrigo A

    2016-04-01

    Ndel1 is a DISC1-interacting oligopeptidase that cleaves in vitro neuropeptides as neurotensin and bradykinin, and which has been associated with both neuronal migration and neurite outgrowth. We previously reported that plasma Ndel1 enzyme activity is lower in patients with schizophrenia (SCZ) compared to healthy controls (HCs). To our knowledge, no previous study has investigated the genetic factors associated with the plasma Ndel1 enzyme activity. In the current analyses, samples from 83 SCZ patients and 92 control subjects that were assayed for plasma Ndel1 enzyme activity were genotyped on Illumina Omni Express arrays. A genetic relationship matrix using genome-wide information was then used for ancestry correction, and association statistics were calculated genome-wide. Ndel1 enzyme activity was significantly lower in patients with SCZ (t=4.9; pCAMK1D, MAGI2, CCDC25, and GABGR3, at a level of suggestive significance (p<10(-6)), independent of the clinical status. Then, we performed a model to investigate the observed differences for case/control measures. 2 SNPs at region 1p22.2 reached the p<10(-7) level. ZFPM2 and MAD1L1 were the only two genes with more than one hit at 10(-6) order of p value. Therefore, Ndel1 enzyme activity is a complex trait influenced by many different genetic variants that may contribute to SCZ physiopathology.

  7. Genome-wide Selective Sweeps in Natural Bacterial Populations Revealed by Time-series Metagenomics

    Energy Technology Data Exchange (ETDEWEB)

    Chan, Leong-Keat; Bendall, Matthew L.; Malfatti, Stephanie; Schwientek, Patrick; Tremblay, Julien; Schackwitz, Wendy; Martin, Joel; Pati, Amrita; Bushnell, Brian; Foster, Brian; Kang, Dongwan; Tringe, Susannah G.; Bertilsson, Stefan; Moran, Mary Ann; Shade, Ashley; Newton, Ryan J.; Stevens, Sarah; McMahon, Katherine D.; Malmstrom, Rex R.

    2014-06-18

    Multiple evolutionary models have been proposed to explain the formation of genetically and ecologically distinct bacterial groups. Time-series metagenomics enables direct observation of evolutionary processes in natural populations, and if applied over a sufficiently long time frame, this approach could capture events such as gene-specific or genome-wide selective sweeps. Direct observations of either process could help resolve how distinct groups form in natural microbial assemblages. Here, from a three-year metagenomic study of a freshwater lake, we explore changes in single nucleotide polymorphism (SNP) frequencies and patterns of gene gain and loss in populations of Chlorobiaceae and Methylophilaceae. SNP analyses revealed substantial genetic heterogeneity within these populations, although the degree of heterogeneity varied considerably among closely related, co-occurring Methylophilaceae populations. SNP allele frequencies, as well as the relative abundance of certain genes, changed dramatically over time in each population. Interestingly, SNP diversity was purged at nearly every genome position in one of the Chlorobiaceae populations over the course of three years, while at the same time multiple genes either swept through or were swept from this population. These patterns were consistent with a genome-wide selective sweep, a process predicted by the ‘ecotype model’ of diversification, but not previously observed in natural populations.

  8. Genome-wide association for sensitivity to chronic oxidative stress in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Katherine W Jordan

    Full Text Available Reactive oxygen species (ROS are a common byproduct of mitochondrial energy metabolism, and can also be induced by exogenous sources, including UV light, radiation, and environmental toxins. ROS generation is essential for maintaining homeostasis by triggering cellular signaling pathways and host defense mechanisms. However, an imbalance of ROS induces oxidative stress and cellular death and is associated with human disease, including age-related locomotor impairment. To identify genes affecting sensitivity and resistance to ROS-induced locomotor decline, we assessed locomotion of aged flies of the sequenced, wild-derived lines from the Drosophila melanogaster Genetics Reference Panel on standard medium and following chronic exposure to medium supplemented with 3 mM menadione sodium bisulfite (MSB. We found substantial genetic variation in sensitivity to oxidative stress with respect to locomotor phenotypes. We performed genome-wide association analyses to identify candidate genes associated with variation in sensitivity to ROS-induced decline in locomotor performance, and confirmed the effects for 13 of 16 mutations tested in these candidate genes. Candidate genes associated with variation in sensitivity to MSB-induced oxidative stress form networks of genes involved in neural development, immunity, and signal transduction. Many of these genes have human orthologs, highlighting the utility of genome-wide association in Drosophila for studying complex human disease.

  9. Genome-wide association for sensitivity to chronic oxidative stress in Drosophila melanogaster.

    Science.gov (United States)

    Jordan, Katherine W; Craver, Kyle L; Magwire, Michael M; Cubilla, Carmen E; Mackay, Trudy F C; Anholt, Robert R H

    2012-01-01

    Reactive oxygen species (ROS) are a common byproduct of mitochondrial energy metabolism, and can also be induced by exogenous sources, including UV light, radiation, and environmental toxins. ROS generation is essential for maintaining homeostasis by triggering cellular signaling pathways and host defense mechanisms. However, an imbalance of ROS induces oxidative stress and cellular death and is associated with human disease, including age-related locomotor impairment. To identify genes affecting sensitivity and resistance to ROS-induced locomotor decline, we assessed locomotion of aged flies of the sequenced, wild-derived lines from the Drosophila melanogaster Genetics Reference Panel on standard medium and following chronic exposure to medium supplemented with 3 mM menadione sodium bisulfite (MSB). We found substantial genetic variation in sensitivity to oxidative stress with respect to locomotor phenotypes. We performed genome-wide association analyses to identify candidate genes associated with variation in sensitivity to ROS-induced decline in locomotor performance, and confirmed the effects for 13 of 16 mutations tested in these candidate genes. Candidate genes associated with variation in sensitivity to MSB-induced oxidative stress form networks of genes involved in neural development, immunity, and signal transduction. Many of these genes have human orthologs, highlighting the utility of genome-wide association in Drosophila for studying complex human disease.

  10. Genome-wide analysis of a Wnt1-regulated transcriptional network implicates neurodegenerative pathways.

    Science.gov (United States)

    Wexler, Eric M; Rosen, Ezra; Lu, Daning; Osborn, Gregory E; Martin, Elizabeth; Raybould, Helen; Geschwind, Daniel H

    2011-10-04

    Wnt proteins are critical to mammalian brain development and function. The canonical Wnt signaling pathway involves the stabilization and nuclear translocation of β-catenin; however, Wnt also signals through alternative, noncanonical pathways. To gain a systems-level, genome-wide view of Wnt signaling, we analyzed Wnt1-stimulated changes in gene expression by transcriptional microarray analysis in cultured human neural progenitor (hNP) cells at multiple time points over a 72-hour time course. We observed a widespread oscillatory-like pattern of changes in gene expression, involving components of both the canonical and the noncanonical Wnt signaling pathways. A higher-order, systems-level analysis that combined independent component analysis, waveform analysis, and mutual information-based network construction revealed effects on pathways related to cell death and neurodegenerative disease. Wnt effectors were tightly clustered with presenilin1 (PSEN1) and granulin (GRN), which cause dominantly inherited forms of Alzheimer's disease and frontotemporal dementia (FTD), respectively. We further explored a potential link between Wnt1 and GRN and found that Wnt1 decreased GRN expression by hNPs. Conversely, GRN knockdown increased WNT1 expression, demonstrating that Wnt and GRN reciprocally regulate each other. Finally, we provided in vivo validation of the in vitro findings by analyzing gene expression data from individuals with FTD. These unbiased and genome-wide analyses provide evidence for a connection between Wnt signaling and the transcriptional regulation of neurodegenerative disease genes.

  11. Profiling the genome-wide DNA methylation pattern of porcine ovaries using reduced representation bisulfite sequencing.

    Science.gov (United States)

    Yuan, Xiao-Long; Gao, Ning; Xing, Yan; Zhang, Hai-Bin; Zhang, Ai-Ling; Liu, Jing; He, Jin-Long; Xu, Yuan; Lin, Wen-Mian; Chen, Zan-Mou; Zhang, Hao; Zhang, Zhe; Li, Jia-Qi

    2016-02-25

    Substantial evidence has shown that DNA methylation regulates the initiation of ovarian and sexual maturation. Here, we investigated the genome-wide profile of DNA methylation in porcine ovaries at single-base resolution using reduced representation bisulfite sequencing. The biological variation was minimal among the three ovarian replicates. We found hypermethylation frequently occurred in regions with low gene abundance, while hypomethylation in regions with high gene abundance. The DNA methylation around transcriptional start sites was negatively correlated with their own CpG content. Additionally, the methylation level in the bodies of genes was higher than that in their 5' and 3' flanking regions. The DNA methylation pattern of the low CpG content promoter genes differed obviously from that of the high CpG content promoter genes. The DNA methylation level of the porcine ovary was higher than that of the porcine intestine. Analyses of the genome-wide DNA methylation in porcine ovaries would advance the knowledge and understanding of the porcine ovarian methylome.

  12. High quality and quantity Genome-wide germline genotypes from FFPE normal tissue

    Directory of Open Access Journals (Sweden)

    Georgelas Ann

    2011-05-01

    Full Text Available Abstract Background Although collections of formalin fixed paraffin embedded (FFPE samples exist, sometimes representing decades of stored samples, they have not typically been utilized to their full potential. Normal tissue from such samples would be extremely valuable for generation of genotype data for individuals who cannot otherwise provide a DNA sample. Findings We extracted DNA from normal tissue identified in FFPE tissue blocks from prostate surgery and obtained complete genome wide genotype data for over 500,000 SNP markers for these samples, and for DNA extracted from whole blood for 2 of the cases, for comparison. Four of the five FFPE samples of varying age and amount of tissue had identifiable normal tissue. We obtained good quality genotype data for between 89 and 99% of all SNP markers for the 4 samples from FFPE. Concordance rates of over 99% were observed for the 2 samples with DNA from both FFPE and from whole blood. Conclusions DNA extracted from normal FFPE tissue provides excellent quality and quantity genome-wide genotyping data representing germline DNA, sufficient for both linkage and association analyses. This allows genetic analysis of informative individuals who are no longer available for sampling in genetic studies.

  13. Genome-wide association scan suggests basis for microtia in Awassi sheep.

    Science.gov (United States)

    Jawasreh, K; Boettcher, P J; Stella, A

    2016-08-01

    Hereditary underdevelopment of the ear, a condition also known as microtia, has been observed in several sheep breeds as well as in humans and other species. Its genetic basis in sheep is unknown. The Awassi sheep, a breed native to southwest Asia, carries this phenotype and was targeted for molecular characterization via a genome-wide association study. DNA samples were collected from sheep in Jordan. Eight affected and 12 normal individuals were genotyped with the Illumina OvineSNP50(®) chip. Multilocus analyses failed to identify any genotypic association. In contrast, a single-locus analysis revealed a statistically significant association (P = 0.012, genome-wide) with a SNP at basepair 34 647 499 on OAR23. This marker is adjacent to the gene encoding transcription factor GATA-6, which has been shown to play a role in many developmental processes, including chondrogenesis. The lack of extended homozygosity in this region suggests a fairly ancient mutation, and the time of occurrence was estimated to be approximately 3000 years ago. Many of the earless sheep breeds may thus share the causative mutation, especially within the subgroup of fat-tailed, wool sheep.

  14. Genome-wide association study of handedness excludes simple genetic models

    Science.gov (United States)

    Armour, J AL; Davison, A; McManus, I C

    2014-01-01

    Handedness is a human behavioural phenotype that appears to be congenital, and is often assumed to be inherited, but for which the developmental origin and underlying causation(s) have been elusive. Models of the genetic basis of variation in handedness have been proposed that fit different features of the observed resemblance between relatives, but none has been decisively tested or a corresponding causative locus identified. In this study, we applied data from well-characterised individuals studied at the London Twin Research Unit. Analysis of genome-wide SNP data from 3940 twins failed to identify any locus associated with handedness at a genome-wide level of significance. The most straightforward interpretation of our analyses is that they exclude the simplest formulations of the ‘right-shift' model of Annett and the ‘dextral/chance' model of McManus, although more complex modifications of those models are still compatible with our observations. For polygenic effects, our study is inadequately powered to reliably detect alleles with effect sizes corresponding to an odds ratio of 1.2, but should have good power to detect effects at an odds ratio of 2 or more. PMID:24065183

  15. Genome-wide Selective Sweeps in Natural Bacterial Populations Revealed by Time-series Metagenomics

    Energy Technology Data Exchange (ETDEWEB)

    Chan, Leong-Keat; Bendall, Matthew L.; Malfatti, Stephanie; Schwientek, Patrick; Tremblay, Julien; Schackwitz, Wendy; Martin, Joel; Pati, Amrita; Bushnell, Brian; Foster, Brian; Kang, Dongwan; Tringe, Susannah G.; Bertilsson, Stefan; Moran, Mary Ann; Shade, Ashley; Newton, Ryan J.; Stevens, Sarah; McMcahon, Katherine D.; Mamlstrom, Rex R.

    2014-05-12

    Multiple evolutionary models have been proposed to explain the formation of genetically and ecologically distinct bacterial groups. Time-series metagenomics enables direct observation of evolutionary processes in natural populations, and if applied over a sufficiently long time frame, this approach could capture events such as gene-specific or genome-wide selective sweeps. Direct observations of either process could help resolve how distinct groups form in natural microbial assemblages. Here, from a three-year metagenomic study of a freshwater lake, we explore changes in single nucleotide polymorphism (SNP) frequencies and patterns of gene gain and loss in populations of Chlorobiaceae and Methylophilaceae. SNP analyses revealed substantial genetic heterogeneity within these populations, although the degree of heterogeneity varied considerably among closely related, co-occurring Methylophilaceae populations. SNP allele frequencies, as well as the relative abundance of certain genes, changed dramatically over time in each population. Interestingly, SNP diversity was purged at nearly every genome position in one of the Chlorobiaceae populations over the course of three years, while at the same time multiple genes either swept through or were swept from this population. These patterns were consistent with a genome-wide selective sweep, a process predicted by the ecotype model? of diversification, but not previously observed in natural populations.

  16. Genome-wide DNA methylation patterns and transcription analysis in sheep muscle.

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    Christine Couldrey

    Full Text Available DNA methylation plays a central role in regulating many aspects of growth and development in mammals through regulating gene expression. The development of next generation sequencing technologies have paved the way for genome-wide, high resolution analysis of DNA methylation landscapes using methodology known as reduced representation bisulfite sequencing (RRBS. While RRBS has proven to be effective in understanding DNA methylation landscapes in humans, mice, and rats, to date, few studies have utilised this powerful method for investigating DNA methylation in agricultural animals. Here we describe the utilisation of RRBS to investigate DNA methylation in sheep Longissimus dorsi muscles. RRBS analysis of ∼1% of the genome from Longissimus dorsi muscles provided data of suitably high precision and accuracy for DNA methylation analysis, at all levels of resolution from genome-wide to individual nucleotides. Combining RRBS data with mRNAseq data allowed the sheep Longissimus dorsi muscle methylome to be compared with methylomes from other species. While some species differences were identified, many similarities were observed between DNA methylation patterns in sheep and other more commonly studied species. The RRBS data presented here highlights the complexity of epigenetic regulation of genes. However, the similarities observed across species are promising, in that knowledge gained from epigenetic studies in human and mice may be applied, with caution, to agricultural species. The ability to accurately measure DNA methylation in agricultural animals will contribute an additional layer of information to the genetic analyses currently being used to maximise production gains in these species.

  17. Genome-Wide Analysis of Salicylate and Dibenzofuran Metabolism in Sphingomonas wittichii RW1

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    Edith eCoronado

    2012-08-01

    Full Text Available Sphingomonas wittichii RW1 is a bacterium isolated for its ability to degrade the xenobiotic compounds dibenzodioxin and dibenzofuran (DBF. A number of genes involved in DBF degradation have been previously characterized, such as the dxn cluster, dbfB, and the electron transfer components fdx1, fdx3 and redA2. Here we use a combination of whole genome transcriptome analysis and transposon library screening to characterize RW1 catabolic and other genes implicated in the reaction to or degradation of DBF. To detect differentially expressed genes upon exposure to DBF, we applied three different growth exposure experiments, using either short DBF exposures to actively growing cells or growing them with DBF as sole carbon and energy source. Genome-wide gene expression was examined using a custom-made microarray. In addition, proportional abundance determination of transposon insertions in RW1 libraries grown on salicylate or DBF by ultra-high throughput sequencing was used to infer genes whose interruption caused a fitness loss for growth on DBF. Expression patterns showed that batch and chemostat growth conditions, and short or long exposure of cells to DBF produced very different responses. Numerous other uncharacterized catabolic gene clusters putatively involved in aromatic compound metabolism increased expression in response to DBF. In addition, only very few transposon insertions completely abolished growth on DBF. Some of those (e.g., in dxnA1 were expected, whereas others (in a gene cluster for phenylacetate degradation were not. Both transcriptomic data and transposon screening suggest operation of multiple redundant and parallel aromatic pathways, depending on DBF exposure. In addition, increased expression of other non-catabolic genes suggests that during initial exposure, S. wittichii RW1 perceives DBF as a stressor, whereas after longer exposure, the compound is recognized as a carbon source and metabolized using several pathways in

  18. Genome-wide analysis of chimpanzee genes with premature termination codons

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    Cavelier Lucia

    2009-01-01

    Full Text Available Abstract Background Premature termination codons (PTCs cause mRNA degradation or a truncated protein and thereby contribute to the transcriptome and proteome divergence between species. Here we present the first genome-wide study of PTCs in the chimpanzee. By comparing the human and chimpanzee genome sequences we identify and characterize genes with PTCs, in order to understand the contribution of these mutations to the transcriptome diversity between the species. Results We have studied a total of 13,487 human-chimpanzee gene pairs and found that ~8% were affected by PTCs in the chimpanzee. A majority (764/1,109 of PTCs were caused by insertions or deletions and the remaining part was caused by substitutions. The distribution of PTC genes varied between chromosomes, with Y having the highest proportion. Furthermore, the density of PTC genes varied on a megabasepair scale within chromosomes and we found the density to be correlated both with indel divergence and proximity to the telomere. Within genes, PTCs were more common close to the 5' and 3' ends of the amino acid sequence. Gene Ontology classification revealed that olfactory receptor genes were over represented among the PTC genes. Conclusion Our results showed that the density of PTC genes fluctuated across the genome depending on the local genomic context. PTCs were preferentially located in the terminal parts of the transcript, which generally have a lower frequency of functional domains, indicating that selection was operating against PTCs at sites central to protein function. The enrichment of GO terms associated with olfaction suggests that PTCs may have influenced the difference in the repertoire of olfactory genes between humans and chimpanzees. In summary, 8% of the chimpanzee genes were affected by PTCs and this type of variation is likely to have an important effect on the transcript and proteomic divergence between humans and chimpanzees.

  19. Genome-Wide Analysis Reveals Novel Regulators of Growth in Drosophila melanogaster.

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    Sibylle Chantal Vonesch

    2016-01-01

    Full Text Available Organismal size depends on the interplay between genetic and environmental factors. Genome-wide association (GWA analyses in humans have implied many genes in the control of height but suffer from the inability to control the environment. Genetic analyses in Drosophila have identified conserved signaling pathways controlling size; however, how these pathways control phenotypic diversity is unclear. We performed GWA of size traits using the Drosophila Genetic Reference Panel of inbred, sequenced lines. We find that the top associated variants differ between traits and sexes; do not map to canonical growth pathway genes, but can be linked to these by epistasis analysis; and are enriched for genes and putative enhancers. Performing GWA on well-studied developmental traits under controlled conditions expands our understanding of developmental processes underlying phenotypic diversity.

  20. Genome-Wide Analysis Reveals Novel Regulators of Growth in Drosophila melanogaster.

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    Sibylle Chantal Vonesch

    2016-01-01

    Full Text Available Organismal size depends on the interplay between genetic and environmental factors. Genome-wide association (GWA analyses in humans have implied many genes in the control of height but suffer from the inability to control the environment. Genetic analyses in Drosophila have identified conserved signaling pathways controlling size; however, how these pathways control phenotypic diversity is unclear. We performed GWA of size traits using the Drosophila Genetic Reference Panel of inbred, sequenced lines. We find that the top associated variants differ between traits and sexes; do not map to canonical growth pathway genes, but can be linked to these by epistasis analysis; and are enriched for genes and putative enhancers. Performing GWA on well-studied developmental traits under controlled conditions expands our understanding of developmental processes underlying phenotypic diversity.

  1. Genome-Wide Analysis of the RNA Helicase Gene Family in Gossypium raimondii

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    Jie Chen

    2014-03-01

    Full Text Available The RNA helicases, which help to unwind stable RNA duplexes, and have important roles in RNA metabolism, belong to a class of motor proteins that play important roles in plant development and responses to stress. Although this family of genes has been the subject of systematic investigation in Arabidopsis, rice, and tomato, it has not yet been characterized in cotton. In this study, we identified 161 putative RNA helicase genes in the genome of the diploid cotton species Gossypium raimondii. We classified these genes into three subfamilies, based on the presence of either a DEAD-box (51 genes, DEAH-box (52 genes, or DExD/H-box (58 genes in their coding regions. Chromosome location analysis showed that the genes that encode RNA helicases are distributed across all 13 chromosomes of G. raimondii. Syntenic analysis revealed that 62 of the 161 G. raimondii helicase genes (38.5% are within the identified syntenic blocks. Sixty-six (40.99% helicase genes from G. raimondii have one or several putative orthologs in tomato. Additionally, GrDEADs have more conserved gene structures and more simple domains than GrDEAHs and GrDExD/Hs. Transcriptome sequencing data demonstrated that many of these helicases, especially GrDEADs, are highly expressed at the fiber initiation stage and in mature leaves. To our knowledge, this is the first report of a genome-wide analysis of the RNA helicase gene family in cotton.

  2. Bidirectional promoters of insects: genome-wide comparison, evolutionary implication and influence on gene expression.

    Science.gov (United States)

    Behura, Susanta K; Severson, David W

    2015-01-30

    Bidirectional promoters are widespread in insect genomes. By analyzing 23 insect genomes we show that the frequency of bidirectional gene pairs varies according to genome compactness and density of genes among the species. The density of bidirectional genes expected based on number of genes per megabase of genome explains the observed density suggesting that bidirectional pairing of genes may be due to random event. We identified specific transcription factor binding motifs that are enriched in bidirectional promoters across insect species. Furthermore, we observed that bidirectional promoters may act as transcriptional hotspots in insect genomes where protein coding genes tend to aggregate in significantly biased (p promoters. Natural selection seems to have an association with the extent of bidirectionality of genes among the species. The rate of non-synonymous-to-synonymous changes (dN/dS) shows a second-order polynomial distribution with bidirectionality between species indicating that bidirectionality is dependent upon evolutionary pressure acting on the genomes. Analysis of genome-wide microarray expression data of multiple insect species suggested that bidirectionality has a similar association with transcriptome variation across species. Furthermore, bidirectional promoters show significant association with correlated expression of the divergent gene pairs depending upon their motif composition. Analysis of gene ontology showed that bidirectional genes tend to have a common association with functions related to "binding" (including ion binding, nucleotide binding and protein binding) across genomes. Such functional constraint of bidirectional genes may explain their widespread persistence in genome of diverse insect species.

  3. Genome-wide transcript profiling reveals novel breast cancer-associated intronic sense RNAs.

    Science.gov (United States)

    Kim, Sang Woo; Fishilevich, Elane; Arango-Argoty, Gustavo; Lin, Yuefeng; Liu, Guodong; Li, Zhihua; Monaghan, A Paula; Nichols, Mark; John, Bino

    2015-01-01

    Non-coding RNAs (ncRNAs) play major roles in development and cancer progression. To identify novel ncRNAs that may identify key pathways in breast cancer development, we performed high-throughput transcript profiling of tumor and normal matched-pair tissue samples. Initial transcriptome profiling using high-density genome-wide tiling arrays revealed changes in over 200 novel candidate genomic regions that map to intronic regions. Sixteen genomic loci were identified that map to the long introns of five key protein-coding genes, CRIM1, EPAS1, ZEB2, RBMS1, and RFX2. Consistent with the known role of the tumor suppressor ZEB2 in the cancer-associated epithelial to mesenchymal transition (EMT), in situ hybridization reveals that the intronic regions deriving from ZEB2 as well as those from RFX2 and EPAS1 are down-regulated in cells of epithelial morphology, suggesting that these regions may be important for maintaining normal epithelial cell morphology. Paired-end deep sequencing analysis reveals a large number of distinct genomic clusters with no coding potential within the introns of these genes. These novel transcripts are only transcribed from the coding strand. A comprehensive search for breast cancer associated genes reveals enrichment for transcribed intronic regions from these loci, pointing to an underappreciated role of introns or mechanisms relating to their biology in EMT and breast cancer.

  4. Genome-wide transcript profiling reveals novel breast cancer-associated intronic sense RNAs.

    Directory of Open Access Journals (Sweden)

    Sang Woo Kim

    Full Text Available Non-coding RNAs (ncRNAs play major roles in development and cancer progression. To identify novel ncRNAs that may identify key pathways in breast cancer development, we performed high-throughput transcript profiling of tumor and normal matched-pair tissue samples. Initial transcriptome profiling using high-density genome-wide tiling arrays revealed changes in over 200 novel candidate genomic regions that map to intronic regions. Sixteen genomic loci were identified that map to the long introns of five key protein-coding genes, CRIM1, EPAS1, ZEB2, RBMS1, and RFX2. Consistent with the known role of the tumor suppressor ZEB2 in the cancer-associated epithelial to mesenchymal transition (EMT, in situ hybridization reveals that the intronic regions deriving from ZEB2 as well as those from RFX2 and EPAS1 are down-regulated in cells of epithelial morphology, suggesting that these regions may be important for maintaining normal epithelial cell morphology. Paired-end deep sequencing analysis reveals a large number of distinct genomic clusters with no coding potential within the introns of these genes. These novel transcripts are only transcribed from the coding strand. A comprehensive search for breast cancer associated genes reveals enrichment for transcribed intronic regions from these loci, pointing to an underappreciated role of introns or mechanisms relating to their biology in EMT and breast cancer.

  5. Genome-wide analysis of complex wheat gliadins, the dominant carriers of celiac disease epitopes.

    Science.gov (United States)

    Wang, Da-Wei; Li, Da; Wang, Junjun; Zhao, Yue; Wang, Zhaojun; Yue, Guidong; Liu, Xin; Qin, Huanju; Zhang, Kunpu; Dong, Lingli; Wang, Daowen

    2017-03-16

    Gliadins, specified by six compound chromosomal loci (Gli-A1/B1/D1 and Gli-A2/B2/D2) in hexaploid bread wheat, are the dominant carriers of celiac disease (CD) epitopes. Because of their complexity, genome-wide characterization of gliadins is a strong challenge. Here, we approached this challenge by combining transcriptomic, proteomic and bioinformatic investigations. Through third-generation RNA sequencing, full-length transcripts were identified for 52 gliadin genes in the bread wheat cultivar Xiaoyan 81. Of them, 42 were active and predicted to encode 25 α-, 11 γ-, one δ- and five ω-gliadins. Comparative proteomic analysis between Xiaoyan 81 and six newly-developed mutants each lacking one Gli locus indicated the accumulation of 38 gliadins in the mature grains. A novel group of α-gliadins (the CSTT group) was recognized to contain very few or no CD epitopes. The δ-gliadins identified here or previously did not carry CD epitopes. Finally, the mutant lacking Gli-D2 showed significant reductions in the most celiac-toxic α-gliadins and derivative CD epitopes. The insights and resources generated here should aid further studies on gliadin functions in CD and the breeding of healthier wheat.

  6. Genome wide transcriptional response of Saccharomyces cerevisiae to stress-induced perturbations

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    Hilal eTaymaz-Nikerel

    2016-02-01

    Full Text Available Cells respond to environmental and/or genetic perturbations in order to survive and proliferate. Characterization of the changes after various stimuli at different -omics levels is crucial to comprehend the adaptation of cells to changing conditions. Genome wide quantification and analysis of transcript levels, the genes affected by perturbations, extends our understanding of cellular metabolism by pointing out the mechanisms that play role in sensing the stress caused by those perturbations and related signaling pathways, and in this way guides us to achieve endeavors such as rational engineering of cells or interpretation of disease mechanisms. Saccharomyces cerevisiae as a model system has been studied in response to different perturbations and corresponding transcriptional profiles were followed either statically or/and dynamically, short- and long- term. This review focuses on response of yeast cells to diverse stress inducing perturbations including nutritional changes, ionic stress, salt stress, oxidative stress, osmotic shock, as well as to genetic interventions such as deletion and over-expression of genes. It is aimed to conclude on common regulatory phenomena that allow yeast to organize its transcriptomic response after any perturbation under different external conditions.

  7. Genome-wide nucleosome specificity and function of chromatin remodellers in ES cells.

    Science.gov (United States)

    de Dieuleveult, Maud; Yen, Kuangyu; Hmitou, Isabelle; Depaux, Arnaud; Boussouar, Fayçal; Bou Dargham, Daria; Jounier, Sylvie; Humbertclaude, Hélène; Ribierre, Florence; Baulard, Céline; Farrell, Nina P; Park, Bongsoo; Keime, Céline; Carrière, Lucie; Berlivet, Soizick; Gut, Marta; Gut, Ivo; Werner, Michel; Deleuze, Jean-François; Olaso, Robert; Aude, Jean-Christophe; Chantalat, Sophie; Pugh, B Franklin; Gérard, Matthieu

    2016-02-01

    ATP-dependent chromatin remodellers allow access to DNA for transcription factors and the general transcription machinery, but whether mammalian chromatin remodellers target specific nucleosomes to regulate transcription is unclear. Here we present genome-wide remodeller-nucleosome interaction profiles for the chromatin remodellers Chd1, Chd2, Chd4, Chd6, Chd8, Chd9, Brg1 and Ep400 in mouse embryonic stem (ES) cells. These remodellers bind one or both full nucleosomes that flank micrococcal nuclease (MNase)-defined nucleosome-free promoter regions (NFRs), where they separate divergent transcription. Surprisingly, large CpG-rich NFRs that extend downstream of annotated transcriptional start sites are nevertheless bound by non-nucleosomal or subnucleosomal histone variants (H3.3 and H2A.Z) and marked by H3K4me3 and H3K27ac modifications. RNA polymerase II therefore navigates hundreds of base pairs of altered chromatin in the sense direction before encountering an MNase-resistant nucleosome at the 3' end of the NFR. Transcriptome analysis after remodeller depletion reveals reciprocal mechanisms of transcriptional regulation by remodellers. Whereas at active genes individual remodellers have either positive or negative roles via altering nucleosome stability, at polycomb-enriched bivalent genes the same remodellers act in an opposite manner. These findings indicate that remodellers target specific nucleosomes at the edge of NFRs, where they regulate ES cell transcriptional programs.

  8. Genome-wide analysis of homeobox genes from Mesobuthus martensii reveals Hox gene duplication in scorpions.

    Science.gov (United States)

    Di, Zhiyong; Yu, Yao; Wu, Yingliang; Hao, Pei; He, Yawen; Zhao, Huabin; Li, Yixue; Zhao, Guoping; Li, Xuan; Li, Wenxin; Cao, Zhijian

    2015-06-01

    Homeobox genes belong to a large gene group, which encodes the famous DNA-binding homeodomain that plays a key role in development and cellular differentiation during embryogenesis in animals. Here, one hundred forty-nine homeobox genes were identified from the Asian scorpion, Mesobuthus martensii (Chelicerata: Arachnida: Scorpiones: Buthidae) based on our newly assembled genome sequence with approximately 248 × coverage. The identified homeobox genes were categorized into eight classes including 82 families: 67 ANTP class genes, 33 PRD genes, 11 LIM genes, five POU genes, six SINE genes, 14 TALE genes, five CUT genes, two ZF genes and six unclassified genes. Transcriptome data confirmed that more than half of the genes were expressed in adults. The homeobox gene diversity of the eight classes is similar to the previously analyzed Mandibulata arthropods. Interestingly, it is hypothesized that the scorpion M. martensii may have two Hox clusters. The first complete genome-wide analysis of homeobox genes in Chelicerata not only reveals the repertoire of scorpion, arachnid and chelicerate homeobox genes, but also shows some insights into the evolution of arthropod homeobox genes.

  9. Genome-wide analysis of complex wheat gliadins, the dominant carriers of celiac disease epitopes

    Science.gov (United States)

    Wang, Da-Wei; Li, Da; Wang, Junjun; Zhao, Yue; Wang, Zhaojun; Yue, Guidong; Liu, Xin; Qin, Huanju; Zhang, Kunpu; Dong, Lingli; Wang, Daowen

    2017-01-01

    Gliadins, specified by six compound chromosomal loci (Gli-A1/B1/D1 and Gli-A2/B2/D2) in hexaploid bread wheat, are the dominant carriers of celiac disease (CD) epitopes. Because of their complexity, genome-wide characterization of gliadins is a strong challenge. Here, we approached this challenge by combining transcriptomic, proteomic and bioinformatic investigations. Through third-generation RNA sequencing, full-length transcripts were identified for 52 gliadin genes in the bread wheat cultivar Xiaoyan 81. Of them, 42 were active and predicted to encode 25 α-, 11 γ-, one δ- and five ω-gliadins. Comparative proteomic analysis between Xiaoyan 81 and six newly-developed mutants each lacking one Gli locus indicated the accumulation of 38 gliadins in the mature grains. A novel group of α-gliadins (the CSTT group) was recognized to contain very few or no CD epitopes. The δ-gliadins identified here or previously did not carry CD epitopes. Finally, the mutant lacking Gli-D2 showed significant reductions in the most celiac-toxic α-gliadins and derivative CD epitopes. The insights and resources generated here should aid further studies on gliadin functions in CD and the breeding of healthier wheat. PMID:28300172

  10. Genome-wide nucleosome specificity and function of chromatin remodellers in ES cells

    Science.gov (United States)

    de Dieuleveult, Maud; Yen, Kuangyu; Hmitou, Isabelle; Depaux, Arnaud; Boussouar, Fayçal; Dargham, Daria Bou; Jounier, Sylvie; Humbertclaude, Hélène; Ribierre, Florence; Baulard, Céline; Farrell, Nina P.; Park, Bongsoo; Keime, Céline; Carrière, Lucie; Berlivet, Soizick; Gut, Marta; Gut, Ivo; Werner, Michel; Deleuze, Jean-François; Olaso, Robert; Aude, Jean-Christophe; Chantalat, Sophie; Pugh, B. Franklin; Gérard, Matthieu

    2015-01-01

    Summary ATP-dependent chromatin remodellers allow access to DNA for transcription factors and the general transcription machinery, but whether mammalian chromatin remodellers1–3 target specific nucleosomes to regulate transcription is unclear. Here, we present genome-wide remodeller-nucleosome interaction profiles for Chd1, Chd2, Chd4, Chd6, Chd8, Chd9, Brg1 and Ep400 in mouse embryonic stem (ES) cells. These remodellers bind one or both full nucleosomes that flank MNase-defined nucleosome-free promoter regions (NFRs), where they separate divergent transcription. Surprisingly, large CpG-rich NFRs that extend downstream of annotated transcriptional start sites (TSSs) are nevertheless chromatinized with non-nucleosomal or subnucleosomal histone variants (H3.3 and H2A.Z) and modifications (H3K4me3 and H3K27ac). RNA polymerase (pol) II therefore navigates hundreds of bp of altered chromatin in the sense direction before encountering an MNase-resistant nucleosome at the 3′ end of the NFR. Transcriptome analysis upon remodeller depletion reveals reciprocal mechanisms of transcriptional regulation by remodellers. Whereas at active genes individual remodellers play either positive or negative roles via altering nucleosome stability, at polycomb-enriched bivalent genes the same remodellers act in an opposite manner. These findings indicate that remodellers target specific nucleosomes at the edge of NFRs, where they regulate ES cell transcriptional programs. PMID:26814966

  11. Transcriptomics resources of human tissues and organs.

    Science.gov (United States)

    Uhlén, Mathias; Hallström, Björn M; Lindskog, Cecilia; Mardinoglu, Adil; Pontén, Fredrik; Nielsen, Jens

    2016-04-04

    Quantifying the differential expression of genes in various human organs, tissues, and cell types is vital to understand human physiology and disease. Recently, several large-scale transcriptomics studies have analyzed the expression of protein-coding genes across tissues. These datasets provide a framework for defining the molecular constituents of the human body as well as for generating comprehensive lists of proteins expressed across tissues or in a tissue-restricted manner. Here, we review publicly available human transcriptome resources and discuss body-wide data from independent genome-wide transcriptome analyses of different tissues. Gene expression measurements from these independent datasets, generated using samples from fresh frozen surgical specimens and postmortem tissues, are consistent. Overall, the different genome-wide analyses support a distribution in which many proteins are found in all tissues and relatively few in a tissue-restricted manner. Moreover, we discuss the applications of publicly available omics data for building genome-scale metabolic models, used for analyzing cell and tissue functions both in physiological and in disease contexts. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

  12. Genome-wide significant risk associations for mucinous ovarian carcinoma

    Science.gov (United States)

    Kelemen, Linda E.; Lawrenson, Kate; Tyrer, Jonathan; Li, Qiyuan; M. Lee, Janet; Seo, Ji-Heui; Phelan, Catherine M.; Beesley, Jonathan; Chen, Xiaoqin; Spindler, Tassja J.; Aben, Katja K.H.; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bandera, Elisa V.; Bean, Yukie; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Chen, Y. Ann; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas T.; Edwards, Robert P.; Eilber, Ursula; Ekici, Arif B.; Engelholm, Svend Aage; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goode, Ellen L.; Goodman, Marc T.; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kellar, Melissa; Kelley, Joseph L.; Kiemeney, Lambertus A.; Krakstad, Camilla; Kjaer, Susanne K.; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Moes-Sosnowska, Joanna; Moysich, Kirsten B.; Narod, Steven A.; Nedergaard, Lotte; Ness, Roberta B.; Nevanlinna, Heli; Azmi, Mat Adenan Noor; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Paul, James; Pearce, Celeste Leigh; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Pike, Malcolm C.; Poole, Elizabeth M.; Ramus, Susan J.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schildkraut, Joellen M.; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Sucheston, Lara; Tangen, Ingvild L.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J; Tworoger, Shelley S.; van Altena, Anne M.; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A.; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wlodzimierz, Sawicki; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Sellers, Thomas A.; Freedman, Matthew L.; Chenevix-Trench, Georgia; Pharoah, Paul D.; Gayther, Simon A.; Berchuck, Andrew

    2015-01-01

    Genome-wide association studies have identified several risk associations for ovarian carcinomas (OC) but not for mucinous ovarian carcinomas (MOC). Genotypes from OC cases and controls were imputed into the 1000 Genomes Project reference panel. Analysis of 1,644 MOC cases and 21,693 controls identified three novel risk associations: rs752590 at 2q13 (P = 3.3 × 10−8), rs711830 at 2q31.1 (P = 7.5 × 10−12) and rs688187 at 19q13.2 (P = 6.8 × 10−13). Expression Quantitative Trait Locus (eQTL) analysis in ovarian and colorectal tumors (which are histologically similar to MOC) identified significant eQTL associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10−4, FDR = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors, and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease. PMID:26075790

  13. Genome-Wide Analysis of Human MicroRNA Stability

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    Yang Li

    2013-01-01

    Full Text Available Increasing studies have shown that microRNA (miRNA stability plays important roles in physiology. However, the global picture of miRNA stability remains largely unknown. Here, we had analyzed genome-wide miRNA stability across 10 diverse cell types using miRNA arrays. We found that miRNA stability shows high dynamics and diversity both within individual cells and across cell types. Strikingly, we observed a negative correlation between miRNA stability and miRNA expression level, which is different from current findings on other biological molecules such as proteins and mRNAs that show positive and not negative correlations between stability and expression level. This finding indicates that miRNA has a distinct action mode, which we called “rapid production, rapid turnover; slow production, slow turnover.” This mode further suggests that high expression miRNAs normally degrade fast and may endow the cell with special properties that facilitate cellular status-transition. Moreover, we revealed that the stability of miRNAs is affected by cohorts of factors that include miRNA targets, transcription factors, nucleotide content, evolution, associated disease, and environmental factors. Together, our results provided an extensive description of the global landscape, dynamics, and distinct mode of human miRNA stability, which provide help in investigating their functions in physiology and pathophysiology.

  14. Genome-wide association study and premature ovarian failure.

    Science.gov (United States)

    Christin-Maitre, S; Tachdjian, G

    2010-05-01

    Premature ovarian failure (POF) is defined as an amenorrhea for more than 4months, associated with elevated gonadotropins, usually higher than 20mIU/ml, occurring in a woman before the age of 40. Some candidate genes have been identified in the past 15years, such as FOXL2, FSHR, BMP15, GDF9, Xfra premutation. However, POF etiology remains unknown in more than 90% of cases. The first strategy to identify candidate gene, apart from studying genes involved in ovarian failure in animal models, relies on the study of X chromosome deletions and X;autosome translocations in patients. The second strategy is based on linkage analysis, the third one on Comparative Genomic Hybridization (CGH) array. The latest strategy relies on Genome-Wide Association Studies (GWAS). This technique consists in screening single nucleotide polymorphisms (SNPs) in patients and controls. So far, three studies have been performed and have identified different loci potentially linked to POF, such as PTHB1 and ADAMTS19. However, replications in independent cohorts need to be performed. GWAS studies on large cohorts of women with POF should find new candidate genes in the near future.

  15. Reconstructing Roma history from genome-wide data.

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    Priya Moorjani

    Full Text Available The Roma people, living throughout Europe and West Asia, are a diverse population linked by the Romani language and culture. Previous linguistic and genetic studies have suggested that the Roma migrated into Europe from South Asia about 1,000-1,500 years ago. Genetic inferences about Roma history have mostly focused on the Y chromosome and mitochondrial DNA. To explore what additional information can be learned from genome-wide data, we analyzed data from six Roma groups that we genotyped at hundreds of thousands of single nucleotide polymorphisms (SNPs. We estimate that the Roma harbor about 80% West Eurasian ancestry-derived from a combination of European and South Asian sources-and that the date of admixture of South Asian and European ancestry was about 850 years before present. We provide evidence for Eastern Europe being a major source of European ancestry, and North-west India being a major source of the South Asian ancestry in the Roma. By computing allele sharing as a measure of linkage disequilibrium, we estimate that the migration of Roma out of the Indian subcontinent was accompanied by a severe founder event, which appears to have been followed by a major demographic expansion after the arrival in Europe.

  16. Insights into kidney diseases from genome-wide association studies.

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    Wuttke, Matthias; Köttgen, Anna

    2016-09-01

    Over the past decade, genome-wide association studies (GWAS) have considerably improved our understanding of the genetic basis of kidney function and disease. Population-based studies, used to investigate traits that define chronic kidney disease (CKD), have identified >50 genomic regions in which common genetic variants associate with estimated glomerular filtration rate or urinary albumin-to-creatinine ratio. Case-control studies, used to study specific CKD aetiologies, have yielded risk loci for specific kidney diseases such as IgA nephropathy and membranous nephropathy. In this Review, we summarize important findings from GWAS and clinical and experimental follow-up studies. We also compare risk allele frequency, effect sizes, and specificity in GWAS of CKD-defining traits and GWAS of specific CKD aetiologies and the implications for study design. Genomic regions identified in GWAS of CKD-defining traits can contain causal genes for monogenic kidney diseases. Population-based research on kidney function traits can therefore generate insights into more severe forms of kidney diseases. Experimental follow-up studies have begun to identify causal genes and variants, which are potential therapeutic targets, and suggest mechanisms underlying the high allele frequency of causal variants. GWAS are thus a useful approach to advance knowledge in nephrology.

  17. Genome-Wide Association Study of Serum Selenium Concentrations

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    Ulrike Peters

    2013-05-01

    Full Text Available Selenium is an essential trace element and circulating selenium concentrations have been associated with a wide range of diseases. Candidate gene studies suggest that circulating selenium concentrations may be impacted by genetic variation; however, no study has comprehensively investigated this hypothesis. Therefore, we conducted a two-stage genome-wide association study to identify genetic variants associated with serum selenium concentrations in 1203 European descents from two cohorts: the Prostate, Lung, Colorectal, and Ovarian (PLCO Cancer Screening and the Women’s Health Initiative (WHI. We tested association between 2,474,333 single nucleotide polymorphisms (SNPs and serum selenium concentrations using linear regression models. In the first stage (PLCO 41 SNPs clustered in 15 regions had p < 1 × 10−5. None of these 41 SNPs reached the significant threshold (p = 0.05/15 regions = 0.003 in the second stage (WHI. Three SNPs had p < 0.05 in the second stage (rs1395479 and rs1506807 in 4q34.3/AGA-NEIL3; and rs891684 in 17q24.3/SLC39A11 and had p between 2.62 × 10−7 and 4.04 × 10−7 in the combined analysis (PLCO + WHI. Additional studies are needed to replicate these findings. Identification of genetic variation that impacts selenium concentrations may contribute to a better understanding of which genes regulate circulating selenium concentrations.

  18. Genome-wide search for strabismus susceptibility loci.

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    Fujiwara H

    2003-06-01

    Full Text Available The purpose of this study was to search for chromosomal susceptibility loci for comitant strabismus. Genomic DNA was isolated from 10mL blood taken from each member of 30 nuclear families in which 2 or more siblings are affected by either esotropia or exotropia. A genome-wide search was performed with amplification by polymerase chain reaction of 400 markers in microsatellite regions with approximately 10 cM resolution. For each locus, non-parametric affected sib-pair analysis and non-parametric linkage analysis for multiple pedigrees (Genehunter software, http://linkage.rockefeller.edu/soft/ were used to calculate multipoint lod scores and non-parametric linkage (NPL scores, respectively. In sib-pair analysis, lod scores showed basically flat lines with several peaks of 0.25 on all chromosomes. In non-parametric linkage analysis for multiple pedigrees, NPL scores showed one peak as high as 1.34 on chromosomes 1, 2, 4, 7, 10, 15, and 16, while 2 such peaks were found on chromosomes 3, 9, 11, 12, 18, and 20. Non-parametric linkage analysis for multiple pedigrees of 30 families with comitant strabismus suggested a number of chromosomal susceptibility loci. Our ongoing study involving a larger number of families will refine the accuracy of statistical analysis to pinpoint susceptibility loci for comitant strabismus.

  19. Genome-wide identification of KANADI1 target genes.

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    Paz Merelo

    Full Text Available Plant organ development and polarity establishment is mediated by the action of several transcription factors. Among these, the KANADI (KAN subclade of the GARP protein family plays important roles in polarity-associated processes during embryo, shoot and root patterning. In this study, we have identified a set of potential direct target genes of KAN1 through a combination of chromatin immunoprecipitation/DNA sequencing (ChIP-Seq and genome-wide transcriptional profiling using tiling arrays. Target genes are over-represented for genes involved in the regulation of organ development as well as in the response to auxin. KAN1 affects directly the expression of several genes previously shown to be important in the establishment of polarity during lateral organ and vascular tissue development. We also show that KAN1 controls through its target genes auxin effects on organ development at different levels: transport and its regulation, and signaling. In addition, KAN1 regulates genes involved in the response to abscisic acid, jasmonic acid, brassinosteroids, ethylene, cytokinins and gibberellins. The role of KAN1 in organ polarity is antagonized by HD-ZIPIII transcription factors, including REVOLUTA (REV. A comparison of their target genes reveals that the REV/KAN1 module acts in organ patterning through opposite regulation of shared targets. Evidence of mutual repression between closely related family members is also shown.

  20. Natural selection on functional modules, a genome-wide analysis.

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    Serra, François; Arbiza, Leonardo; Dopazo, Joaquín; Dopazo, Hernán

    2011-03-01

    Classically, the functional consequences of natural selection over genomes have been analyzed as the compound effects of individual genes. The current paradigm for large-scale analysis of adaptation is based on the observed significant deviations of rates of individual genes from neutral evolutionary expectation. This approach, which assumed independence among genes, has not been able to identify biological functions significantly enriched in positively selected genes in individual species. Alternatively, pooling related species has enhanced the search for signatures of selection. However, grouping signatures does not allow testing for adaptive differences between species. Here we introduce the Gene-Set Selection Analysis (GSSA), a new genome-wide approach to test for evidences of natural selection on functional modules. GSSA is able to detect lineage specific evolutionary rate changes in a notable number of functional modules. For example, in nine mammal and Drosophilae genomes GSSA identifies hundreds of functional modules with significant associations to high and low rates of evolution. Many of the detected functional modules with high evolutionary rates have been previously identified as biological functions under positive selection. Notably, GSSA identifies conserved functional modules with many positively selected genes, which questions whether they are exclusively selected for fitting genomes to environmental changes. Our results agree with previous studies suggesting that adaptation requires positive selection, but not every mutation under positive selection contributes to the adaptive dynamical process of the evolution of species.

  1. Natural selection on functional modules, a genome-wide analysis.

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    François Serra

    2011-03-01

    Full Text Available Classically, the functional consequences of natural selection over genomes have been analyzed as the compound effects of individual genes. The current paradigm for large-scale analysis of adaptation is based on the observed significant deviations of rates of individual genes from neutral evolutionary expectation. This approach, which assumed independence among genes, has not been able to identify biological functions significantly enriched in positively selected genes in individual species. Alternatively, pooling related species has enhanced the search for signatures of selection. However, grouping signatures does not allow testing for adaptive differences between species. Here we introduce the Gene-Set Selection Analysis (GSSA, a new genome-wide approach to test for evidences of natural selection on functional modules. GSSA is able to detect lineage specific evolutionary rate changes in a notable number of functional modules. For example, in nine mammal and Drosophilae genomes GSSA identifies hundreds of functional modules with significant associations to high and low rates of evolution. Many of the detected functional modules with high evolutionary rates have been previously identified as biological functions under positive selection. Notably, GSSA identifies conserved functional modules with many positively selected genes, which questions whether they are exclusively selected for fitting genomes to environmental changes. Our results agree with previous studies suggesting that adaptation requires positive selection, but not every mutation under positive selection contributes to the adaptive dynamical process of the evolution of species.

  2. Genome-Wide Analysis of DNA Methylation in Human Amnion

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    Jinsil Kim