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  1. Protein functional links in Trypanosoma brucei, identified by gene fusion analysis

    Directory of Open Access Journals (Sweden)

    Trimpalis Philip

    2011-07-01

    Full Text Available Abstract Background Domain or gene fusion analysis is a bioinformatics method for detecting gene fusions in one organism by comparing its genome to that of other organisms. The occurrence of gene fusions suggests that the two original genes that participated in the fusion are functionally linked, i.e. their gene products interact either as part of a multi-subunit protein complex, or in a metabolic pathway. Gene fusion analysis has been used to identify protein functional links in prokaryotes as well as in eukaryotic model organisms, such as yeast and Drosophila. Results In this study we have extended this approach to include a number of recently sequenced protists, four of which are pathogenic, to identify fusion linked proteins in Trypanosoma brucei, the causative agent of African sleeping sickness. We have also examined the evolution of the gene fusion events identified, to determine whether they can be attributed to fusion or fission, by looking at the conservation of the fused genes and of the individual component genes across the major eukaryotic and prokaryotic lineages. We find relatively limited occurrence of gene fusions/fissions within the protist lineages examined. Our results point to two trypanosome-specific gene fissions, which have recently been experimentally confirmed, one fusion involving proteins involved in the same metabolic pathway, as well as two novel putative functional links between fusion-linked protein pairs. Conclusions This is the first study of protein functional links in T. brucei identified by gene fusion analysis. We have used strict thresholds and only discuss results which are highly likely to be genuine and which either have already been or can be experimentally verified. We discuss the possible impact of the identification of these novel putative protein-protein interactions, to the development of new trypanosome therapeutic drugs.

  2. A Systems Approach Identifies Networks and Genes Linking Sleep and Stress: Implications for Neuropsychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Peng Jiang

    2015-05-01

    Full Text Available Sleep dysfunction and stress susceptibility are comorbid complex traits that often precede and predispose patients to a variety of neuropsychiatric diseases. Here, we demonstrate multilevel organizations of genetic landscape, candidate genes, and molecular networks associated with 328 stress and sleep traits in a chronically stressed population of 338 (C57BL/6J × A/J F2 mice. We constructed striatal gene co-expression networks, revealing functionally and cell-type-specific gene co-regulations important for stress and sleep. Using a composite ranking system, we identified network modules most relevant for 15 independent phenotypic categories, highlighting a mitochondria/synaptic module that links sleep and stress. The key network regulators of this module are overrepresented with genes implicated in neuropsychiatric diseases. Our work suggests that the interplay among sleep, stress, and neuropathology emerges from genetic influences on gene expression and their collective organization through complex molecular networks, providing a framework for interrogating the mechanisms underlying sleep, stress susceptibility, and related neuropsychiatric disorders.

  3. Affected Kindred Analysis of Human X Chromosome Exomes to Identify Novel X-Linked Intellectual Disability Genes

    OpenAIRE

    Niranjan, Tejasvi S.; Skinner, Cindy; May, Melanie; Turner, Tychele; Rose, Rebecca; Stevenson, Roger,; Schwartz, Charles E; Wang, Tao

    2015-01-01

    X-linked Intellectual Disability (XLID) is a group of genetically heterogeneous disorders caused by mutations in genes on the X chromosome. Deleterious mutations in ~10% of X chromosome genes are implicated in causing XLID disorders in ~50% of known and suspected XLID families. The remaining XLID genes are expected to be rare and even private to individual families. To systematically identify these XLID genes, we sequenced the X chromosome exome (X-exome) in 56 well-established XLID families ...

  4. IDENTIFYING GENES CONTROLLING FERULATE CROSS-LINKING FORMATION IN GRASS CELL WALLS

    Energy Technology Data Exchange (ETDEWEB)

    de O Buanafina, Marcia Maria

    2013-10-16

    DESCRIPTION/ABSTRACT This proposal focuses on cell wall feruloylation and our long term goal is to identify and isolate novel genes controlling feruloylation and to characterize the phenotype of mutants in this pathway, with a spotlight on cell wall properties. Currently, the genes underlying AX feruloylation have not been identified and the isolation of such genes could be of great importance in manipulating ferulates accretion to the wall. Mutation of the feruloyl transferase gene(s) should lead to less ferulates secreted to the cell wall and reduced ferulate cross-linking. Our current research is based on the hypothesis that controlling the level of total feruloylation will have a direct impact on the level of cross-linking and in turn impact biomass utility for forage and biofuel production. Our results/accomplishments for this project so far include: 1. Mutagenised Brachypodium population. We have developed EMS mutagenized populations of model grass species Brachypodium distachyon. EMS populations have been developed from over 28,000 mutagenized seeds generating 5,184 M2 families. A total of 20,793 plants have been screened and 1,233 were originally selected. 2. Selected Brachypodium mutants: Potential mutants on their levels of cell wall ferulates and cell wall AX ? have been selected from 708 M2 families. A total of 303 back-crosses to no-mutagenized parental stock have been done, followed by selfing selected genotypes in order to confirm heritability of traits and to remove extraneous mutations generated by EMS mutagenesis. We are currently growing 12 F5 and F6 populations in order to assess CW composition. If low level of ferulates are confirmed in the candidate lines selected the mutation could be altered in different in one or several kinds of genes such as genes encoding an AX feruloyl transferase; genes encoding the arabinosyl transferase; genes encoding the synthesis of the xylan backbone; genes encoding enzymes of the monolignol pathway affecting FA formation or genes encoding transcription factors that control feruloylation. So it will require further investigations to confirm if we have a mutation on the ferulloyltransferase gene(s). We have also identified severe phenotypes which showed a significant change in the level of cell wall ferulates and sugars and have not survived. As this genotype did not reach flowering stage there was no seed production and so further analysis could not be done. 3. Candidate Gene Approach: Because of the likely long time expected to generate and identify candidate with mutation(s) on the feruloyltransferase gene, from our screening, we have in addition taken a bioinformatics approach in order to try to identify candidates gene(s) involved in feruloylation. Homologues of the rice feruloyl transferase genes belonging to Pfam PF02458 family were identified in Brachypodium distachyon by blasting EST sequences of putative rice arabinoxylan feruloyl transferase genes against Brachypodium and homologous sequences identified were tested for their expression level in Brachypodium. Sequences of the two Brachypodium genes, which showed highest expression and similarity to rice sequences, were used to design primers for construction of RNAi and over-expression vectors. These were transformed into Brachypodium using Agrobacterium transformation and plants generated have been analyzed for levels of cell wall ferulates and diferulates over generations T0 to T2 or T3. Our data shows a significant reduction if ferulates monomers and dimers from plants generated from RNAi::BdAT2 over 2-3 generations indicating that this gene might be a positive candidate for feruloylation in Brachypodium. However when BdAT2 was up regulated there was not much increase in the level of ferulates as would be expected. This lack of effect on the level of cell wall ferulates could be due to the CaMV::35S promoter used to drive the expression of the putative BdAT2 gene. We have shown previously that Aspergillus FAEA expression in tall fescue under CaMV::35S resulted in 1.9 fold decrease in activity compared to activity when FAEA was driven by the rice actin promoter (Buanafina et al., 2008) and indicates that the CaMV::35S promoter might not be ideal to drive gene expression in grasses. Our results also shows that the level of cell wall esterified ferulates and diferulates did not change when BdAT8 was down regulated indicating that wall ferulates indicating this is not a feruloyl transferase candidate. We are currently preparing plant material from these selected transgenic plants to assess putative feruloyltransferase transcripts levels among different transgenic lines produced. 4. Cell Wall Characterization of Brachypodium accessions. We have also been assessing how the level of cell wall esterified ferulates and diferulates, arabinoxylan, lignification and cellulose mediated sugar release varies among different Brachypodium diploid and tetraploid lines at different stages of development. Considerable variation has been found for the different cell wall components studied. We have also found significant variation for cellulase-mediated release of sugars from leaves of different Brachypodium accession lines. This will give us a good ground to assess the mutants and will be useful for producing a mapping population. The analyses are still ongoing as plant material needs to collected from different genotypes at the flowering stage for cell wall characterization. We aim to have this study completed and published. 5. Based on our previous findings where FAE expression in planta resulted in increased cell wall degradability and the positive synergism between FAEA and xylanase, we have tested if co-expression of FAEA and XYN2 in planta could improve the digestion of polysaccharides and increase cell wall degradability and post harvest cell wall deconstruction in grasses more effectively than expression of xylanase (Buanafina et al., 2012) or FAE (Buanafina et al. 2008, 2009, 2010) alone. As such we have studied the effects of constitutive co-expression of FAEA in the vacuole or apoplast combined with senescence inducible expression of XYN2 in the apoplast, on plant growth, levels of cell wall hydroxycinnamic acids (HCAs) and cell wall sugar composition, lignification and cell wall degradability of tall fescue (as we had this material available). FAE+XYN expression showed to be more efficient than FAE or XYN expression alone in changing HCA and AX levels, increasing cell wall in vitro dry matter digestibility, and increasing release of reduced sugars when plants were treated with cellulase compared with sugar release by the action of cellulase alone. These results reinforce the role of cell wall ferulates in hindering cell wall degradability and the relevance of such approach for the bioethanol industry. An additional interesting aspect of the work is that it showed that FAEA+ XYN2 expression in planta does not alter total Klason lignin levels but significantly increases the level of acetyl bromide soluble lignin from about 56% in controls for up to 86 % in some plants co-expressing FAEA +XYN with a significant negative correlation between ferulates and acetyl lignin. THESE RESULTS ARE BEING WRITTEN FOR PUBLICATION. 6. New protein identified: In the course of our work we have also identified a new protein (enzyme). We have characterised the novel enzyme in maize and this WORK IS CURRENTLY BEING WRITTEN FOR PUBLICATION. We have also attempted to identify the putative gene sequence in maize and respective UFMu seed stocks with Mu inserts in each of the putative sequences and one Mu illumina seed stock with inserts common to all four putative genes identified. These seeds have been ordered from MaizeGDB.org and are to be tested. It will be important to clone the gene in order to study the its role in plant processes. As a longer term goal it might also be possible to over express the cloned gene in the cell wall of maize or other biofuel crops, aiming to improve their degradability as it might be more effective than the fungal enzymes at degrading maize lignocellulose if overexpressed in the cell wall. Publications supported by this grant: Buanafina, M.M. de O. (2009). Feruloylation in Grasses: Current and Future Perspectives. Molecular Plant, 2:861-872. Buanafina, M. M. de O., Langdon, T., Hauck, B., Dalton, S., Timms-Taravella, E. and Morris, P. (2010). Targeting expression of a fungal ferulic acid esterase to the apoplast, endoplasmic reticulum or golgi can disrupt feruloylation of the growing cell wall and increase the biodegradability of tall fescue (Festuca arundinacea): Plant Biot. J. 8:316-33. Michael L. Robbins, Ansuman Roy, Po-Hao Wang, Iffa Gaffoor, Rajandeep S. Sekhon, Marcia M. de O. Buanafina, Jai S. Rohila, Surinder Chopra (2013). Comparative Proteomics Analysis by DIGE and iTRAQ Provides Insight into the Regulation of Phenylpropanoids in Maize. Journal of Proteomics (In Press http://dx.doi.org/10.1016/j.jprot.2013.06.018)) Publications in Preparation Marcia M. de O. Buanafina, Sue Dalton, Tim Langdon, Emma-Timms-Tavarella, Erica A. Shearer, and Phillip Morris. Improved post harvest cell wall deconstruction of tall fescue by co-expression of a fungal ferulic acid esterase with a 1-4-endoxylanase. Marcia M. de O. Buanafina, Mandeep Sharma, Howard W. Fescemyer and Erica A. Shearer. Functional testing of two PF02458 homologues of putative rice arabinoxylan feruloyl transferase genes in Brachypodium distachyon. Marcia M. de O. Buanafina and Erica A. Shearer. Novel protein identified in maize and other grasses. Presentations/ Posters presented at major scientific meetings: Identifying genes controlling feruloylation in grass cell walls. Genomics: GTL Annual Contractor-Grantee Workshop held jointly with the USDA-DOE Plant Feedstock Genomics for Bioenergy awardees meeting. February 8-11/2009, Bethesda, Maryland. Identifying genes controlling feruloylation in grass cell walls. The American Society of Plant Biologists (ASPB). July 18-22, 2009 Honolulu, Hawaii at the ?Bioenergy Crops and Biofuels? section Identifying genes controlling feruloylation in grass cell walls. Plant & Animal Genome Conference XVIII and Plant Feedstock Genomics for Bioenergy Workshop January 9-13, 2010. Town & Country Hotel - San Diego, CA. Poster Identifying genes controlling feruloylation in grass cell walls. Genomic Sciences Contractor-grantee Meeting IX USDA-DOE Plant Feedstock Genomics for Bioenergy Awardee Meeting April 10-13, 2011.Cryatal City, Virginia. Brachypodium distachyon-pathogen interactions: exploring the cell wall barrier and defense-related compounds?. ASPB July 20-24, 2012, Austin TX. Presentation and Poster Expression of putative arabinoxylan feruloyl transferase genes in Brachypodium distachyon. Genomic Sciences Contractor-Grantee Meeting XI USDA-DOE Plant Feedstock Genomics for Bioenergy Awardee Meeting 2013 February 24-27, 2013 Bethesda, MD. Poster Differential responses of Brachypodium distachyon genotypes to fungal pathogens: exploring the cell wall barrier and defense-related compounds. First International Brachypodium Conference. June 19-21, 2013. Modena, Italy. Presentation Ferulates in Cell Walls of Forage Grasses: Their Significance for Wall Degradability and Resistance to Insects and Pathogens. Plant Pathology and Environmental Microbiology Fall Seminar Series 13 October 2013, The Pennsylvania State University. Invited Presentation. Training Technical personnel: Sharon Hoover; Ruth Haldeman (replaced Sharon Hoover who resigned for illness); Erica Sheere (replaced Ruth Haldeman whose performance was well bellow expectation): Students: Andrea Hendershot; Nil Dhanani:, Anthony Rosario; Kathleen Tanner; David Apont; Brandon Armsted; Maria Frrnanda Buanafina Maia; Vishakha Mahajan Postdoctoral Fellow: Mandeep Sharma:

  5. Identifying new sex-linked genes through BAC sequencing in the dioecious plant Silene latifolia

    Czech Academy of Sciences Publication Activity Database

    Blavet, Nicolas; Blavet, Hana; Muyle, A.; Käfer, J.; Cegan, R.; Deschamps, C.; Zemp, N.; Mousset, S.; Aubourg, S.; Bergero, R.; Charlesworth, D.; Hobza, Roman; Widmer, A.; Marais, G.A.B.

    2015-01-01

    Roč. 16, JUL 25 (2015), s. 546. ISSN 1471-2164 R&D Projects: GA ČR GAP501/12/2220 Institutional support: RVO:61389030 Keywords : Sex chromosomes * Sex-linked genes * Plant Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.986, year: 2014

  6. Use of Isogenic Lines and Simultaneous Probing to Identify DNA Markers Tightly Linked to the Tm-2a Gene in Tomato

    OpenAIRE

    Young, N. D.; Zamir, D.; Ganal, M. W.; Tanksley, S.D.

    1988-01-01

    The Tm-2a gene of tomato confers resistance to the viral pathogen, tobacco mosaic virus. Like many economically important plant genes, Tm-2a has been characterized phenotypically and by classical linkage analysis, yet nothing is known about its gene product. We report here the isolation of two DNA clones which are very tightly linked to the Tm-2a gene. These clones were identified by testing 122 genomic clones as hybridization probes against Southern blots consisting of DNA from pairs of near...

  7. Co-regulation analysis of closely linked genes identifies a highly recurrent gain on chromosome 17q25.3 in prostate cancer

    Directory of Open Access Journals (Sweden)

    Martnez-A Carlos

    2008-10-01

    Full Text Available Abstract Background Transcriptional profiling of prostate cancer (PC has unveiled new markers of neoplasia and allowed insights into mechanisms underlying this disease. Genomewide analyses have also identified new chromosomal abnormalities associated with PC. The combination of both classes of data for the same sample cohort might provide better criteria for identifying relevant factors involved in neoplasia. Here we describe transcriptional signatures identifying distinct normal and tumoral prostate tissue compartments, and the inference and demonstration of a new, highly recurrent copy number gain on chromosome 17q25.3. Methods We have applied transcriptional profiling to tumoral and non-tumoral prostate samples with relatively homogeneous epithelial representations as well as pure stromal tissue from peripheral prostate and cultured cell lines, followed by quantitative RT-PCR validations and immunohistochemical analysis. In addition, we have performed in silico colocalization analysis of co-regulated genes and validation by fluorescent in situ hybridization (FISH. Results The transcriptomic analysis has allowed us to identify signatures corresponding to non-tumoral luminal and tumoral epithelium, basal epithelial cells, and prostate stromal tissue. In addition, in silico analysis of co-regulated expression of physically linked genes has allowed us to predict the occurrence of a copy number gain at chromosomal region 17q25.3. This computational inference was validated by fluorescent in situ hybridization, which showed gains in this region in over 65% of primary and metastatic tumoral samples. Conclusion Our approach permits to directly link gene copy number variations with transcript co-regulation in association with neoplastic states. Therefore, transcriptomic studies of carefully selected samples can unveil new diagnostic markers and transcriptional signatures highly specific of PC, and lead to the discovery of novel genomic abnormalities that may provide additional insights into the causes and mechanisms of prostate cancer.

  8. Co-regulation analysis of closely linked genes identifies a highly recurrent gain on chromosome 17q25.3 in prostate cancer

    International Nuclear Information System (INIS)

    Transcriptional profiling of prostate cancer (PC) has unveiled new markers of neoplasia and allowed insights into mechanisms underlying this disease. Genomewide analyses have also identified new chromosomal abnormalities associated with PC. The combination of both classes of data for the same sample cohort might provide better criteria for identifying relevant factors involved in neoplasia. Here we describe transcriptional signatures identifying distinct normal and tumoral prostate tissue compartments, and the inference and demonstration of a new, highly recurrent copy number gain on chromosome 17q25.3. We have applied transcriptional profiling to tumoral and non-tumoral prostate samples with relatively homogeneous epithelial representations as well as pure stromal tissue from peripheral prostate and cultured cell lines, followed by quantitative RT-PCR validations and immunohistochemical analysis. In addition, we have performed in silico colocalization analysis of co-regulated genes and validation by fluorescent in situ hybridization (FISH). The transcriptomic analysis has allowed us to identify signatures corresponding to non-tumoral luminal and tumoral epithelium, basal epithelial cells, and prostate stromal tissue. In addition, in silico analysis of co-regulated expression of physically linked genes has allowed us to predict the occurrence of a copy number gain at chromosomal region 17q25.3. This computational inference was validated by fluorescent in situ hybridization, which showed gains in this region in over 65% of primary and metastatic tumoral samples. Our approach permits to directly link gene copy number variations with transcript co-regulation in association with neoplastic states. Therefore, transcriptomic studies of carefully selected samples can unveil new diagnostic markers and transcriptional signatures highly specific of PC, and lead to the discovery of novel genomic abnormalities that may provide additional insights into the causes and mechanisms of prostate cancer

  9. Predicting missing links and identifying spurious links via likelihood analysis

    Science.gov (United States)

    Pan, Liming; Zhou, Tao; Lü, Linyuan; Hu, Chin-Kun

    2016-03-01

    Real network data is often incomplete and noisy, where link prediction algorithms and spurious link identification algorithms can be applied. Thus far, it lacks a general method to transform network organizing mechanisms to link prediction algorithms. Here we use an algorithmic framework where a network’s probability is calculated according to a predefined structural Hamiltonian that takes into account the network organizing principles, and a non-observed link is scored by the conditional probability of adding the link to the observed network. Extensive numerical simulations show that the proposed algorithm has remarkably higher accuracy than the state-of-the-art methods in uncovering missing links and identifying spurious links in many complex biological and social networks. Such method also finds applications in exploring the underlying network evolutionary mechanisms.

  10. Predicting missing links and identifying spurious links via likelihood analysis.

    Science.gov (United States)

    Pan, Liming; Zhou, Tao; Lü, Linyuan; Hu, Chin-Kun

    2016-01-01

    Real network data is often incomplete and noisy, where link prediction algorithms and spurious link identification algorithms can be applied. Thus far, it lacks a general method to transform network organizing mechanisms to link prediction algorithms. Here we use an algorithmic framework where a network's probability is calculated according to a predefined structural Hamiltonian that takes into account the network organizing principles, and a non-observed link is scored by the conditional probability of adding the link to the observed network. Extensive numerical simulations show that the proposed algorithm has remarkably higher accuracy than the state-of-the-art methods in uncovering missing links and identifying spurious links in many complex biological and social networks. Such method also finds applications in exploring the underlying network evolutionary mechanisms. PMID:26961965

  11. Whole-genome sequencing identifies a novel ABCB7 gene mutation for X-linked congenital cerebellar ataxia in a large family of Mongolian ancestry.

    Science.gov (United States)

    Protasova, Maria S; Grigorenko, Anastasia P; Tyazhelova, Tatiana V; Andreeva, Tatiana V; Reshetov, Denis A; Gusev, Fedor E; Laptenko, Alexander E; Kuznetsova, Irina L; Goltsov, Andrey Y; Klyushnikov, Sergey A; Illarioshkin, Sergey N; Rogaev, Evgeny I

    2016-04-01

    X-linked congenital cerebellar ataxia is a heterogeneous nonprogressive neurodevelopmental disorder with onset in early childhood. We searched for a genetic cause of this condition, previously reported in a Buryat pedigree of Mongolian ancestry from southeastern Russia. Using whole-genome sequencing on Illumina HiSeq 2000 platform, we found a missense mutation in the ABCB7 (ABC-binding cassette transporter B7) gene, encoding a mitochondrial transporter, involved in heme synthesis and previously associated with sideroblastic anemia and ataxia. The mutation resulting in a substitution of a highly conserved glycine to serine in position 682 is apparently a major causative factor of the cerebellar hypoplasia/atrophy found in affected individuals of a Buryat family who had no evidence of sideroblastic anemia. Moreover, in these affected men we also found the genetic defects in two other genes closely linked to ABCB7 on chromosome X: a deletion of a genomic region harboring the second exon of copper-transporter gene (ATP7A) and a complete deletion of PGAM4 (phosphoglycerate mutase family member 4) retrogene located in the intronic region of the ATP7A gene. Despite the deletion, eliminating the first of six metal-binding domains in ATP7A, no signs for Menkes disease or occipital horn syndrome associated with ATP7A mutations were found in male carriers. The role of the PGAM4 gene has been previously implicated in human reproduction, but our data indicate that its complete loss does not disrupt male fertility. Our finding links cerebellar pathology to the genetic defect in ABCB7 and ATP7A structural variant inherited as X-linked trait, and further reveals the genetic heterogeneity of X-linked cerebellar disorders. PMID:26242992

  12. Identifying links between origami and compliant mechanisms

    OpenAIRE

    H. C. Greenberg; M. L. Gong; Magleby, S. P.; Howell, L.L.

    2011-01-01

    Origami is the art of folding paper. In the context of engineering, orimimetics is the application of folding to solve problems. Kinetic origami behavior can be modeled with the pseudo-rigid-body model since the origami are compliant mechanisms. These compliant mechanisms, when having a flat initial state and motion emerging out of the fabrication plane, are classified as lamina emergent mechanisms (LEMs). To demonstrate the feasibility of identifying links between origami and compliant mecha...

  13. Identifying links between origami and compliant mechanisms

    Directory of Open Access Journals (Sweden)

    H. C. Greenberg

    2011-12-01

    Full Text Available Origami is the art of folding paper. In the context of engineering, orimimetics is the application of folding to solve problems. Kinetic origami behavior can be modeled with the pseudo-rigid-body model since the origami are compliant mechanisms. These compliant mechanisms, when having a flat initial state and motion emerging out of the fabrication plane, are classified as lamina emergent mechanisms (LEMs. To demonstrate the feasibility of identifying links between origami and compliant mechanism analysis and design methods, four flat folding paper mechanisms are presented with their corresponding kinematic and graph models. Principles from graph theory are used to abstract the mechanisms to show them as coupled, or inter-connected, mechanisms. It is anticipated that this work lays a foundation for exploring methods for LEM synthesis based on the analogy between flat-folding origami models and linkage assembly.

  14. Do Genes Link Headaches, Irritable Bowel Syndrome?

    Science.gov (United States)

    ... nih.gov/medlineplus/news/fullstory_157419.html Do Genes Link Headaches, Irritable Bowel Syndrome? Study finds evidence ... focused on genetics, in particular, the serotonin transporter gene and the serotonin receptor 2A gene. The study ...

  15. Gene expression profiling: can we identify the right target genes?

    Directory of Open Access Journals (Sweden)

    J. E. Loyd

    2008-12-01

    Full Text Available Gene expression profiling allows the simultaneous monitoring of the transcriptional behaviour of thousands of genes, which may potentially be involved in disease development. Several studies have been performed in idiopathic pulmonary fibrosis (IPF, which aim to define genetic links to the disease in an attempt to improve the current understanding of the underlying pathogenesis of the disease and target pathways for intervention. Expression profiling has shown a clear difference in gene expression between IPF and normal lung tissue, and has identified a wide range of candidate genes, including those known to encode for proteins involved in extracellular matrix formation and degradation, growth factors and chemokines. Recently, familial pulmonary fibrosis cohorts have been examined in an attempt to detect specific genetic mutations associated with IPF. To date, these studies have identified families in which IPF is associated with mutations in the gene encoding surfactant protein C, or with mutations in genes encoding components of telomerase. Although rare and clearly not responsible for the disease in all individuals, the nature of these mutations highlight the importance of the alveolar epithelium in disease pathogenesis and demonstrate the potential for gene expression profiling in helping to advance the current understanding of idiopathic pulmonary fibrosis.

  16. Identifying & linking corporate entrepreneurial characteristics to innovation

    OpenAIRE

    Thomas, Robin Luke

    2010-01-01

    Prominent academicians, investors and successful entrepreneurs would unanimously agree that the terms “Entrepreneur” and “Innovation” are undoubtedly the most important determinants in the new knowledge economy. Unfortunately, empirical and theoretical understanding of the influence of the entrepreneur on innovation has long been stymied. Studies of entrepreneurial characteristics have failed to demonstrate convincing links with entrepreneurial states of being, though studies of the former ha...

  17. NIH Researchers Identify OCD Risk Gene

    Science.gov (United States)

    ... News From NIH NIH Researchers Identify OCD Risk Gene Past Issues / Summer 2006 Table of Contents For ... and Alcoholism (NIAAA) have identified a previously unknown gene variant that doubles an individual's risk for obsessive- ...

  18. Gene expression analysis identifies global gene dosage sensitivity in cancer

    DEFF Research Database (Denmark)

    Fehrmann, Rudolf S. N.; Karjalainen, Juha M.; Krajewska, Malgorzata; Westra, Harm-Jan; Maloney, David; Simeonov, Anton; Pers, Tune Hannes; Hirschhorn, Joel N.; Jansen, Ritsert C.; Schultes, Erik A.; van Haagenl, Herman H. H. B. M.; de Vries, Elisabeth G. E.; Meerman, Gerard J. te; Wijmenga, Cisca; van Vugt, Marcel A. T. M.; Franke, Lude

    2015-01-01

    Many cancer-associated somatic copy number alterations (SCNAs) are known. Currently, one of the challenges is to identify the molecular downstream effects of these variants. Although several SCNAs are known to change gene expression levels, it is not clear whether each individual SCNA affects gene...... expression. We reanalyzed 77,840 expression profiles and observed a limited set of 'transcriptional components' that describe well-known biology, explain the vast majority of variation in gene expression and enable us to predict the biological function of genes. On correcting expression profiles for these...... components, we observed that the residual expression levels (in 'functional genomic mRNA' profiling) correlated strongly with copy number. DNA copy number correlated positively with expression levels for 99% of all abundantly expressed human genes, indicating global gene dosage sensitivity. By applying this...

  19. Phenoscape: Identifying Candidate Genes for Evolutionary Phenotypes.

    Science.gov (United States)

    Edmunds, Richard C; Su, Baofeng; Balhoff, James P; Eames, B Frank; Dahdul, Wasila M; Lapp, Hilmar; Lundberg, John G; Vision, Todd J; Dunham, Rex A; Mabee, Paula M; Westerfield, Monte

    2016-01-01

    Phenotypes resulting from mutations in genetic model organisms can help reveal candidate genes for evolutionarily important phenotypic changes in related taxa. Although testing candidate gene hypotheses experimentally in nonmodel organisms is typically difficult, ontology-driven information systems can help generate testable hypotheses about developmental processes in experimentally tractable organisms. Here, we tested candidate gene hypotheses suggested by expert use of the Phenoscape Knowledgebase, specifically looking for genes that are candidates responsible for evolutionarily interesting phenotypes in the ostariophysan fishes that bear resemblance to mutant phenotypes in zebrafish. For this, we searched ZFIN for genetic perturbations that result in either loss of basihyal element or loss of scales phenotypes, because these are the ancestral phenotypes observed in catfishes (Siluriformes). We tested the identified candidate genes by examining their endogenous expression patterns in the channel catfish, Ictalurus punctatus. The experimental results were consistent with the hypotheses that these features evolved through disruption in developmental pathways at, or upstream of, brpf1 and eda/edar for the ancestral losses of basihyal element and scales, respectively. These results demonstrate that ontological annotations of the phenotypic effects of genetic alterations in model organisms, when aggregated within a knowledgebase, can be used effectively to generate testable, and useful, hypotheses about evolutionary changes in morphology. PMID:26500251

  20. Candidate genes for panhypopituitarism identified by gene expression profiling

    OpenAIRE

    Mortensen, Amanda H; MacDonald, James W.; Ghosh, Debashis; Camper, Sally A.

    2011-01-01

    Mutations in the transcription factors PROP1 and PIT1 (POU1F1) lead to pituitary hormone deficiency and hypopituitarism in mice and humans. The dysmorphology of developing Prop1 mutant pituitaries readily distinguishes them from those of Pit1 mutants and normal mice. This and other features suggest that Prop1 controls the expression of genes besides Pit1 that are important for pituitary cell migration, survival, and differentiation. To identify genes involved in these processes we used microa...

  1. Scientists Spot Three More Genes Linked to Glaucoma Risk

    Science.gov (United States)

    ... html Scientists Spot Three More Genes Linked to Glaucoma Risk Findings could help in battle against the ... genes linked to the most common type of glaucoma could boost efforts to fight the eye disease, ...

  2. A 6-gene signature identifies four molecular subgroups of neuroblastoma

    Directory of Open Access Journals (Sweden)

    Kogner Per

    2011-04-01

    Full Text Available Abstract Background There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB; Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK was associated to unfavourable biology of sporadic NB. Also, various other genes have been linked to NB pathogenesis. Results The present study explores subgroup discrimination by gene expression profiling using three published microarray studies on NB (47 samples. Four distinct clusters were identified by Principal Components Analysis (PCA in two separate data sets, which could be verified by an unsupervised hierarchical clustering in a third independent data set (101 NB samples using a set of 74 discriminative genes. The expression signature of six NB-associated genes ALK, BIRC5, CCND1, MYCN, NTRK1, and PHOX2B, significantly discriminated the four clusters (p ALK, BIRC5, and PHOX2B, and was significantly associated with higher tumour stage, poor outcome and poor survival compared to the Type 1-corresponding favourable group (INSS stage 4 and/or dead of disease, p Conclusions Based on expression profiling we have identified four molecular subgroups of neuroblastoma, which can be distinguished by a 6-gene signature. The fourth subgroup has not been described elsewhere, and efforts are currently made to further investigate this group's specific characteristics.

  3. Identifying Gene Interaction Enrichment for Gene Expression Data

    OpenAIRE

    Zhang, Jigang; Li, Jian; Deng, Hong-Wen

    2009-01-01

    Gene set analysis allows the inclusion of knowledge from established gene sets, such as gene pathways, and potentially improves the power of detecting differentially expressed genes. However, conventional methods of gene set analysis focus on gene marginal effects in a gene set, and ignore gene interactions which may contribute to complex human diseases. In this study, we propose a method of gene interaction enrichment analysis, which incorporates knowledge of predefined gene sets (e.g. gene ...

  4. G-Links: a gene-centric link acquisition service [version 2; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Kazuki Oshita

    2015-11-01

    Full Text Available With the availability of numerous curated databases, researchers are now able to efficiently use the multitude of biological data by integrating these resources via hyperlinks and cross-references. A large proportion of bioinformatics research tasks, however, may include labor-intensive tasks such as fetching, parsing, and merging datasets and functional annotations from distributed multi-domain databases. This data integration issue is one of the key challenges in bioinformatics. We aim to provide an identifier conversion and data aggregation system as a part of solution to solve this problem with a service named G-Links, 1 by gathering resource URI information from 130 databases and 30 web services in a gene-centric manner so that users can retrieve all available links about a given gene, 2 by providing RESTful API for easy retrieval of links including facet searching based on keywords and/or predicate types, and 3 by producing a variety of outputs as visual HTML page, tab-delimited text, and in Semantic Web formats such as Notation3 and RDF. G-Links as well as other relevant documentation are available at http://link.g-language.org/

  5. NIH Researchers Identify New Gene Mutation Associated with ALS and Dementia

    Science.gov (United States)

    ... NIH researchers identify new gene mutation associated with ALS and dementia April 7, 2014 A rare mutation ... cell, has been linked with development of familial amyotrophic lateral sclerosis (ALS). This finding, from a research team led ...

  6. A 6-gene signature identifies four molecular subgroups of neuroblastoma

    LENUS (Irish Health Repository)

    Abel, Frida

    2011-04-14

    Abstract Background There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB); Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA) and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK) was associated to unfavourable biology of sporadic NB. Also, various other genes have been linked to NB pathogenesis. Results The present study explores subgroup discrimination by gene expression profiling using three published microarray studies on NB (47 samples). Four distinct clusters were identified by Principal Components Analysis (PCA) in two separate data sets, which could be verified by an unsupervised hierarchical clustering in a third independent data set (101 NB samples) using a set of 74 discriminative genes. The expression signature of six NB-associated genes ALK, BIRC5, CCND1, MYCN, NTRK1, and PHOX2B, significantly discriminated the four clusters (p < 0.05, one-way ANOVA test). PCA clusters p1, p2, and p3 were found to correspond well to the postulated subtypes 1, 2A, and 2B, respectively. Remarkably, a fourth novel cluster was detected in all three independent data sets. This cluster comprised mainly 11q-deleted MNA-negative tumours with low expression of ALK, BIRC5, and PHOX2B, and was significantly associated with higher tumour stage, poor outcome and poor survival compared to the Type 1-corresponding favourable group (INSS stage 4 and\\/or dead of disease, p < 0.05, Fisher\\'s exact test). Conclusions Based on expression profiling we have identified four molecular subgroups of neuroblastoma, which can be distinguished by a 6-gene signature. The fourth subgroup has not been described elsewhere, and efforts are currently made to further investigate this group\\'s specific characteristics.

  7. Gene Mutations Linked to Rare Form of Female Infertility

    Science.gov (United States)

    ... nlm.nih.gov/medlineplus/news/fullstory_156801.html Gene Mutations Linked to Rare Form of Female Infertility ... of women with infertility, mutations in a particular gene may be to blame, a new study finds. ...

  8. Gene Linked to Excess Male Hormones in Female Infertility Disorder

    Science.gov (United States)

    ... News Releases News Release Tuesday, April 15, 2014 Gene linked to excess male hormones in female infertility ... form cyst-like structures. A variant in a gene active in cells of the ovary may lead ...

  9. NIH Researchers Link Single Gene Variation to Obesity

    Science.gov (United States)

    ... 2015 NIH researchers link single gene variation to obesity Variation in the BDNF gene may affect brains ... for brain-derived neurotropic factor (BDNF) may influence obesity in children and adults, according to a new ...

  10. Bioinformatics methods for identifying candidate disease genes

    Directory of Open Access Journals (Sweden)

    van Driel Marc A

    2006-06-01

    Full Text Available Abstract With the explosion in genomic and functional genomics information, methods for disease gene identification are rapidly evolving. Databases are now essential to the process of selecting candidate disease genes. Combining positional information with disease characteristics and functional information is the usual strategy by which candidate disease genes are selected. Enrichment for candidate disease genes, however, depends on the skills of the operating researcher. Over the past few years, a number of bioinformatics methods that enrich for the most likely candidate disease genes have been developed. Such in silico prioritisation methods may further improve by completion of datasets, by development of standardised ontologies across databases and species and, ultimately, by the integration of different strategies.

  11. Translational informatics approach for identifying the functional molecular communicators linking coronary artery disease, infection and inflammation.

    Science.gov (United States)

    Sharma, Ankit; Ghatge, Madankumar; Mundkur, Lakshmi; Vangala, Rajani Kanth

    2016-05-01

    Translational informatics approaches are required for the integration of diverse and accumulating data to enable the administration of effective translational medicine specifically in complex diseases such as coronary artery disease (CAD). In the current study, a novel approach for elucidating the association between infection, inflammation and CAD was used. Genes for CAD were collected from the CAD‑gene database and those for infection and inflammation were collected from the UniProt database. The cytomegalovirus (CMV)‑induced genes were identified from the literature and the CAD‑associated clinical phenotypes were obtained from the Unified Medical Language System. A total of 55 gene ontologies (GO) termed functional communicator ontologies were identified in the gene sets linking clinical phenotypes in the diseasome network. The network topology analysis suggested that important functions including viral entry, cell adhesion, apoptosis, inflammatory and immune responses networked with clinical phenotypes. Microarray data was extracted from the Gene Expression Omnibus (dataset: GSE48060) for highly networked disease myocardial infarction. Further analysis of differentially expressed genes and their GO terms suggested that CMV infection may trigger a xenobiotic response, oxidative stress, inflammation and immune modulation. Notably, the current study identified γ‑glutamyl transferase (GGT)‑5 as a potential biomarker with an odds ratio of 1.947, which increased to 2.561 following the addition of CMV and CMV‑neutralizing antibody (CMV‑NA) titers. The C‑statistics increased from 0.530 for conventional risk factors (CRFs) to 0.711 for GGT in combination with the above mentioned infections and CRFs. Therefore, the translational informatics approach used in the current study identified a potential molecular mechanism for CMV infection in CAD, and a potential biomarker for risk prediction. PMID:27035874

  12. Translational informatics approach for identifying the functional molecular communicators linking coronary artery disease, infection and inflammation

    Science.gov (United States)

    SHARMA, ANKIT; GHATGE, MADANKUMAR; MUNDKUR, LAKSHMI; VANGALA, RAJANI KANTH

    2016-01-01

    Translational informatics approaches are required for the integration of diverse and accumulating data to enable the administration of effective translational medicine specifically in complex diseases such as coronary artery disease (CAD). In the current study, a novel approach for elucidating the association between infection, inflammation and CAD was used. Genes for CAD were collected from the CAD-gene database and those for infection and inflammation were collected from the UniProt database. The cytomegalovirus (CMV)-induced genes were identified from the literature and the CAD-associated clinical phenotypes were obtained from the Unified Medical Language System. A total of 55 gene ontologies (GO) termed functional communicator ontologies were identifed in the gene sets linking clinical phenotypes in the diseasome network. The network topology analysis suggested that important functions including viral entry, cell adhesion, apoptosis, inflammatory and immune responses networked with clinical phenotypes. Microarray data was extracted from the Gene Expression Omnibus (dataset: GSE48060) for highly networked disease myocardial infarction. Further analysis of differentially expressed genes and their GO terms suggested that CMV infection may trigger a xenobiotic response, oxidative stress, inflammation and immune modulation. Notably, the current study identified γ-glutamyl transferase (GGT)-5 as a potential biomarker with an odds ratio of 1.947, which increased to 2.561 following the addition of CMV and CMV-neutralizing antibody (CMV-NA) titers. The C-statistics increased from 0.530 for conventional risk factors (CRFs) to 0.711 for GGT in combination with the above mentioned infections and CRFs. Therefore, the translational informatics approach used in the current study identified a potential molecular mechanism for CMV infection in CAD, and a potential biomarker for risk prediction. PMID:27035874

  13. REPTREE CLASSIFIER FOR IDENTIFYING LINK SPAM IN WEB SEARCH ENGINES

    Directory of Open Access Journals (Sweden)

    S.K. Jayanthi

    2013-01-01

    Full Text Available Search Engines are used for retrieving the information from the web. Most of the times, the importance is laid on top 10 results sometimes it may shrink as top 5, because of the time constraint and reliability on the search engines. Users believe that top 10 or 5 of total results are more relevant. Here comes the problem of spamdexing. It is a method to deceive the search result quality. Falsified metrics such as inserting enormous amount of keywords or links in website may take that website to the top 10 or 5 positions. This paper proposes a classifier based on the Reptree (Regression tree representative. As an initial step Link-based features such as neighbors, pagerank, truncated pagerank, trustrank and assortativity related attributes are inferred. Based on this features, tree is constructed. The tree uses the feature inference to differentiate spam sites from legitimate sites. WEBSPAM-UK-2007 dataset is taken as a base. It is preprocessed and converted into five datasets FEATA, FEATB, FEATC, FEATD and FEATE. Only link based features are taken for experiments. This paper focus on link spam alone. Finally a representative tree is created which will more precisely classify the web spam entries. Results are given. Regression tree classification seems to perform well as shown through experiments.

  14. Molecular basis of genetic polymorphism in major histocompatibility complex-linked proteasome gene (Lmp-2).

    OpenAIRE

    Zhou, P.; Cao, H; Smart, M; David, C

    1993-01-01

    Four genes, closely linked to major histocompatibility complex (MHC) class II genes, have been identified in humans, mice, and rats and are thought to be involved in the generation and transport of endogenous immunogenic peptides for the MHC class I antigen-processing pathway. The Tap-1 and Tap-2 genes presumably encode a heterodimeric protein complex responsible for transporting endogenous immunogenic peptides to the lumen of the endoplasmic reticulum. The Lmp-2 and Lmp-7 gene products are t...

  15. Identifying Driver Genes in Cancer by Triangulating Gene Expression, Gene Location, and Survival Data

    Science.gov (United States)

    Rouam, Sigrid; Miller, Lance D; Karuturi, R Krishna Murthy

    2014-01-01

    Driver genes are directly responsible for oncogenesis and identifying them is essential in order to fully understand the mechanisms of cancer. However, it is difficult to delineate them from the larger pool of genes that are deregulated in cancer (ie, passenger genes). In order to address this problem, we developed an approach called TRIAngulating Gene Expression (TRIAGE through clinico-genomic intersects). Here, we present a refinement of this approach incorporating a new scoring methodology to identify putative driver genes that are deregulated in cancer. TRIAGE triangulates or integrates three levels of information: gene expression, gene location, and patient survival. First, TRIAGE identifies regions of deregulated expression (ie, expression footprints) by deriving a newly established measure called the Local Singular Value Decomposition (LSVD) score for each locus. Driver genes are then distinguished from passenger genes using dual survival analyses. Incorporating measurements of gene expression and weighting them according to the LSVD weight of each tumor, these analyses are performed using the genes located in significant expression footprints. Here, we first use simulated data to characterize the newly established LSVD score. We then present the results of our application of this refined version of TRIAGE to gene expression data from five cancer types. This refined version of TRIAGE not only allowed us to identify known prominent driver genes, such as MMP1, IL8, and COL1A2, but it also led us to identify several novel ones. These results illustrate that TRIAGE complements existing tools, allows for the identification of genes that drive cancer and could perhaps elucidate potential future targets of novel anticancer therapeutics. PMID:25949096

  16. Identifying genes and gene networks involved in chromium metabolism and detoxification in Crambe abyssinica

    Energy Technology Data Exchange (ETDEWEB)

    Zulfiqar, Asma, E-mail: asmazulfiqar08@yahoo.com [Department of Plant, Soil, and Insect Sciences, 270 Stockbridge Road, University of Massachusetts Amherst, MA 01003 (United States); Paulose, Bibin, E-mail: bpaulose@psis.umass.edu [Department of Plant, Soil, and Insect Sciences, 270 Stockbridge Road, University of Massachusetts Amherst, MA 01003 (United States); Chhikara, Sudesh, E-mail: sudesh@psis.umass.edu [Department of Plant, Soil, and Insect Sciences, 270 Stockbridge Road, University of Massachusetts Amherst, MA 01003 (United States); Dhankher, Om Parkash, E-mail: parkash@psis.umass.edu [Department of Plant, Soil, and Insect Sciences, 270 Stockbridge Road, University of Massachusetts Amherst, MA 01003 (United States)

    2011-10-15

    Chromium pollution is a serious environmental problem with few cost-effective remediation strategies available. Crambe abyssinica (a member of Brassicaseae), a non-food, fast growing high biomass crop, is an ideal candidate for phytoremediation of heavy metals contaminated soils. The present study used a PCR-Select Suppression Subtraction Hybridization approach in C. abyssinica to isolate differentially expressed genes in response to Cr exposure. A total of 72 differentially expressed subtracted cDNAs were sequenced and found to represent 43 genes. The subtracted cDNAs suggest that Cr stress significantly affects pathways related to stress/defense, ion transporters, sulfur assimilation, cell signaling, protein degradation, photosynthesis and cell metabolism. The regulation of these genes in response to Cr exposure was further confirmed by semi-quantitative RT-PCR. Characterization of these differentially expressed genes may enable the engineering of non-food, high-biomass plants, including C. abyssinica, for phytoremediation of Cr-contaminated soils and sediments. - Highlights: > Molecular mechanism of Cr uptake and detoxification in plants is not well known. > We identified differentially regulated genes upon Cr exposure in Crambe abyssinica. > 72 Cr-induced subtracted cDNAs were sequenced and found to represent 43 genes. > Pathways linked to stress, ion transport, and sulfur assimilation were affected. > This is the first Cr transcriptome study in a crop with phytoremediation potential. - This study describes the identification and isolation of differentially expressed genes involved in chromium metabolism and detoxification in a non-food industrial oil crop Crambe abyssinica.

  17. Locator/identifier split using the data link layer

    CERN Document Server

    Grishchenko, Victor

    2008-01-01

    The locator/identifier split approach assumes separating functions of a locator (i.e. topology--dependent attachment point address) and identifier (topology-independent unique identifier) currently both served by an IP address. This work is an attempt to redefine semantics of MAC address to make it a pure layer-2 locator instead of a pure globally-unique identifier. Such an exercise might be interesting from the standpoint of Ethernet scaling and Metro Ethernet technologies. From the global routing perspective, introduction of multihoming, traffic engineering and failover at the 2nd layer may reduce pressure on the 3rd layer.

  18. REPTREE CLASSIFIER FOR IDENTIFYING LINK SPAM IN WEB SEARCH ENGINES

    OpenAIRE

    Jayanthi, S. K.; Sasikala, S.

    2013-01-01

    Search Engines are used for retrieving the information from the web. Most of the times, the importance is laid on top 10 results sometimes it may shrink as top 5, because of the time constraint and reliability on the search engines. Users believe that top 10 or 5 of total results are more relevant. Here comes the problem of spamdexing. It is a method to deceive the search result quality. Falsified metrics such as inserting enormous amount of keywords or links in website may take that website ...

  19. Multiplex PCR for identifying DMD gene deletions.

    Science.gov (United States)

    den Dunnen, Johan T; Beggs, Alan H

    2006-05-01

    The identification of dystrophin as the defective protein in patients with Duchenne and Becker muscular dystrophies (DMD and BMD) has allowed the development of sensitive and specific tests to establish a diagnosis and to aid in genetic counseling and prenatal diagnosis. The Basic Protocol describes three complementary multiplex PCR assays that detect 26 dystrophin gene exons. The multiplex nature of these assays allows the detection of up to ten different exons in a single reaction. At least one of these exons is missing in >95% of deletions. The Support Protocol describes preparation and storage of stock PCR reaction mixes with primers for each of the three diagnostic assays. The Alternate Protocol is a modification of the Basic Protocol for radioactive detection of duplications in males and deletions in carrier females. PMID:18428400

  20. Practical identifiability of the manipulator link stiffness parameters

    OpenAIRE

    Klimchik, Alexandr; Caro, Stéphane; Pashkevich, Anatol

    2013-01-01

    The paper addresses a problem of the manipulator stiffness modeling, which is extremely important for the precise manufacturing of contemporary aeronautic materials where the machining force causes significant compliance errors in the robot end-effector position. The main contributions are in the area of the elastostatic parameters identification. Particular attention is paid to the practical identifiability of the model parameters, which completely differs from the theoretical one that relie...

  1. Gene variant linked to lung cancer risk

    Science.gov (United States)

    A variation of the gene NFKB1, called rs4648127, is associated with an estimated 44 percent reduction in lung cancer risk. When this information, derived from samples obtained as part of a large NCI-sponsored prevention clinical trial, was compared with d

  2. Midlife gene expressions identify modulators of aging through dietary interventions

    OpenAIRE

    ZHOU, BING; Yang, Liu; Li, Shoufeng; Huang, Jialiang; Chen, Haiyang; HOU, LEI; Wang, Jinbo; Green, Christopher D.; Yan, Zhen; Huang, Xun; Kaeberlein, Matt; Zhu, Li; Xiao, Huasheng; Liu, Yong; Han, Jing-Dong J.

    2012-01-01

    Dietary interventions are effective ways to extend or shorten lifespan. By examining midlife hepatic gene expressions in mice under different dietary conditions, which resulted in different lifespans and aging-related phenotypes, we were able to identify genes and pathways that modulate the aging process. We found that pathways transcriptionally correlated with diet-modulated lifespan and physiological changes were enriched for lifespan-modifying genes. Intriguingly, mitochondrial gene expres...

  3. Sequence analysis of two tandemly linked Em genes from wheat.

    Science.gov (United States)

    Futers, T S; Onde, S; Turet, M; Cuming, A C

    1993-12-01

    DNA sequences are presented for two members of the wheat Em gene family. The sequences correspond to the two linked genes at the Xem-1AL locus. Comparisons of these sequences with that of another wheat Em gene and two Em cDNA clones reveals substantial homology within the protein-coding regions, and the presence in the 5'-flanking regions of the genomic sequences of motifs characteristic of ABA-responsive cis-acting elements. PMID:8260627

  4. LGscore: A method to identify disease-related genes using biological literature and Google data.

    Science.gov (United States)

    Kim, Jeongwoo; Kim, Hyunjin; Yoon, Youngmi; Park, Sanghyun

    2015-04-01

    Since the genome project in 1990s, a number of studies associated with genes have been conducted and researchers have confirmed that genes are involved in disease. For this reason, the identification of the relationships between diseases and genes is important in biology. We propose a method called LGscore, which identifies disease-related genes using Google data and literature data. To implement this method, first, we construct a disease-related gene network using text-mining results. We then extract gene-gene interactions based on co-occurrences in abstract data obtained from PubMed, and calculate the weights of edges in the gene network by means of Z-scoring. The weights contain two values: the frequency and the Google search results. The frequency value is extracted from literature data, and the Google search result is obtained using Google. We assign a score to each gene through a network analysis. We assume that genes with a large number of links and numerous Google search results and frequency values are more likely to be involved in disease. For validation, we investigated the top 20 inferred genes for five different diseases using answer sets. The answer sets comprised six databases that contain information on disease-gene relationships. We identified a significant number of disease-related genes as well as candidate genes for Alzheimer's disease, diabetes, colon cancer, lung cancer, and prostate cancer. Our method was up to 40% more accurate than existing methods. PMID:25617670

  5. Identifying genes and gene networks involved in chromium metabolism and detoxification in Crambe abyssinica

    International Nuclear Information System (INIS)

    Chromium pollution is a serious environmental problem with few cost-effective remediation strategies available. Crambe abyssinica (a member of Brassicaseae), a non-food, fast growing high biomass crop, is an ideal candidate for phytoremediation of heavy metals contaminated soils. The present study used a PCR-Select Suppression Subtraction Hybridization approach in C. abyssinica to isolate differentially expressed genes in response to Cr exposure. A total of 72 differentially expressed subtracted cDNAs were sequenced and found to represent 43 genes. The subtracted cDNAs suggest that Cr stress significantly affects pathways related to stress/defense, ion transporters, sulfur assimilation, cell signaling, protein degradation, photosynthesis and cell metabolism. The regulation of these genes in response to Cr exposure was further confirmed by semi-quantitative RT-PCR. Characterization of these differentially expressed genes may enable the engineering of non-food, high-biomass plants, including C. abyssinica, for phytoremediation of Cr-contaminated soils and sediments. - Highlights: → Molecular mechanism of Cr uptake and detoxification in plants is not well known. → We identified differentially regulated genes upon Cr exposure in Crambe abyssinica. → 72 Cr-induced subtracted cDNAs were sequenced and found to represent 43 genes. → Pathways linked to stress, ion transport, and sulfur assimilation were affected. → This is the first Cr transcriptome study in a crop with phytoremediation potential. - This study describes the identification and isolation of differentially expressed genes involved in chromium metabolism and detoxification in a non-food industrial oil crop Crambe abyssinica.

  6. A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder

    Directory of Open Access Journals (Sweden)

    David G Ashbrook

    2015-07-01

    Full Text Available Bipolar disorder (BD is a significant neuropsychiatric disorder with a lifetime prevalence of ~1%. To identify genetic variants underlying BD genome-wide association studies (GWAS have been carried out. While many variants of small effect associated with BD have been identified few have yet been confirmed, partly because of the low power of GWAS due to multiple comparisons being made. Complementary mapping studies using murine models have identified genetic variants for behavioral traits linked to BD, often with high power, but these identified regions often contain too many genes for clear identification of candidate genes. In the current study we have aligned human BD GWAS results and mouse linkage studies to help define and evaluate candidate genes linked to BD, seeking to use the power of the mouse mapping with the precision of GWAS. We use quantitative trait mapping for open field test and elevated zero maze data in the largest mammalian model system, the BXD recombinant inbred mouse population, to identify genomic regions associated with these BD-like phenotypes. We then investigate these regions in whole genome data from the Psychiatric Genomics Consortium’s bipolar disorder GWAS to identify candidate genes associated with BD. Finally we establish the biological relevance and pathways of these genes in a comprehensive systems genetics analysis. We identify four genes associated with both mouse anxiety and human BD. While TNR is a novel candidate for BD, we can confirm previously suggested associations with CMYA5, MCTP1 and RXRG. A cross-species, systems genetics analysis shows that MCTP1, RXRG and TNR coexpress with genes linked to psychiatric disorders and identify the striatum as a potential site of action. CMYA5, MCTP1, RXRG and TNR are associated with mouse anxiety and human BD. We hypothesize that MCTP1, RXRG and TNR influence intercellular signaling in the striatum.

  7. Application of an Efficient Gene Targeting System Linking Secondary Metabolites to their Biosynthetic Genes in Aspergillus terreus

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Chun-Jun; Knox, Benjamin P.; Sanchez, James F.; Chiang, Yi-Ming; Bruno, Kenneth S.; Wang, Clay C.

    2013-07-19

    Nonribosomal peptides (NRPs) are natural products biosynthesized by NRP synthetases. A kusA-, pyrG- mutant strain of Aspergillusterreus NIH 2624 was developed that greatly facilitated the gene targeting efficiency in this organism. Application of this tool allowed us to link four major types of NRP related secondary metabolites to their responsible genes in A. terreus. In addition, an NRP related melanin synthetase was also identified in this species.

  8. A sequence-based approach to identify reference genes for gene expression analysis

    OpenAIRE

    Chari Raj; Lonergan Kim M; Pikor Larissa A; Coe Bradley P; Zhu Chang; Chan Timothy HW; MacAulay Calum E; Tsao Ming-Sound; Lam Stephen; Ng Raymond T; Lam Wan L

    2010-01-01

    Abstract Background An important consideration when analyzing both microarray and quantitative PCR expression data is the selection of appropriate genes as endogenous controls or reference genes. This step is especially critical when identifying genes differentially expressed between datasets. Moreover, reference genes suitable in one context (e.g. lung cancer) may not be suitable in another (e.g. breast cancer). Currently, the main approach to identify reference genes involves the mining of ...

  9. Reducible, Dibromomaleimide-linked Polymers for Gene Delivery

    OpenAIRE

    Tan, James-Kevin Y.; Choi, Jennifer L.; Wei, Hua; Schellinger, Joan G.; Pun, Suzie H

    2014-01-01

    Polycations have been successfully used as gene transfer vehicles both in vitro and in vivo; however, their cytotoxicity has been associated with increasing molecular weight. Polymers that can be rapidly degraded after internalization are typically better tolerated by mammalian cells compared to their non-degradable counterparts. Here, we report the use of a dibromomaleimide-alkyne (DBM-alkyne) linking agent to reversibly bridge cationic polymer segments for gene delivery and to provide site-...

  10. X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes

    DEFF Research Database (Denmark)

    Hu, H; Haas, S A; Chelly, J; Van Esch, H; Raynaud, M; de Brouwer, A P M; Weinert, S; Froyen, G; Frints, S G M; Laumonnier, F; Zemojtel, T; Love, M I; Richard, H; Emde, A-K; Bienek, M; Jensen, C; Hambrock, M; Fischer, U; Langnick, C; Feldkamp, M; Wissink-Lindhout, W; Lebrun, N; Castelnau, L; Rucci, J; Montjean, R; Dorseuil, O; Billuart, P; Stuhlmann, T; Shaw, M; Corbett, M A; Gardner, A; Willis-Owen, S; Tan, C; Friend, K L; Belet, S; van Roozendaal, K E P; Jimenez-Pocquet, M; Moizard, M-P; Ronce, N; Sun, R; O'Keeffe, S; Chenna, R; van Bömmel, A; Göke, J; Hackett, A; Field, M; Christie, L; Boyle, J; Haan, E; Nelson, J; Turner, G; Baynam, G; Gillessen-Kaesbach, G; Müller, U; Steinberger, D; Budny, B; Badura-Stronka, M; Latos-Bieleńska, A; Ousager, L B; Wieacker, P; Rodríguez Criado, G; Bondeson, M-L; Annerén, G; Dufke, A; Cohen, M; Van Maldergem, L; Vincent-Delorme, C; Echenne, B; Simon-Bouy, B; Kleefstra, T; Willemsen, M; Fryns, J-P; Devriendt, K; Ullmann, R; Vingron, M; Wrogemann, K; Wienker, T F; Tzschach, A; van Bokhoven, H; Gecz, J; Jentsch, T J; Chen, W; Ropers, H-H; Kalscheuer, V M

    2016-01-01

    X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or...... established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases....

  11. Identification of DNA markers linked to a blast resistance gene in rice

    International Nuclear Information System (INIS)

    Identification of DNA markers closely linked to a blast (Pyricularia oryzae Cav.) resistance gene and establishment of an indirect selection method for the blast resistance gene based on linked DNA markers are reported. A pair of near isogenic lines, K80R and K79S, were developed using a local Chinese indica rice cultivar, Hong-jiao-zhan, as the resistant donor and IR24 as the recurrent parent. Ten putatitvely positive markers were identified by screening 177 mapped DNA markers. Using 143 plants composed of the F2 population of K80R/K79S, three restriction fragment length polymorphism (RFLP) markers (RG81, RG869 and RZ397) on chromosome 12 of rice were verified to be closely linked to the blast resistance gene. The resistance genotypes of each F2 resistant individual were determined by inoculation of the F3 lines. RG869 was found to be most closely linked to the resistance gene, with a genetic distance of 5.1 cM. To fine map this gene with more DNA markers, the bulk segregation analysis procedure was employed to identify the random amplified polymorphic DNA (RAPD) markers linked to the resistance gene. Six of 199 arbitrary primers were able to produce positive RAPD bands. Tight linkage between the resistance gene and the three RAPD bands, each from a different primer, was confirmed after amplification of the DNA of all the F2 individuals. The linked DNA fragments were cloned and sequenced. The results of specific amplification were in agreement with those of RAPD analysis. The half-seed RAPD analysis procedure for blast resistance detection was established. The amplified DNA patterns on the extract from the endosperm half of the mature seeds were identical to those of the total DNA from the leaves. (author). 13 refs, 3 figs

  12. New genes linked to lung cancer susceptibility in Asian women

    Science.gov (United States)

    An international group of scientists has identified three genes that predispose Asian women who have never smoked to lung cancer. The discovery of specific genetic variations, which have not previously been associated with lung cancer risk in other popul

  13. #DDOD Use Case: Link Open Payments Dataset to National Provider Identifier

    Data.gov (United States)

    U.S. Department of Health & Human Services — SUMMARY DDOD use case to link Centers for Medicare and Medicaid Services (CMS) Open Payments dataset to a physician's National Provider Identifier (NPI). WHAT IS A...

  14. Crossref an update on article level linking and digital object identifiers

    CERN Multimedia

    2002-01-01

    Description of the CrossRef initiative, "an independent non-profit membership organization that was established by the publishing community to permit article linking based on digital object identifiers (DOIs)" (1 page).

  15. CoreGenes: A computational tool for identifying and cataloging "core" genes in a set of small genomes

    Directory of Open Access Journals (Sweden)

    Seto Donald

    2002-04-01

    Full Text Available Abstract Background Improvements in DNA sequencing technology and methodology have led to the rapid expansion of databases comprising DNA sequence, gene and genome data. Lower operational costs and heightened interest resulting from initial intriguing novel discoveries from genomics are also contributing to the accumulation of these data sets. A major challenge is to analyze and to mine data from these databases, especially whole genomes. There is a need for computational tools that look globally at genomes for data mining. Results CoreGenes is a global JAVA-based interactive data mining tool that identifies and catalogs a "core" set of genes from two to five small whole genomes simultaneously. CoreGenes performs hierarchical and iterative BLASTP analyses using one genome as a reference and another as a query. Subsequent query genomes are compared against each newly generated "consensus." These iterations lead to a matrix comprising related genes from this set of genomes, e. g., viruses, mitochondria and chloroplasts. Currently the software is limited to small genomes on the order of 330 kilobases or less. Conclusion A computational tool CoreGenes has been developed to analyze small whole genomes globally. BLAST score-related and putatively essential "core" gene data are displayed as a table with links to GenBank for further data on the genes of interest. This web resource is available at http://pumpkins.ib3.gmu.edu:8080/CoreGenes or http://www.bif.atcc.org/CoreGenes.

  16. PhenoLink - a web-tool for linking phenotype to ~omics data for bacteria: application to gene-trait matching for Lactobacillus plantarum strains

    Directory of Open Access Journals (Sweden)

    Bayjanov Jumamurat R

    2012-05-01

    Full Text Available Abstract Background Linking phenotypes to high-throughput molecular biology information generated by ~omics technologies allows revealing cellular mechanisms underlying an organism's phenotype. ~Omics datasets are often very large and noisy with many features (e.g., genes, metabolite abundances. Thus, associating phenotypes to ~omics data requires an approach that is robust to noise and can handle large and diverse data sets. Results We developed a web-tool PhenoLink (http://bamics2.cmbi.ru.nl/websoftware/phenolink/ that links phenotype to ~omics data sets using well-established as well new techniques. PhenoLink imputes missing values and preprocesses input data (i to decrease inherent noise in the data and (ii to counterbalance pitfalls of the Random Forest algorithm, on which feature (e.g., gene selection is based. Preprocessed data is used in feature (e.g., gene selection to identify relations to phenotypes. We applied PhenoLink to identify gene-phenotype relations based on the presence/absence of 2847 genes in 42 Lactobacillus plantarum strains and phenotypic measurements of these strains in several experimental conditions, including growth on sugars and nitrogen-dioxide production. Genes were ranked based on their importance (predictive value to correctly predict the phenotype of a given strain. In addition to known gene to phenotype relations we also found novel relations. Conclusions PhenoLink is an easily accessible web-tool to facilitate identifying relations from large and often noisy phenotype and ~omics datasets. Visualization of links to phenotypes offered in PhenoLink allows prioritizing links, finding relations between features, finding relations between phenotypes, and identifying outliers in phenotype data. PhenoLink can be used to uncover phenotype links to a multitude of ~omics data, e.g., gene presence/absence (determined by e.g.: CGH or next-generation sequencing, gene expression (determined by e.g.: microarrays or RNA-seq, or metabolite abundance (determined by e.g.: GC-MS.

  17. Identifying lipid metabolism genes in pig liver after clenbuterol administration.

    Science.gov (United States)

    Liu, Qiuyue; Zhang, Jin; Guo, Wei; Zhao, Yiqiang; Hu, Xiaoxiang; Li, Ning

    2012-01-01

    Clenbuterol is a repartition agent (beta 2-adrenoceptor agonist) that can decrease fat deposition and increase skeletal muscle growth at manageable dose. To better understand the molecular mechanism of Clenbuterol's action, GeneChips and real-time PCR were used to compare the gene expression profiles of liver tissue in pigs with/without administration of Clenbuterol. Metabolism effects and the global gene expression profiles of liver tissue from Clenbuterol-treated and untreated pigs were conducted. Function enrichment tests showed that the differentially expressed genes are enriched in glycoprotein protein, plasma membrane, fatty acid and amino acid metabolic process, and cell differentiation and signal transduction groups. Pathway mining analysis revealed that physiological pathways such as MAPK, cell adhesion molecules, and the insulin signaling pathway, were remarkably regulated when Clenbuterol was administered. Gene prioritization algorithm was used to associate a number of important differentially expressed genes with lipid metabolism in response to Clenbuterol. Genes identified as differentially expressed in this study will be candidates for further investigation of the molecular mechanisms involved in Clenbuterol's effects on adipose and skeletal muscle tissue. PMID:22652664

  18. X-linked intellectual disability related genes disrupted by balanced X-autosome translocations.

    Science.gov (United States)

    Moysés-Oliveira, Mariana; Guilherme, Roberta Santos; Meloni, Vera Ayres; Di Battista, Adriana; de Mello, Claudia Berlim; Bragagnolo, Silvia; Moretti-Ferreira, Danilo; Kosyakova, Nadezda; Liehr, Thomas; Carvalheira, Gianna Maria; Melaragno, Maria Isabel

    2015-12-01

    Detailed molecular characterization of chromosomal rearrangements involving X-chromosome has been a key strategy in identifying X-linked intellectual disability-causing genes. We fine-mapped the breakpoints in four women with balanced X-autosome translocations and variable phenotypes, in order to investigate the corresponding genetic contribution to intellectual disability. We addressed the impact of the gene interruptions in transcription and discussed the consequences of their functional impairment in neurodevelopment. Three patients presented with cognitive impairment, reinforcing the association between the disrupted genes (TSPAN7-MRX58, KIAA2022-MRX98, and IL1RAPL1-MRX21/34) and intellectual disability. While gene expression analysis showed absence of TSPAN7 and KIAA2022 expression in the patients, the unexpected expression of IL1RAPL1 suggested a fusion transcript ZNF611-IL1RAPL1 under the control of the ZNF611 promoter, gene disrupted at the autosomal breakpoint. The X-chromosomal breakpoint definition in the fourth patient, a woman with normal intellectual abilities, revealed disruption of the ZDHHC15 gene (MRX91). The expression assays did not detect ZDHHC15 gene expression in the patient, thus questioning its involvement in intellectual disability. Revealing the disruption of an X-linked intellectual disability-related gene in patients with balanced X-autosome translocation is a useful tool for a better characterization of critical genes in neurodevelopment. © 2015 Wiley Periodicals, Inc. PMID:26290131

  19. Animal Models of GWAS-Identified Type 2 Diabetes Genes

    OpenAIRE

    Gabriela da Silva Xavier; Bellomo, Elisa A.; McGinty, James A.; French, Paul M.; Rutter, Guy A.

    2013-01-01

    More than 65 loci, encoding up to 500 different genes, have been implicated by genome-wide association studies (GWAS) as conferring an increased risk of developing type 2 diabetes (T2D). Whilst mouse models have in the past been central to understanding the mechanisms through which more penetrant risk genes for T2D, for example, those responsible for neonatal or maturity-onset diabetes of the young, only a few of those identified by GWAS, notably TCF7L2 and ZnT8/SLC30A8, have to date been exa...

  20. Using SCOPE to identify potential regulatory motifs in coregulated genes.

    Science.gov (United States)

    Martyanov, Viktor; Gross, Robert H

    2011-01-01

    SCOPE is an ensemble motif finder that uses three component algorithms in parallel to identify potential regulatory motifs by over-representation and motif position preference. Each component algorithm is optimized to find a different kind of motif. By taking the best of these three approaches, SCOPE performs better than any single algorithm, even in the presence of noisy data. In this article, we utilize a web version of SCOPE to examine genes that are involved in telomere maintenance. SCOPE has been incorporated into at least two other motif finding programs and has been used in other studies. The three algorithms that comprise SCOPE are BEAM, which finds non-degenerate motifs (ACCGGT), PRISM, which finds degenerate motifs (ASCGWT), and SPACER, which finds longer bipartite motifs (ACCnnnnnnnnGGT). These three algorithms have been optimized to find their corresponding type of motif. Together, they allow SCOPE to perform extremely well. Once a gene set has been analyzed and candidate motifs identified, SCOPE can look for other genes that contain the motif which, when added to the original set, will improve the motif score. This can occur through over-representation or motif position preference. Working with partial gene sets that have biologically verified transcription factor binding sites, SCOPE was able to identify most of the rest of the genes also regulated by the given transcription factor. Output from SCOPE shows candidate motifs, their significance, and other information both as a table and as a graphical motif map. FAQs and video tutorials are available at the SCOPE web site which also includes a "Sample Search" button that allows the user to perform a trial run. Scope has a very friendly user interface that enables novice users to access the algorithm's full power without having to become an expert in the bioinformatics of motif finding. As input, SCOPE can take a list of genes, or FASTA sequences. These can be entered in browser text fields, or read from a file. The output from SCOPE contains a list of all identified motifs with their scores, number of occurrences, fraction of genes containing the motif, and the algorithm used to identify the motif. For each motif, result details include a consensus representation of the motif, a sequence logo, a position weight matrix, and a list of instances for every motif occurrence (with exact positions and "strand" indicated). Results are returned in a browser window and also optionally by email. Previous papers describe the SCOPE algorithms in detail. PMID:21673638

  1. Identifying root system genes using induced mutants in barley

    International Nuclear Information System (INIS)

    Root systems play an important role in plant growth and development. They absorb water and nutrients, anchor plant in the soil and affect plant tolerance to various abiotic stresses. Despite their importance, the progress in understanding the molecular processes underlying root development has been achieved only in Arabidopsis thaliana. It was accomplished through detailed analysis of root mutants with the use of advanced molecular, genomic and bioinformatic tools. Recently, similar studies performed with rice and maize root mutants have led to the identification of homologous and novel genes controlling root system formation in monocots. The collection of barley mutants with changes in root system development and morphology has been developed in our Department after mutagenic treatments of spring barley varieties with N-methyl N-nitosourea (MNU) and sodium azide. Among these mutants, the majority was characterized by seminal roots significantly shorter than roots of a parent variety throughout a whole vegetation period. Additionally, several mutants with root hairs impaired at different stages of development have been identified. These mutants have become the material of studies aimed at genetic and molecular dissection of seminal root and root hair formation in barley. The studies included the molecular mapping of genes responsible for mutant phenotype using DNA markers and root transcriptome analysis in the mutant/parent variety system. Using cDNA RDA approach, we have identified the HvEXPB1 gene encoding root specific beta expansin related to the root hair initiation in barley. We have also initiated the database search for barley sequences homologous to the known Arabodopsis, maize and rice genes. The identified homologous ESTs are now used for isolation of the complete coding sequences and gene function will be validated through identification of mutations related to the altered phenotype. This work was supported by the IAEA Research Contracts 12611 and 12849, and Polish Ministry of Science and Higher Education grant 2 P04C 056 30. (author)

  2. Sleeping Beauty mouse models identify candidate genes involved in gliomagenesis.

    Science.gov (United States)

    Vyazunova, Irina; Maklakova, Vilena I; Berman, Samuel; De, Ishani; Steffen, Megan D; Hong, Won; Lincoln, Hayley; Morrissy, A Sorana; Taylor, Michael D; Akagi, Keiko; Brennan, Cameron W; Rodriguez, Fausto J; Collier, Lara S

    2014-01-01

    Genomic studies of human high-grade gliomas have discovered known and candidate tumor drivers. Studies in both cell culture and mouse models have complemented these approaches and have identified additional genes and processes important for gliomagenesis. Previously, we found that mobilization of Sleeping Beauty transposons in mice ubiquitously throughout the body from the Rosa26 locus led to gliomagenesis with low penetrance. Here we report the characterization of mice in which transposons are mobilized in the Glial Fibrillary Acidic Protein (GFAP) compartment. Glioma formation in these mice did not occur on an otherwise wild-type genetic background, but rare gliomas were observed when mobilization occurred in a p19Arf heterozygous background. Through cloning insertions from additional gliomas generated by transposon mobilization in the Rosa26 compartment, several candidate glioma genes were identified. Comparisons to genetic, epigenetic and mRNA expression data from human gliomas implicates several of these genes as tumor suppressor genes and oncogenes in human glioblastoma. PMID:25423036

  3. Sleeping Beauty Mouse Models Identify Candidate Genes Involved in Gliomagenesis

    Science.gov (United States)

    Vyazunova, Irina; Maklakova, Vilena I.; Berman, Samuel; De, Ishani; Steffen, Megan D.; Hong, Won; Lincoln, Hayley; Morrissy, A. Sorana; Taylor, Michael D.; Akagi, Keiko; Brennan, Cameron W.; Rodriguez, Fausto J.; Collier, Lara S.

    2014-01-01

    Genomic studies of human high-grade gliomas have discovered known and candidate tumor drivers. Studies in both cell culture and mouse models have complemented these approaches and have identified additional genes and processes important for gliomagenesis. Previously, we found that mobilization of Sleeping Beauty transposons in mice ubiquitously throughout the body from the Rosa26 locus led to gliomagenesis with low penetrance. Here we report the characterization of mice in which transposons are mobilized in the Glial Fibrillary Acidic Protein (GFAP) compartment. Glioma formation in these mice did not occur on an otherwise wild-type genetic background, but rare gliomas were observed when mobilization occurred in a p19Arf heterozygous background. Through cloning insertions from additional gliomas generated by transposon mobilization in the Rosa26 compartment, several candidate glioma genes were identified. Comparisons to genetic, epigenetic and mRNA expression data from human gliomas implicates several of these genes as tumor suppressor genes and oncogenes in human glioblastoma. PMID:25423036

  4. Using SCOPE to Identify Potential Regulatory Motifs in Coregulated Genes

    OpenAIRE

    Martyanov, Viktor; Gross, Robert H.

    2011-01-01

    SCOPE is an ensemble motif finder that uses three component algorithms in parallel to identify potential regulatory motifs by over-representation and motif position preference1. Each component algorithm is optimized to find a different kind of motif. By taking the best of these three approaches, SCOPE performs better than any single algorithm, even in the presence of noisy data1. In this article, we utilize a web version of SCOPE2 to examine genes that are involved in telomere maintenance. SC...

  5. Bayesian gene set analysis for identifying significant biological pathways

    OpenAIRE

    Shahbaba, Babak; Tibshirani, Robert; Shachaf, Catherine M.; Plevritis, Sylvia K

    2011-01-01

    We propose a hierarchical Bayesian model for analyzing gene expression data to identify pathways differentiating between two biological states (e.g., cancer vs. non-cancer and mutant vs. normal). Finding significant pathways can improve our understanding of biological processes. When the biological process of interest is related to a specific disease, eliciting a better understanding of the underlying pathways can lead to designing a more effective treatment. We apply our method to data obtai...

  6. Sleeping Beauty Mouse Models Identify Candidate Genes Involved in Gliomagenesis

    OpenAIRE

    Vyazunova, Irina; Maklakova, Vilena I.; Berman, Samuel; Ishani; Steffen, Megan D.; Hong, Won; Lincoln, Hayley; Morrissy, A. Sorana; Taylor, Michael D; Akagi, Keiko; Brennan, Cameron W.; Rodriguez, Fausto J.; Collier, Lara S

    2014-01-01

    Genomic studies of human high-grade gliomas have discovered known and candidate tumor drivers. Studies in both cell culture and mouse models have complemented these approaches and have identified additional genes and processes important for gliomagenesis. Previously, we found that mobilization of Sleeping Beauty transposons in mice ubiquitously throughout the body from the Rosa26 locus led to gliomagenesis with low penetrance. Here we report the characterization of mice in which transposons a...

  7. Blood pressure loci identified with a gene-centric array

    OpenAIRE

    Johnson, Toby; Gaunt, Tom R.; Newhouse, Stephen J.; Padmanabhan, Sandosh; Tomaszewski, Maciej; Kumari, Meena; Morris, Richard W.; Tzoulaki, Ioanna; O'Brien, Eoin T.; Poulter, Neil R.; Sever, Peter; Shields, Denis C.; Thom, Simon; Wannamethee, Sasiwarang G.; Whincup, Peter H.

    2011-01-01

    Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated ...

  8. DNA markers linked to a T10 loose smut resistance gene in wheat (Triticum aestivum L.).

    Science.gov (United States)

    Procunier, J D; Gray, M A; Howes, N K; Knox, R E; Bernier, A M

    1997-04-01

    Screening for loose smut resistance in wheat is difficult. Selecting lines with DNA markers linked to loose smut resistance would be more reliable and less costly. Molecular markers linked to a race T10 loose smut resistance gene were identified using a F6 single seed descent segregating population. A RAPD marker and a RFLP marker were located on opposite flanks of the resistance gene and were shown to be loosely linked. The RAPD marker was converted to a user friendly polymorphic SCAR marker that represented a single genetically defined locus in hexaploid wheat. Using these two bracketing markers simultaneously, the error rate for T10 resistance selection due to crossing-over was reduced to 4%. These markers can be used for a faster and more reliable selection of T10 resistant plants than previous conventional loose smut ratings. PMID:18464816

  9. A sequence-based approach to identify reference genes for gene expression analysis

    Directory of Open Access Journals (Sweden)

    Chari Raj

    2010-08-01

    Full Text Available Abstract Background An important consideration when analyzing both microarray and quantitative PCR expression data is the selection of appropriate genes as endogenous controls or reference genes. This step is especially critical when identifying genes differentially expressed between datasets. Moreover, reference genes suitable in one context (e.g. lung cancer may not be suitable in another (e.g. breast cancer. Currently, the main approach to identify reference genes involves the mining of expression microarray data for highly expressed and relatively constant transcripts across a sample set. A caveat here is the requirement for transcript normalization prior to analysis, and measurements obtained are relative, not absolute. Alternatively, as sequencing-based technologies provide digital quantitative output, absolute quantification ensues, and reference gene identification becomes more accurate. Methods Serial analysis of gene expression (SAGE profiles of non-malignant and malignant lung samples were compared using a permutation test to identify the most stably expressed genes across all samples. Subsequently, the specificity of the reference genes was evaluated across multiple tissue types, their constancy of expression was assessed using quantitative RT-PCR (qPCR, and their impact on differential expression analysis of microarray data was evaluated. Results We show that (i conventional references genes such as ACTB and GAPDH are highly variable between cancerous and non-cancerous samples, (ii reference genes identified for lung cancer do not perform well for other cancer types (breast and brain, (iii reference genes identified through SAGE show low variability using qPCR in a different cohort of samples, and (iv normalization of a lung cancer gene expression microarray dataset with or without our reference genes, yields different results for differential gene expression and subsequent analyses. Specifically, key established pathways in lung cancer exhibit higher statistical significance using a dataset normalized with our reference genes relative to normalization without using our reference genes. Conclusions Our analyses found NDUFA1, RPL19, RAB5C, and RPS18 to occupy the top ranking positions among 15 suitable reference genes optimal for normalization of lung tissue expression data. Significantly, the approach used in this study can be applied to data generated using new generation sequencing platforms for the identification of reference genes optimal within diverse contexts.

  10. Comprehensive Ex Vivo Transposon Mutagenesis Identifies Genes That Promote Growth Factor Independence and Leukemogenesis.

    Science.gov (United States)

    Guo, Yabin; Updegraff, Barrett L; Park, Sunho; Durakoglugil, Deniz; Cruz, Victoria H; Maddux, Sarah; Hwang, Tae Hyun; O'Donnell, Kathryn A

    2016-02-15

    Aberrant signaling through cytokine receptors and their downstream signaling pathways is a major oncogenic mechanism underlying hematopoietic malignancies. To better understand how these pathways become pathologically activated and to potentially identify new drivers of hematopoietic cancers, we developed a high-throughput functional screening approach using ex vivo mutagenesis with the Sleeping Beauty transposon. We analyzed over 1,100 transposon-mutagenized pools of Ba/F3 cells, an IL3-dependent pro-B-cell line, which acquired cytokine independence and tumor-forming ability. Recurrent transposon insertions could be mapped to genes in the JAK/STAT and MAPK pathways, confirming the ability of this strategy to identify known oncogenic components of cytokine signaling pathways. In addition, recurrent insertions were identified in a large set of genes that have been found to be mutated in leukemia or associated with survival, but were not previously linked to the JAK/STAT or MAPK pathways nor shown to functionally contribute to leukemogenesis. Forced expression of these novel genes resulted in IL3-independent growth in vitro and tumorigenesis in vivo, validating this mutagenesis-based approach for identifying new genes that promote cytokine signaling and leukemogenesis. Therefore, our findings provide a broadly applicable approach for classifying functionally relevant genes in diverse malignancies and offer new insights into the impact of cytokine signaling on leukemia development. Cancer Res; 76(4); 773-86. 2015 AACR. PMID:26676752

  11. Semantic interrogation of a multi knowledge domain ontological model of tendinopathy identifies four strong candidate risk genes

    Science.gov (United States)

    Saunders, Colleen J.; Jalali Sefid Dashti, Mahjoubeh; Gamieldien, Junaid

    2016-01-01

    Tendinopathy is a multifactorial syndrome characterised by tendon pain and thickening, and impaired performance during activity. Candidate gene association studies have identified genetic factors that contribute to intrinsic risk of developing tendinopathy upon exposure to extrinsic factors. Bioinformatics approaches that data-mine existing knowledge for biological relationships may assist with the identification of candidate genes. The aim of this study was to data-mine functional annotation of human genes and identify candidate genes by ontology-seeded queries capturing the features of tendinopathy. Our BioOntological Relationship Graph database (BORG) integrates multiple sources of genomic and biomedical knowledge into an on-disk semantic network where human genes and their orthologs in mouse and rat are central concepts mapped to ontology terms. The BORG was used to screen all human genes for potential links to tendinopathy. Following further prioritisation, four strong candidate genes (COL11A2, ELN, ITGB3, LOX) were identified. These genes are differentially expressed in tendinopathy, functionally linked to features of tendinopathy and previously implicated in other connective tissue diseases. In conclusion, cross-domain semantic integration of multiple sources of biomedical knowledge, and interrogation of phenotypes and gene functions associated with disease, may significantly increase the probability of identifying strong and unobvious candidate genes in genetic association studies. PMID:26804977

  12. Distinct gene expression profiles in ovarian cancer linked to Lynch syndrome

    OpenAIRE

    Jönsson, Jenny-Maria; Bartuma, Katarina; Dominguez, Mev; Harbst, Katja; Ketabi, Zohreh; Malander, Susanne; Jönsson, Mats; Carneiro, Ana; Måsbäck, Anna; Jönsson, Göran B; Nilbert, Mef

    2014-01-01

    Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer with the aim to identify key discriminators and central tumorigenic mechanisms in hereditary ovarian cancer. Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extensio...

  13. Blood pressure loci identified with a gene-centric array.

    Science.gov (United States)

    Johnson, Toby; Gaunt, Tom R; Newhouse, Stephen J; Padmanabhan, Sandosh; Tomaszewski, Maciej; Kumari, Meena; Morris, Richard W; Tzoulaki, Ioanna; O'Brien, Eoin T; Poulter, Neil R; Sever, Peter; Shields, Denis C; Thom, Simon; Wannamethee, Sasiwarang G; Whincup, Peter H; Brown, Morris J; Connell, John M; Dobson, Richard J; Howard, Philip J; Mein, Charles A; Onipinla, Abiodun; Shaw-Hawkins, Sue; Zhang, Yun; Davey Smith, George; Day, Ian N M; Lawlor, Debbie A; Goodall, Alison H; Fowkes, F Gerald; Abecasis, Gonçalo R; Elliott, Paul; Gateva, Vesela; Braund, Peter S; Burton, Paul R; Nelson, Christopher P; Tobin, Martin D; van der Harst, Pim; Glorioso, Nicola; Neuvrith, Hani; Salvi, Erika; Staessen, Jan A; Stucchi, Andrea; Devos, Nabila; Jeunemaitre, Xavier; Plouin, Pierre-François; Tichet, Jean; Juhanson, Peeter; Org, Elin; Putku, Margus; Sõber, Siim; Veldre, Gudrun; Viigimaa, Margus; Levinsson, Anna; Rosengren, Annika; Thelle, Dag S; Hastie, Claire E; Hedner, Thomas; Lee, Wai K; Melander, Olle; Wahlstrand, Björn; Hardy, Rebecca; Wong, Andrew; Cooper, Jackie A; Palmen, Jutta; Chen, Li; Stewart, Alexandre F R; Wells, George A; Westra, Harm-Jan; Wolfs, Marcel G M; Clarke, Robert; Franzosi, Maria Grazia; Goel, Anuj; Hamsten, Anders; Lathrop, Mark; Peden, John F; Seedorf, Udo; Watkins, Hugh; Ouwehand, Willem H; Sambrook, Jennifer; Stephens, Jonathan; Casas, Juan-Pablo; Drenos, Fotios; Holmes, Michael V; Kivimaki, Mika; Shah, Sonia; Shah, Tina; Talmud, Philippa J; Whittaker, John; Wallace, Chris; Delles, Christian; Laan, Maris; Kuh, Diana; Humphries, Steve E; Nyberg, Fredrik; Cusi, Daniele; Roberts, Robert; Newton-Cheh, Christopher; Franke, Lude; Stanton, Alice V; Dominiczak, Anna F; Farrall, Martin; Hingorani, Aroon D; Samani, Nilesh J; Caulfield, Mark J; Munroe, Patricia B

    2011-12-01

    Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p studied previously even when the sample size is smaller than that in previous studies. PMID:22100073

  14. Multidisciplinary approach to identify gene-environment interplay triggering autism

    Directory of Open Access Journals (Sweden)

    Alessandra Mezzelani

    2015-05-01

    Further ASD patients suffering from GID and healthy controls will be recruited and samples of blood, serum and feces collected as well as clinical data and dietary diary. GWAs, circulating RNAseq and stool metagenomics analyses will be performed on biological samples in order to identify the endogenous (genetic risk and human circulating microRNAs and exogenous (microbiota and xenomiRs profile of ASD patients and controls. All the data obtained will be submitted to a neuroinformatics integration and systems biology analysis to find a possible gene-environmental cross-talk via epigenetic mechanisms.

  15. [Microsatellite marker linked with stripe rust resistant gene Yr9 in wheat].

    Science.gov (United States)

    Weng, Dong-Xu; Xu, Shi-Chang; Lin, Rui-Ming; Wan, An-Min; Li, Jing-Peng; Wu, Li-Ren

    2005-09-01

    SSR analysis was performed using a wheat near-isogenic line (NIL) Taichuang29 * 6/ Lovrin13, which carried the resistance gene Yr9 against wheat stripe rust and its recurrent parent Taichung29 as materials. After screening with 32 SSR primers on 1B chromosome, reproducible polymorphic DNA fragment amplified by Xgwm582 was identified. Genetic linkage was tested in 177 segregating F2 plants. The results indicated that microsatellite marker Xgwm582 was linked with gene Yr9 resistant to wheat stripe rust. A genetic distance of 3. 7 cM was calculated. PMID:16201237

  16. DAWN: a framework to identify autism genes and subnetworks using gene expression and genetics

    OpenAIRE

    LIU, LI; Lei, Jing; Sanders, Stephan J; Willsey, Arthur Jeremy; Kou, Yan; Cicek, Abdullah Ercument; Klei, Lambertus; Lu, Cong; HE Xin; Li, Mingfeng; Muhle, Rebecca A; Ma’ayan, Avi; Noonan, James P; Šestan, Nenad; McFadden, Kathryn A

    2014-01-01

    Background De novo loss-of-function (dnLoF) mutations are found twofold more often in autism spectrum disorder (ASD) probands than their unaffected siblings. Multiple independent dnLoF mutations in the same gene implicate the gene in risk and hence provide a systematic, albeit arduous, path forward for ASD genetics. It is likely that using additional non-genetic data will enhance the ability to identify ASD genes. Methods To accelerate the search for ASD genes, we developed a novel algorithm,...

  17. Origination of an X-linked testes chimeric gene by illegitimate recombination in Drosophila.

    Directory of Open Access Journals (Sweden)

    2006-05-01

    Full Text Available The formation of chimeric gene structures provides important routes by which novel proteins and functions are introduced into genomes. Signatures of these events have been identified in organisms from wide phylogenic distributions. However, the ability to characterize the early phases of these evolutionary processes has been difficult due to the ancient age of the genes or to the limitations of strictly computational approaches. While examples involving retrotransposition exist, our understanding of chimeric genes originating via illegitimate recombination is limited to speculations based on ancient genes or transfection experiments. Here we report a case of a young chimeric gene that has originated by illegitimate recombination in Drosophila. This gene was created within the last 2-3 million years, prior to the speciation of Drosophila simulans, Drosophila sechellia, and Drosophila mauritiana. The duplication, which involved the Bällchen gene on Chromosome 3R, was partial, removing substantial 3' coding sequence. Subsequent to the duplication onto the X chromosome, intergenic sequence was recruited into the protein-coding region creating a chimeric peptide with approximately 33 new amino acid residues. In addition, a novel intron-containing 5' UTR and novel 3' UTR evolved. We further found that this new X-linked gene has evolved testes-specific expression. Following speciation of the D. simulans complex, this novel gene evolved lineage-specifically with evidence for positive selection acting along the D. simulans branch.

  18. Transcriptomic Analysis Using Olive Varieties and Breeding Progenies Identifies Candidate Genes Involved in Plant Architecture

    Science.gov (United States)

    González-Plaza, Juan J.; Ortiz-Martín, Inmaculada; Muñoz-Mérida, Antonio; García-López, Carmen; Sánchez-Sevilla, José F.; Luque, Francisco; Trelles, Oswaldo; Bejarano, Eduardo R.; De La Rosa, Raúl; Valpuesta, Victoriano; Beuzón, Carmen R.

    2016-01-01

    Plant architecture is a critical trait in fruit crops that can significantly influence yield, pruning, planting density and harvesting. Little is known about how plant architecture is genetically determined in olive, were most of the existing varieties are traditional with an architecture poorly suited for modern growing and harvesting systems. In the present study, we have carried out microarray analysis of meristematic tissue to compare expression profiles of olive varieties displaying differences in architecture, as well as seedlings from their cross pooled on the basis of their sharing architecture-related phenotypes. The microarray used, previously developed by our group has already been applied to identify candidates genes involved in regulating juvenile to adult transition in the shoot apex of seedlings. Varieties with distinct architecture phenotypes and individuals from segregating progenies displaying opposite architecture features were used to link phenotype to expression. Here, we identify 2252 differentially expressed genes (DEGs) associated to differences in plant architecture. Microarray results were validated by quantitative RT-PCR carried out on genes with functional annotation likely related to plant architecture. Twelve of these genes were further analyzed in individual seedlings of the corresponding pool. We also examined Arabidopsis mutants in putative orthologs of these targeted candidate genes, finding altered architecture for most of them. This supports a functional conservation between species and potential biological relevance of the candidate genes identified. This study is the first to identify genes associated to plant architecture in olive, and the results obtained could be of great help in future programs aimed at selecting phenotypes adapted to modern cultivation practices in this species. PMID:26973682

  19. Exonuclease-mediated degradation of nascent RNA silences genes linked to severe malaria

    DEFF Research Database (Denmark)

    Zhang, Qingfeng; Siegel, T Nicolai; Martins, Rafael M; Wang, Fei; Cao, Jun; Gao, Qi; Cheng, Xiu; Jiang, Lubin; Hon, Chung-Chau; Scheidig-Benatar, Christine; Sakamoto, Hiroshi; Turner, Louise; Jensen, Anja Tatiana Ramstedt; Claes, Aurelie; Guizetti, Julien; Malmquist, Nicholas A; Scherf, Artur

    2014-01-01

    malaria. The mechanism determining upsA activation remains unknown. Here we show that an entirely new type of gene silencing mechanism involving an exonuclease-mediated degradation of nascent RNA controls the silencing of genes linked to severe malaria. We identify a novel chromatin......-associated exoribonuclease, termed PfRNase II, that controls the silencing of upsA var genes by marking their transcription start site and intron-promoter regions leading to short-lived cryptic RNA. Parasites carrying a deficient PfRNase II gene produce full-length upsA var transcripts and intron-derived antisense long non......-coding RNA. The presence of stable upsA var transcripts overcomes monoallelic expression, resulting in the simultaneous expression of both upsA and upsC type PfEMP1 proteins on the surface of individual infected red blood cells. In addition, we observe an inverse relationship between transcript levels of Pf...

  20. LINKING DEAFNESS GENES TO HAIR-BUNDLE DEVELOPMENT AND FUNCTION

    OpenAIRE

    Petit, Christine; Richardson, Guy P.

    2009-01-01

    The identification of genes underlying monogenic, early-onset forms of deafness in humans has provided unprecedented insight into the molecular mechanisms of hearing in the peripheral auditory system. The molecules involved in the development and function of the cochlea eluded characterization until recently due to the paucity of the principle cell types present in cochlear hair cells, yet a genetic approach has circumvented this problem and succeeded in identifying proteins and deciphering s...

  1. Identifying Cyclic Genes in Time-Course Gene Expression Studies Using Proc Traj

    Directory of Open Access Journals (Sweden)

    Mehmet KOCAK

    2015-10-01

    Full Text Available Jones and Nagin developed PROC TRAJ to study developmental trajectories for the areas of psychology, sociology, and criminology. We tested the utility of the TRAJ procedure in identifying cyclic (i.e., periodic genes based on their time-course expression measurements. We have shown through extensive simulations that PROC TRAJ offers practical solutions in identifying gene-sets with different profiles including cyclic patterns over cell division cycles. We then applied the procedure to an S. Pombe gene-expression data and showed that through the use of TRAJ procedure, different sets of periodic genes can be obtained, where truly periodic genes are ranked much higher overall compared to not-periodic genes, thus making their identification easier. As a conclusion, we present convincing preliminary evidence for the utility of PROC TRAJ in cell-cycle gene expression data analysis although its utility must be tested more stringently in future simulation studies as well as by its application to other real-experimental data where identifying cyclic patterns is the primary goal.

  2. Blood Pressure Loci Identified with a Gene-Centric Array

    Science.gov (United States)

    Johnson, Toby; Gaunt, Tom R.; Newhouse, Stephen J.; Padmanabhan, Sandosh; Tomaszewski, Maciej; Kumari, Meena; Morris, Richard W.; Tzoulaki, Ioanna; O'Brien, Eoin T.; Poulter, Neil R.; Sever, Peter; Shields, Denis C.; Thom, Simon; Wannamethee, Sasiwarang G.; Whincup, Peter H.; Brown, Morris J.; Connell, John M.; Dobson, Richard J.; Howard, Philip J.; Mein, Charles A.; Onipinla, Abiodun; Shaw-Hawkins, Sue; Zhang, Yun; Smith, George Davey; Day, Ian N.M.; Lawlor, Debbie A.; Goodall, Alison H.; Fowkes, F. Gerald; Abecasis, Gonçalo R.; Elliott, Paul; Gateva, Vesela; Braund, Peter S.; Burton, Paul R.; Nelson, Christopher P.; Tobin, Martin D.; van der Harst, Pim; Glorioso, Nicola; Neuvrith, Hani; Salvi, Erika; Staessen, Jan A.; Stucchi, Andrea; Devos, Nabila; Jeunemaitre, Xavier; Plouin, Pierre-François; Tichet, Jean; Juhanson, Peeter; Org, Elin; Putku, Margus; Sõber, Siim; Veldre, Gudrun; Viigimaa, Margus; Levinsson, Anna; Rosengren, Annika; Thelle, Dag S.; Hastie, Claire E.; Hedner, Thomas; Lee, Wai K.; Melander, Olle; Wahlstrand, Björn; Hardy, Rebecca; Wong, Andrew; Cooper, Jackie A.; Palmen, Jutta; Chen, Li; Stewart, Alexandre F.R.; Wells, George A.; Westra, Harm-Jan; Wolfs, Marcel G.M.; Clarke, Robert; Franzosi, Maria Grazia; Goel, Anuj; Hamsten, Anders; Lathrop, Mark; Peden, John F.; Seedorf, Udo; Watkins, Hugh; Ouwehand, Willem H.; Sambrook, Jennifer; Stephens, Jonathan; Casas, Juan-Pablo; Drenos, Fotios; Holmes, Michael V.; Kivimaki, Mika; Shah, Sonia; Shah, Tina; Talmud, Philippa J.; Whittaker, John; Wallace, Chris; Delles, Christian; Laan, Maris; Kuh, Diana; Humphries, Steve E.; Nyberg, Fredrik; Cusi, Daniele; Roberts, Robert; Newton-Cheh, Christopher; Franke, Lude; Stanton, Alice V.; Dominiczak, Anna F.; Farrall, Martin; Hingorani, Aroon D.; Samani, Nilesh J.; Caulfield, Mark J.; Munroe, Patricia B.

    2011-01-01

    Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10−7 study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r2 = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10−7 at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies. PMID:22100073

  3. Similar interstitial deletions of the KAL-1 gene in two Brazilian families with X-linked Kallmann Syndrome

    OpenAIRE

    Ericka Barbosa Trarbach; Isabella Lopes Monlleo; Carlos Guilherme Gaelzer Porciuncula; Marshall Italo Barros Fontes; Maria Teresa Mathias Baptista; Christine Hackel

    2004-01-01

    Mutations in the KAL-1 gene localized at Xp22.3 have been shown to be responsible for the X-linked Kallmann syndrome (KS), a disorder characterized by the association of hypogonadotropic hypogonadism and anosmia. In this paper, we describe the investigation of two families with X-linked KS, in which similar interstitial deletions ning exons 5 to 10 of the KAL-1 gene were identified. The presence of interspersed repetitive DNA sequences within the KAL-1 gene might have predisposed to this type...

  4. Similar interstitial deletions of the KAL-1 gene in two Brazilian families with X-linked Kallmann Syndrome

    Directory of Open Access Journals (Sweden)

    Ericka Barbosa Trarbach

    2004-01-01

    Full Text Available Mutations in the KAL-1 gene localized at Xp22.3 have been shown to be responsible for the X-linked Kallmann syndrome (KS, a disorder characterized by the association of hypogonadotropic hypogonadism and anosmia. In this paper, we describe the investigation of two families with X-linked KS, in which similar interstitial deletions ning exons 5 to 10 of the KAL-1 gene were identified. The presence of interspersed repetitive DNA sequences within the KAL-1 gene might have predisposed to this type of mutation.

  5. Changes in gene expression linked to methamphetamine-induced dopaminergic neurotoxicity.

    Science.gov (United States)

    Xie, Tao; Tong, Liqiong; Barrett, Tanya; Yuan, Jie; Hatzidimitriou, George; McCann, Una D; Becker, Kevin G; Donovan, David M; Ricaurte, George A

    2002-01-01

    The purpose of these studies was to examine the role of gene expression in methamphetamine (METH)-induced dopamine (DA) neurotoxicity. First, the effects of the mRNA synthesis inhibitor, actinomycin-D, and the protein synthesis inhibitor, cycloheximide, were examined. Both agents afforded complete protection against METH-induced DA neurotoxicity and did so independently of effects on core temperature, DA transporter function, or METH brain levels, suggesting that gene transcription and mRNA translation play a role in METH neurotoxicity. Next, microarray technology, in combination with an experimental approach designed to facilitate recognition of relevant gene expression patterns, was used to identify gene products linked to METH-induced DA neurotoxicity. This led to the identification of several genes in the ventral midbrain associated with the neurotoxic process, including genes for energy metabolism [cytochrome c oxidase subunit 1 (COX1), reduced nicotinamide adenine dinucleotide ubiquinone oxidoreductase chain 2, and phosphoglycerate mutase B], ion regulation (members of sodium/hydrogen exchanger and sodium/bile acid cotransporter family), signal transduction (adenylyl cyclase III), and cell differentiation and degeneration (N-myc downstream-regulated gene 3 and tau protein). Of these differentially expressed genes, we elected to further examine the increase in COX1 expression, because of data implicating energy utilization in METH neurotoxicity and the known role of COX1 in energy metabolism. On the basis of time course studies, Northern blot analyses, in situ hybridization results, and temperature studies, we now report that increased COX1 expression in the ventral midbrain is linked to METH-induced DA neuronal injury. The precise role of COX1 and other genes in METH neurotoxicity remains to be elucidated. PMID:11756511

  6. Global Methylation Profiling of Lung Cancer Identifies Novel Methylated Genes

    Directory of Open Access Journals (Sweden)

    Zunyan Dai

    2001-01-01

    Full Text Available Epigenetic changes, including DNA methylation, are a common finding in cancer. In lung cancers methylation of cytosine residues may affect tumor initiation and progression in several ways, including the silencing of tumor suppressor genes through promoter methylation and by providing the targets for adduct formation of polycyclic aromatic hydrocarbons present in combustion products of cigarette smoke. Although the importance of aberrant DNA methylation is well established, the extent of DNA methylation in lung cancers has never been determined. Restriction landmark genomic scanning (RLGS is a highly reproducible two-dimensional gel electrophoresis that allows the determination of the methylation status of up to 2000 promoter sequences in a single gel. We selected 1184 CpG islands for RLGS analysis and determined their methylation status in 16 primary non-small cell lung cancers. Some tumors did not show methylation whereas others showed up to 5.3% methylation in all CpG islands of the profile. Cloning of 21 methylated loci identified 11 genes and 6 ESTs. We demonstrate that methylation is part of the silencing process of BMP3B in primary tumors and lung cancer cell lines.

  7. Investigation of the gene mutations in two Chinese families with X-linked infantile nystagmus

    Science.gov (United States)

    Li, Ningdong; Wang, Xiaojuan; Wang, Yuchuan; Wang, Liming; Ying, Ming; Han, Ruifang; Liu, Yuyan

    2011-01-01

    Purpose To identify the gene mutations causing X-linked infantile nystagmus in two Chinese families (NYS003 and NYS008), of which the NYS003 family was assigned to the FERM domaincontaining 7 (FRMD7) gene linked region in our previous study, and no mutations were found by direct sequencing. Methods Two microsatellites, DXS1047 and DXS1001, were amplified using a PCR reaction for the linkage study in the NYS008 family. FRMD7 was sequenced and mutations were analyzed. Multiplex ligation-dependent probe amplification (MLPA) was used to detect FRMD7 mutations in the NYS003 family. Results The NYS008 family yielded a maximum logarithm of odds (LOD) score of 1.91 at ?=0 with DXS1001. FRMD7 sequencing showed a nucleotide change of c. 623A>G in exon7 of the patients FRMD7 gene, which was predicted to result in an H208R amino acid change. This novel mutation was absent in 100 normal Han Chinese controls. No FRMD7 gene mutations were detected by MLPA in the NYS003 family. Conclusions We identified a novel mutation, c. 623A>G (p. H208R), in a Han Chinese family with infantile nystagmus. This mutation expands the mutation spectrum of FRMD7 and contributes to the research on the molecular pathogenesis of FRMD7. PMID:21365021

  8. A CRISPR-Based Screen Identifies Genes Essential for West-Nile-Virus-Induced Cell Death

    Directory of Open Access Journals (Sweden)

    Hongming Ma

    2015-07-01

    Full Text Available West Nile virus (WNV causes an acute neurological infection attended by massive neuronal cell death. However, the mechanism(s behind the virus-induced cell death is poorly understood. Using a library containing 77,406 sgRNAs targeting 20,121 genes, we performed a genome-wide screen followed by a second screen with a sub-library. Among the genes identified, seven genes, EMC2, EMC3, SEL1L, DERL2, UBE2G2, UBE2J1, and HRD1, stood out as having the strongest phenotype, whose knockout conferred strong protection against WNV-induced cell death with two different WNV strains and in three cell lines. Interestingly, knockout of these genes did not block WNV replication. Thus, these appear to be essential genes that link WNV replication to downstream cell death pathway(s. In addition, the fact that all of these genes belong to the ER-associated protein degradation (ERAD pathway suggests that this might be the primary driver of WNV-induced cell death.

  9. Cross-species global and subset gene expression profiling identifies genes involved in prostate cancer response to selenium

    Directory of Open Access Journals (Sweden)

    Dhir Rajiv

    2004-08-01

    Full Text Available Abstract Background Gene expression technologies have the ability to generate vast amounts of data, yet there often resides only limited resources for subsequent validation studies. This necessitates the ability to perform sorting and prioritization of the output data. Previously described methodologies have used functional pathways or transcriptional regulatory grouping to sort genes for further study. In this paper we demonstrate a comparative genomics based method to leverage data from animal models to prioritize genes for validation. This approach allows one to develop a disease-based focus for the prioritization of gene data, a process that is essential for systems that lack significant functional pathway data yet have defined animal models. This method is made possible through the use of highly controlled spotted cDNA slide production and the use of comparative bioinformatics databases without the use of cross-species slide hybridizations. Results Using gene expression profiling we have demonstrated a similar whole transcriptome gene expression patterns in prostate cancer cells from human and rat prostate cancer cell lines both at baseline expression levels and after treatment with physiologic concentrations of the proposed chemopreventive agent Selenium. Using both the human PC3 and rat PAII prostate cancer cell lines have gone on to identify a subset of one hundred and fifty-four genes that demonstrate a similar level of differential expression to Selenium treatment in both species. Further analysis and data mining for two genes, the Insulin like Growth Factor Binding protein 3, and Retinoic X Receptor alpha, demonstrates an association with prostate cancer, functional pathway links, and protein-protein interactions that make these genes prime candidates for explaining the mechanism of Selenium's chemopreventive effect in prostate cancer. These genes are subsequently validated by western blots showing Selenium based induction and using tissue microarrays to demonstrate a significant association between downregulated protein expression and tumorigenesis, a process that is the reverse of what is seen in the presence of Selenium. Conclusions Thus the outlined process demonstrates similar baseline and selenium induced gene expression profiles between rat and human prostate cancers, and provides a method for identifying testable functional pathways for the action of Selenium's chemopreventive properties in prostate cancer.

  10. Sex-dimorphic gene expression and ineffective dosage compensation of Z-linked genes in gastrulating chicken embryos

    Directory of Open Access Journals (Sweden)

    Mathur Sachin

    2010-01-01

    Full Text Available Abstract Background Considerable progress has been made in our understanding of sex determination and dosage compensation mechanisms in model organisms such as C. elegans, Drosophila and M. musculus. Strikingly, the mechanism involved in sex determination and dosage compensation are very different among these three model organisms. Birds present yet another situation where the heterogametic sex is the female. Sex determination is still poorly understood in birds and few key determinants have so far been identified. In contrast to most other species, dosage compensation of bird sex chromosomal genes appears rather ineffective. Results By comparing microarrays from microdissected primitive streak from single chicken embryos, we identified a large number of genes differentially expressed between male and female embryos at a very early stage (Hamburger and Hamilton stage 4, long before any sexual differentiation occurs. Most of these genes are located on the Z chromosome, which indicates that dosage compensation is ineffective in early chicken embryos. Gene ontology analyses, using an enhanced annotation tool for Affymetrix probesets of the chicken genome developed in our laboratory (called Manteia, show that among these male-biased genes found on the Z chromosome, more than 20 genes play a role in sex differentiation. Conclusions These results corroborate previous studies demonstrating the rather inefficient dosage compensation for Z chromosome in birds and show that this sexual dimorphism in gene regulation is observed long before the onset of sexual differentiation. These data also suggest a potential role of non-compensated Z-linked genes in somatic sex differentiation in birds.

  11. A New Glabrous Gene (csgl3) Identified in Trichome Development in Cucumber (Cucumis sativus L.).

    Science.gov (United States)

    Cui, Jin-Ying; Miao, Han; Ding, Li-Hong; Wehner, Todd C; Liu, Pan-Na; Wang, Ye; Zhang, Sheng-Ping; Gu, Xing-Fang

    2016-01-01

    Spines or trichomes on the fruit of cucumbers enhance their commercial value in China. In addition, glabrous mutants exhibit resistance to aphids and therefore their use by growers can reduce pesticide residues. Previous studies have reported two glabrous mutant plants containing the genes, csgl1 and csgl2. In the present study, a new glabrous mutant, NCG157, was identified showing a gene interaction effect with csgl1 and csgl2. This mutant showed the glabrous character on stems, leaves, tendrils, receptacles and ovaries, and there were no spines or tumors on the fruit surface. Inheritance analysis showed that a single recessive gene, named csgl3, determined the glabrous trait. An F2 population derived from the cross of two inbred lines 9930 (a fresh market type from Northern China that exhibits trichomes) and NCG157 (an American processing type with glabrous surfaces) was used for genetic mapping of the csgl3 gene. By combining bulked segregant analysis (BAS) with molecular markers, 18 markers, including two simple sequence repeats (SSR), nine insertion deletions (InDel) and seven derived cleaved amplified polymorphism sequences (dCAPs), were identified to link to the csgl3 gene. All of the linked markers were used as anchor loci to locate the csgl3 gene on cucumber chromosome 6. The csgl3 gene was mapped between the dCAPs markers dCAPs-21 and dCAPs-19, at genetic distances of 0.05 cM and 0.15 cM, respectively. The physical distance of this region was 19.6 kb. Three markers, InDel-19, dCAPs-2 and dCAPs-11, co-segregated with csgl3. There were two candidate genes in the region, Csa6M514860 and Csa6M514870. Quantitative real-time PCR showed that the expression of Csa6M514870 was higher in the tissues of 9930 than that of NCG157, and this was consistent with their phenotypic characters. Csa6M514870 is therefore postulated to be the candidate gene for the development of trichomes in cucumber. This study will facilitate marker-assisted selection (MAS) of the smooth plant trait in cucumber breeding and provide for future cloning of csgl3. PMID:26845560

  12. New Family With Catecholaminergic Polymorphic Ventricular Tachycardia Linked to the Triadin Gene.

    Science.gov (United States)

    Rooryck, Caroline; Kyndt, Florence; Bozon, Dominique; Roux-Buisson, Nathalie; Sacher, Frederic; Probst, Vincent; Thambo, Jean-Benoit

    2015-10-01

    We describe a new family with cathecholaminergic polymorphic ventricular tachycardia (CPVT) linked to the Triadin gene. This is the second report of such a CPVT of autosomal recessive inheritance. Using an NGS panel including 42 genes involved in cardiac sudden death, 2 heterozygous pathogenic mutations (c.613C> T/p.Gln205* and c.22 + 29 A>G) were identified in the Triadin gene in 2 sibs who experienced early severe arrhythmias without evidence of CPVT diagnosis at first cardiac evaluation. However, significant arrhythmias occurred after catecholaminergic stimulation. Each of the TRDN mutations was inherited from a healthy parent. In this family, genetic studies permit confirmation of the CPVT diagnosis in the 2 affected sibs and permit the early diagnosis of the third asymptomatic child. It also helped guide the therapeutic strategy in this family. PMID:26200674

  13. Identifying paediatric nursing-sensitive outcomes in linked administrative health data

    Directory of Open Access Journals (Sweden)

    Wilson Sally

    2012-07-01

    Full Text Available Abstract Background There is increasing interest in the contribution of the quality of nursing care to patient outcomes. Due to different casemix and risk profiles, algorithms for administrative health data that identify nursing-sensitive outcomes in adult hospitalised patients may not be applicable to paediatric patients. The study purpose was to test adult algorithms in a paediatric hospital population and make amendments to increase the accuracy of identification of hospital acquired events. The study also aimed to determine whether the use of linked hospital records improved the likelihood of correctly identifying patient outcomes as nursing sensitive rather than being related to their pre-morbid conditions. Methods Using algorithms developed by Needleman et al. (2001, proportions and rates of records that identified nursing-sensitive outcomes for pressure ulcers, pneumonia and surgical wound infections were determined from administrative hospitalisation data for all paediatric patients discharged from a tertiary paediatric hospital in Western Australia between July 1999 and June 2009. The effects of changes to inclusion and exclusion criteria for each algorithm on the calculated proportion or rate in the paediatric population were explored. Linked records were used to identify comorbid conditions that increased nursing-sensitive outcome risk. Rates were calculated using algorithms revised for paediatric patients. Results Linked records of 129,719 hospital separations for 79,016 children were analysed. Identification of comorbid conditions was enhanced through access to prior and/or subsequent hospitalisation records (43% of children with pressure ulcers had a form of paralysis recorded only on a previous admission. Readmissions with a surgical wound infection were identified for 103 (4.8/1,000 surgical separations using linked data. After amendment of each algorithm for paediatric patients, rates of pressure ulcers and pneumonia reduced by 53% and 15% (from 1.3 to 0.6 and from 9.1 to 7.7 per 10,000 patient days respectively, and an 84% increase in the proportion of surgical wound infection (from 5.7 to 10.4 per 1,000 separations. Conclusions Algorithms for nursing-sensitive outcomes used in adult populations have to be amended before application to paediatric populations. Using unlinked individual hospitalisation records to estimate rates of nursing-sensitive outcomes is likely to result in inaccurate rates.

  14. Differentially expressed genes in pancreatic ductal adenocarcinomas identified through serial analysis of gene expression

    DEFF Research Database (Denmark)

    Hustinx, Steven R; Cao, Dengfeng; Maitra, Anirban; Sato, Norihiro; Martin, Sean T; Sudhir, D; Iacobuzio-Donahue, Christine; Cameron, John L; Yeo, Charles J; Kern, Scott E; Goggins, Michael; Mollenhauer, Jan; Pandey, Akhilesh; Hruban, Ralph H

    2004-01-01

    Serial analysis of gene expression (SAGE) is a powerful tool for the discovery of novel tumor markers. The publicly available online SAGE libraries of normal and neoplastic tissues (http://www.ncbi.nlm.nih.gov/SAGE/) have recently been expanded; in addition, a more complete annotation of the human...... genome and better biocomputational techniques have substantially improved the assignment of differentially expressed SAGE "tags" to human genes. These improvements have provided us with an opportunity to re-evaluate global gene expression in pancreatic cancer using existing SAGE libraries. SAGE libraries...... generated from six pancreatic cancers were compared to SAGE libraries generated from 11 non-neoplastic tissues. Compared to normal tissue libraries, we identified 453 SAGE tags as differentially expressed in pancreatic cancer, including 395 that mapped to known genes and 58 "uncharacterized" tags. Of the...

  15. A gene-trap strategy identifies quiescence-induced genes in synchronized myoblasts

    Indian Academy of Sciences (India)

    Ramkumar Sambasivan; Grace K Pavlath; Jyotsna Dhawan

    2008-03-01

    Cellular quiescence is characterized not only by reduced mitotic and metabolic activity but also by altered gene expression. Growing evidence suggests that quiescence is not merely a basal state but is regulated by active mechanisms. To understand the molecular programme that governs reversible cell cycle exit, we focused on quiescence-related gene expression in a culture model of myogenic cell arrest and activation. Here we report the identification of quiescence-induced genes using a gene-trap strategy. Using a retroviral vector, we generated a library of gene traps in C2C12 myoblasts that were screened for arrest-induced insertions by live cell sorting (FACS-gal). Several independent genetrap lines revealed arrest-dependent induction of gal activity, confirming the efficacy of the FACS screen. The locus of integration was identified in 15 lines. In three lines, insertion occurred in genes previously implicated in the control of quiescence, i.e. EMSY – a BRCA2-interacting protein, p8/com1– a p300HAT-binding protein and MLL5 – a SET domain protein. Our results demonstrate that expression of chromatin modulatory genes is induced in G0, providing support to the notion that this reversibly arrested state is actively regulated.

  16. Combining gene expression and genetic analyses to identify candidate genes involved in cold responses in pea.

    Science.gov (United States)

    Legrand, Sylvain; Marque, Gilles; Blassiau, Christelle; Bluteau, Aurélie; Canoy, Anne-Sophie; Fontaine, Véronique; Jaminon, Odile; Bahrman, Nasser; Mautord, Julie; Morin, Julie; Petit, Aurélie; Baranger, Alain; Rivière, Nathalie; Wilmer, Jeroen; Delbreil, Bruno; Lejeune-Hénaut, Isabelle

    2013-09-01

    Cold stress affects plant growth and development. In order to better understand the responses to cold (chilling or freezing tolerance), we used two contrasted pea lines. Following a chilling period, the Champagne line becomes tolerant to frost whereas the Terese line remains sensitive. Four suppression subtractive hybridisation libraries were obtained using mRNAs isolated from pea genotypes Champagne and Terese. Using quantitative polymerase chain reaction (qPCR) performed on 159 genes, 43 and 54 genes were identified as differentially expressed at the initial time point and during the time course study, respectively. Molecular markers were developed from the differentially expressed genes and were genotyped on a population of 164 RILs derived from a cross between Champagne and Terese. We identified 5 candidate genes colocalizing with 3 different frost damage quantitative trait loci (QTL) intervals and a protein quantity locus (PQL) rich region previously reported. This investigation revealed the role of constitutive differences between both genotypes in the cold responses, in particular with genes related to glycine degradation pathway that could confer to Champagne a better frost tolerance. We showed that freezing tolerance involves a decrease of expression of genes related to photosynthesis and the expression of a gene involved in the production of cysteine and methionine that could act as cryoprotectant molecules. Although it remains to be confirmed, this study could also reveal the involvement of the jasmonate pathway in the cold responses, since we observed that two genes related to this pathway were mapped in a frost damage QTL interval and in a PQL rich region interval, respectively. PMID:23632303

  17. Identifying and classifying trait linked polymorphisms in non-reference species by walking coloured de bruijn graphs.

    Science.gov (United States)

    Leggett, Richard M; Ramirez-Gonzalez, Ricardo H; Verweij, Walter; Kawashima, Cintia G; Iqbal, Zamin; Jones, Jonathan D G; Caccamo, Mario; Maclean, Daniel

    2013-01-01

    Single Nucleotide Polymorphisms are invaluable markers for tracing the genetic basis of inheritable traits and the ability to create marker libraries quickly is vital for timely identification of target genes. Next-generation sequencing makes it possible to sample a genome rapidly, but polymorphism detection relies on having a reference genome to which reads can be aligned and variants detected. We present Bubbleparse, a method for detecting variants directly from next-generation reads without a reference sequence. Bubbleparse uses the de Bruijn graph implementation in the Cortex framework as a basis and allows the user to identify bubbles in these graphs that represent polymorphisms, quickly, easily and sensitively. We show that the Bubbleparse algorithm is sensitive and can detect many polymorphisms quickly and that it performs well when compared with polymorphism detection methods based on alignment to a reference in Arabidopsis thaliana. We show that the heuristic can be used to maximise the number of true polymorphisms returned, and with a proof-of-principle experiment show that Bubbleparse is very effective on data from unsequenced wild relatives of potato and enabled us to identify disease resistance linked genes quickly and easily. PMID:23536903

  18. Prediction potential of candidate biomarker sets identified and validated on gene expression data from multiple datasets

    Directory of Open Access Journals (Sweden)

    Karacali Bilge

    2007-10-01

    Full Text Available Abstract Background Independently derived expression profiles of the same biological condition often have few genes in common. In this study, we created populations of expression profiles from publicly available microarray datasets of cancer (breast, lymphoma and renal samples linked to clinical information with an iterative machine learning algorithm. ROC curves were used to assess the prediction error of each profile for classification. We compared the prediction error of profiles correlated with molecular phenotype against profiles correlated with relapse-free status. Prediction error of profiles identified with supervised univariate feature selection algorithms were compared to profiles selected randomly from a all genes on the microarray platform and b a list of known disease-related genes (a priori selection. We also determined the relevance of expression profiles on test arrays from independent datasets, measured on either the same or different microarray platforms. Results Highly discriminative expression profiles were produced on both simulated gene expression data and expression data from breast cancer and lymphoma datasets on the basis of ER and BCL-6 expression, respectively. Use of relapse-free status to identify profiles for prognosis prediction resulted in poorly discriminative decision rules. Supervised feature selection resulted in more accurate classifications than random or a priori selection, however, the difference in prediction error decreased as the number of features increased. These results held when decision rules were applied across-datasets to samples profiled on the same microarray platform. Conclusion Our results show that many gene sets predict molecular phenotypes accurately. Given this, expression profiles identified using different training datasets should be expected to show little agreement. In addition, we demonstrate the difficulty in predicting relapse directly from microarray data using supervised machine learning approaches. These findings are relevant to the use of molecular profiling for the identification of candidate biomarker panels.

  19. How to Link to GeneReviews - GeneReviews - NCBI Bookshelf [GeneReviews

    Lifescience Database Archive (English)

    Full Text Available p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .body-content h2 {border ... m MP, Ardinger HH, et al., editors. GeneReviews? [Internet ]. Seattle (WA): University of Washington, Seattle; ... 1993-2014. GeneReviews ? [Internet ]. Show details Pagon RA, Adam MP, Ardinger HH, et ...

  20. Analysis of the retinal gene expression profile after hypoxic preconditioning identifies candidate genes for neuroprotection

    Directory of Open Access Journals (Sweden)

    Wenzel Andreas

    2008-02-01

    Full Text Available Abstract Background Retinal degeneration is a main cause of blindness in humans. Neuroprotective therapies may be used to rescue retinal cells and preserve vision. Hypoxic preconditioning stabilizes the transcription factor HIF-1? in the retina and strongly protects photoreceptors in an animal model of light-induced retinal degeneration. To address the molecular mechanisms of the protection, we analyzed the transcriptome of the hypoxic retina using microarrays and real-time PCR. Results Hypoxic exposure induced a marked alteration in the retinal transcriptome with significantly different expression levels of 431 genes immediately after hypoxic exposure. The normal expression profile was restored within 16 hours of reoxygenation. Among the differentially regulated genes, several candidates for neuroprotection were identified like metallothionein-1 and -2, the HIF-1 target gene adrenomedullin and the gene encoding the antioxidative and cytoprotective enzyme paraoxonase 1 which was previously not known to be a hypoxia responsive gene in the retina. The strongly upregulated cyclin dependent kinase inhibitor p21 was excluded from being essential for neuroprotection. Conclusion Our data suggest that neuroprotection after hypoxic preconditioning is the result of the differential expression of a multitude of genes which may act in concert to protect visual cells against a toxic insult.

  1. Identifying novel genes in C. elegans using SAGE tags

    Directory of Open Access Journals (Sweden)

    Chen Nansheng

    2010-12-01

    Full Text Available Abstract Background Despite extensive efforts devoted to predicting protein-coding genes in genome sequences, many bona fide genes have not been found and many existing gene models are not accurate in all sequenced eukaryote genomes. This situation is partly explained by the fact that gene prediction programs have been developed based on our incomplete understanding of gene feature information such as splicing and promoter characteristics. Additionally, full-length cDNAs of many genes and their isoforms are hard to obtain due to their low level or rare expression. In order to obtain full-length sequences of all protein-coding genes, alternative approaches are required. Results In this project, we have developed a method of reconstructing full-length cDNA sequences based on short expressed sequence tags which is called sequence tag-based amplification of cDNA ends (STACE. Expressed tags are used as anchors for retrieving full-length transcripts in two rounds of PCR amplification. We have demonstrated the application of STACE in reconstructing full-length cDNA sequences using expressed tags mined in an array of serial analysis of gene expression (SAGE of C. elegans cDNA libraries. We have successfully applied STACE to recover sequence information for 12 genes, for two of which we found isoforms. STACE was used to successfully recover full-length cDNA sequences for seven of these genes. Conclusions The STACE method can be used to effectively reconstruct full-length cDNA sequences of genes that are under-represented in cDNA sequencing projects and have been missed by existing gene prediction methods, but their existence has been suggested by short sequence tags such as SAGE tags.

  2. Identifying multiple causative genes at a single GWAS locus

    OpenAIRE

    Flister, Michael J.; Tsaih, Shirng-Wern; O'Meara, Caitlin C.; Endres, Bradley; Hoffman, Matthew J.; Geurts, Aron M.; Dwinell, Melinda R.; Lazar, Jozef; Jacob, Howard J.; Moreno, Carol

    2013-01-01

    Genome-wide association studies (GWAS) are useful for nominating candidate genes, but typically are unable to establish disease causality or differentiate between the effects of variants in linkage disequilibrium (LD). Additionally, some GWAS loci might contain multiple causative variants or genes that contribute to the overall disease susceptibility at a single locus. However, the majority of current GWAS lack the statistical power to test whether multiple causative genes underlie the same l...

  3. Three novel PHEX gene mutations in four Chinese families with X-linked dominant hypophosphatemic rickets

    International Nuclear Information System (INIS)

    Highlights: ► In our study, all of the patients were of Han Chinese ethnicity, which were rarely reported. ► We identified three novel PHEX gene mutations in four unrelated families with XLH. ► We found that the relationship between the phenotype and genotype of the PHEX gene was not invariant. ► We found that two PHEX gene sites, p.534 and p.731, were conserved. -- Abstract: Background: X-linked hypophosphatemia (XLH), the most common form of inherited rickets, is a dominant disorder that is characterized by renal phosphate wasting with hypophosphatemia, abnormal bone mineralization, short stature, and rachitic manifestations. The related gene with inactivating mutations associated with XLH has been identified as PHEX, which is a phosphate-regulating gene with homologies to endopeptidases on the X chromosome. In this study, a variety of PHEX mutations were identified in four Chinese families with XLH. Methods: We investigated four unrelated Chinese families who exhibited typical features of XLH by using PCR to analyze mutations that were then sequenced. The laboratory and radiological investigations were conducted simultaneously. Results: Three novel mutations were found in these four families: one frameshift mutation, c.2033dupT in exon 20, resulting in p.T679H; one nonsense mutation, c.1294A > T in exon 11, resulting in p.K432X; and one missense mutation, c.2192T > C in exon 22, resulting in p.F731S. Conclusions: We found that the PHEX gene mutations were responsible for XLH in these Chinese families. Our findings are useful for understanding the genetic basis of Chinese patients with XLH.

  4. Three novel PHEX gene mutations in four Chinese families with X-linked dominant hypophosphatemic rickets

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Qing-lin [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People' s Hospital, Shanghai 200233 (China); Xu, Jia [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People' s Hospital, Shanghai 200233 (China); Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People' s Hospital, Shanghai 200233 (China); Medical College of Soochow University, Suzhou, Jiangsu province 215000 (China); Zhang, Zeng [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People' s Hospital, Shanghai 200233 (China); Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People' s Hospital, Shanghai 200233 (China); He, Jin-wei [Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People' s Hospital, Shanghai 200233 (China); Lu, Lian-song [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People' s Hospital, Shanghai 200233 (China); Medical College of Soochow University, Suzhou, Jiangsu province 215000 (China); Fu, Wen-zhen [Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People' s Hospital, Shanghai 200233 (China); Zhang, Zhen-lin, E-mail: zzl2002@medmail.com.cn [Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People' s Hospital, Shanghai 200233 (China)

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer In our study, all of the patients were of Han Chinese ethnicity, which were rarely reported. Black-Right-Pointing-Pointer We identified three novel PHEX gene mutations in four unrelated families with XLH. Black-Right-Pointing-Pointer We found that the relationship between the phenotype and genotype of the PHEX gene was not invariant. Black-Right-Pointing-Pointer We found that two PHEX gene sites, p.534 and p.731, were conserved. -- Abstract: Background: X-linked hypophosphatemia (XLH), the most common form of inherited rickets, is a dominant disorder that is characterized by renal phosphate wasting with hypophosphatemia, abnormal bone mineralization, short stature, and rachitic manifestations. The related gene with inactivating mutations associated with XLH has been identified as PHEX, which is a phosphate-regulating gene with homologies to endopeptidases on the X chromosome. In this study, a variety of PHEX mutations were identified in four Chinese families with XLH. Methods: We investigated four unrelated Chinese families who exhibited typical features of XLH by using PCR to analyze mutations that were then sequenced. The laboratory and radiological investigations were conducted simultaneously. Results: Three novel mutations were found in these four families: one frameshift mutation, c.2033dupT in exon 20, resulting in p.T679H; one nonsense mutation, c.1294A > T in exon 11, resulting in p.K432X; and one missense mutation, c.2192T > C in exon 22, resulting in p.F731S. Conclusions: We found that the PHEX gene mutations were responsible for XLH in these Chinese families. Our findings are useful for understanding the genetic basis of Chinese patients with XLH.

  5. A Generally Applicable Translational Strategy Identifies S100A4 as a Candidate Gene in Allergy

    DEFF Research Database (Denmark)

    Bruhn, Sören; Fang, Yu; Barrenäs, Fredrik; Gustafsson, Mika; Zhang, Huan; Konstantinell, Aelita; Krönke, Andrea; Sönnichsen, Birte; Bresnick, Anne; Dulyaninova, Natalya; Wang, Hui; Zhao, Yelin; Klingelhöfer, Jörg; Ambartsumian, Noona; Beck, Mette Kristina; Nestor, Colm; Bona, Elsa; Xiang, Zou; Benson, Mikael

    2014-01-01

    The identification of diagnostic markers and therapeutic candidate genes in common diseases is complicated by the involvement of thousands of genes. We hypothesized that genes co-regulated with a key gene in allergy, IL13, would form a module that could help to identify candidate genes. We identi...

  6. Gene-based Association Approach Identify Genes Across Stress Traits in Fruit Flies

    OpenAIRE

    Rohde, Palle Duun; Edwards, Stefan McKinnon; Sarup, Pernille Merete; Sørensen, Peter

    2014-01-01

    Identification of genes explaining variation in quantitative traits or genetic risk factors of human diseases requires both good phenotypic- and genotypic data, but also efficient statistical methods. Genome-wide association studies may reveal association between phenotypic variation and variation at nucleotide level, thus potentially identify genetic variants. However, testing million of polymorphic nucleotide positions requires conservative correction for multiple testing which lowers the p...

  7. An RCOR1 loss-associated gene expression signature identifies a prognostically significant DLBCL subgroup.

    Science.gov (United States)

    Chan, Fong Chun; Telenius, Adele; Healy, Shannon; Ben-Neriah, Susana; Mottok, Anja; Lim, Raymond; Drake, Marie; Hu, Sandy; Ding, Jiarui; Ha, Gavin; Scott, David W; Kridel, Robert; Bashashati, Ali; Rogic, Sanja; Johnson, Nathalie; Morin, Ryan D; Rimsza, Lisa M; Sehn, Laurie; Connors, Joseph M; Marra, Marco A; Gascoyne, Randy D; Shah, Sohrab P; Steidl, Christian

    2015-02-01

    Effective treatment of diffuse large B-cell lymphoma (DLBCL) is plagued by heterogeneous responses to standard therapy, and molecular mechanisms underlying unfavorable outcomes in lymphoma patients remain elusive. Here, we profiled 148 genomes with 91 matching transcriptomes in a DLBCL cohort treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to uncover molecular subgroups linked to treatment failure. Systematic integration of high-resolution genotyping arrays and RNA sequencing data revealed novel deletions in RCOR1 to be associated with unfavorable progression-free survival (P = .001). Integration of expression data from the clinical samples with data from RCOR1 knockdowns in the lymphoma cell lines KM-H2 and Raji yielded an RCOR1 loss-associated gene signature comprising 233 genes. This signature identified a subgroup of patients with unfavorable overall survival (P = .023). The prognostic significance of the 233-gene signature for overall survival was reproduced in an independent cohort comprising 195 R-CHOP-treated patients (P = .039). Additionally, we discovered that within the International Prognostic Index low-risk group, the gene signature provides additional prognostic value that was independent of the cell-of-origin phenotype. We present a novel and reproducible molecular subgroup of DLBCL that impacts risk-stratification of R-CHOP-treated DLBCL patients and reveals a possible new avenue for therapeutic intervention strategies. PMID:25395426

  8. Identification of AFLP Molecular Markers Linked to Row-Type Gene in Barley

    Directory of Open Access Journals (Sweden)

    B. E. Sayed-Tabatabaei

    2005-01-01

    Full Text Available Formation of the two- and six-rowed types in barley is predominantly controlled by alleles at a single locus (vrs1 which is located in long arm of chromosome 2H. This gene is a key character on the study of barley domestication and yield. Near-isogenic lines (NILs of barley were produced from crosses between Kanto Nakate Gold (tow-rowed and Azumamugi (six-rowed. The selected lines were used for screening of AFLP polymorphic bands which are linked to vrs1 locus. After screening of a total of 1792 primer combination, five polymorphic bands were identified. A construction of high resolution map around the vrs1 locus was made using recombinant inbred lines. These markers can be used for a map-based cloning of the genes at the vrs1 locus.

  9. Distinct gene expression profiles in ovarian cancer linked to Lynch syndrome.

    Science.gov (United States)

    Jönsson, Jenny-Maria; Bartuma, Katarina; Dominguez-Valentin, Mev; Harbst, Katja; Ketabi, Zohreh; Malander, Susanne; Jönsson, Mats; Carneiro, Ana; Måsbäck, Anna; Jönsson, Göran; Nilbert, Mef

    2014-12-01

    Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer with the aim to identify key discriminators and central tumorigenic mechanisms in hereditary ovarian cancer. Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation was applied to 48 histopathologically matched Lynch syndrome-associated and sporadic ovarian cancers. Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, including PTPRH, BIRC3, SHH and TNFRSF6B. The genes involved were predominantly linked to cell growth, proliferation, and cell-to-cell signaling and interaction. When stratified for histologic subtype, hierarchical clustering confirmed distinct differences related to heredity in the endometrioid and serous subtypes. Furthermore, separate clustering was achieved in an independent, publically available data set. The distinct genetic signatures in Lynch syndrome-associated and sporadic ovarian cancers point to alternative preferred tumorigenic routes and suggest that genetic discriminators may be relevant for molecular diagnostics and targeted therapeutics. PMID:24848881

  10. Linkage and candidate gene analysis of X-linked familial exudative vitreoretinopathy

    Energy Technology Data Exchange (ETDEWEB)

    Shastry, B.S.; Hartzer, M.K. [Oakland Univ., Rochester, MI (United States); Hejtmancik, J.F. [National Eye Institute, Bethesda, MD (United States)] [and others

    1995-05-20

    Familial exudative vitreoretinopathy (FEVR) is a hereditary eye disorder characterized by avascularity of the peripheral retina, retinal exudates, tractional detachment, and retinal folds. The disorder is most commonly transmitted as an autosomal dominant trait, but X-linked transmission also occurs. To initiate the process of identifying the gene responsible for the X-linked disorder, linkage analysis has been performed with three previously unreported three- or four-generation families. Two-point analysis showed linkage to MAOA (Z{sub max} = 2.1, {theta}{sub max} = 0) and DXS228 (Z{sub max} = 0.5, {theta}{sub max} = 0.11), and this was further confirmed by multipoint analysis with these same markers (Z{sub max} = 2.81 at MAOA), which both lie near the gene causing Norrie disease. Molecular genetic analysis further reveals a missense mutation (R121W) in the third exon of the Norrie`s disease gene that perfectly cosegregates with the disease through three generations in one family. This mutation was not detected in the unaffected family members and six normal unrelated controls, suggesting that it is likely to be the pathogenic mutation. Additionally, a polymorphic missense mutation (H127R) was detected in a severely affected patient. 21 refs., 3 figs., 1 tab.

  11. Novel integrative genomics strategies to identify genes for complex traits

    OpenAIRE

    Schadt, E. E.

    2006-01-01

    Forward genetics is a common approach to dissecting complex traits like common human diseases. The ultimate aim of this approach was the identification of genes that are causal for disease or other phenotypes of interest. However, the forward genetics approach is by definition restricted to the identification of genes that have incurred mutations over the course of evolution or that incurred mutations as a result of chemical mutagenesis, and that as a result lead to disease or to variations i...

  12. Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry

    OpenAIRE

    Morrow, Eric M.; Yoo, Seung-Yun; Flavell, Steven W; Kim, Tae-Kyung; Lin, Yingxi; Hill, Robert Sean; Mukaddes, Nahit M; Balkhy, Soher; Gascon, Generoso; Hashmi, Asif; Al-Saad, Samira; Ware, Janice; Joseph, Robert M; Greenblatt, Rachel; Gleason, Danielle

    2008-01-01

    To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that un...

  13. Protein networks identify novel symbiogenetic genes resulting from plastid endosymbiosis

    Science.gov (United States)

    Méheust, Raphaël; Zelzion, Ehud; Bhattacharya, Debashish; Lopez, Philippe; Bapteste, Eric

    2016-01-01

    The integration of foreign genetic information is central to the evolution of eukaryotes, as has been demonstrated for the origin of the Calvin cycle and of the heme and carotenoid biosynthesis pathways in algae and plants. For photosynthetic lineages, this coordination involved three genomes of divergent phylogenetic origins (the nucleus, plastid, and mitochondrion). Major hurdles overcome by the ancestor of these lineages were harnessing the oxygen-evolving organelle, optimizing the use of light, and stabilizing the partnership between the plastid endosymbiont and host through retargeting of proteins to the nascent organelle. Here we used protein similarity networks that can disentangle reticulate gene histories to explore how these significant challenges were met. We discovered a previously hidden component of algal and plant nuclear genomes that originated from the plastid endosymbiont: symbiogenetic genes (S genes). These composite proteins, exclusive to photosynthetic eukaryotes, encode a cyanobacterium-derived domain fused to one of cyanobacterial or another prokaryotic origin and have emerged multiple, independent times during evolution. Transcriptome data demonstrate the existence and expression of S genes across a wide swath of algae and plants, and functional data indicate their involvement in tolerance to oxidative stress, phototropism, and adaptation to nitrogen limitation. Our research demonstrates the “recycling” of genetic information by photosynthetic eukaryotes to generate novel composite genes, many of which function in plastid maintenance. PMID:26976593

  14. Protein networks identify novel symbiogenetic genes resulting from plastid endosymbiosis.

    Science.gov (United States)

    Méheust, Raphaël; Zelzion, Ehud; Bhattacharya, Debashish; Lopez, Philippe; Bapteste, Eric

    2016-03-29

    The integration of foreign genetic information is central to the evolution of eukaryotes, as has been demonstrated for the origin of the Calvin cycle and of the heme and carotenoid biosynthesis pathways in algae and plants. For photosynthetic lineages, this coordination involved three genomes of divergent phylogenetic origins (the nucleus, plastid, and mitochondrion). Major hurdles overcome by the ancestor of these lineages were harnessing the oxygen-evolving organelle, optimizing the use of light, and stabilizing the partnership between the plastid endosymbiont and host through retargeting of proteins to the nascent organelle. Here we used protein similarity networks that can disentangle reticulate gene histories to explore how these significant challenges were met. We discovered a previously hidden component of algal and plant nuclear genomes that originated from the plastid endosymbiont: symbiogenetic genes (S genes). These composite proteins, exclusive to photosynthetic eukaryotes, encode a cyanobacterium-derived domain fused to one of cyanobacterial or another prokaryotic origin and have emerged multiple, independent times during evolution. Transcriptome data demonstrate the existence and expression of S genes across a wide swath of algae and plants, and functional data indicate their involvement in tolerance to oxidative stress, phototropism, and adaptation to nitrogen limitation. Our research demonstrates the "recycling" of genetic information by photosynthetic eukaryotes to generate novel composite genes, many of which function in plastid maintenance. PMID:26976593

  15. GeneLink: a database to facilitate genetic studies of complex traits

    OpenAIRE

    Wolfsberg Tyra G; Trout Ken; Ibay Grace; Freas-Lutz Diana; Klein Alison P; Jones Mary; Duggal Priya; Umayam Lowell; Gildea Derek; Masiello Anthony; Gillanders Elizabeth M; Trent Jeffrey M; Bailey-Wilson Joan E; Baxevanis Andreas D

    2004-01-01

    Abstract Background In contrast to gene-mapping studies of simple Mendelian disorders, genetic analyses of complex traits are far more challenging, and high quality data management systems are often critical to the success of these projects. To minimize the difficulties inherent in complex trait studies, we have developed GeneLink, a Web-accessible, password-protected Sybase database. Results GeneLink is a powerful tool for complex trait mapping, enabling genotypic data to be easily merged wi...

  16. Sparse canonical correlation analysis for identifying, connecting and completing gene-expression networks

    Directory of Open Access Journals (Sweden)

    Zwinderman Aeilko H

    2009-09-01

    Full Text Available Abstract Background We generalized penalized canonical correlation analysis for analyzing microarray gene-expression measurements for checking completeness of known metabolic pathways and identifying candidate genes for incorporation in the pathway. We used Wold's method for calculation of the canonical variates, and we applied ridge penalization to the regression of pathway genes on canonical variates of the non-pathway genes, and the elastic net to the regression of non-pathway genes on the canonical variates of the pathway genes. Results We performed a small simulation to illustrate the model's capability to identify new candidate genes to incorporate in the pathway: in our simulations it appeared that a gene was correctly identified if the correlation with the pathway genes was 0.3 or more. We applied the methods to a gene-expression microarray data set of 12, 209 genes measured in 45 patients with glioblastoma, and we considered genes to incorporate in the glioma-pathway: we identified more than 25 genes that correlated > 0.9 with canonical variates of the pathway genes. Conclusion We concluded that penalized canonical correlation analysis is a powerful tool to identify candidate genes in pathway analysis.

  17. A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets

    DEFF Research Database (Denmark)

    Taneera, Jalal; Lang, Stefan; Sharma, Amitabh; Fadista, Joao; Zhou, Yuedan; Ahlqvist, Emma; Jonsson, Anna Elisabet; Lyssenko, Valeriya; Vikman, Petter; Hansson, Ola; Parikh, Hemang; Korsgren, Olle; Soni, Arvind; Krus, Ulrika; Zhang, Enming; Jing, Xing-Jun; Esguerra, Jonathan L S; Wollheim, Claes B; Salehi, Albert; Rosengren, Anders; Renstrm, Erik; Groop, Leif

    2012-01-01

    Close to 50 genetic loci have been associated with type 2 diabetes (T2D), but they explain only 15% of the heritability. In an attempt to identify additional T2D genes, we analyzed global gene expression in human islets from 63 donors. Using 48 genes located near T2D risk variants, we identified ...

  18. Homeobox genes: a molecular link between development and cancer Genes homeobox: uma relao molecular entre o desenvolvimento e o cncer

    OpenAIRE

    Fabio Daumas Nunes; Fernanda Campos Souza de Almeida; Renata Tucci; Suzana Cantanhede Orsini Machado de Sousa

    2003-01-01

    Homeobox genes are regulatory genes encoding nuclear proteins that act as transcription factors, regulating aspects of morphogenesis and cell differentiation during normal embryonic development of several animals. Vertebrate homeobox genes can be divided in two subfamilies: clustered, or HOX genes, and nonclustered, or divergent, homeobox genes. During the last decades, several homeobox genes, clustered and nonclustered ones, were identified in normal tissue, in malignant cells, and in differ...

  19. Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation.

    Science.gov (United States)

    Yang, Yawei J; Baltus, Andrew E; Mathew, Rebecca S; Murphy, Elisabeth A; Evrony, Gilad D; Gonzalez, Dilenny M; Wang, Estee P; Marshall-Walker, Christine A; Barry, Brenda J; Murn, Jernej; Tatarakis, Antonis; Mahajan, Muktar A; Samuels, Herbert H; Shi, Yang; Golden, Jeffrey A; Mahajnah, Muhammad; Shenhav, Ruthie; Walsh, Christopher A

    2012-11-21

    Microcephaly is a neurodevelopmental disorder causing significantly reduced cerebral cortex size. Many known microcephaly gene products localize to centrosomes, regulating cell fate and proliferation. Here, we identify and characterize a nuclear zinc finger protein, ZNF335/NIF-1, as a causative gene for severe microcephaly, small somatic size, and neonatal death. Znf335 null mice are embryonically lethal, and conditional knockout leads to severely reduced cortical size. RNA-interference and postmortem human studies show that ZNF335 is essential for neural progenitor self-renewal, neurogenesis, and neuronal differentiation. ZNF335 is a component of a vertebrate-specific, trithorax H3K4-methylation complex, directly regulating REST/NRSF, a master regulator of neural gene expression and cell fate, as well as other essential neural-specific genes. Our results reveal ZNF335 as an essential link between H3K4 complexes and REST/NRSF and provide the first direct genetic evidence that this pathway regulates human neurogenesis and neuronal differentiation. PMID:23178126

  20. Integrated analysis of DNA methylation profiles and gene expression profiles to identify genes associated with pilocytic astrocytomas

    Science.gov (United States)

    ZHOU, RUIGANG; MAN, YIGANG

    2016-01-01

    The present study performed an integral analysis of the gene expression and DNA methylation profile of pilocytic astrocytomas (PAs). Weighted gene co-expression network analysis (WGCNA) was also performed to examine and identify the genes correlated to PAs, to identify candidate therapeutic targets for the treatment of PAs. The DNA methylation profile and gene expression profile were downloaded from the Gene Expression Omnibus database. Following screening of the differentially expressed genes (DEGs) and differentially methylated regions (DMRs), respectively, integrated analysis of the DEGs and DMRs was performed to detect their correlation. Subsequently, the WGCNA algorithm was applied to identify the significant modules and construct the co-expression network associated with PAs. Furthermore, Gene Ontology enrichment analysis of the associated genes was performed using the Database for Annotation, Visualization and Integrated Discovery. A total number of 2,259 DEGs and 235 DMRs were screened out. Integrated analysis revealed that 30 DEGs were DMRs with prominent negative correlation (cor=−0.82; P=0.02). Based on the DEGs, the gene co-expression network was constructed, and nine network modules associated with PAs were identified. The functional analysis results showed that genes relevant to PAs were closely associated with cell differentiation modulation. The screened PA-associated genes were significantly different at the expression and methylation levels. These genes may be used as reliable candidate target genes for the treatment of PAs. PMID:26934913

  1. Integrated analysis of DNA methylation profiles and gene expression profiles to identify genes associated with pilocytic astrocytomas.

    Science.gov (United States)

    Zhou, Ruigang; Man, Yigang

    2016-04-01

    The present study performed an integral analysis of the gene expression and DNA methylation profile of pilocytic astrocytomas (PAs). Weighted gene co-expression network analysis (WGCNA) was also performed to examine and identify the genes correlated to PAs, to identify candidate therapeutic targets for the treatment of PAs. The DNA methylation profile and gene expression profile were downloaded from the Gene Expression Omnibus database. Following screening of the differentially expressed genes (DEGs) and differentially methylated regions (DMRs), respectively, integrated analysis of the DEGs and DMRs was performed to detect their correlation. Subsequently, the WGCNA algorithm was applied to identify the significant modules and construct the co‑expression network associated with PAs. Furthermore, Gene Ontology enrichment analysis of the associated genes was performed using the Database for Annotation, Visualization and Integrated Discovery. A total number of 2,259 DEGs and 235 DMRs were screened out. Integrated analysis revealed that 30 DEGs were DMRs with prominent negative correlation (cor=‑0.82; P=0.02). Based on the DEGs, the gene co‑expression network was constructed, and nine network modules associated with PAs were identified. The functional analysis results showed that genes relevant to PAs were closely associated with cell differentiation modulation. The screened PA-associated genes were significantly different at the expression and methylation levels. These genes may be used as reliable candidate target genes for the treatment of PAs. PMID:26934913

  2. Exploiting natural variation to identify insect-resistance genes

    OpenAIRE

    Broekgaarden, C.; Snoeren, T.A.L.; Dicke, M.; Vosman, B.

    2011-01-01

    Herbivorous insects are widespread and often serious constraints to crop production. The use of insect-resistant crops is a very effective way to control insect pests in agriculture, and the development of such crops can be greatly enhanced by knowledge on plant resistance mechanisms and the genes involved. Plants have evolved diverse ways to cope with insect attack that has resulted in natural variation for resistance towards herbivorous insects. Studying the molecular genetics and transcrip...

  3. Identifying Sarcomere Gene Mutations in HCM: A Personal History

    OpenAIRE

    Seidman, Christine E.; J. G. Seidman

    2011-01-01

    This article provides an historical and personal perspective on the discovery of genetic causes for hypertrophic cardiomyopathy (HCM). Extraordinary insights of physicians who initially detailed remarkable and varied manifestations of the disorder, collaboration among multidisciplinary teams with skills in clinical diagnostics and molecular genetics, and hard work by scores of trainees, solved the etiologic riddle of HCM, and unexpectedly demonstrated mutations in sarcomere protein genes as t...

  4. A gene sets approach for identifying prognostic gene signatures for outcome prediction

    OpenAIRE

    Kim Yong Sung; Kim Seon-Young

    2008-01-01

    Abstract Background Gene expression profiling is a promising approach to better estimate patient prognosis; however, there are still unresolved problems, including little overlap among similarly developed gene sets and poor performance of a developed gene set in other datasets. Results We applied a gene sets approach to develop a prognostic gene set from multiple gene expression datasets. By analyzing 12 independent breast cancer gene expression datasets comprising 1,756 tissues with 2,411 pr...

  5. MIClique: An Algorithm to Identify Differentially Coexpressed Disease Gene Subset from Microarray Data

    Directory of Open Access Journals (Sweden)

    Huanping Zhang

    2009-01-01

    Full Text Available Computational analysis of microarray data has provided an effective way to identify disease-related genes. Traditional disease gene selection methods from microarray data such as statistical test always focus on differentially expressed genes in different samples by individual gene prioritization. These traditional methods might miss differentially coexpressed (DCE gene subsets because they ignore the interaction between genes. In this paper, MIClique algorithm is proposed to identify DEC gene subsets based on mutual information and clique analysis. Mutual information is used to measure the coexpression relationship between each pair of genes in two different kinds of samples. Clique analysis is a commonly used method in biological network, which generally represents biological module of similar function. By applying the MIClique algorithm to real gene expression data, some DEC gene subsets which correlated under one experimental condition but uncorrelated under another condition are detected from the graph of colon dataset and leukemia dataset.

  6. MIClique: An algorithm to identify differentially coexpressed disease gene subset from microarray data.

    Science.gov (United States)

    Zhang, Huanping; Song, Xiaofeng; Wang, Huinan; Zhang, Xiaobai

    2009-01-01

    Computational analysis of microarray data has provided an effective way to identify disease-related genes. Traditional disease gene selection methods from microarray data such as statistical test always focus on differentially expressed genes in different samples by individual gene prioritization. These traditional methods might miss differentially coexpressed (DCE) gene subsets because they ignore the interaction between genes. In this paper, MIClique algorithm is proposed to identify DEC gene subsets based on mutual information and clique analysis. Mutual information is used to measure the coexpression relationship between each pair of genes in two different kinds of samples. Clique analysis is a commonly used method in biological network, which generally represents biological module of similar function. By applying the MIClique algorithm to real gene expression data, some DEC gene subsets which correlated under one experimental condition but uncorrelated under another condition are detected from the graph of colon dataset and leukemia dataset. PMID:20169000

  7. Application of network properties and signal strength to identify face-to-face links in an electronic dataset

    CERN Document Server

    Sekara, Vedran

    2014-01-01

    Understanding how people interact and socialize is important in many contexts, from disease control to urban planning. Datasets that capture this specific aspect of human life have increased in size and availability over the last few years. We have yet to understand, however, to what extent such electronic datasets may serve as a valid proxy for real life face-to-face interactions. For an observational dataset, gathered by mobile phones, we attack the problem of identifying transient and non-important links, as well as how to highlight important interactions. Using the Bluetooth signal strength parameter to distinguish between observations, we demonstrate that weak links, compared to strong links, have a lower probability of being observed at later times, while such links--on average--also have lower link-weights and a lower probability of sharing an online friendship. Further, the role of link-strength is investigated in relation to social network properties.

  8. O-linked glycosylation of retroviral envelope gene products

    International Nuclear Information System (INIS)

    Treatment of [3H]glucosamine-labeled Friend mink cell focus-forming virus (FrMCF) gp70 with excess peptide:N-glycanase F (PNGase F) resulted in removal of the expected seven N-linked oligosaccharide chains; however, approximately 10% of the glucosamine label was retained in the resulting 49,000-Mr (49K) product. For [3H]mannose-labeled gp70, similar treatment led to removal of all the carbohydrate label from the protein. Prior digestion of the PNGase F-treated gp70 with neuraminidase resulted in an addition size shift, and treatment with O-glycanase led to the removal of almost all of the PNGase F-resistant sugars. These results indicate that gp70 possesses sialic acid-containing O-linked oligosaccharides. Analysis of intracellular env precursors demonstrated that O-linked sugars were present in gPr90env, the polyprotein intermediate which contains complex sugars, but not in the primary translation product, gPr80env, and proteolytic digestion studies allowed localization of the O-linked carbohydrates to a 10K region near the center of the gp70 molecule. similar substituents were detected on the gp70s of ecotropic and xenotropic murine leukemia viruses and two subgroups of feline leukemia virus, indicting that O-linked glycosylation is a conserved feature of retroviral env proteins

  9. Structure and evolution of Apetala3, a sex-linked gene in Silene latifolia

    Directory of Open Access Journals (Sweden)

    Cegan Radim

    2010-08-01

    Full Text Available Abstract Background The evolution of sex chromosomes is often accompanied by gene or chromosome rearrangements. Recently, the gene AP3 was characterized in the dioecious plant species Silene latifolia. It was suggested that this gene had been transferred from an autosome to the Y chromosome. Results In the present study we provide evidence for the existence of an X linked copy of the AP3 gene. We further show that the Y copy is probably located in a chromosomal region where recombination restriction occurred during the first steps of sex chromosome evolution. A comparison of X and Y copies did not reveal any clear signs of degenerative processes in exon regions. Instead, both X and Y copies show evidence for relaxed selection compared to the autosomal orthologues in S. vulgaris and S. conica. We further found that promoter sequences differ significantly. Comparison of the genic region of AP3 between the X and Y alleles and the corresponding autosomal copies in the gynodioecious species S. vulgaris revealed a massive accumulation of retrotransposons within one intron of the Y copy of AP3. Analysis of the genomic distribution of these repetitive elements does not indicate that these elements played an important role in the size increase characteristic of the Y chromosome. However, in silico expression analysis shows biased expression of individual domains of the identified retroelements in male plants. Conclusions We characterized the structure and evolution of AP3, a sex linked gene with copies on the X and Y chromosomes in the dioecious plant S. latifolia. These copies showed complementary expression patterns and relaxed evolution at protein level compared to autosomal orthologues, which suggests subfunctionalization. One intron of the Y-linked allele was invaded by retrotransposons that display sex-specific expression patterns that are similar to the expression pattern of the corresponding allele, which suggests that these transposable elements may have influenced evolution of expression patterns of the Y copy. These data could help researchers decipher the role of transposable elements in degenerative processes during sex chromosome evolution.

  10. Specifically regulated genes in malignant melanoma tissues identified by subtractive hybridization

    OpenAIRE

    Hipfel, R; Schittek, B; Bodingbauer, Y; Garbe, C.

    2000-01-01

    A polymerase chain reaction (PCR)-based subtractive hybridization technique was used to identify transformation-related genes in malignant melanoma. Melanoma biopsies were compared with tissues of benign melanocytic naevi and 549 gene fragments were screened using arrayed filters. Thirty-eight clones were confirmed to be differentially expressed representing 30 different genes (18 melanoma-specific and 12 naevus-specific genes). To further confirm differential gene expression, Northern blot a...

  11. Birth and death of genes linked to chromosomal inversion

    OpenAIRE

    Furuta, Yoshikazu; Kawai, Mikihiko; Yahara, Koji; Takahashi, Noriko; Handa, Naofumi; Tsuru, Takeshi; Oshima, Kenshiro; Yoshida, Masaru; Azuma, Takeshi; Hattori, Masahira; Uchiyama, Ikuo; Kobayashi, Ichizo

    2011-01-01

    The birth and death of genes is central to adaptive evolution, yet the underlying genome dynamics remain elusive. The availability of closely related complete genome sequences helps to follow changes in gene contents and clarify their relationship to overall genome organization. Helicobacter pylori, bacteria in our stomach, are known for their extreme genome plasticity through mutation and recombination and will make a good target for such an analysis. In comparing their complete genome seque...

  12. GeneLink: a database to facilitate genetic studies of complex traits

    Directory of Open Access Journals (Sweden)

    Wolfsberg Tyra G

    2004-10-01

    Full Text Available Abstract Background In contrast to gene-mapping studies of simple Mendelian disorders, genetic analyses of complex traits are far more challenging, and high quality data management systems are often critical to the success of these projects. To minimize the difficulties inherent in complex trait studies, we have developed GeneLink, a Web-accessible, password-protected Sybase database. Results GeneLink is a powerful tool for complex trait mapping, enabling genotypic data to be easily merged with pedigree and extensive phenotypic data. Specifically designed to facilitate large-scale (multi-center genetic linkage or association studies, GeneLink securely and efficiently handles large amounts of data and provides additional features to facilitate data analysis by existing software packages and quality control. These include the ability to download chromosome-specific data files containing marker data in map order in various formats appropriate for downstream analyses (e.g., GAS and LINKAGE. Furthermore, an unlimited number of phenotypes (either qualitative or quantitative can be stored and analyzed. Finally, GeneLink generates several quality assurance reports, including genotyping success rates of specified DNA samples or success and heterozygosity rates for specified markers. Conclusions GeneLink has already proven an invaluable tool for complex trait mapping studies and is discussed primarily in the context of our large, multi-center study of hereditary prostate cancer (HPC. GeneLink is freely available at http://research.nhgri.nih.gov/genelink.

  13. Nucleotide diversity in Silene latifolia autosomal and sex-linked genes

    Science.gov (United States)

    Qiu, Suo; Bergero, Roberta; Forrest, Alan; Kaiser, Vera B.; Charlesworth, Deborah

    2010-01-01

    The plant Silene latifolia has separate sexes and sex chromosomes, and is of interest for studying the early stages of sex chromosome evolution, especially the evolution of non-recombining regions on the Y chromosome. Hitch-hiking processes associated with ongoing genetic degeneration of the non-recombining Y chromosome are predicted to reduce Y-linked genes' effective population sizes, and S. latifolia Y-linked genes indeed have lower diversity than X-linked ones. We tested whether this represents a true diversity reduction on the Y, versus the alternative possibility, elevated diversity at X-linked genes, by collecting new data on nucleotide diversity for autosomal genes, which had previously been little studied. We find clear evidence that Y-linked genes have reduced diversity. However, another alternative explanation for a low Y effective size is a high variance in male reproductive success. Autosomal genes should then also have lower diversity than expected, relative to the X, but this is not found in our loci. Taking into account the higher mutation rate of Y-linked genes, their low sequence diversity indicates a strong effect of within-population hitch-hiking on the Y chromosome. PMID:20519224

  14. A transcription map of the 6p22.3 reading disability locus identifying candidate genes

    Directory of Open Access Journals (Sweden)

    Gruen Jeffrey R

    2003-06-01

    Full Text Available Abstract Background Reading disability (RD is a common syndrome with a large genetic component. Chromosome 6 has been identified in several linkage studies as playing a significant role. A more recent study identified a peak of transmission disequilibrium to marker JA04 (G72384 on chromosome 6p22.3, suggesting that a gene is located near this marker. Results In silico cloning was used to identify possible candidate genes located near the JA04 marker. The 2 million base pairs of sequence surrounding JA04 was downloaded and searched against the dbEST database to identify ESTs. In total, 623 ESTs from 80 different tissues were identified and assembled into 153 putative coding regions from 19 genes and 2 pseudogenes encoded near JA04. The identified genes were tested for their tissue specific expression by RT-PCR. Conclusions In total, five possible candidate genes for RD and other diseases mapping to this region were identified.

  15. A Gene Recommender Algorithm to Identify Coexpressed Genes in C. elegans

    OpenAIRE

    Owen, Art B.; Stuart, Josh; Mach, Kathy; Villeneuve, Anne M.; Kim, Stuart

    2003-01-01

    One of the most important uses of whole-genome expression data is for the discovery of new genes with similar function to a given list of genes (the query) already known to have closely related function. We have developed an algorithm, called the gene recommender, that ranks genes according to how strongly they correlate with a set of query genes in those experiments for which the query genes are most strongly coregulated. We used the gene recommender to find other genes coexpressed wit...

  16. A multistep screening method to identify genes using evolutionary transcriptome of plants.

    Science.gov (United States)

    Kim, Chang-Kug; Lim, Hye-Min; Na, Jong-Kuk; Choi, Ji-Weon; Sohn, Seong-Han; Park, Soo-Chul; Kim, Young-Hwan; Kim, Yong-Kab; Kim, Dool-Yi

    2014-01-01

    We introduced a multistep screening method to identify the genes in plants using microarrays and ribonucleic acid (RNA)-seq transcriptome data. Our method describes the process for identifying genes using the salt-tolerance response pathways of the potato (Solanum tuberosum) plant. Gene expression was analyzed using microarrays and RNA-seq experiments that examined three potato lines (high, intermediate, and low salt tolerance) under conditions of salt stress. We screened the orthologous genes and pathway genes involved in salinity-related biosynthetic pathways, and identified nine potato genes that were candidates for salinity-tolerance pathways. The nine genes were selected to characterize their phylogenetic reconstruction with homologous genes of Arabidopsis thaliana, and a Circos diagram was generated to understand the relationships among the selected genes. The involvement of the selected genes in salt-tolerance pathways was verified by reverse transcription polymerase chain reaction analysis. One candidate potato gene was selected for physiological validation by generating dehydration-responsive element-binding 1 (DREB1)-overexpressing transgenic potato plants. The DREB1 overexpression lines exhibited increased salt tolerance and plant growth when compared to that of the control. Although the nine genes identified by our multistep screening method require further characterization and validation, this study demonstrates the power of our screening strategy after the initial identification of genes using microarrays and RNA-seq experiments. PMID:24812480

  17. Mutation pattern in the Bruton's tyrosine kinase gene in 26 unrelated patients with X-linked agammaglobulinemia

    DEFF Research Database (Denmark)

    Vorechovsk, I; Luo, L; Hertz, Jens Michael; Frland, S S; Klemola, T; Fiorini, M; Quinti, I; Paganelli, R; Ozsahin, H; Hammarstrm, L; Webster, A D; Smith, C I

    1997-01-01

    Mutation pattern was characterized in the Bruton's tyrosine kinase gene (BTK) in 26 patients with X-linked agammaglobulinemia, the first described immunoglobulin deficiency, and was related to BTK expression. A total of 24 different mutations were identified. Most BTK mutations were found to result...... in premature termination of the translation product. Mutations were detected in most BTK exons with a predominance of frameshift and nonsense mutations in the 5' end of the gene and missense mutations in its 3' part, corresponding to the catalytic domain of the enzyme. Nonsense and frameshift......'s residue, which is mutated in mice bearing the X-linked immunodeficiency phenotype; another substitution (R307G) was identified in the src homology domain 2. All remaining amino acid substitutions were found in the catalytic domain of Btk....

  18. U3 snoRNA genes are multi-copy and frequently linked to U5 snRNA genes in Euglena gracilis

    Directory of Open Access Journals (Sweden)

    Charette J Michael

    2009-11-01

    Full Text Available Abstract Background U3 snoRNA is a box C/D small nucleolar RNA (snoRNA involved in the processing events that liberate 18S rRNA from the ribosomal RNA precursor (pre-rRNA. Although U3 snoRNA is present in all eukaryotic organisms, most investigations of it have focused on fungi (particularly yeasts, animals and plants. Relatively little is known about U3 snoRNA and its gene(s in the phylogenetically broad assemblage of protists (mostly unicellular eukaryotes. In the euglenozoon Euglena gracilis, a distant relative of the kinetoplastid protozoa, Southern analysis had previously revealed at least 13 bands hybridizing with U3 snoRNA, suggesting the existence of multiple copies of U3 snoRNA genes. Results Through screening of a ? genomic library and PCR amplification, we recovered 14 U3 snoRNA gene variants, defined by sequence heterogeneities that are mostly located in the U3 3'-stem-loop domain. We identified three different genomic arrangements of Euglena U3 snoRNA genes: i stand-alone, ii linked to tRNAArg genes, and iii linked to a U5 snRNA gene. In arrangement ii, the U3 snoRNA gene is positioned upstream of two identical tRNAArg genes that are convergently transcribed relative to the U3 gene. This scenario is reminiscent of a U3 snoRNA-tRNA gene linkage previously described in trypanosomatids. We document here twelve different U3 snoRNA-U5 snRNA gene arrangements in Euglena; in each case, the U3 gene is linked to a downstream and convergently oriented U5 gene, with the intergenic region differing in length and sequence among the variants. Conclusion The multiple U3 snoRNA-U5 snRNA gene linkages, which cluster into distinct families based on sequence similarities within the intergenic spacer, presumably arose by genome, chromosome, and/or locus duplications. We discuss possible reasons for the existence of the unusually large number of U3 snoRNA genes in the Euglena genome. Variability in the signal intensities of the multiple Southern hybridization bands raises the possibility that Euglena contains a naturally aneuploid chromosome complement.

  19. Metastatic canine mammary carcinomas can be identified by a gene expression profile that partly overlaps with human breast cancer profiles

    International Nuclear Information System (INIS)

    Similar to human breast cancer mammary tumors of the female dog are commonly associated with a fatal outcome due to the development of distant metastases. However, the molecular defects leading to metastasis are largely unknown and the value of canine mammary carcinoma as a model for human breast cancer is unclear. In this study, we analyzed the gene expression signatures associated with mammary tumor metastasis and asked for parallels with the human equivalent. Messenger RNA expression profiles of twenty-seven lymph node metastasis positive or negative canine mammary carcinomas were established by microarray analysis. Differentially expressed genes were functionally characterized and associated with molecular pathways. The findings were also correlated with published data on human breast cancer. Metastatic canine mammary carcinomas had 1,011 significantly differentially expressed genes when compared to non-metastatic carcinomas. Metastatic carcinomas had a significant up-regulation of genes associated with cell cycle regulation, matrix modulation, protein folding and proteasomal degradation whereas cell differentiation genes, growth factor pathway genes and regulators of actin organization were significantly down-regulated. Interestingly, 265 of the 1,011 differentially expressed canine genes are also related to human breast cancer and, vice versa, parts of a human prognostic gene signature were identified in the expression profiles of the metastatic canine tumors. Metastatic canine mammary carcinomas can be discriminated from non-metastatic carcinomas by their gene expression profiles. More than one third of the differentially expressed genes are also described of relevance for human breast cancer. Many of the differentially expressed genes are linked to functions and pathways which appear to be relevant for the induction and maintenance of metastatic progression and may represent new therapeutic targets. Furthermore, dogs are in some aspects suitable as a translational model for human breast tumors in order to identify prognostic molecular signatures and potential therapeutic targets

  20. Metastatic canine mammary carcinomas can be identified by a gene expression profile that partly overlaps with human breast cancer profiles

    Directory of Open Access Journals (Sweden)

    Hummel Michael

    2010-11-01

    Full Text Available Abstract Background Similar to human breast cancer mammary tumors of the female dog are commonly associated with a fatal outcome due to the development of distant metastases. However, the molecular defects leading to metastasis are largely unknown and the value of canine mammary carcinoma as a model for human breast cancer is unclear. In this study, we analyzed the gene expression signatures associated with mammary tumor metastasis and asked for parallels with the human equivalent. Methods Messenger RNA expression profiles of twenty-seven lymph node metastasis positive or negative canine mammary carcinomas were established by microarray analysis. Differentially expressed genes were functionally characterized and associated with molecular pathways. The findings were also correlated with published data on human breast cancer. Results Metastatic canine mammary carcinomas had 1,011 significantly differentially expressed genes when compared to non-metastatic carcinomas. Metastatic carcinomas had a significant up-regulation of genes associated with cell cycle regulation, matrix modulation, protein folding and proteasomal degradation whereas cell differentiation genes, growth factor pathway genes and regulators of actin organization were significantly down-regulated. Interestingly, 265 of the 1,011 differentially expressed canine genes are also related to human breast cancer and, vice versa, parts of a human prognostic gene signature were identified in the expression profiles of the metastatic canine tumors. Conclusions Metastatic canine mammary carcinomas can be discriminated from non-metastatic carcinomas by their gene expression profiles. More than one third of the differentially expressed genes are also described of relevance for human breast cancer. Many of the differentially expressed genes are linked to functions and pathways which appear to be relevant for the induction and maintenance of metastatic progression and may represent new therapeutic targets. Furthermore, dogs are in some aspects suitable as a translational model for human breast tumors in order to identify prognostic molecular signatures and potential therapeutic targets.

  1. A Multi-Layered Screening Method to Identify Plant Regulatory Genes.

    Science.gov (United States)

    Kim, Chang-Kug; Kim, Jin-A; Choi, Ji-Weon; Jeong, In-Seon; Moon, Yi-Seul; Park, Dong-Suk; Seol, Young-Joo; Kim, Yong-Kab; Kim, Yong-Hwan; Kim, Yeon-Ki

    2014-01-01

    We used a seven-step process to identify genes involved in glucosinolate biosynthesis and metabolism in the Chinese cabbage (Brassica rapa). We constructed an annotated data set with 34,570 unigenes from B. rapa and predicted 11,526 glucosinolate-related candidate genes using expression profiles generated across nine stages of development on a 47k-gene microarray. Using our multi-layered screening method, we screened 392 transcription factors, 843 pathway genes, and 4,162 ortholog genes associated with glucosinolate-related biosynthesis. Finally, we identified five genes by comparison of the pathway-network genes including the transcription-factor genes and the ortholog-ontology genes. The five genes were anchored to the chromosomes of B. rapa to characterize their genetic-map positions, and phylogenetic reconstruction with homologous genes was performed. These anchored genes were verified by reverse-transcription polymerase chain reaction. While the five genes identified by our multi-layered screen require further characterization and validation, our study demonstrates the power of multi-layered screening after initial identification of genes on microarrays. PMID:26355777

  2. Molecular genetics of X-linked retinitis pigmentosa: Progress towards cloning the RP3 gene

    Energy Technology Data Exchange (ETDEWEB)

    Fujita, R.; Yan, D.; McHenry, C. [Univ. of Michigan, Ann Arbor, MI (United States)] [and others

    1994-09-01

    Our goal is to identify the X-linked retinitis pigmentosa (XLRP) gene RP3. The location of RP3 is genetically delimited to a region of 1 Mb, distal to DXS140, CYBB and tctex-1-like gene and proximal to the gene OTC. It is currently thought that RP3 is within 40 kb of the proximal deletion breakpoint of a patient BB. However, a more proximal location of the gene, closer to OTC, is not ruled out. We initiated the isolation of the genomic region between DXS140 to OTC in YACs. One of the clones from DXS140 region (55B) is 460 kb and spans about 200 kb at each side of BB patient`s proximal breakpoint. It contains CYBB, tctex-1-like genes and two additional CpG islands. The 55B clone has been covered by cosmid and phage subclones. Another YAC clone from the OTC region (OTCC) spans about 1 Mb and contains at least 5 CpG islands. In situ hybridization performed with OTCC showed its location in Xp21; however, several derivative cosmids map to chromosome 7, indicating that it is a chimeric YAC. No overlap is evident between 55B and OTCC. We have isolated the YAC end-sequences and isolation of clones to close the gap is in progress. Cosmids are being used for screening eye tissue cDNA libraries, mainly from retina. Screening is done by hybridization to replica filters or by cDNA enrichment methods. Several cDNA clones have been isolated and are being characterized. Exon-amplification is also being used with the cosmids and phages. Genetic analysis is being performed to determine RP3 patients from clinically indistinguishable RP2, located in Xp11.23-p11.4, and to reduce the genetic distance of current flanking markers. For this we are analyzing a number of XLRP families with established markers in the region and with new microsatellites.

  3. Linkage analysis and physical mapping near the gene for x-linked agammaglobulinemia at Xq22

    Energy Technology Data Exchange (ETDEWEB)

    Parolini, O.; Lassiter, G.L.; Henry, M.J.; Conley, M.E. (Univ. of Tennessee College of Medicine, Memphis (United States) St. Jude Children' s Research Hospital, Memphis, TN (United States)); Hejtmancik, J.F. (National Inst. of Health, Bethesda, MD (United States)); Allen, R.C.; Belmont, J.W. (Baylor College of Medicine, Houston, TX (United States)); Barker, D.F. (Univ. of Utah, Salt Lake City (United States))

    1993-02-01

    The gene for x-linked agammaglobulinemia (XLA) has been mapped to Xq22. No recombinations have been reported between the gene and the prob p212 at DXS178; however, this probe is informative in only 30-40% of women and the reported flanking markers, DXS3 and DXS94, and 10-15 cM apart. To identify additional probes that might be useful in genetic counseling, we examined 11 polymorphisms that have been mapped to the Xq21.3-q22 region in 13 families with XLA. In addition, pulsed-field gel electrophoresis and yeast artificial chromosomes (YACs) were used to further characterize the segman of DNA within which the gene for SLA must lie. The results demonstrated that DXS366 and DXS442, which share a 430-kb pulsed-field fragment, could replace DXS3 as proximal flanking markers. Probes at DXS178 and DXS265 identified the same 145-kb pulsed-field fragment, and both loci were contained within a 200-kb YAC identified with the probe p212. A highly polymorphic CA repeat (DCS178CA) was isolated from one end of this YAC and used in linkage analysis. Probes at DXS101 and DXS328 shared several pulsed-field fragments, the smallest of which was 250 kb. No recombinations were seen between XLA and the DXS178-DXS265-DXS178CA complex, DXS101, DXS328, DXS87, or the gene for proteolipid protein (PLP). Key crossovers, when combined with the linkage data from families with Alport syndrome, suggested the following order of loci: cen-DXS3-DXS366-DXS442-(PLP, DXS101, DXS328, DXS178-DXS265-DXS178CA complex, XL)-(DXS87, DXS94)-DXS327-(DXS350, DXS362)-tel. Our studies also limit the segment of DNA within which the XLA gene must lie to the 3- to 4-cM distance between DCS442 and DXS94 and they identify and orient polymorphisms that can be used in genetic counseling not only for XLA but also for Pelizaeus-Merzbacher disease (PLP deficiency), Alport syndrome (COL4A5 deficiency), and Fabry disease ([alpha]-galactosidase A difficiency). 31 refs., 5 figs., 2 tabs.

  4. Identifying Genes Responsible for Tamoxifen Resistance in Breast Cancer

    OpenAIRE

    Meijer, Danille

    2008-01-01

    Breast cancer is one of the leading causes of death of women in western countries. It affects one out of eight females in the USA (1) and one out of nine females in The Netherlands (www.kankerregistratie.nl) during their lifetime. Many risk factors for breast cancer have been identified including gender, familial susceptibility, age, and exposure to hormones i.e. use of exogenous hormones, young age at menarge, and high age at menopause and first pregnancy (2). Familial breast cancer accounts...

  5. Apoptosis-linked gene-2 connects the Raf-1 and ASK1 signalings

    International Nuclear Information System (INIS)

    Raf-1 plays important roles in cell proliferation, differentiation, and survival. However, the unique and essential function of Raf-1 is anti-apoptotic. The molecules that mediate Raf-1's anti-apoptotic function are not known. In the course of identifying new substrates of Raf-1, we found that the Raf-1 kinase domain interacted with apoptosis-linked gene-2 (ALG-2) in yeast two-hybrid system. Our further studies showed that Raf-1 phosphorylated ALG-2 in an in vitro kinase assay. We also found that apoptosis signal-regulating kinase 1 (ASK1) strongly phosphorylated ALG-2. Importantly, Raf-1 blocks the ASK1-dependent ALG-2 phosphorylation. Since ALG-2 associates with ASK1, and both ASK1 and ALG-2 are involved in apoptosis, our observations indicate that Raf-1 may mediate its anti-apoptotic function by interrupting ASK1-dependent phosphorylation of ALG-2

  6. Functional link between Myc and the Werner gene in tumorigenesis.

    Science.gov (United States)

    Grandori, Carla; Robinson, Kristin L; Galloway, Denise A; Swisshelm, Karen

    2004-01-01

    We have recently reported a connection between the expression of the Werner syndrome gene (WRN), whose loss of function has been implicated in a human progeroid syndrome (WS), and the Myc oncoprotein. Myc overexpression directly elevates trancription of the WRN gene, whose presence is required to avoid senescence during Myc proliferative stimuli. Here we discuss several hypotheses to explain why WRN might be required to support oncogenic proliferation in light of the known function of WRNprotein and Myc in genomic instability and transcriptional modulation. In addition, we address the apparent paradox of why patients with WS, lacking WRN function, have increased incidence of certain cancers. PMID:14657658

  7. Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: a personal history.

    Science.gov (United States)

    Seidman, Christine E; Seidman, J G

    2011-03-18

    This review provides an historical and personal perspective on the discovery of genetic causes for hypertrophic cardiomyopathy (HCM). Extraordinary insights by physicians who initially detailed remarkable and varied manifestations of the disorder, collaboration among multidisciplinary teams with skills in clinical diagnostics and molecular genetics, and hard work by scores of trainees solved the etiologic riddle of HCM and unexpectedly demonstrated mutations in sarcomere protein genes as the cause of disease. In addition to celebrating 20 years of genetic research in HCM, this article serves as an introductory overview to a thematic review series that will present contemporary advances in the field of hypertrophic heart disease. Through the continued application of advances in genetic methodologies, combined with biochemical and biophysical analyses of the consequences of human mutations, fundamental knowledge about HCM and sarcomere biology has emerged. Expanding research to elucidate the mechanisms by which subtle genetic variation in contractile proteins remodel the human heart remains an exciting opportunity, one with considerable promise to provide new strategies to limit or even prevent HCM pathogenesis. PMID:21415408

  8. Use of tiling array data and RNA secondary structure predictions to identify noncoding RNA genes

    DEFF Research Database (Denmark)

    Weile, Christian; Gardner, Paul P; Hedegaard, Mads M; Vinther, Jeppe

    2007-01-01

    neuroblastoma cell line SK-N-AS. Using this strategy, we identify thousands of human candidate RNA genes. To further verify the expression of these genes, we focused on candidate genes that had a stable hairpin structures or a high level of covariance. Using northern blotting, we verify the expression of 2 out...

  9. X-linked genes and risk of orofacial clefts

    DEFF Research Database (Denmark)

    Jugessur, Astanand; Skare, Øivind; Lie, Rolv T; Wilcox, Allen J; Christensen, Kaare; Christiansen, Lene; Nguyen, Truc Trung; Murray, Jeff; Gjessing, Håkon K

    2012-01-01

    Orofacial clefts are common birth defects of complex etiology, with an excess of males among babies with cleft lip and palate, and an excess of females among those with cleft palate only. Although genes on the X chromosome have been implicated in clefting, there has been no association analysis of...

  10. Generalist Genes: Genetic Links between Brain, Mind, and Education

    Science.gov (United States)

    Plomin, Robert; Kovas, Yulia; Haworth, Claire M. A.

    2007-01-01

    Genetics contributes importantly to learning abilities and disabilities--not just to reading, the target of most genetic research, but also to mathematics and other academic areas as well. One of the most important recent findings from quantitative genetic research such as twin studies is that the same set of genes is largely responsible for…

  11. Gene expression meta-analysis identifies chromosomal regions and candidate genes involved in breast cancer metastasis

    OpenAIRE

    Thomassen, Mads; Tan, Qihua; Kruse, Torben A.

    2008-01-01

    Abstract Breast cancer cells exhibit complex karyotypic alterations causing deregulation of numerous genes. Some of these genes are probably causal for cancer formation and local growth whereas others are causal for the various steps of metastasis. In a fraction of tumors deregulation of the same genes might be caused by epigenetic modulations, point mutations or the influence of other genes. We have investigated the relation of gene expression and chromosomal position...

  12. Identify the signature genes for diagnose of uveal melanoma by weight gene co-expression network analysis

    Directory of Open Access Journals (Sweden)

    Kai Shi

    2015-04-01

    Full Text Available AIM: To identify and understand the relationship between co-expression pattern and clinic traits in uveal melanoma, weighted gene co-expression network analysis (WGCNA is applied to investigate the gene expression levels and patient clinic features. Uveal melanoma is the most common primary eye tumor in adults. Although many studies have identified some important genes and pathways that were relevant to progress of uveal melanoma, the relationship between co-expression and clinic traits in systems level of uveal melanoma is unclear yet. We employ WGCNA to investigate the relationship underlying molecular and phenotype in this study. METHODS: Gene expression profile of uveal melanoma and patient clinic traits were collected from the Gene Expression Omnibus (GEO database. The gene co-expression is calculated by WGCNA that is the R package software. The package is used to analyze the correlation between pairs of expression levels of genes. The function of the genes were annotated by gene ontology (GO. RESULTS: In this study, we identified four co-expression modules significantly correlated with clinic traits. Module blue positively correlated with radiotherapy treatment. Module purple positively correlates with tumor location (sclera and negatively correlates with patient age. Module red positively correlates with sclera and negatively correlates with thickness of tumor. Module black positively correlates with the largest tumor diameter (LTD. Additionally, we identified the hug gene (top connectivity with other genes in each module. The hub gene RPS15A, PTGDS, CD53 and MSI2 might play a vital role in progress of uveal melanoma. CONCLUSION: From WGCNA analysis and hub gene calculation, we identified RPS15A, PTGDS, CD53 and MSI2 might be target or diagnosis for uveal melanoma.

  13. Integrated analysis of oral tongue squamous cell carcinoma identifies key variants and pathways linked to risk habits, HPV, clinical parameters and tumor recurrence [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Neeraja Krishnan

    2015-11-01

    Full Text Available Oral tongue squamous cell carcinomas (OTSCC are a homogeneous group of tumors characterized by aggressive behavior, early spread to lymph nodes and a higher rate of regional failure. Additionally, the incidence of OTSCC among younger population (<50yrs is on the rise; many of whom lack the typical associated risk factors of alcohol and/or tobacco exposure. We present data on single nucleotide variations (SNVs, indels, regions with loss of heterozygosity (LOH, and copy number variations (CNVs from fifty-paired oral tongue primary tumors and link the significant somatic variants with clinical parameters, epidemiological factors including human papilloma virus (HPV infection and tumor recurrence. Apart from the frequent somatic variants harbored in TP53, CASP8, RASA1, NOTCH and CDKN2A genes, significant amplifications and/or deletions were detected in chromosomes 6-9, and 11 in the tumors. Variants in CASP8 and CDKN2A were mutually exclusive. CDKN2A, PIK3CA, RASA1 and DMD variants were exclusively linked to smoking, chewing, HPV infection and tumor stage. We also performed a whole-genome gene expression study that identified matrix metalloproteases to be highly expressed in tumors and linked pathways involving arachidonic acid and NF-k-B to habits and distant metastasis, respectively. Functional knockdown studies in cell lines demonstrated the role of CASP8 in a HPV-negative OTSCC cell line. Finally, we identified a 38-gene minimal signature that predicts tumor recurrence using an ensemble machine-learning method. Taken together, this study links molecular signatures to various clinical and epidemiological factors in a homogeneous tumor population with a relatively high HPV prevalence.

  14. Genome-wide misexpression of X-linked versus autosomal genes associated with hybrid male sterility

    Science.gov (United States)

    Lu, Xuemei; Shapiro, Joshua A.; Ting, Chau-Ti; Li, Yan; Li, Chunyan; Xu, Jin; Huang, Huanwei; Cheng, Ya-Jen; Greenberg, Anthony J.; Li, Shou-Hsien; Wu, Mao-Lien; Shen, Yang; Wu, Chung-I

    2010-01-01

    Postmating reproductive isolation is often manifested as hybrid male sterility, for which X-linked genes are overrepresented (the so-called large X effect). In contrast, X-linked genes are significantly under-represented among testis-expressing genes. This seeming contradiction may be germane to the X:autosome imbalance hypothesis on hybrid sterility, in which the X-linked effect is mediated mainly through the misexpression of autosomal genes. In this study, we compared gene expression in fertile and sterile males in the hybrids between two Drosophila species. These hybrid males differ only in a small region of the X chromosome containing the Ods-site homeobox (OdsH) (also known as Odysseus) locus of hybrid sterility. Of genes expressed in the testis, autosomal genes were, indeed, more likely to be misexpressed than X-linked genes under the sterilizing action of OdsH. Since this mechanism of X:autosome interaction is only associated with spermatogenesis, a connection between X:autosome imbalance and the high rate of hybrid male sterility seems plausible. PMID:20511493

  15. Differential display identifies overexpression of the USP36 gene, encoding a deubiquitinating enzyme, in ovarian cancer

    OpenAIRE

    Jianduan Li, Lisa M. Olson, Zhengyan Zhang, Lina Li, Miri Bidder, Loan Nguyen, John Pfeifer, Janet S. Rader

    2008-01-01

    Objectives. To find potential diagnostic markers or therapeutic targets, we used differential display technique to identify genes that are over or under expressed in human ovarian cancer. Methods. Genes were initially identified by differential display between two human ovarian surface epithelium cultures and two ovarian cancer cell lines, A2780 and Caov-3. Genes were validated by relative quantitative RT-PCR and RNA in situ hybridization. Results. Twenty-eight non-redundant sequences were ex...

  16. Highly conserved gene order and numerous novel repetitive elements in genomic regions linked to wing pattern variation in Heliconius butterflies

    Directory of Open Access Journals (Sweden)

    Halder Georg

    2008-07-01

    Full Text Available Abstract Background With over 20 parapatric races differing in their warningly colored wing patterns, the butterfly Heliconius erato provides a fascinating example of an adaptive radiation. Together with matching races of its co-mimic Heliconius melpomene, H. erato also represents a textbook case of Müllerian mimicry, a phenomenon where common warning signals are shared amongst noxious organisms. It is of great interest to identify the specific genes that control the mimetic wing patterns of H. erato and H. melpomene. To this end we have undertaken comparative mapping and targeted genomic sequencing in both species. This paper reports on a comparative analysis of genomic sequences linked to color pattern mimicry genes in Heliconius. Results Scoring AFLP polymorphisms in H. erato broods allowed us to survey loci at approximately 362 kb intervals across the genome. With this strategy we were able to identify markers tightly linked to two color pattern genes: D and Cr, which were then used to screen H. erato BAC libraries in order to identify clones for sequencing. Gene density across 600 kb of BAC sequences appeared relatively low, although the number of predicted open reading frames was typical for an insect. We focused analyses on the D- and Cr-linked H. erato BAC sequences and on the Yb-linked H. melpomene BAC sequence. A comparative analysis between homologous regions of H. erato (Cr-linked BAC and H. melpomene (Yb-linked BAC revealed high levels of sequence conservation and microsynteny between the two species. We found that repeated elements constitute 26% and 20% of BAC sequences from H. erato and H. melpomene respectively. The majority of these repetitive sequences appear to be novel, as they showed no significant similarity to any other available insect sequences. We also observed signs of fine scale conservation of gene order between Heliconius and the moth Bombyx mori, suggesting that lepidopteran genome architecture may be conserved over very long evolutionary time scales. Conclusion Here we have demonstrated the tractability of progressing from a genetic linkage map to genomic sequence data in Heliconius butterflies. We have also shown that fine-scale gene order is highly conserved between distantly related Heliconius species, and also between Heliconius and B. mori. Together, these findings suggest that genome structure in macrolepidoptera might be very conserved, and show that mapping and positional cloning efforts in different lepidopteran species can be reciprocally informative.

  17. Identifying subspace gene clusters from microarray data using low-rank representation.

    Science.gov (United States)

    Cui, Yan; Zheng, Chun-Hou; Yang, Jian

    2013-01-01

    Identifying subspace gene clusters from the gene expression data is useful for discovering novel functional gene interactions. In this paper, we propose to use low-rank representation (LRR) to identify the subspace gene clusters from microarray data. LRR seeks the lowest-rank representation among all the candidates that can represent the genes as linear combinations of the bases in the dataset. The clusters can be extracted based on the block diagonal representation matrix obtained using LRR, and they can well capture the intrinsic patterns of genes with similar functions. Meanwhile, the parameter of LRR can balance the effect of noise so that the method is capable of extracting useful information from the data with high level of background noise. Compared with traditional methods, our approach can identify genes with similar functions yet without similar expression profiles. Also, it could assign one gene into different clusters. Moreover, our method is robust to the noise and can identify more biologically relevant gene clusters. When applied to three public datasets, the results show that the LRR based method is superior to existing methods for identifying subspace gene clusters. PMID:23527177

  18. A Female-Specific Lethal Lesion in an X-Linked Positive Regulator of the Drosophila Sex Determination Gene, SEX-LETHAL

    OpenAIRE

    Cline, Thomas W.

    1986-01-01

    Characterization of a partial-loss-of-function, female-specific lethal mutation has identified an X-linked genetic element ( 1-34.3; 10B4) that functions as a positive regulator of Sxl, a central gene controlling sex determination in Drosophila melanogaster . The name, sisterless-a, was chosen both to suggest functional similarities that exist between this gene and another positive regulator of Sxl, the maternally acting gene daughterless (da), and also to highlight an important difference; ...

  19. Soybean Resistance Genes Specific for Different Pseudomonas Syringae Avirulence Genes Are Allelic, or Closely Linked, at the Rpg1 Locus

    Science.gov (United States)

    Ashfield, T.; Keen, N. T.; Buzzell, R. I.; Innes, R. W.

    1995-01-01

    RPG1 and RPM1 are disease resistance genes in soybean and Arabidopsis, respectively, that confer resistance to Pseudomonas syringae strains expressing the avirulence gene avrB. RPM1 has recently been demonstrated to have a second specificity, also conferring resistance to P. syringae strains expressing avrRpm1. Here we show that alleles, or closely linked genes, exist at the RPG1 locus in soybean that are specific for either avrB or avrRpm1 and thus can distinguish between these two avirulence genes. PMID:8601497

  20. Gene-Network Analysis Identifies Susceptibility Genes Related to Glycobiology in Autism

    OpenAIRE

    Van Der Zwaag, Bert; Franke, Lude; Poot, Martin; Hochstenbach, Ron; Spierenburg, Henk A.; Vorstman, Jacob A. S.; van Daalen, Emma; de Jonge, Maretha V; Verbeek, Nienke E; Brilstra, Eva H; van 't Slot, Ruben; Ophoff, Roel A.; van Es, Michael A.; Blauw, Hylke M.; Veldink, Jan H.

    2009-01-01

    The recent identification of copy-number variation in the human genome has opened up new avenues for the discovery of positional candidate genes underlying complex genetic disorders, especially in the field of psychiatric disease. One major challenge that remains is pinpointing the susceptibility genes in the multitude of disease-associated loci. This challenge may be tackled by reconstruction of functional gene-networks from the genes residing in these loci. We applied this approach to autis...

  1. Involvment of MHC-linked hemopoietic-histocompatibility genes in allogeneic bone marrow transplantation in mice

    International Nuclear Information System (INIS)

    Genes controlling resistance of irradiated mice to allogeneic hemopoietic cells were mapped within, or closely linked to the D region of MHC and were designated Hemopoietic-histocompatibility genes (Hhsub(a)). Hhsub(p) genes responsible for resistance to parental hemopoietic cells had also previously been detected on the D-end of MHC. Hh genes are regarded as determinants of cell surface antigens (Hh antigens) phenotypically expressed, in contrast to Histocompatibility antigens (H antigens), only on blood-forming and leukemic cells. The inheritance of Hh genes is not codominant, unlike that of H genes, suggesting that the Hh genes and H genes are independent entities. Hh antigens also seem to exist on rat and dog cells and it is plausible that these antigens also exist in man, and could influence the outcome of clinical bone marrow transplantation. (auth.)

  2. Time course analysis of gene expression identifies multiple genes with differential expression in patients with in-stent restenosis

    Directory of Open Access Journals (Sweden)

    Gudnason Thorarinn

    2011-02-01

    Full Text Available Abstract Background The vascular disease in-stent restenosis (ISR is characterized by formation of neointima and adverse inward remodeling of the artery after injury by coronary stent implantation. We hypothesized that the analysis of gene expression in peripheral blood mononuclear cells (PBMCs would demonstrate differences in transcript expression between individuals who develop ISR and those who do not. Methods and Results We determined and investigated PBMC gene expression of 358 patients undergoing an index procedure to treat in de novo coronary artery lesions with bare metallic stents, using a novel time-varying intercept model to optimally assess the time course of gene expression across a time course of blood samples. Validation analyses were conducted in an independent sample of 97 patients with similar time-course blood sampling and gene expression data. We identified 47 probesets with differential expression, of which 36 were validated upon independent replication testing. The genes identified have varied functions, including some related to cellular growth and metabolism, such as the NAB2 and LAMP genes. Conclusions In a study of patients undergoing bare metallic stent implantation, we have identified and replicated differential gene expression in peripheral blood mononuclear cells, studied across a time series of blood samples. The genes identified suggest alterations in cellular growth and metabolism pathways, and these results provide the basis for further specific functional hypothesis generation and testing of the mechanisms of ISR.

  3. ModuleFinder and CoReg: alternative tools for linking gene expression modules with promoter sequences motifs to uncover gene regulation mechanisms in plants

    Directory of Open Access Journals (Sweden)

    Whelan James

    2006-04-01

    Full Text Available Abstract Background Uncovering the key sequence elements in gene promoters that regulate the expression of plant genomes is a huge task that will require a series of complementary methods for prediction, substantial innovations in experimental validation and a much greater understanding of the role of combinatorial control in the regulation of plant gene expression. Results To add to this larger process and to provide alternatives to existing prediction methods, we have developed several tools in the statistical package R. ModuleFinder identifies sets of genes and treatments that we have found to form valuable sets for analysis of the mechanisms underlying gene co-expression. CoReg then links the hierarchical clustering of these co-expressed sets with frequency tables of promoter elements. These promoter elements can be drawn from known elements or all possible combinations of nucleotides in an element of various lengths. These sets of promoter elements represent putative cis-acting regulatory elements common to sets of co-expressed genes and can be prioritised for experimental testing. We have used these new tools to analyze the response of transcripts for nuclear genes encoding mitochondrial proteins in Arabidopsis to a range of chemical stresses. ModuleFinder provided a subset of co-expressed gene modules that are more logically related to biological functions than did subsets derived from traditional hierarchical clustering techniques. Importantly ModuleFinder linked responses in transcripts for electron transport chain components, carbon metabolism enzymes and solute transporter proteins. CoReg identified several promoter motifs that helped to explain the patterns of expression observed. Conclusion ModuleFinder identifies sets of genes and treatments that form useful sets for analysis of the mechanisms behind co-expression. CoReg links the clustering tree of expression-based relationships in these sets with frequency tables of promoter elements. These sets of promoter elements represent putative cis-acting regulatory elements for sets of genes, and can then be tested experimentally. We consider these tools, both built on an open source software product to provide valuable, alternative tools for the prioritisation of promoter elements for experimental analysis.

  4. Dragon Gene Start Finder identifies approximate locations of the 5′ ends of genes

    OpenAIRE

    Bajic, Vladimir B.; Seah, Seng Hong

    2003-01-01

    Recognition of gene starts is a difficult and yet unsolved problem. We present a program, Dragon Gene Start Finder (DGSF), which assesses the gene start in mammalian genomes and predicts a region which should overlap with the first exon of the gene or be in its proximity. The program has been rigorously tested on human chromosomes 4, 21 and 22, and in a strand specific search achieves an overall sensitivity of ∼65% and a positive predictive value of ∼78%. The sensitivity for the CpG-island re...

  5. Systematic enrichment analysis of gene expression profiling studies identifies consensus pathways implicated in colorectal cancer development

    Directory of Open Access Journals (Sweden)

    Jesús Lascorz

    2011-01-01

    Full Text Available Background: A large number of gene expression profiling (GEP studies on colorectal carcinogenesis have been performed but no reliable gene signature has been identified so far due to the lack of reproducibility in the reported genes. There is growing evidence that functionally related genes, rather than individual genes, contribute to the etiology of complex traits. We used, as a novel approach, pathway enrichment tools to define functionally related genes that are consistently up- or down-regulated in colorectal carcinogenesis. Materials and Methods: We started the analysis with 242 unique annotated genes that had been reported by any of three recent meta-analyses covering GEP studies on genes differentially expressed in carcinoma vs normal mucosa. Most of these genes (218, 91.9% had been reported in at least three GEP studies. These 242 genes were submitted to bioinformatic analysis using a total of nine tools to detect enrichment of Gene Ontology (GO categories or Kyoto Encyclopedia of Genes and Genomes (KEGG pathways. As a final consistency criterion the pathway categories had to be enriched by several tools to be taken into consideration. Results: Our pathway-based enrichment analysis identified the categories of ribosomal protein constituents, extracellular matrix receptor interaction, carbonic anhydrase isozymes, and a general category related to inflammation and cellular response as significantly and consistently overrepresented entities. Conclusions: We triaged the genes covered by the published GEP literature on colorectal carcinogenesis and subjected them to multiple enrichment tools in order to identify the consistently enriched gene categories. These turned out to have known functional relationships to cancer development and thus deserve further investigation.

  6. Cartilage-selective genes identified in genome-scale analysis of non-cartilage and cartilage gene expression

    Directory of Open Access Journals (Sweden)

    Cohn Zachary A

    2007-06-01

    Full Text Available Abstract Background Cartilage plays a fundamental role in the development of the human skeleton. Early in embryogenesis, mesenchymal cells condense and differentiate into chondrocytes to shape the early skeleton. Subsequently, the cartilage anlagen differentiate to form the growth plates, which are responsible for linear bone growth, and the articular chondrocytes, which facilitate joint function. However, despite the multiplicity of roles of cartilage during human fetal life, surprisingly little is known about its transcriptome. To address this, a whole genome microarray expression profile was generated using RNA isolated from 18–22 week human distal femur fetal cartilage and compared with a database of control normal human tissues aggregated at UCLA, termed Celsius. Results 161 cartilage-selective genes were identified, defined as genes significantly expressed in cartilage with low expression and little variation across a panel of 34 non-cartilage tissues. Among these 161 genes were cartilage-specific genes such as cartilage collagen genes and 25 genes which have been associated with skeletal phenotypes in humans and/or mice. Many of the other cartilage-selective genes do not have established roles in cartilage or are novel, unannotated genes. Quantitative RT-PCR confirmed the unique pattern of gene expression observed by microarray analysis. Conclusion Defining the gene expression pattern for cartilage has identified new genes that may contribute to human skeletogenesis as well as provided further candidate genes for skeletal dysplasias. The data suggest that fetal cartilage is a complex and transcriptionally active tissue and demonstrate that the set of genes selectively expressed in the tissue has been greatly underestimated.

  7. Gene expression profiling identifies FYN as an important molecule in tamoxifen resistance and a predictor of early recurrence in patients treated with endocrine therapy

    DEFF Research Database (Denmark)

    Elias, D; (Hansen) Vever, Henriette; Lænkholm, A-V; Gjerstorff, M F; Yde, C W; Lykkesfeldt, A E; Ditzel, H J

    2015-01-01

    functionally linked to cell proliferation, death and control of gene expression, and include FYN, PRKCA, ITPR1, DPYD, DACH1, LYN, GBP1 and PRLR. Treatment with FYN-specific small interfering RNA or a SRC family kinase inhibitor reduced cell growth of TamR cell lines while exerting no significant effect on MCF......To elucidate the molecular mechanisms of tamoxifen resistance in breast cancer, we performed gene array analyses and identified 366 genes with altered expression in four unique tamoxifen-resistant (TamR) cell lines vs the parental tamoxifen-sensitive MCF-7/S0.5 cell line. Most of these genes were...

  8. Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD

    Directory of Open Access Journals (Sweden)

    Rogaeva Ekaterina

    2006-12-01

    Full Text Available Abstract Background A new locus for amyotrophic lateral sclerosis frontotemporal dementia (ALS-FTD has recently been ascribed to chromosome 9p. Methods We identified chromosome 9p segregating haplotypes within two families with ALS-FTD (F476 and F2 and undertook mutational screening of candidate genes within this locus. Results Candidate gene sequencing at this locus revealed the presence of a disease segregating stop mutation (Q342X in the intraflagellar transport 74 (IFT74 gene in family 476 (F476, but no mutation was detected within IFT74 in family 2 (F2. While neither family was sufficiently informative to definitively implicate or exclude IFT74 mutations as a cause of chromosome 9-linked ALS-FTD, the nature of the mutation observed within F476 (predicted to truncate the protein by 258 amino acids led us to sequence the open reading frame of this gene in a large number of ALS and FTD cases (n = 420. An additional sequence variant (G58D was found in a case of sporadic semantic dementia. I55L sequence variants were found in three other unrelated affected individuals, but this was also found in a single individual among 800 Human Diversity Gene Panel samples. Conclusion Confirmation of the pathogenicity of IFT74 sequence variants will require screening of other chromosome 9p-linked families.

  9. Mistaken Identifiers: Gene name errors can be introduced inadvertently when using Excel in bioinformatics

    OpenAIRE

    Barrett J Carl; Linehan W Marston; Uchio Edward; Bussey Kimberly J; Riss Joseph; Kane David W; Zeeberg Barry R; Weinstein John N

    2004-01-01

    Abstract Background When processing microarray data sets, we recently noticed that some gene names were being changed inadvertently to non-gene names. Results A little detective work traced the problem to default date format conversions and floating-point format conversions in the very useful Excel program package. The date conversions affect at least 30 gene names; the floating-point conversions affect at least 2,000 if Riken identifiers are included. These conversions are irreversible; the ...

  10. Exome sequencing identifies NBEAL2 as the causative gene for Gray Platelet Syndrome

    OpenAIRE

    Albers, Cornelis A; CVEJIC, Ana; Favier, Rémi; Bouwmans, Evelien E; Alessi, Marie-Christine; Bertone, Paul; Jordan, Gregory; Kettleborough, Ross NW; Kiddle, Graham; Kostadima, Myrto; Read, Randy J.; Sipos, Botond; Sivapalaratnam, Suthesh; Smethurst, Peter A.; Stephens, Jonathan

    2011-01-01

    Gray platelet syndrome (GPS) is a predominantly recessive platelet disorder characterized by a mild thrombocytopenia with large platelets and a paucity of α-granules; these abnormalities cause mostly moderate but in rare cases severe bleeding. We sequenced the exomes of four unrelated cases and identified as the causative gene NBEAL2, a gene with previously unknown function but a member of a gene family involved in granule development. Silencing of nbeal2 in zebrafish abrogated thrombocyte fo...

  11. Clustering biological annotations and gene expression data to identify putatively co-regulated biological processes.

    OpenAIRE

    Henegar, Corneliu; Cancello, Raffaella; Rome, Sophie; Vidal, Hubert; Clément, Karine; Zucker, Jean-Daniel

    2006-01-01

    MOTIVATION: Functional profiling is a key step of microarray gene expression data analysis. Identifying co-regulated biological processes could help for better understanding of underlying biological interactions within the studied biological frame. RESULTS: We present herein an original approach designed to search for putatively co-regulated biological processes sharing a significant number of co-expressed genes. An R language implementation named "FunCluster" was built and tested on two gene...

  12. Bayesian meta-analysis for identifying periodically expressed genes in fission yeast cell cycle

    OpenAIRE

    Fan, Xiaodan; Pyne, Saumyadipta; Liu, Jun S

    2010-01-01

    The effort to identify genes with periodic expression during the cell cycle from genome-wide microarray time series data has been ongoing for a decade. However, the lack of rigorous modeling of periodic expression as well as the lack of a comprehensive model for integrating information across genes and experiments has impaired the effort for the accurate identification of periodically expressed genes. To address the problem, we introduce a Bayesian model to integrate multiple independent micr...

  13. Using RNA sequencing for identifying gene imprinting and random monoallelic expression in human placenta

    OpenAIRE

    Metsalu, Tauno; Viltrop, Triin; Tiirats, Airi; Rajashekar, Balaji; Reimann, Ene; Kõks, Sulev; Rull, Kristiina; Milani, Lili; ACHARYA, Ganesh; Basnet, Purusotam; Vilo, Jaak; Mägi, Reedik; Metspalu, Andres; Peters, Maire; Haller-Kikkatalo, Kadri

    2014-01-01

    Given the possible critical importance of placental gene imprinting and random monoallelic expression on fetal and infant health, most of those genes must be identified, in order to understand the risks that the baby might meet during pregnancy and after birth. Therefore, the aim of the current study was to introduce a workflow and tools for analyzing imprinted and random monoallelic gene expression in human placenta, by applying whole-transcriptome (WT) RNA sequencing of placental tissue and...

  14. Changes in gene expression linked with adult reproductive diapause in a northern malt fly species: a candidate gene microarray study

    Directory of Open Access Journals (Sweden)

    Hoikkala Anneli

    2010-02-01

    Full Text Available Abstract Background Insect diapause is an important biological process which involves many life-history parameters important for survival and reproductive fitness at both individual and population level. Drosophila montana, a species of D. virilis group, has a profound photoperiodic reproductive diapause that enables the adult flies to survive through the harsh winter conditions of high latitudes and altitudes. We created a custom-made microarray for D. montana with 101 genes known to affect traits important in diapause, photoperiodism, reproductive behaviour, circadian clock and stress tolerance in model Drosophila species. This array gave us a chance to filter out genes showing expression changes during photoperiodic reproductive diapause in a species adapted to live in northern latitudes with high seasonal changes in environmental conditions. Results Comparisons among diapausing, reproducing and young D. montana females revealed expression changes in 24 genes on microarray; for example in comparison between diapausing and reproducing females one gene (Drosophila cold acclimation gene, Dca showed up-regulation and 15 genes showed down-regulation in diapausing females. Down-regulation of seven of these genes was specific to diapause state while in five genes the expression changes were linked with the age of the females rather than with their reproductive status. Also, qRT-PCR experiments confirmed couch potato (cpo gene to be involved in diapause of D. montana. Conclusions A candidate gene microarray proved to offer a practical and cost-effective way to trace genes that are likely to play an important role in photoperiodic reproductive diapause and further in adaptation to seasonally varying environmental conditions. The present study revealed two genes, Dca and cpo, whose role in photoperiodic diapause in D. montana is worth of studying in more details. Also, further studies using the candidate gene microarray with more specific experimental designs and target tissues may reveal additional genes with more restricted expression patterns.

  15. The compact Selaginella genome identifies changes in gene content associated with the evolution of vascular plants

    Energy Technology Data Exchange (ETDEWEB)

    Grigoriev, Igor V.; Banks, Jo Ann; Nishiyama, Tomoaki; Hasebe, Mitsuyasu; Bowman, John L.; Gribskov, Michael; dePamphilis, Claude; Albert, Victor A.; Aono, Naoki; Aoyama, Tsuyoshi; Ambrose, Barbara A.; Ashton, Neil W.; Axtell, Michael J.; Barker, Elizabeth; Barker, Michael S.; Bennetzen, Jeffrey L.; Bonawitz, Nicholas D.; Chapple, Clint; Cheng, Chaoyang; Correa, Luiz Gustavo Guedes; Dacre, Michael; DeBarry, Jeremy; Dreyer, Ingo; Elias, Marek; Engstrom, Eric M.; Estelle, Mark; Feng, Liang; Finet, Cedric; Floyd, Sandra K.; Frommer, Wolf B.; Fujita, Tomomichi; Gramzow, Lydia; Gutensohn, Michael; Harholt, Jesper; Hattori, Mitsuru; Heyl, Alexander; Hirai, Tadayoshi; Hiwatashi, Yuji; Ishikawa, Masaki; Iwata, Mineko; Karol, Kenneth G.; Koehler, Barbara; Kolukisaoglu, Uener; Kubo, Minoru; Kurata, Tetsuya; Lalonde, Sylvie; Li, Kejie; Li, Ying; Litt, Amy; Lyons, Eric; Manning, Gerard; Maruyama, Takeshi; Michael, Todd P.; Mikami, Koji; Miyazaki, Saori; Morinaga, Shin-ichi; Murata, Takashi; Mueller-Roeber, Bernd; Nelson, David R.; Obara, Mari; Oguri, Yasuko; Olmstead, Richard G.; Onodera, Naoko; Petersen, Bent Larsen; Pils, Birgit; Prigge, Michael; Rensing, Stefan A.; Riano-Pachon, Diego Mauricio; Roberts, Alison W.; Sato, Yoshikatsu; Scheller, Henrik Vibe; Schulz, Burkhard; Schulz, Christian; Shakirov, Eugene V.; Shibagaki, Nakako; Shinohara, Naoki; Shippen, Dorothy E.; Sorensen, Iben; Sotooka, Ryo; Sugimoto, Nagisa; Sugita, Mamoru; Sumikawa, Naomi; Tanurdzic, Milos; Theilsen, Gunter; Ulvskov, Peter; Wakazuki, Sachiko; Weng, Jing-Ke; Willats, William W.G.T.; Wipf, Daniel; Wolf, Paul G.; Yang, Lixing; Zimmer, Andreas D.; Zhu, Qihui; Mitros, Therese; Hellsten, Uffe; Loque, Dominique; Otillar, Robert; Salamov, Asaf; Schmutz, Jeremy; Shapiro, Harris; Lindquist, Erika; Lucas, Susan; Rokhsar, Daniel

    2011-04-28

    We report the genome sequence of the nonseed vascular plant, Selaginella moellendorffii, and by comparative genomics identify genes that likely played important roles in the early evolution of vascular plants and their subsequent evolution

  16. Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation

    DEFF Research Database (Denmark)

    Sinner, Moritz F; Tucker, Nathan R; Lunetta, Kathryn L; Ozaki, Kouichi; Smith, J Gustav; Trompet, Stella; Bis, Joshua C; Lin, Honghuang; Chung, Mina K; Nielsen, Jonas B; Lubitz, Steven A; Krijthe, Bouwe P; Magnani, Jared W; Ye, Jiangchuan; Gollob, Michael H; Tsunoda, Tatsuhiko; Müller-Nurasyid, Martina; Lichtner, Peter; Peters, Annette; Dolmatova, Elena; Kubo, Michiaki; Smith, Jonathan D; Psaty, Bruce M; Smith, Nicholas L; Jukema, J Wouter; Chasman, Daniel I; Albert, Christine M; Ebana, Yusuke; Furukawa, Tetsushi; Macfarlane, Peter W; Harris, Tamara B; Darbar, Dawood; Dörr, Marcus; Holst, Anders G; Svendsen, Jesper H; Hofman, Albert; Uitterlinden, Andre G; Gudnason, Vilmundur; Isobe, Mitsuaki; Malik, Rainer; Dichgans, Martin; Rosand, Jonathan; Van Wagoner, David R; Benjamin, Emelia J; Milan, David J; Melander, Olle; Heckbert, Susan R; Ford, Ian; Liu, Yongmei; Barnard, John; Olesen, Morten S; Stricker, Bruno H C; Tanaka, Toshihiro; Kääb, Stefan; Ellinor, Patrick T

    2014-01-01

    -related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative...

  17. A novel retroviral mutagenesis screen identifies prognostic genes in RUNX1 mediated myeloid leukemogenesis.

    Science.gov (United States)

    Rae, Dustin T; Hocum, Jonah D; Bii, Victor; Deeg, H Joachim; Trobridge, Grant D

    2015-10-13

    Using a novel retroviral shuttle vector approach we identified genes that collaborate with a patient derived RUNX1 (AML1) mutant. RUNX1 mutations occurs in 40% of myelodysplastic syndromes (MDS). MDS are a group of hematopoietic stem cell disorders that are characterized by dysplasia that often progress to acute myeloid leukemia (AML). Our goal was to identify genes dysregulated by vector-mediated genotoxicity that may collaborate with the RUNX1 mutant (D171N). D171N expressing cells have a survival and engraftment disadvantage and require additional genetic lesions to survive and persist. By dysregulating genes near the integrated vector provirus, the shuttle vector can promote transformation of D171N cells and tag the nearby genes that collaborate with D171N. In our approach, a gammaretroviral shuttle vector that expresses D171N is used to transduce CD105+, Sca-1+ mouse bone marrow. Mutagenized cells are expanded in liquid culture and vector integration sites from surviving cells are then identified using a retroviral shuttle vector approach. We repeatedly recovered integrated vector proviruses near genes (Itpkb, Ccdc12, and Nbeal2). To assess the prognostic significance of the genes identified we examined differential expression, overall survival, and relapse free survival of AML patients with alteration in the genes identified using The Cancer Genome Atlas (TCGA) AML data set. We found that ITPKB functions as an independent factor for poor prognoses and RUNX1 mutations in conjunction with ITPKB, CCDC12, and NBEAL2 have prognostic potential in AML. PMID:26384344

  18. Cloning by function: an alternative approach for identifying yeast homologs of genes from other organisms.

    OpenAIRE

    Kranz, J E; Holm, C.

    1990-01-01

    Studies of cell physiology and structure have identified many intriguing proteins that could be analyzed for function by using the power of yeast genetics. Unfortunately, identifying the homologous yeast gene with the two most commonly used approaches--DNA hybridization and antibody cross-reaction--is often difficult. We describe a strategy to identify yeast homologs based on protein function itself. This cloning-by-function strategy involves first identifying a yeast mutant that depends on a...

  19. New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism

    DEFF Research Database (Denmark)

    Horikoshi, Momoko; Yaghootkar, Hanieh; Mook-Kanamori, Dennis O; Sovio, Ulla; Taal, H Rob; Hennig, Branwen J; Bradfield, Jonathan P; St Pourcain, Beate; Evans, David M; Charoen, Pimphen; Kaakinen, Marika; Cousminer, Diana L; Lehtimki, Terho; Kreiner-Mller, Eskil; Warrington, Nicole M; Bustamante, Mariona; Feenstra, Bjarke; Berry, Diane J; Thiering, Elisabeth; Pfab, Thiemo; Barton, Sheila J; Shields, Beverley M; Kerkhof, Marjan; van Leeuwen, Elisabeth M; Fulford, Anthony J; Kutalik, Zoltn; Zhao, Jing Hua; den Hoed, Marcel; Mahajan, Anubha; Lindi, Virpi; Goh, Liang-Kee; Hottenga, Jouke-Jan; Wu, Ying; Raitakari, Olli T; Harder, Marie N; Meirhaeghe, Aline; Ntalla, Ioanna; Salem, Rany M; Jameson, Karen A; Zhou, Kaixin; Monies, Dorota M; Lagou, Vasiliki; Kirin, Mirna; Heikkinen, Jani; Adair, Linda S; Alkuraya, Fowzan S; Al-Odaib, Ali; Amouyel, Philippe; Andersson, Ehm Astrid; Bennett, Amanda J; Blakemore, Alexandra I F; Buxton, Jessica L; Dallongeville, Jean; Das, Shikta; de Geus, Eco J C; Estivill, Xavier; Flexeder, Claudia; Froguel, Philippe; Geller, Frank; Godfrey, Keith M; Gottrand, Frdric; Groves, Christopher J; Hansen, Torben; Hirschhorn, Joel N; Hofman, Albert; Hollegaard, Mads Vilhelm; Hougaard, David M; Hyppnen, Elina; Inskip, Hazel M; Isaacs, Aaron; Jrgensen, Torben; Kanaka-Gantenbein, Christina; Kemp, John P; Kiess, Wieland; Kilpelinen, Tuomas O; Klopp, Norman; Knight, Bridget A; Kuzawa, Christopher W; McMahon, George; Newnham, John P; Niinikoski, Harri; Oostra, Ben A; Pedersen, Louise; Postma, Dirkje S; Ring, Susan M; Rivadeneira, Fernando; Robertson, Neil R; Sebert, Sylvain; Simell, Olli; Slowinski, Torsten; Tiesler, Carla M T; Tnjes, Anke; Vaag, Allan; Viikari, Jorma S; Vink, Jacqueline M; Vissing, Nadja Hawwa; Wareham, Nicholas J; Willemsen, Gonneke; Witte, Daniel R; Zhang, Haitao; Zhao, Jianhua; Wilson, James; Stumvoll, Michael; Prentice, Andrew M; Meyer, Brian F; Pearson, Ewan R; Boreham, Colin A G; Cooper, Cyrus; Gillman, Matthew W; Dedoussis, George V; Moreno, Luis A; Pedersen, Oluf; Saarinen, Maiju; Mohlke, Karen L; Boomsma, Dorret I; Saw, Seang-Mei; Lakka, Timo A; Krner, Antje; Loos, Ruth J F; Ong, Ken K; Vollenweider, Peter; van Duijn, Cornelia M; Koppelman, Gerard H; Hattersley, Andrew T; Holloway, John W; Hocher, Berthold; Heinrich, Joachim; Power, Chris; Melbye, Mads; Guxens, Mnica; Pennell, Craig E; Bnnelykke, Klaus; Bisgaard, Hans; Eriksson, Johan G; Widn, Elisabeth; Hakonarson, Hakon; Uitterlinden, Andr G; Pouta, Anneli; Lawlor, Debbie A; Smith, George Davey; Frayling, Timothy M; McCarthy, Mark I; Grant, Struan F A; Jaddoe, Vincent W V; Jarvelin, Marjo-Riitta; Timpson, Nicholas J; Prokopenko, Inga; Freathy, Rachel M

    2013-01-01

    Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type...

  20. GRBase, a database linking information on proteins involved in gene regulation.

    OpenAIRE

    Collier, B.; M. Danielsen

    1996-01-01

    The Gene Regulation Database (GRBase) is a compendium of information on the structure and function of proteins involved in the control of gene expression in eukaryotes. These proteins include transcription factors, proteins involved in signal transduction, and receptors. GRBase is now accessible via the World Wide Web (http://www.access.digex.net/regulate). A key feature of this database is the linking of each entry to data in other databases. The database is also available by anonymous ftp (...

  1. Faced with inequality: chicken do not have a general dosage compensation of sex-linked genes

    Directory of Open Access Journals (Sweden)

    Kultima Kim

    2007-09-01

    Full Text Available Abstract Background The contrasting dose of sex chromosomes in males and females potentially introduces a large-scale imbalance in levels of gene expression between sexes, and between sex chromosomes and autosomes. In many organisms, dosage compensation has thus evolved to equalize sex-linked gene expression in males and females. In mammals this is achieved by X chromosome inactivation and in flies and worms by up- or down-regulation of X-linked expression, respectively. While otherwise widespread in systems with heteromorphic sex chromosomes, the case of dosage compensation in birds (males ZZ, females ZW remains an unsolved enigma. Results Here, we use a microarray approach to show that male chicken embryos generally express higher levels of Z-linked genes than female birds, both in soma and in gonads. The distribution of male-to-female fold-change values for Z chromosome genes is wide and has a mean of 1.41.6, which is consistent with absence of dosage compensation and sex-specific feedback regulation of gene expression at individual loci. Intriguingly, without global dosage compensation, the female chicken has significantly lower expression levels of Z-linked compared to autosomal genes, which is not the case in male birds. Conclusion The pronounced sex difference in gene expression is likely to contribute to sexual dimorphism among birds, and potentially has implication to avian sex determination. Importantly, this report, together with a recent study of sex-biased expression in somatic tissue of chicken, demonstrates the first example of an organism with a lack of global dosage compensation, providing an unexpected case of a viable system with large-scale imbalance in gene expression between sexes.

  2. Molecular patterns of X chromosome-linked color vision genes among 134 menof European ancestry

    International Nuclear Information System (INIS)

    The authors used Southern blot hybridization to study X chromosome-linked color vision genes encoding the apoproteins of red and green visual pigments in 134 unselected Caucasian men. One hundred and thirteen individuals (84.3%) had a normal arrangement of their color vision pigment genes. All had one red pigment gene; the number of green pigment genes ranged from one to five with a mode of two. The frequency of molecular genotypes indicative of normal color vision (84.3%) was significantly lower than had been observed in previous studies of color vision phenotypes. Color vision defects can be due to deletions of red or green pigment genes or due to formation of hybrid genes comprising portions of both red and green pigment genes. Characteristic anomalous patterns were seen in 15 (11.2%) individuals: 7 (5.2%) had patterns characteristic of deuteranomaly, 2 (1.5%) had patterns characteristic of deuteranopia, and 6 (4.5%) had protan patterns. Previously undescribed hybrid gene patterns consisting of both green and red pigment gene fragments in addition to normal red and green genes were observed in another 6 individuals (4.5%). Thus, DNA testing detected anomalous color vision pigment genes at a higher frequency than expected from phenotypic color vision tests

  3. Identifying and prioritizing disease-related genes based on the network topological features.

    Science.gov (United States)

    Li, Zhan-Chao; Lai, Yan-Hua; Chen, Li-Li; Xie, Yun; Dai, Zong; Zou, Xiao-Yong

    2014-08-23

    Identifying and prioritizing disease-related genes are the most important steps for understanding the pathogenesis and discovering the therapeutic targets. The experimental examination of these genes is very expensive and laborious, and usually has a higher false positive rate. Therefore, it is highly desirable to develop computational methods for the identification and prioritization of disease-related genes. In this study, we develop a powerful method to identify and prioritize candidate disease genes. The novel network topological features with local and global information are proposed and adopted to characterize genes. The performance of these novel features is verified based on the 10-fold cross-validation test and leave-one-out cross-validation test. The proposed features are compared with the published features, and fused strategy is investigated by combining the current features with the published features. And, these combination features are also utilized to identify and prioritize Parkinson's disease-related genes. The results indicate that identified genes are highly related to some molecular process and biological function, which provides new clues for researching pathogenesis of Parkinson's disease. The source code of Matlab is freely available on request from the authors. PMID:25183318

  4. Utilization of digital differential display to identify differentially expressed genes related to rumen development.

    Science.gov (United States)

    Kato, Daichi; Suzuki, Yutaka; Haga, Satoshi; So, KyoungHa; Yamauchi, Eri; Nakano, Miwa; Ishizaki, Hiroshi; Choi, Kichoon; Katoh, Kazuo; Roh, Sang-Gun

    2016-04-01

    This study aimed to identify the genes associated with the development of the rumen epithelium by screening for candidate genes by digital differential display (DDD) in silico. Using DDD in NCBI's UniGene database, expressed sequence tag (EST)-based gene expression profiles were analyzed in rumen, reticulum, omasum, abomasum and other tissues in cattle. One hundred and ten candidate genes with high expression in the rumen were derived from a library of all tissues. The expression levels of 11 genes in all candidate genes were analyzed in the rumen, reticulum, omasum and abomasum of nine Japanese Black male calves (5-week-old pre-weaning: n = 3; 15-week-old weaned calves: n = 6). Among the 11 genes, only 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), aldo-keto reductase family 1, member C1-like (AKR1C1), and fatty acid binding protein 3 (FABP3) showed significant changes in the levels of gene expression in the rumen between the pre- and post-weaning of calves. These results indicate that DDD analysis in silico can be useful for screening candidate genes related to rumen development, and that the changes in expression levels of three genes in the rumen may have been caused by weaning, aging or both. © 2015 Japanese Society of Animal Science. PMID:26388291

  5. UV cross-linking identifies four polypeptides that require the TATA box to bind to the Drosophila hsp70 promoter

    Energy Technology Data Exchange (ETDEWEB)

    Gilmour, D.S.; Dietz, T.J.; Elgin, S.C. (Washington Univ., St. Louis, MO (USA))

    1990-08-01

    A protein fraction that requires the TATA sequence to bind to the hsp70 promoter has been partially purified from nuclear extracts of Drosophila embryos. This TATA factor produces a large DNase I footprint that extends from -44 to +35 on the promoter. A mutation that changes TATA to TATG interferes both with the binding of this complex and with the transcription of the hsp70 promoter in vitro, indicating that this interaction is important for transcriptional activity. Using a highly specific protein-DNA cross-linking assay, we have identified four polypeptides that require the TATA sequence to bind to the hsp70 promoter. Polypeptides of 26 and 42 kilodaltons are in intimate contact with the TATA sequence. Polypeptides of 150 and 60 kilodaltons interact within the region from +24 to +47 in a TATA-dependent manner. Both the extended footprint and the polypeptides identified by UV cross-linking indicate that the Drosophila TATA factor is a multicomponent complex.

  6. UV cross-linking identifies four polypeptides that require the TATA box to bind to the Drosophila hsp70 promoter

    International Nuclear Information System (INIS)

    A protein fraction that requires the TATA sequence to bind to the hsp70 promoter has been partially purified from nuclear extracts of Drosophila embryos. This TATA factor produces a large DNase I footprint that extends from -44 to +35 on the promoter. A mutation that changes TATA to TATG interferes both with the binding of this complex and with the transcription of the hsp70 promoter in vitro, indicating that this interaction is important for transcriptional activity. Using a highly specific protein-DNA cross-linking assay, we have identified four polypeptides that require the TATA sequence to bind to the hsp70 promoter. Polypeptides of 26 and 42 kilodaltons are in intimate contact with the TATA sequence. Polypeptides of 150 and 60 kilodaltons interact within the region from +24 to +47 in a TATA-dependent manner. Both the extended footprint and the polypeptides identified by UV cross-linking indicate that the Drosophila TATA factor is a multicomponent complex

  7. How physicians identify with predetermined personalities and links to perceived performance and wellness outcomes: a cross-sectional study

    OpenAIRE

    Lemaire, Jane B; Wallace, Jean E

    2014-01-01

    Background Certain personalities are ascribed to physicians. This research aims to measure the extent to which physicians identify with three predetermined personalities (workaholic, Type A and control freak) and to explore links to perceptions of professional performance, and wellness outcomes. Methods This is a cross-sectional study using a mail-out questionnaire sent to all practicing physicians (2957 eligible, 1178 responses, 40% response rate) in a geographical health region within a wes...

  8. Identifying Gene Regulatory Networks in Arabidopsis by In Silico Prediction, Yeast-1-Hybrid, and Inducible Gene Profiling Assays.

    Science.gov (United States)

    Sparks, Erin E; Benfey, Philip N

    2016-01-01

    A system-wide understanding of gene regulation will provide deep insights into plant development and physiology. In this chapter we describe a threefold approach to identify the gene regulatory networks in Arabidopsis thaliana that function in a specific tissue or biological process. Since no single method is sufficient to establish comprehensive and high-confidence gene regulatory networks, we focus on the integration of three approaches. First, we describe an in silico prediction method of transcription factor-DNA binding, then an in vivo assay of transcription factor-DNA binding by yeast-1-hybrid and lastly the identification of co-expression clusters by transcription factor induction in planta. Each of these methods provides a unique tool to advance our understanding of gene regulation, and together provide a robust model for the generation of gene regulatory networks. PMID:26659952

  9. Detection of denitrification genes by in situ rolling circle amplification - fluorescence in situ hybridization (in situ RCA-FISH) to link metabolic potential with identity inside bacterial cells

    DEFF Research Database (Denmark)

    Hoshino, Tatsuhiko; Schramm, Andreas

    2010-01-01

    A target-primed in situ rolling circle amplification (in situ RCA) protocol was developed for detection of single-copy genes inside bacterial cells and optimized with Pseudomonas stutzeri, targeting nitrite and nitrous oxide reductase genes (nirS and nosZ). Two padlock probes were designed per gene...... identified as Candidatus Accumulibacter phosphatis by combining in situ RCA-FISH with 16S rRNA-targeted FISH. While not suitable for quantification because of its low detection frequency, in situ RCA-FISH will allow to link metabolic potential with 16S rRNA (gene)-based identification of single microbial...

  10. Identifying paediatric nursing-sensitive outcomes in linked administrative health data

    OpenAIRE

    Wilson Sally; Bremner Alexandra P; Hauck Yvonne; Finn Judith

    2012-01-01

    Abstract Background There is increasing interest in the contribution of the quality of nursing care to patient outcomes. Due to different casemix and risk profiles, algorithms for administrative health data that identify nursing-sensitive outcomes in adult hospitalised patients may not be applicable to paediatric patients. The study purpose was to test adult algorithms in a paediatric hospital population and make amendments to increase the accuracy of identification of hospital acquired event...

  11. Feature selection and classification for microarray data analysis: Evolutionary methods for identifying predictive genes

    Directory of Open Access Journals (Sweden)

    Aitken Stuart

    2005-06-01

    Full Text Available Abstract Background In the clinical context, samples assayed by microarray are often classified by cell line or tumour type and it is of interest to discover a set of genes that can be used as class predictors. The leukemia dataset of Golub et al. 1 and the NCI60 dataset of Ross et al. 2 present multiclass classification problems where three tumour types and nine cell lines respectively must be identified. We apply an evolutionary algorithm to identify the near-optimal set of predictive genes that classify the data. We also examine the initial gene selection step whereby the most informative genes are selected from the genes assayed. Results In the absence of feature selection, classification accuracy on the training data is typically good, but not replicated on the testing data. Gene selection using the RankGene software 3 is shown to significantly improve performance on the testing data. Further, we show that the choice of feature selection criteria can have a significant effect on accuracy. The evolutionary algorithm is shown to perform stably across the space of possible parameter settings – indicating the robustness of the approach. We assess performance using a low variance estimation technique, and present an analysis of the genes most often selected as predictors. Conclusion The computational methods we have developed perform robustly and accurately, and yield results in accord with clinical knowledge: A Z-score analysis of the genes most frequently selected identifies genes known to discriminate AML and Pre-T ALL leukemia. This study also confirms that significantly different sets of genes are found to be most discriminatory as the sample classes are refined.

  12. Integrated Bioinformatics, Environmental Epidemiologic and Genomic Approaches to Identify Environmental and Molecular Links between Endometriosis and Breast Cancer

    Directory of Open Access Journals (Sweden)

    Deodutta Roy

    2015-10-01

    Full Text Available We present a combined environmental epidemiologic, genomic, and bioinformatics approach to identify: exposure of environmental chemicals with estrogenic activity; epidemiologic association between endocrine disrupting chemical (EDC and health effects, such as, breast cancer or endometriosis; and gene-EDC interactions and disease associations. Human exposure measurement and modeling confirmed estrogenic activity of three selected class of environmental chemicals, polychlorinated biphenyls (PCBs, bisphenols (BPs, and phthalates. Meta-analysis showed that PCBs exposure, not Bisphenol A (BPA and phthalates, increased the summary odds ratio for breast cancer and endometriosis. Bioinformatics analysis of gene-EDC interactions and disease associations identified several hundred genes that were altered by exposure to PCBs, phthalate or BPA. EDCs-modified genes in breast neoplasms and endometriosis are part of steroid hormone signaling and inflammation pathways. All three EDCs–PCB 153, phthalates, and BPA influenced five common genes—CYP19A1, EGFR, ESR2, FOS, and IGF1—in breast cancer as well as in endometriosis. These genes are environmentally and estrogen responsive, altered in human breast and uterine tumors and endometriosis lesions, and part of Mitogen Activated Protein Kinase (MAPK signaling pathways in cancer. Our findings suggest that breast cancer and endometriosis share some common environmental and molecular risk factors.

  13. Integrated Bioinformatics, Environmental Epidemiologic and Genomic Approaches to Identify Environmental and Molecular Links between Endometriosis and Breast Cancer

    Science.gov (United States)

    Roy, Deodutta; Morgan, Marisa; Yoo, Changwon; Deoraj, Alok; Roy, Sandhya; Yadav, Vijay Kumar; Garoub, Mohannad; Assaggaf, Hamza; Doke, Mayur

    2015-01-01

    We present a combined environmental epidemiologic, genomic, and bioinformatics approach to identify: exposure of environmental chemicals with estrogenic activity; epidemiologic association between endocrine disrupting chemical (EDC) and health effects, such as, breast cancer or endometriosis; and gene-EDC interactions and disease associations. Human exposure measurement and modeling confirmed estrogenic activity of three selected class of environmental chemicals, polychlorinated biphenyls (PCBs), bisphenols (BPs), and phthalates. Meta-analysis showed that PCBs exposure, not Bisphenol A (BPA) and phthalates, increased the summary odds ratio for breast cancer and endometriosis. Bioinformatics analysis of gene-EDC interactions and disease associations identified several hundred genes that were altered by exposure to PCBs, phthalate or BPA. EDCs-modified genes in breast neoplasms and endometriosis are part of steroid hormone signaling and inflammation pathways. All three EDCs–PCB 153, phthalates, and BPA influenced five common genes—CYP19A1, EGFR, ESR2, FOS, and IGF1—in breast cancer as well as in endometriosis. These genes are environmentally and estrogen responsive, altered in human breast and uterine tumors and endometriosis lesions, and part of Mitogen Activated Protein Kinase (MAPK) signaling pathways in cancer. Our findings suggest that breast cancer and endometriosis share some common environmental and molecular risk factors. PMID:26512648

  14. Gap junction beta 1 (GJB1) gene mutations in Italian patients with X-linked Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Mandich, Paola; Grandis, Marina; Geroldi, Alessandro; Acquaviva, Massimo; Varese, Alessandra; Gulli, Rossella; Ciotti, Paola; Bellone, Emilia

    2008-01-01

    X-linked Charcot-Marie-Tooth disease (CMT1X) is a peripheral neuropathy transmitted in a dominant manner and caused by mutations in the Connexin 32 (Cx32) gene (GJB1, gap junction beta 1). Here we report the mutation analysis of the GJB1 gene in 76 subjects with possible CMT1 and absence of 17p11.2 duplication, and in 38 CMT2 patients without mutations in CMT2-associated-genes, selected from a cohort of 684 patients with peripheral sensory-motor neuropathy. The analysis was performed by direct sequencing of the coding sequence and exon/intron boundaries of the GJB1 gene. The mutation screening identified 22 mutations in GJB1, eight of which have not been previously published: six point mutations (c.50C > G, c.107T > A, c.545C > T, c.545C > G, c.548G > C, c.791G > T) and two deletions (c.84delC, c.573_581delCGTCTTCAT). The GJB1 mutation frequency (19.3%) and the clinical heterogeneity of our patients suggest searching for GJB1 mutations in all CMT cases without the 17p11.2 duplication, regardless of the gender of the proband, as well as in CMT2 patients with possible X-linked inheritance. PMID:18379723

  15. Candidate Luminal B Breast Cancer Genes Identified by Genome, Gene Expression and DNA Methylation Profiling

    OpenAIRE

    Cornen, Stphanie; Guille, Arnaud; Adlade, Jos; Addou-Klouche, Lynda; Finetti, Pascal; Saade, Marie-Rose; Manai, Marwa; Carbuccia, Nadine; Bekhouche, Ismahane; Letessier, Anne; Raynaud, Stphane; Charafe-Jauffret, Emmanuelle; Jacquemier, Jocelyne; spicuglia, salvatore; de The, Hugues

    2014-01-01

    Breast cancers (BCs) of the luminal B subtype are estrogen receptor-positive (ER+), highly proliferative, resistant to standard therapies and have a poor prognosis. To better understand this subtype we compared DNA copy number aberrations (CNAs), DNA promoter methylation, gene expression profiles, and somatic mutations in nine selected genes, in 32 luminal B tumors with those observed in 156 BCs of the other molecular subtypes. Frequent CNAs included 8p11-p12 and 11q13.1-q13.2 amplifications,...

  16. Suppression subtractive hybridization identified differentially expressed genes in lung adenocarcinoma: ERGIC3 as a novel lung cancer-related gene

    International Nuclear Information System (INIS)

    To understand the carcinogenesis caused by accumulated genetic and epigenetic alterations and seek novel biomarkers for various cancers, studying differentially expressed genes between cancerous and normal tissues is crucial. In the study, two cDNA libraries of lung cancer were constructed and screened for identification of differentially expressed genes. Two cDNA libraries of differentially expressed genes were constructed using lung adenocarcinoma tissue and adjacent nonmalignant lung tissue by suppression subtractive hybridization. The data of the cDNA libraries were then analyzed and compared using bioinformatics analysis. Levels of mRNA and protein were measured by quantitative real-time polymerase chain reaction (q-RT-PCR) and western blot respectively, as well as expression and localization of proteins were determined by immunostaining. Gene functions were investigated using proliferation and migration assays after gene silencing and gene over-expression. Two libraries of differentially expressed genes were obtained. The forward-subtracted library (FSL) and the reverse-subtracted library (RSL) contained 177 and 59 genes, respectively. Bioinformatic analysis demonstrated that these genes were involved in a wide range of cellular functions. The vast majority of these genes were newly identified to be abnormally expressed in lung cancer. In the first stage of the screening for 16 genes, we compared lung cancer tissues with their adjacent non-malignant tissues at the mRNA level, and found six genes (ERGIC3, DDR1, HSP90B1, SDC1, RPSA, and LPCAT1) from the FSL were significantly up-regulated while two genes (GPX3 and TIMP3) from the RSL were significantly down-regulated (P < 0.05). The ERGIC3 protein was also over-expressed in lung cancer tissues and cultured cells, and expression of ERGIC3 was correlated with the differentiated degree and histological type of lung cancer. The up-regulation of ERGIC3 could promote cellular migration and proliferation in vitro. The two libraries of differentially expressed genes may provide the basis for new insights or clues for finding novel lung cancer-related genes; several genes were newly found in lung cancer with ERGIC3 seeming a novel lung cancer-related gene. ERGIC3 may play an active role in the development and progression of lung cancer

  17. Suppression subtractive hybridization identified differentially expressed genes in lung adenocarcinoma: ERGIC3 as a novel lung cancer-related gene

    Directory of Open Access Journals (Sweden)

    Wu Mingsong

    2013-02-01

    Full Text Available Abstract Background To understand the carcinogenesis caused by accumulated genetic and epigenetic alterations and seek novel biomarkers for various cancers, studying differentially expressed genes between cancerous and normal tissues is crucial. In the study, two cDNA libraries of lung cancer were constructed and screened for identification of differentially expressed genes. Methods Two cDNA libraries of differentially expressed genes were constructed using lung adenocarcinoma tissue and adjacent nonmalignant lung tissue by suppression subtractive hybridization. The data of the cDNA libraries were then analyzed and compared using bioinformatics analysis. Levels of mRNA and protein were measured by quantitative real-time polymerase chain reaction (q-RT-PCR and western blot respectively, as well as expression and localization of proteins were determined by immunostaining. Gene functions were investigated using proliferation and migration assays after gene silencing and gene over-expression. Results Two libraries of differentially expressed genes were obtained. The forward-subtracted library (FSL and the reverse-subtracted library (RSL contained 177 and 59 genes, respectively. Bioinformatic analysis demonstrated that these genes were involved in a wide range of cellular functions. The vast majority of these genes were newly identified to be abnormally expressed in lung cancer. In the first stage of the screening for 16 genes, we compared lung cancer tissues with their adjacent non-malignant tissues at the mRNA level, and found six genes (ERGIC3, DDR1, HSP90B1, SDC1, RPSA, and LPCAT1 from the FSL were significantly up-regulated while two genes (GPX3 and TIMP3 from the RSL were significantly down-regulated (P? Conclusions The two libraries of differentially expressed genes may provide the basis for new insights or clues for finding novel lung cancer-related genes; several genes were newly found in lung cancer with ERGIC3 seeming a novel lung cancer-related gene. ERGIC3 may play an active role in the development and progression of lung cancer.

  18. Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus

    DEFF Research Database (Denmark)

    Colombo, Carlo; Porzio, Ottavia; Liu, Ming; Massa, Ornella; Vasta, Mario; Salardi, Silvana; Beccaria, Luciano; Monciotti, Carla; Toni, Sonia; Pedersen, Oluf; Hansen, Torben; Federici, Luca; Pesavento, Roberta; Cadario, Francesco; Federici, Giorgio; Ghirri, Paolo; Arvan, Peter; Iafusco, Dario; Barbetti, Fabrizio

    2008-01-01

    Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth. Although several genes have been linked to this disorder, in almost half the cases documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the...... Ins2 gene exhibits PNDM associated with pancreatic beta cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but...

  19. Methylation of the Glucocorticoid Receptor Gene Promoter in Preschoolers: Links with Internalizing Behavior Problems

    Science.gov (United States)

    Parade, Stephanie H.; Ridout, Kathryn K.; Seifer, Ronald; Armstrong, David A.; Marsit, Carmen J.; McWilliams, Melissa A.; Tyrka, Audrey R.

    2016-01-01

    Accumulating evidence suggests that early adversity is linked to methylation of the glucocorticoid receptor (GR) gene, "NR3C1," which is a key regulator of the hypothalamic-pituitary-adrenal axis. Yet no prior work has considered the contribution of methylation of "NR3C1" to emerging behavior problems and psychopathology in…

  20. Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation

    DEFF Research Database (Denmark)

    Kalscheuer, Vera M; Freude, Kristine; Musante, Luciana; Jensen, Lars R; Yntema, Helger G; Gécz, Jozef; Sefiani, Abdelaziz; Hoffmann, Kirsten; Moser, Bettina; Haas, Stefan; Gurok, Ulf; Haesler, Sebastian; Aranda, Beatriz; Nshedjan, Arpik; Tzschach, Andreas; Hartmann, Nils; Roloff, Tim-Christoph; Shoichet, Sarah; Hagens, Olivier; Tao, Jiong; Van Bokhoven, Hans; Turner, Gillian; Chelly, Jamel; Moraine, Claude; Fryns, Jean-Pierre; Nuber, Ulrike; Hoeltzenbein, Maria; Scharff, Constance; Scherthan, Harry; Lenzner, Steffen; Hamel, Ben C J; Schweiger, Susann; Ropers, Hans-Hilger; Freude, Karla Kristine

    2003-01-01

    We found mutations in the gene PQBP1 in 5 of 29 families with nonsyndromic (MRX) and syndromic (MRXS) forms of X-linked mental retardation (XLMR). Clinical features in affected males include mental retardation, microcephaly, short stature, spastic paraplegia and midline defects. PQBP1 has previou...

  1. Candidate luminal B breast cancer genes identified by genome, gene expression and DNA methylation profiling.

    Science.gov (United States)

    Cornen, Stphanie; Guille, Arnaud; Adlade, Jos; Addou-Klouche, Lynda; Finetti, Pascal; Saade, Marie-Rose; Manai, Marwa; Carbuccia, Nadine; Bekhouche, Ismahane; Letessier, Anne; Raynaud, Stphane; Charafe-Jauffret, Emmanuelle; Jacquemier, Jocelyne; Spicuglia, Salvatore; de The, Hugues; Viens, Patrice; Bertucci, Franois; Birnbaum, Daniel; Chaffanet, Max

    2014-01-01

    Breast cancers (BCs) of the luminal B subtype are estrogen receptor-positive (ER+), highly proliferative, resistant to standard therapies and have a poor prognosis. To better understand this subtype we compared DNA copy number aberrations (CNAs), DNA promoter methylation, gene expression profiles, and somatic mutations in nine selected genes, in 32 luminal B tumors with those observed in 156 BCs of the other molecular subtypes. Frequent CNAs included 8p11-p12 and 11q13.1-q13.2 amplifications, 7q11.22-q34, 8q21.12-q24.23, 12p12.3-p13.1, 12q13.11-q24.11, 14q21.1-q23.1, 17q11.1-q25.1, 20q11.23-q13.33 gains and 6q14.1-q24.2, 9p21.3-p24,3, 9q21.2, 18p11.31-p11.32 losses. A total of 237 and 101 luminal B-specific candidate oncogenes and tumor suppressor genes (TSGs) presented a deregulated expression in relation with their CNAs, including 11 genes previously reported associated with endocrine resistance. Interestingly, 88% of the potential TSGs are located within chromosome arm 6q, and seven candidate oncogenes are potential therapeutic targets. A total of 100 candidate oncogenes were validated in a public series of 5,765 BCs and the overexpression of 67 of these was associated with poor survival in luminal tumors. Twenty-four genes presented a deregulated expression in relation with a high DNA methylation level. FOXO3, PIK3CA and TP53 were the most frequent mutated genes among the nine tested. In a meta-analysis of next-generation sequencing data in 875 BCs, KCNB2 mutations were associated with luminal B cases while candidate TSGs MDN1 (6q15) and UTRN (6q24), were mutated in this subtype. In conclusion, we have reported luminal B candidate genes that may play a role in the development and/or hormone resistance of this aggressive subtype. PMID:24416132

  2. Analysis of promoter regions of co-expressed genes identified by microarray analysis

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    Höglund Mattias

    2006-08-01

    Full Text Available Abstract Background The use of global gene expression profiling to identify sets of genes with similar expression patterns is rapidly becoming a widespread approach for understanding biological processes. A logical and systematic approach to study co-expressed genes is to analyze their promoter sequences to identify transcription factors that may be involved in establishing specific profiles and that may be experimentally investigated. Results We introduce promoter clustering i.e. grouping of promoters with respect to their high scoring motif content, and show that this approach greatly enhances the identification of common and significant transcription factor binding sites (TFBS in co-expressed genes. We apply this method to two different dataset, one consisting of micro array data from 108 leukemias (AMLs and a second from a time series experiment, and show that biologically relevant promoter patterns may be obtained using phylogenetic foot-printing methodology. In addition, we also found that 15% of the analyzed promoter regions contained transcription factors start sites for additional genes transcribed in the opposite direction. Conclusion Promoter clustering based on global promoter features greatly improve the identification of shared TFBS in co-expressed genes. We believe that the outlined approach may be a useful first step to identify transcription factors that contribute to specific features of gene expression profiles.

  3. Progress in the identification of DNA markers linked to the Yd2 gene in barley

    International Nuclear Information System (INIS)

    Barley yellow dwarf (BYD) is the most damaging virus disease in wheat and other cereal crops worldwide and the yield loss inflicted by the virus (BYDV) and be quite severe. While some protection against the disease can be realized by crop management practices, resistant varieties clearly offer the greatest opportunity for reducing yield losses. Possible sources of BYD resistance have been found in wheat, barely, rye and wheatgrass species. Among them, the Yd2 gene from chromosome 3H of barley currently shows the best genetic resistance in any cereal species and it has been widely deployed in many leading barley varieties. We have developed 94 F2 derived families from the cross between Betzes, a susceptible barley variety that does not carry Yd2, and Atlas 68, a resistant variety that has Yd2. These families were evaluated in two and three replicate tests for BYD symptom expression in field nurseries at Davis, California, and at Aberdeen, Idaho, respectively. To minimize the mapping effort at this early stage, we used 18 and 23 homozygous resistant and susceptible F2 derived families, respectively, and have identified RFLP markers that are closely linked to Yd2. We are now moving to the next phase of this work, which is to extend the RFLP mapping population size to include all the F2 derived families and to saturate the region carrying Yd2 with marker loci available to us from genome mapping programmes in barley, wheat and other related species

  4. What can HPA axis-linked genes tell us about anxiety disorders in adolescents?

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    Andressa Bortoluzzi

    2015-12-01

    Full Text Available Introduction: Anxiety disorders (AD share features of both anxiety and fear linked to stress response. The hypothalamic-pituitary-adrenal (HPA axis is considered the core biological pathway of the stress system and it is known that an inappropriate response to environmental stimuli may be related to individual genetic vulnerability in HPA-linked genes. Despite the biological plausibility of a relationship between the HPA axis and AD, few studies have investigated associations between genetic polymorphisms linked to the HPA axis and this complex disorder. Objective: To investigate whether AD are associated with genetic polymorphisms in HPA-linked genes in adolescents. Methods: Our study consisted of a cross-sectional evaluation of a community sample comprising a total of 228 adolescents (131 cases of AD. We extracted DNA from saliva and genotyped polymorphisms in HPA-linked genes (FKBP5: rs3800373, rs9296158, rs1360780, rs9470080 and rs4713916; NR3C1: rs6198; CRHR1: rs878886; and SERPINA6: rs746530 with real time polymerase chain reaction (PCR. The instruments used to diagnose and assess the severity of AD were the Schedule for Affective Disorder and Schizophrenia for School-Age Children - Present and Lifetime (K-SADS-PL and the Screen for Child and Anxiety related Emotional Disorders (SCARED. Results: We failed to detect any associations between AD and genetic polymorphisms in HPA-linked genes (p > 0.05. Conclusion: To our knowledge, this is the first study evaluating these specific polymorphisms in relation to AD in adolescents, which encourages us to design further research on the subject.

  5. Analysis of global gene expression profiles to identify differentially expressed genes critical for embryo development in Brassica rapa.

    Science.gov (United States)

    Zhang, Yu; Peng, Lifang; Wu, Ya; Shen, Yanyue; Wu, Xiaoming; Wang, Jianbo

    2014-11-01

    Embryo development represents a crucial developmental period in the life cycle of flowering plants. To gain insights into the genetic programs that control embryo development in Brassica rapa L., RNA sequencing technology was used to perform transcriptome profiling analysis of B. rapa developing embryos. The results generated 42,906,229 sequence reads aligned with 32,941 genes. In total, 27,760, 28,871, 28,384, and 25,653 genes were identified from embryos at globular, heart, early cotyledon, and mature developmental stages, respectively, and analysis between stages revealed a subset of stage-specific genes. We next investigated 9,884 differentially expressed genes with more than fivefold changes in expression and false discovery rate ? 0.001 from three adjacent-stage comparisons; 1,514, 3,831, and 6,633 genes were detected between globular and heart stage embryo libraries, heart stage and early cotyledon stage, and early cotyledon and mature stage, respectively. Large numbers of genes related to cellular process, metabolism process, response to stimulus, and biological process were expressed during the early and middle stages of embryo development. Fatty acid biosynthesis, biosynthesis of secondary metabolites, and photosynthesis-related genes were expressed predominantly in embryos at the middle stage. Genes for lipid metabolism and storage proteins were highly expressed in the middle and late stages of embryo development. We also identified 911 transcription factor genes that show differential expression across embryo developmental stages. These results increase our understanding of the complex molecular and cellular events during embryo development in B. rapa and provide a foundation for future studies on other oilseed crops. PMID:25214014

  6. Use of RFLPs to identify genes for aluminium tolerance in maize

    International Nuclear Information System (INIS)

    The objective of this study was to identify restriction fragment length polymorphism (RFLP) markers linked to quantitative trait loci that control Al tolerance in maize. The strategy used was bulked segregant analysis, which is based on selecting for bulk bred true F2 individuals. The genetic material used consisted of an F2 population derived from a cross between Al susceptible (L53) and Al tolerant (L1327) maize inbred lines. Both lines were developed in the maize breeding programme of the Centro Nacional de Pesquisa de Milho e Sorgo. The relative seminal root length (RSRL) index was used as the phenotypic measure of tolerance. The frequency distribution of RSRL showed continuous distribution, which is typical of a quantitatively inherited character, with a tendency towards Al susceptible individuals. The estimated heritability [(?2F2 - ?2E)/?2F2] was found to be 60%. This moderately high heritability value suggests that, although the character has a quantitative nature, it may be controlled by a small number of genes. Those seedlings of the F2 population that scored the highest and lowest values for RSRL were subsequently selfed to obtain the F3 families. These families were evaluated in nutrient solution to identify those that were not segregating. On the basis of the results, five individuals were chosen for each bulk. Sixty-five probes were selected at an average interval of 30 cM, covering all ten maize chromosomes. For the hybridization work, a non-radioactive labelling system, using dig-dUTP and alkaline phosphatase, proved to be quite efficient and reliable, resulting in Southern blots with good resolution and allowing the membranes to be stripped and reprobed at least three times. Twenty-three markers showed a co-drominant effect, identifying 40 RFLP loci that could distinguish the parental inbred lines. These 23 probes are now being hybridized with DNA from the two contrasting bulks. Also, a search for other informative markers is being carried out to increase genome coverage. (author). 29 refs, 2 figs, 1 tab

  7. GENETIC AND PHYSICAL MAPPING OF THE SOYBEAN RPG1-B DISEASE RESISTANCE GENE REVEALS A COMPLEX LOCUS CONTAINING SEVERAL TIGHTLY LINKED FAMILIES OF NBS-LRR-GENES

    Science.gov (United States)

    Alleles, or tightly linked genes, at the soybean (Glycine max L. Merr.) Rpg1 locus confer resistance to strains of Pseudomonas syringae pv. glycinea that express the avirulence genes avrB or avrRpm1. We have previously mapped Rpg1-b (the gene specific for avrB) to a cluster of resistance genes (R-ge...

  8. Identification of microsatellite markers (SSR linked to a new bacterial blight resistance gene xa33(t in rice cultivar ‘Ba7’

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    Theerayut Toojinda

    2009-05-01

    Full Text Available This study attempts to identify a new source of bacterial blight (BB resistance gene and microsatellite makers (SSR linked to it. A total number of 139 F2 progenies generated from a cross between the resistant donor ‘Ba7’and ‘Pin Kaset’ were developed and used for this study. A Thai Xoo isolate, TXO16, collected from Phitsanulok province, was used to evaluate the resistance reaction in the F2 population. The segregation ratio of resistance (R and susceptibility (S was statistically fitted to 1R:3S model indicating single recessive gene segregation. Twenty F2 individuals consisting of 10 resistant and 10 susceptible plants were chosen for DNA analysis. Sixty-two polymorphic markers covering all rice chromosomes were used to identify the location and linked markers of the resistance gene. Four SSR markers, viz. RM30, RM7243, RM5509 and RM400, located on the long arm of rice chromosome 6, could clearly discriminate between resistant and susceptible phenotypes, and 161 BC2F2:3 individuals carrying BB resistance gene were developed through MAS using these SSR markers. This population was inoculated with TXO16 to validate and confirm the location of the gene and linked markers. The segregation ratio was statistically fitted to 1R:3S model confirming a recessive nature of the gene action in this germplasm. Phenotypic-genotypic association including five additional markers suggested that RM20590 was tightly linked to this resistance gene (R2=59.12 %. The BB phenotype was controlled by a recessive gene with incomplete dominance of susceptible allele providing intermediate resistance to Xoo pathogen in heterozygotes. The location of the gene was in the vicinity of a dominant gene, Xa7, which was previously reported. However, the resistance gene identified here was different from Xa7 because of the different nature of gene action. Consequently, this gene was tentatively designated as xa33(t. The resistance gene from rice cultivar ‘Ba7’ and the closely linked markers found in this study will be useful for rice breeders as a source to improve BB resistance through MAS in rice breeding programs.

  9. De Novo Transcriptome Sequencing of Oryza officinalis Wall ex Watt to Identify Disease-Resistance Genes

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    Bin He

    2015-12-01

    Full Text Available Oryza officinalis Wall ex Watt is one of the most important wild relatives of cultivated rice and exhibits high resistance to many diseases. It has been used as a source of genes for introgression into cultivated rice. However, there are limited genomic resources and little genetic information publicly reported for this species. To better understand the pathways and factors involved in disease resistance and accelerating the process of rice breeding, we carried out a de novo transcriptome sequencing of O. officinalis. In this research, 137,229 contigs were obtained ranging from 200 to 19,214 bp with an N50 of 2331 bp through de novo assembly of leaves, stems and roots in O. officinalis using an Illumina HiSeq 2000 platform. Based on sequence similarity searches against a non-redundant protein database, a total of 88,249 contigs were annotated with gene descriptions and 75,589 transcripts were further assigned to GO terms. Candidate genes for plant–pathogen interaction and plant hormones regulation pathways involved in disease-resistance were identified. Further analyses of gene expression profiles showed that the majority of genes related to disease resistance were all expressed in the three tissues. In addition, there are two kinds of rice bacterial blight-resistant genes in O. officinalis, including two Xa1 genes and three Xa26 genes. All 2 Xa1 genes showed the highest expression level in stem, whereas one of Xa26 was expressed dominantly in leaf and other 2 Xa26 genes displayed low expression level in all three tissues. This transcriptomic database provides an opportunity for identifying the genes involved in disease-resistance and will provide a basis for studying functional genomics of O. officinalis and genetic improvement of cultivated rice in the future.

  10. De Novo Transcriptome Sequencing of Oryza officinalis Wall ex Watt to Identify Disease-Resistance Genes.

    Science.gov (United States)

    He, Bin; Gu, Yinghong; Tao, Xiang; Cheng, Xiaojie; Wei, Changhe; Fu, Jian; Cheng, Zaiquan; Zhang, Yizheng

    2015-01-01

    Oryza officinalis Wall ex Watt is one of the most important wild relatives of cultivated rice and exhibits high resistance to many diseases. It has been used as a source of genes for introgression into cultivated rice. However, there are limited genomic resources and little genetic information publicly reported for this species. To better understand the pathways and factors involved in disease resistance and accelerating the process of rice breeding, we carried out a de novo transcriptome sequencing of O. officinalis. In this research, 137,229 contigs were obtained ranging from 200 to 19,214 bp with an N50 of 2331 bp through de novo assembly of leaves, stems and roots in O. officinalis using an Illumina HiSeq 2000 platform. Based on sequence similarity searches against a non-redundant protein database, a total of 88,249 contigs were annotated with gene descriptions and 75,589 transcripts were further assigned to GO terms. Candidate genes for plant-pathogen interaction and plant hormones regulation pathways involved in disease-resistance were identified. Further analyses of gene expression profiles showed that the majority of genes related to disease resistance were all expressed in the three tissues. In addition, there are two kinds of rice bacterial blight-resistant genes in O. officinalis, including two Xa1 genes and three Xa26 genes. All 2 Xa1 genes showed the highest expression level in stem, whereas one of Xa26 was expressed dominantly in leaf and other 2 Xa26 genes displayed low expression level in all three tissues. This transcriptomic database provides an opportunity for identifying the genes involved in disease-resistance and will provide a basis for studying functional genomics of O. officinalis and genetic improvement of cultivated rice in the future. PMID:26690414

  11. CRISPR/Cas9 Promotes Functional Study of Testis Specific X-Linked Gene In Vivo

    Science.gov (United States)

    Jiang, Xue; Chen, Yuxi; Zhang, Zhen; Zhang, Xiya; Liang, Puping; Zhan, Shaoquan; Cao, Shanbo; Songyang, Zhou; Huang, Junjiu

    2015-01-01

    Mammalian spermatogenesis is a highly regulated multistage process of sperm generation. It is hard to uncover the real function of a testis specific gene in vitro since the in vitro model is not yet mature. With the development of the CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated 9) system, we can now rapidly generate knockout mouse models of testis specific genes to study the process of spermatogenesis in vivo. SYCP3-like X-linked 2 (SLX2) is a germ cell specific component, which contains a Cor1 domain and belongs to the XLR (X-linked, lymphocyte regulated) family. Previous studies suggested that SLX2 might play an important role in mouse spermatogenesis based on its subcellular localization and interacting proteins. However, the function of SLX2 in vivo is still elusive. Here, to investigate the functions of SLX2 in spermatogenesis, we disrupted the Slx2 gene by using the CRISPR/Cas9 system. Since Slx2 is a testis specific X-linked gene, we obtained knockout male mice in the first generation and accelerated the study process. Compared with wild-type mice, Slx2 knockout mice have normal testis and epididymis. Histological observation of testes sections showed that Slx2 knockout affected none of the three main stages of spermatogenesis: mitosis, meiosis and spermiogenesis. In addition, we further confirmed that disruption of Slx2 did not affect the number of spermatogonial stem cells, meiosis progression or XY body formation by immunofluorescence analysis. As spermatogenesis was normal in Slx2 knockout mice, these mice were fertile. Taken together, we showed that Slx2 itself is not an essential gene for mouse spermatogenesis and CRISPR/Cas9 technique could speed up the functional study of testis specific X-linked gene in vivo. PMID:26599493

  12. Dissecting the Gene Network of Dietary Restriction to Identify Evolutionarily Conserved Pathways and New Functional Genes

    OpenAIRE

    Wuttke, Daniel; Connor, Richard; Vora, Chintan; Craig, Thomas; Li, Yang; Wood, Shona; Vasieva, Olga; Shmookler Reis, Robert; Tang, Fusheng; de Magalhes, Joo Pedro

    2012-01-01

    Dietary restriction (DR), limiting nutrient intake from diet without causing malnutrition, delays the aging process and extends lifespan in multiple organisms. The conserved life-extending effect of DR suggests the involvement of fundamental mechanisms, although these remain a subject of debate. To help decipher the life-extending mechanisms of DR, we first compiled a list of genes that if genetically altered disrupt or prevent the life-extending effects of DR. We called these DRessential ge...

  13. Identifying the most suitable endogenous control for determining gene expression in hearts from organ donors

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    Gmez Enrique

    2007-12-01

    Full Text Available Abstract Background Quantitative real-time reverse transcription PCR (qRT-PCR is a useful tool for assessing gene expression in different tissues, but the choice of adequate controls is critical to normalise the results, thereby avoiding differences and maximizing sensitivity and accuracy. So far, many genes have been used as a single reference gene, without having previously verified their value as controls. This practice can lead to incorrect conclusions and recent evidence indicates a need to use the geometric mean of data from several control genes. Here, we identified an appropriate set of genes to be used as an endogenous reference for quantifying gene expression in human heart tissue. Results Our findings indicate that out of ten commonly used reference genes (GADPH, PPIA, ACTB, YWHAZ, RRN18S, B2M, UBC, TBP, RPLP and HPRT, PPIA, RPLP and GADPH show the most stable gene transcription levels in left ventricle specimens obtained from organ donors, as assessed using geNorm and Normfinder software. The expression of TBP was found to be highly regulated. Conclusion We propose the use of PPIA, RPLP and GADPH as reference genes for the accurate normalisation of qRT-PCR performed on heart tissue. TBP should not be used as a control in this type of tissue.

  14. High-throughput screening of mouse gene knockouts identifies established and novel skeletal phenotypes.

    Science.gov (United States)

    Brommage, Robert; Liu, Jeff; Hansen, Gwenn M; Kirkpatrick, Laura L; Potter, David G; Sands, Arthur T; Zambrowicz, Brian; Powell, David R; Vogel, Peter

    2014-01-01

    Screening gene function in vivo is a powerful approach to discover novel drug targets. We present high-throughput screening (HTS) data for 3 762 distinct global gene knockout (KO) mouse lines with viable adult homozygous mice generated using either gene-trap or homologous recombination technologies. Bone mass was determined from DEXA scans of male and female mice at 14 weeks of age and by microCT analyses of bones from male mice at 16 weeks of age. Wild-type (WT) cagemates/littermates were examined for each gene KO. Lethality was observed in an additional 850 KO lines. Since primary HTS are susceptible to false positive findings, additional cohorts of mice from KO lines with intriguing HTS bone data were examined. Aging, ovariectomy, histomorphometry and bone strength studies were performed and possible non-skeletal phenotypes were explored. Together, these screens identified multiple genes affecting bone mass: 23 previously reported genes (Calcr, Cebpb, Crtap, Dcstamp, Dkk1, Duoxa2, Enpp1, Fgf23, Kiss1/Kiss1r, Kl (Klotho), Lrp5, Mstn, Neo1, Npr2, Ostm1, Postn, Sfrp4, Slc30a5, Slc39a13, Sost, Sumf1, Src, Wnt10b), five novel genes extensively characterized (Cldn18, Fam20c, Lrrk1, Sgpl1, Wnt16), five novel genes with preliminary characterization (Agpat2, Rassf5, Slc10a7, Slc26a7, Slc30a10) and three novel undisclosed genes coding for potential osteoporosis drug targets. PMID:26273529

  15. Identifying overrepresented concepts in gene lists from literature: a statistical approach based on Poisson mixture model

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    Zhai Chengxiang

    2010-05-01

    Full Text Available Abstract Background Large-scale genomic studies often identify large gene lists, for example, the genes sharing the same expression patterns. The interpretation of these gene lists is generally achieved by extracting concepts overrepresented in the gene lists. This analysis often depends on manual annotation of genes based on controlled vocabularies, in particular, Gene Ontology (GO. However, the annotation of genes is a labor-intensive process; and the vocabularies are generally incomplete, leaving some important biological domains inadequately covered. Results We propose a statistical method that uses the primary literature, i.e. free-text, as the source to perform overrepresentation analysis. The method is based on a statistical framework of mixture model and addresses the methodological flaws in several existing programs. We implemented this method within a literature mining system, BeeSpace, taking advantage of its analysis environment and added features that facilitate the interactive analysis of gene sets. Through experimentation with several datasets, we showed that our program can effectively summarize the important conceptual themes of large gene sets, even when traditional GO-based analysis does not yield informative results. Conclusions We conclude that the current work will provide biologists with a tool that effectively complements the existing ones for overrepresentation analysis from genomic experiments. Our program, Genelist Analyzer, is freely available at: http://workerbee.igb.uiuc.edu:8080/BeeSpace/Search.jsp

  16. Systematically identify key genes in inflammatory and non-inflammatory breast cancer.

    Science.gov (United States)

    Chai, Fan; Liang, Yan; Zhang, Fan; Wang, Minghao; Zhong, Ling; Jiang, Jun

    2016-01-10

    Although the gene expression in breast tumor stroma, playing a critical role in determining inflammatory breast cancer (IBC) phenotype, has been proved to be significantly different between IBC and non-inflammatory breast cancer (non-IBC), more effort needs to systematically investigate the gene expression profiles between tumor epithelium and stroma and to efficiently uncover the potential molecular networks and critical genes for IBC and non-IBC. Here, we comprehensively analyzed and compared the transcriptional profiles from IBC and non-IBC patients using hierarchical clustering, protein-protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database analyses, and identified PDGFRβ, SUMO1, COL1A1, FYN, CAV1, COL5A1 and MMP2 to be the key genes for breast cancer. Interestingly, PDGFRβ was found to be the hub gene in both IBC and non-IBC; SUMO1 and COL1A1 were respectively the key genes for IBC and non-IBC. These analysis results indicated that those key genes might play important role in IBC and non-IBC and provided some clues for future studies. PMID:26403314

  17. Use of In-Biofilm Expression Technology To Identify Genes Involved in Pseudomonas aeruginosa Biofilm Development†

    OpenAIRE

    Finelli, Antonio; Gallant, Claude V.; Jarvi, Keith; Burrows, Lori L.

    2003-01-01

    Mature Pseudomonas aeruginosa biofilms form complex three-dimensional architecture and are tolerant of antibiotics and other antimicrobial compounds. In this work, an in vivo expression technology system, originally designed to study virulence-associated genes in complex mammalian environments, was used to identify genes up-regulated in P. aeruginosa grown to a mature (5-day) biofilm. Five unique cloned promoters unable to promote in vitro growth in the absence of purines after recovery from ...

  18. Genome-wide Expression and Copy Number Analysis Identifies Driver Genes in Gingivobuccal Cancers

    OpenAIRE

    Ambatipudi, Srikant; Gerstung, Moritz; Pandey, Manishkumar; Samant, Tanuja; Patil, Asawari; Kane, Shubhada; Rajiv S. Desai; Schäffer, Alejandro A; Beerenwinkel, Niko; Mahimkar, Manoj B.

    2011-01-01

    The molecular mechanisms contributing to the development and progression of gingivobuccal complex (GBC) cancers–a sub-site of oral cancer, comprising the buccal mucosa, the gingivobuccal sulcus, the lower gingival region and the retromolar trigone-remain poorly understood. Identifying the GBC cancer-related gene expression signature and the driver genes residing on the altered chromosomal regions is critical for understanding the molecular basis of its pathogenesis. Genome-wide expression pro...

  19. Insect Innate Immunity Database (IIID): An Annotation Tool for Identifying Immune Genes in Insect Genomes

    OpenAIRE

    Brucker, Robert M.; Funkhouser, Lisa J.; Setia, Shefali; Pauly, Rini; Bordenstein, Seth R.

    2012-01-01

    The innate immune system is an ancient component of host defense. Since innate immunity pathways are well conserved throughout many eukaryotes, immune genes in model animals can be used to putatively identify homologous genes in newly sequenced genomes of non-model organisms. With the initiation of the “i5k” project, which aims to sequence 5,000 insect genomes by 2016, many novel insect genomes will soon become publicly available, yet few annotation resources are currently available for insec...

  20. Combining Pareto-optimal clusters using supervised learning for identifying co-expressed genes

    OpenAIRE

    Bandyopadhyay Sanghamitra; Mukhopadhyay Anirban; Maulik Ujjwal

    2009-01-01

    Abstract Background The landscape of biological and biomedical research is being changed rapidly with the invention of microarrays which enables simultaneous view on the transcription levels of a huge number of genes across different experimental conditions or time points. Using microarray data sets, clustering algorithms have been actively utilized in order to identify groups of co-expressed genes. This article poses the problem of fuzzy clustering in microarray data as a multiobjective opti...

  1. Comparative Transcriptional Profiling of the Axolotl Limb Identifies a Tripartite Regeneration-Specific Gene Program

    OpenAIRE

    Knapp, D.; Schulz, H; Rascon, C.A.; Volkmer, M.; Scholz, J.; Nacu, E.; Le, M.; Novozhilov, S.; Tazaki, A; Protze, S.; Jacob, T.; Hubner, N.; Habermann, B.; Tanaka, E.M.

    2013-01-01

    Understanding how the limb blastema is established after the initial wound healing response is an important aspect of regeneration research. Here we performed parallel expression profile time courses of healing lateral wounds versus amputated limbs in axolotl. This comparison between wound healing and regeneration allowed us to identify amputation-specific genes. By clustering the expression profiles of these samples, we could detect three distinguishable phases of gene expression - early wou...

  2. A gene expression biomarker identifies in vitro and in vivo ERα modulators in a human gene expression compendium

    Science.gov (United States)

    We propose the use of gene expression profiling to complement the chemical characterization currently based on HTS assay data and present a case study relevant to the Endocrine Disruptor Screening Program. We have developed computational methods to identify estrogen receptor &alp...

  3. Two cases of 5-fluorouracil toxicity linked with gene variants in the DPYD gene

    OpenAIRE

    Ofverholm, Anna; Arkblad, Eva; Skrtic, Stanko; ALBERTSSON, PER; Shubbar, Emman; Enerbäck, Charlotta

    2010-01-01

    Objectives: Dihydropyrimidine dehydrogenase (DPD) is the initial rate-limiting enzyme in endogenous pyrimidine catabolism and is responsible for the reduction of the pyrimidine analog 5-fluorouracil (5-FU). DPD deficiency is known to cause potentially lethal toxicity in patients receiving 5-FU. We here report a frequency analysis of one of the major splice-site mutations in the DPDY gene, and further two new DPYD gene variants. Design and methods: Restriction fragment length polymorphisin (RF...

  4. Functional characterization of two newly identified Human Endogenous Retrovirus coding envelope genes

    Directory of Open Access Journals (Sweden)

    Heidmann Thierry

    2005-03-01

    Full Text Available Abstract A recent in silico search for coding sequences of retroviral origin present in the human genome has unraveled two new envelope genes that add to the 16 genes previously identified. A systematic search among the latter for a fusogenic activity had led to the identification of two bona fide genes, named syncytin-1 and syncytin-2, most probably co-opted by primate genomes for a placental function related to the formation of the syncytiotrophoblast by cell-cell fusion. Here, we show that one of the newly identified envelope gene, named envP(b, is fusogenic in an ex vivo assay, but that its expression – as quantified by real-time RT-PCR on a large panel of human tissues – is ubiquitous, albeit with a rather low value in most tissues. Conversely, the second envelope gene, named envV, discloses a placenta-specific expression, but is not fusogenic in any of the cells tested. Altogether, these results suggest that at least one of these env genes may play a role in placentation, but most probably through a process different from that of the two previously identified syncytins.

  5. Methylation-sensitive linking libraries enhance gene-enriched sequencing of complex genomes and map DNA methylation domains

    Directory of Open Access Journals (Sweden)

    Bharti Arvind K

    2008-12-01

    Full Text Available Abstract Background Many plant genomes are resistant to whole-genome assembly due to an abundance of repetitive sequence, leading to the development of gene-rich sequencing techniques. Two such techniques are hypomethylated partial restriction (HMPR and methylation spanning linker libraries (MSLL. These libraries differ from other gene-rich datasets in having larger insert sizes, and the MSLL clones are designed to provide reads localized to "epigenetic boundaries" where methylation begins or ends. Results A large-scale study in maize generated 40,299 HMPR sequences and 80,723 MSLL sequences, including MSLL clones exceeding 100 kb. The paired end reads of MSLL and HMPR clones were shown to be effective in linking existing gene-rich sequences into scaffolds. In addition, it was shown that the MSLL clones can be used for anchoring these scaffolds to a BAC-based physical map. The MSLL end reads effectively identified epigenetic boundaries, as indicated by their preferential alignment to regions upstream and downstream from annotated genes. The ability to precisely map long stretches of fully methylated DNA sequence is a unique outcome of MSLL analysis, and was also shown to provide evidence for errors in gene identification. MSLL clones were observed to be significantly more repeat-rich in their interiors than in their end reads, confirming the correlation between methylation and retroelement content. Both MSLL and HMPR reads were found to be substantially gene-enriched, with the SalI MSLL libraries being the most highly enriched (31% align to an EST contig, while the HMPR clones exhibited exceptional depletion of repetitive DNA (to ~11%. These two techniques were compared with other gene-enrichment methods, and shown to be complementary. Conclusion MSLL technology provides an unparalleled approach for mapping the epigenetic status of repetitive blocks and for identifying sequences mis-identified as genes. Although the types and natures of epigenetic boundaries are barely understood at this time, MSLL technology flags both approximate boundaries and methylated genes that deserve additional investigation. MSLL and HMPR sequences provide a valuable resource for maize genome annotation, and are a uniquely valuable complement to any plant genome sequencing project. In order to make these results fully accessible to the community, a web display was developed that shows the alignment of MSLL, HMPR, and other gene-rich sequences to the BACs; this display is continually updated with the latest ESTs and BAC sequences.

  6. Identifying differentially methylated genes using mixed effect and generalized least square models

    Directory of Open Access Journals (Sweden)

    Yan Pearlly S

    2009-12-01

    Full Text Available Abstract Background DNA methylation plays an important role in the process of tumorigenesis. Identifying differentially methylated genes or CpG islands (CGIs associated with genes between two tumor subtypes is thus an important biological question. The methylation status of all CGIs in the whole genome can be assayed with differential methylation hybridization (DMH microarrays. However, patient samples or cell lines are heterogeneous, so their methylation pattern may be very different. In addition, neighboring probes at each CGI are correlated. How these factors affect the analysis of DMH data is unknown. Results We propose a new method for identifying differentially methylated (DM genes by identifying the associated DM CGI(s. At each CGI, we implement four different mixed effect and generalized least square models to identify DM genes between two groups. We compare four models with a simple least square regression model to study the impact of incorporating random effects and correlations. Conclusions We demonstrate that the inclusion (or exclusion of random effects and the choice of correlation structures can significantly affect the results of the data analysis. We also assess the false discovery rate of different models using CGIs associated with housekeeping genes.

  7. Preferential Allele Expression Analysis Identifies Shared Germline and Somatic Driver Genes in Advanced Ovarian Cancer

    Science.gov (United States)

    Halabi, Najeeb M.; Martinez, Alejandra; Al-Farsi, Halema; Mery, Eliane; Puydenus, Laurence; Pujol, Pascal; Khalak, Hanif G.; McLurcan, Cameron; Ferron, Gwenael; Querleu, Denis; Al-Azwani, Iman; Al-Dous, Eman; Mohamoud, Yasmin A.; Malek, Joel A.; Rafii, Arash

    2016-01-01

    Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy. However, tumor sample heterogeneity complicates standard approaches for detecting preferential allele expression. We therefore developed a novel approach combining genome and transcriptome sequencing data from the same sample that corrects for sample heterogeneity and identifies significant preferentially expressed alleles. We applied this analysis to epithelial ovarian cancer samples consisting of matched primary ovary and peritoneum and lymph node metastasis. We find that preferentially expressed variant alleles include germline and somatic variants, are shared at a relatively high frequency between patients, and are in gene networks known to be involved in cancer processes. Analysis at a patient level identifies patient-specific preferentially expressed alleles in genes that are targets for known drugs. Analysis at a site level identifies patterns of site specific preferential allele expression with similar pathways being impacted in the primary and metastasis sites. We conclude that genes with preferentially expressed variant alleles can act as cancer drivers and that targeting those genes could lead to new therapeutic strategies. PMID:26735499

  8. Identification and mapping of molecular markers linked to the tuberculate fruit gene in the cucumber (Cucumis sativus L.).

    Science.gov (United States)

    Zhang, Weiwei; He, Huanle; Guan, Yuan; Du, Hui; Yuan, Lihua; Li, Zheng; Yao, Danqing; Pan, Junsong; Cai, Run

    2010-02-01

    Warty fruit is one of the highly valuable external quality traits related to the market values of cucumber. Genetic analysis has shown that a single dominant gene, Tu (Tuberculate fruit), determines the warty fruit trait in the cucumber plant. An F(2) population (247 individuals) from the cross of S06 x S52 was used for the mapping of the Tu/tu locus. By combining bulked segregant analysis with the sequence-related amplified polymorphism (SRAP) and simple sequence repeat (SSR) markers, 15 markers (9 SRAPs and 6 SSRs) linked to the Tu/tu locus were identified. Of nine SRAP markers, three closely linked to the Tu/tu locus were successfully converted into sequence characterized amplified region (SCAR) markers. The Tu/tu locus was mapped between the co-dominant SSR marker SSR16203 and the SCAR marker C_SC933, at a genetic distance of 1.4 and 5.9 cM, respectively. Then the linked SSR markers in the study were used as anchor loci to locate the Tu/tu locus on cucumber chromosome 5. Moreover, the validity analysis of the C_SC69 and C_SC24 markers was performed with 62 cucumber lines of diverse origins, showing that the two SCAR markers can be used for marker-assisted selection (MAS) of the warty fruit trait in cucumber breeding. The information provided in this study will facilitate the map-based cloning of the Tu/tu gene. PMID:19847386

  9. Microarray and differential display identify genes involved in jasmonate-dependent anther development.

    Science.gov (United States)

    Mandaokar, Ajin; Kumar, V Dinesh; Amway, Matt; Browse, John

    2003-07-01

    Jasmonate (JA) is a signaling compound essential for anther development and pollen fertility in Arabidopsis. Mutations that block the pathway of JA synthesis result into male sterility. To understand the processes of anther and pollen maturation, we used microarray and differential display approaches to compare gene expression pattern in anthers of wild-type Arabidopsis and the male-sterile mutant, opr3. Microarray experiment revealed 25 genes that were up-regulated more than 1.8-fold in wild-type anthers as compared to mutant anthers. Experiments based on differential display identified 13 additional genes up-regulated in wild-type anthers compared to opr3 for a total of 38 differentially expressed genes. Searches of the Arabidopsis and non-redundant databases disclosed known or likely functions for 28 of the 38 genes identified, while 10 genes encode proteins of unknown function. Northern blot analysis of eight representative clones as probes confirmed low expression in opr3 anthers compared with wild-type anthers. JA responsiveness of these same genes was also investigated by northern blot analysis of anther RNA isolated from wild-type and opr3 plants, In these experiments, four genes were induced in opr3 anthers within 0.5-1 h of JA treatment while the remaining genes were up-regulated only 1-8 h after JA application. None of these genes was induced by JA in anthers of the coil mutant that is deficient in JA responsiveness. The four early-induced genes in opr3 encode lipoxygenase, a putative bHLH transcription factor, epithiospecifier protein and an unknown protein. We propose that these and other early components may be involved in JA signaling and in the initiation of developmental processes. The four late genes encode an extensin-like protein, a peptide transporter and two unknown proteins, which may represent components required later in anther and pollen maturation. Transcript profiling has provided a successful approach to identify genes involved in anther and pollen maturation in Arabidopsis. PMID:13677466

  10. A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis.

    Science.gov (United States)

    Moriarity, Branden S; Otto, George M; Rahrmann, Eric P; Rathe, Susan K; Wolf, Natalie K; Weg, Madison T; Manlove, Luke A; LaRue, Rebecca S; Temiz, Nuri A; Molyneux, Sam D; Choi, Kwangmin; Holly, Kevin J; Sarver, Aaron L; Scott, Milcah C; Forster, Colleen L; Modiano, Jaime F; Khanna, Chand; Hewitt, Stephen M; Khokha, Rama; Yang, Yi; Gorlick, Richard; Dyer, Michael A; Largaespada, David A

    2015-06-01

    Osteosarcomas are sarcomas of the bone, derived from osteoblasts or their precursors, with a high propensity to metastasize. Osteosarcoma is associated with massive genomic instability, making it problematic to identify driver genes using human tumors or prototypical mouse models, many of which involve loss of Trp53 function. To identify the genes driving osteosarcoma development and metastasis, we performed a Sleeping Beauty (SB) transposon-based forward genetic screen in mice with and without somatic loss of Trp53. Common insertion site (CIS) analysis of 119 primary tumors and 134 metastatic nodules identified 232 sites associated with osteosarcoma development and 43 sites associated with metastasis, respectively. Analysis of CIS-associated genes identified numerous known and new osteosarcoma-associated genes enriched in the ErbB, PI3K-AKT-mTOR and MAPK signaling pathways. Lastly, we identified several oncogenes involved in axon guidance, including Sema4d and Sema6d, which we functionally validated as oncogenes in human osteosarcoma. PMID:25961939

  11. Locus for a human hereditary cataract is closely linked to the ?-crystallin gene family

    International Nuclear Information System (INIS)

    Within the human ?-crystallin gene cluster polymorphic Taq I sites are present. These give rise to three sets of allelic fragments from the ?-crystallin genes. Together these restriction fragment length polymorphisms define eight possible haplotypes, three of which (Q, R, and S) were found in the Dutch and English population. A fourth haplotype (P) was detected within a family in which a hereditary Coppock-like cataract of the embryonic lens nucleus occurs in heterozygotes. Haplotype P was found only in family members who suffered from cataract, and all family members who suffered from cataract had haplotype P. The absolute correlation between the presence of haplotype P and cataract within this family shows that the ?-crystallin gene cluster and the locus for the Coppock-like cataract are closely linked. This linkage provides genetic evidence that the primary cause of a cataract in humans could possibly be a lesion in a crystallin gene

  12. Identification of AFLP and microsatellite markers linked with an aluminium tolerance gene in barley ( Hordeum vulgare L.).

    Science.gov (United States)

    Raman, H.; Moroni, S.; Sato, K.; Read, J.; Scott, J.

    2002-08-01

    Barley is the most sensitive among the cereals to aluminium (Al) stress and breeding for more tolerant cultivars is a priority. To enhance selection efficiency for Al tolerance in barley, PCR-based AFLP and microsatellite markers linked to a locus conferring tolerance to aluminium were identified. The study used F(2) progeny derived from a single cross between Yambla (moderately tolerant of Al) and WB229 (tolerant of Al) and developed hydroponic pulse-recovery screening methods to assess tolerance of phenotypes based on root growth. The segregation ratios of tolerant and sensitive genotypes and F(3) progeny testing suggest that a single major gene controlled Al tolerance ( Alt). In order to determine the chromosomal location of the Alt gene, we used the AFLP technique coupled with bulk segregant analysis. We evaluated tolerant and sensitive bulks using 30 combinations of EcoRI/ MseI primers, and 12 of these permitted differentiation of the sensitive and tolerant bulks. More than 1,000 amplified fragments were obtained, and 98 polymorphic bands were scored. AFLP analysis of wheat-barley chromosome addition lines indicated that the Alt gene was located on barley chromosome 4H. Four chromosome 4H-specific microsatellite markers (Bmac310, Bmag353, HVM68 and HVMCABG) were tightly linked to Alt. The large allelic variation detected with microsatellite marker Bmag353 allowed us to implement this marker for routine marker-assisted selection for Al tolerance, and 396 plants could be screened on a single gel. PMID:12582551

  13. Computational Characterization of Osteoporosis Associated SNPs and Genes Identified by Genome-Wide Association Studies

    Science.gov (United States)

    Wang, Ya; Wu, Guiju; Chen, Jie; Ye, Weiyuan; Yang, Jiancai; Huang, Qingyang

    2016-01-01

    Objectives Genome-wide association studies (GWASs) have revealed many SNPs and genes associated with osteoporosis. However, influence of these SNPs and genes on the predisposition to osteoporosis is not fully understood. We aimed to identify osteoporosis GWASs-associated SNPs potentially influencing the binding affinity of transcription factors and miRNAs, and reveal enrichment signaling pathway and hub genes of osteoporosis GWAS-associated genes. Methods We conducted multiple computational analyses to explore function and mechanisms of osteoporosis GWAS-associated SNPs and genes, including SNP conservation analysis and functional annotation (influence of SNPs on transcription factors and miRNA binding), gene ontology analysis, pathway analysis and protein-protein interaction analysis. Results Our results suggested that a number of SNPs potentially influence the binding affinity of transcription factors (NFATC2, MEF2C, SOX9, RUNX2, ESR2, FOXA1 and STAT3) and miRNAs. Osteoporosis GWASs-associated genes showed enrichment of Wnt signaling pathway, basal cell carcinoma and Hedgehog signaling pathway. Highly interconnected hub genes revealed by interaction network analysis are RUNX2, SP7, TNFRSF11B, LRP5, DKK1, ESR1 and SOST. Conclusions Our results provided the targets for further experimental assessment and further insight on osteoporosis pathophysiology. PMID:26930606

  14. A catalogue of genes in mouse embryonal carcinoma F9 cells identified with expressed sequence tags.

    Science.gov (United States)

    Nishiguchi, S; Sakuma, R; Nomura, M; Zou, Z; Jearanaisilavong, J; Joh, T; Yasunaga, T; Shimada, K

    1996-04-01

    We used expressed sequence tags (ESTs) to identify genes expressed in mouse embryonal carcinoma F9 cells and prepared 2132 ESTs from undifferentiated F9 cDNA libraries: 1026 were prepared after randomly selecting clones from one of the libraries and the remaining 1106 ESTs were prepared after classifying 2896 clones of the libraries into four classes, according to the levels and patterns of expression. Among the former 1026 ESTs, 797 (78%) matched known genes, 61 (6%) matched database sequences of uncharacterized cDNAs, and 168 (16%) represented novel genes. The ESTs matching known genes were catalogued according to putative structural and cellular functions. As many as 53% were related to transcription and translation, and 19% were related to energy metabolism, including transcripts of mitochondrial DNA. These percentages were significantly higher in F9 cells than in the human heart and brain, and a human liver cell line, HepG2. We found that approximately 7% of the ESTs corresponding to low-abundance mRNAs are either related to retinoic acid-regulated genes or mammalian development- and/or differentiation-related genes. Cataloguing of the genes expressed in the F9 cells paves the way for isolating genes involved in early mammalian development. PMID:8743579

  15. Previously unidentified changes in renal cell carcinoma gene expression identified by parametric analysis of microarray data

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    Cohen Herbert T

    2003-11-01

    Full Text Available Abstract Background Renal cell carcinoma is a common malignancy that often presents as a metastatic-disease for which there are no effective treatments. To gain insights into the mechanism of renal cell carcinogenesis, a number of genome-wide expression profiling studies have been performed. Surprisingly, there is very poor agreement among these studies as to which genes are differentially regulated. To better understand this lack of agreement we profiled renal cell tumor gene expression using genome-wide microarrays (45,000 probe sets and compare our analysis to previous microarray studies. Methods We hybridized total RNA isolated from renal cell tumors and adjacent normal tissue to Affymetrix U133A and U133B arrays. We removed samples with technical defects and removed probesets that failed to exhibit sequence-specific hybridization in any of the samples. We detected differential gene expression in the resulting dataset with parametric methods and identified keywords that are overrepresented in the differentially expressed genes with the Fisher-exact test. Results We identify 1,234 genes that are more than three-fold changed in renal tumors by t-test, 800 of which have not been previously reported to be altered in renal cell tumors. Of the only 37 genes that have been identified as being differentially expressed in three or more of five previous microarray studies of renal tumor gene expression, our analysis finds 33 of these genes (89%. A key to the sensitivity and power of our analysis is filtering out defective samples and genes that are not reliably detected. Conclusions The widespread use of sample-wise voting schemes for detecting differential expression that do not control for false positives likely account for the poor overlap among previous studies. Among the many genes we identified using parametric methods that were not previously reported as being differentially expressed in renal cell tumors are several oncogenes and tumor suppressor genes that likely play important roles in renal cell carcinogenesis. This highlights the need for rigorous statistical approaches in microarray studies.

  16. Previously unidentified changes in renal cell carcinoma gene expression identified by parametric analysis of microarray data

    International Nuclear Information System (INIS)

    Renal cell carcinoma is a common malignancy that often presents as a metastatic-disease for which there are no effective treatments. To gain insights into the mechanism of renal cell carcinogenesis, a number of genome-wide expression profiling studies have been performed. Surprisingly, there is very poor agreement among these studies as to which genes are differentially regulated. To better understand this lack of agreement we profiled renal cell tumor gene expression using genome-wide microarrays (45,000 probe sets) and compare our analysis to previous microarray studies. We hybridized total RNA isolated from renal cell tumors and adjacent normal tissue to Affymetrix U133A and U133B arrays. We removed samples with technical defects and removed probesets that failed to exhibit sequence-specific hybridization in any of the samples. We detected differential gene expression in the resulting dataset with parametric methods and identified keywords that are overrepresented in the differentially expressed genes with the Fisher-exact test. We identify 1,234 genes that are more than three-fold changed in renal tumors by t-test, 800 of which have not been previously reported to be altered in renal cell tumors. Of the only 37 genes that have been identified as being differentially expressed in three or more of five previous microarray studies of renal tumor gene expression, our analysis finds 33 of these genes (89%). A key to the sensitivity and power of our analysis is filtering out defective samples and genes that are not reliably detected. The widespread use of sample-wise voting schemes for detecting differential expression that do not control for false positives likely account for the poor overlap among previous studies. Among the many genes we identified using parametric methods that were not previously reported as being differentially expressed in renal cell tumors are several oncogenes and tumor suppressor genes that likely play important roles in renal cell carcinogenesis. This highlights the need for rigorous statistical approaches in microarray studies

  17. Transcriptome Analysis to Identify Cold-Responsive Genes in Amur Carp (Cyprinus carpio haematopterus)

    Science.gov (United States)

    He, XuLing

    2015-01-01

    The adaptation of fish to low temperatures is the result of long-term evolution. Amur carp (Cyprinus carpio haematopterus) survives low temperatures (0-4C) for six months per year. Therefore, we chose this fish as a model organism to study the mechanisms of cold-adaptive responses using high-throughput sequencing technology. This system provided an excellent model for exploring the relationship between evolutionary genomic changes and environmental adaptations. The Amur carp transcriptome was sequenced using the Illumina platform and was assembled into 163,121 cDNA contigs, with an average read length of 594 bp and an N50 length of 913 bp. A total of 162,339 coding sequences (CDSs) were identified and of 32,730 unique CDSs were annotated. Gene Ontology (GO), EuKaryotic Orthologous Groups (KOG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to classify all CDSs into different functional categories. A large number of cold-responsive genes were detected in different tissues at different temperatures. A total of 9,427 microsatellites were identified and classified, with 1952 identifying in cold-responsive genes. Based on GO enrichment analysis of the cold-induced genes, protein localization and protein transport were the most highly represented biological processes. Circadian rhythm, protein processing in endoplasmic reticulum, endocytosis, insulin signaling pathway, and lysosome were the most highly enriched pathways for the genes induced by cold stress. Our data greatly contribute to the common carp (C. carpio) transcriptome resource, and the identification of cold-responsive genes in different tissues at different temperatures will aid in deciphering the genetic basis of ecological and environmental adaptations in this species. Based on our results, the Amur carp has evolved special strategies to survive low temperatures, and these strategies include the system-wide or tissue-specific induction of gene expression during their six-month overwintering period. PMID:26098567

  18. Combining Pareto-optimal clusters using supervised learning for identifying co-expressed genes

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    Bandyopadhyay Sanghamitra

    2009-01-01

    Full Text Available Abstract Background The landscape of biological and biomedical research is being changed rapidly with the invention of microarrays which enables simultaneous view on the transcription levels of a huge number of genes across different experimental conditions or time points. Using microarray data sets, clustering algorithms have been actively utilized in order to identify groups of co-expressed genes. This article poses the problem of fuzzy clustering in microarray data as a multiobjective optimization problem which simultaneously optimizes two internal fuzzy cluster validity indices to yield a set of Pareto-optimal clustering solutions. Each of these clustering solutions possesses some amount of information regarding the clustering structure of the input data. Motivated by this fact, a novel fuzzy majority voting approach is proposed to combine the clustering information from all the solutions in the resultant Pareto-optimal set. This approach first identifies the genes which are assigned to some particular cluster with high membership degree by most of the Pareto-optimal solutions. Using this set of genes as the training set, the remaining genes are classified by a supervised learning algorithm. In this work, we have used a Support Vector Machine (SVM classifier for this purpose. Results The performance of the proposed clustering technique has been demonstrated on five publicly available benchmark microarray data sets, viz., Yeast Sporulation, Yeast Cell Cycle, Arabidopsis Thaliana, Human Fibroblasts Serum and Rat Central Nervous System. Comparative studies of the use of different SVM kernels and several widely used microarray clustering techniques are reported. Moreover, statistical significance tests have been carried out to establish the statistical superiority of the proposed clustering approach. Finally, biological significance tests have been carried out using a web based gene annotation tool to show that the proposed method is able to produce biologically relevant clusters of co-expressed genes. Conclusion The proposed clustering method has been shown to perform better than other well-known clustering algorithms in finding clusters of co-expressed genes efficiently. The clusters of genes produced by the proposed technique are also found to be biologically significant, i.e., consist of genes which belong to the same functional groups. This indicates that the proposed clustering method can be used efficiently to identify co-expressed genes in microarray gene expression data. Supplementary Website The pre-processed and normalized data sets, the matlab code and other related materials are available at http://anirbanmukhopadhyay.50webs.com/mogasvm.html.

  19. Gene expression meta-analysis identifies metastatic pathways and transcription factors in breast cancer

    International Nuclear Information System (INIS)

    Metastasis is believed to progress in several steps including different pathways but the determination and understanding of these mechanisms is still fragmentary. Microarray analysis of gene expression patterns in breast tumors has been used to predict outcome in recent studies. Besides classification of outcome, these global expression patterns may reflect biological mechanisms involved in metastasis of breast cancer. Our purpose has been to investigate pathways and transcription factors involved in metastasis by use of gene expression data sets. We have analyzed 8 publicly available gene expression data sets. A global approach, 'gene set enrichment analysis' as well as an approach focusing on a subset of significantly differently regulated genes, GenMAPP, has been applied to rank pathway gene sets according to differential regulation in metastasizing tumors compared to non-metastasizing tumors. Meta-analysis has been used to determine overrepresentation of pathways and transcription factors targets, concordant deregulated in metastasizing breast tumors, in several data sets. The major findings are up-regulation of cell cycle pathways and a metabolic shift towards glucose metabolism reflected in several pathways in metastasizing tumors. Growth factor pathways seem to play dual roles; EGF and PDGF pathways are decreased, while VEGF and sex-hormone pathways are increased in tumors that metastasize. Furthermore, migration, proteasome, immune system, angiogenesis, DNA repair and several signal transduction pathways are associated to metastasis. Finally several transcription factors e.g. E2F, NFY, and YY1 are identified as being involved in metastasis. By pathway meta-analysis many biological mechanisms beyond major characteristics such as proliferation are identified. Transcription factor analysis identifies a number of key factors that support central pathways. Several previously proposed treatment targets are identified and several new pathways that may constitute new targets are identified

  20. Yeast-based assay identifies novel Shh/Gli target genes in vertebrate development

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    Milla Luis A

    2012-01-01

    Full Text Available Abstract Background The increasing number of developmental events and molecular mechanisms associated with the Hedgehog (Hh pathway from Drosophila to vertebrates, suggest that gene regulation is crucial for diverse cellular responses, including target genes not yet described. Although several high-throughput, genome-wide approaches have yielded information at the genomic, transcriptional and proteomic levels, the specificity of Gli binding sites related to direct target gene activation still remain elusive. This study aims to identify novel putative targets of Gli transcription factors through a protein-DNA binding assay using yeast, and validating a subset of targets both in-vitro and in-vivo. Testing in different Hh/Gli gain- and loss-of-function scenarios we here identified known (e.g., ptc1 and novel Hh-regulated genes in zebrafish embryos. Results The combined yeast-based screening and MEME/MAST analysis were able to predict Gli transcription factor binding sites, and position mapping of these sequences upstream or in the first intron of promoters served to identify new putative target genes of Gli regulation. These candidates were validated by qPCR in combination with either the pharmacological Hh/Gli antagonist cyc or the agonist pur in Hh-responsive C3H10T1/2 cells. We also used small-hairpin RNAs against Gli proteins to evaluate targets and confirm specific Gli regulation their expression. Taking advantage of mutants that have been identified affecting different components of the Hh/Gli signaling system in the zebrafish model, we further analyzed specific novel candidates. Studying Hh function with pharmacological inhibition or activation complemented these genetic loss-of-function approaches. We provide evidence that in zebrafish embryos, Hh signaling regulates sfrp2, neo1, and c-myc expression in-vivo. Conclusion A recently described yeast-based screening allowed us to identify new Hh/Gli target genes, functionally important in different contexts of vertebrate embryonic development.

  1. Gene expression meta-analysis identifies metastatic pathways and transcription factors in breast cancer

    Directory of Open Access Journals (Sweden)

    Tan Qihua

    2008-12-01

    Full Text Available Abstract Background Metastasis is believed to progress in several steps including different pathways but the determination and understanding of these mechanisms is still fragmentary. Microarray analysis of gene expression patterns in breast tumors has been used to predict outcome in recent studies. Besides classification of outcome, these global expression patterns may reflect biological mechanisms involved in metastasis of breast cancer. Our purpose has been to investigate pathways and transcription factors involved in metastasis by use of gene expression data sets. Methods We have analyzed 8 publicly available gene expression data sets. A global approach, "gene set enrichment analysis" as well as an approach focusing on a subset of significantly differently regulated genes, GenMAPP, has been applied to rank pathway gene sets according to differential regulation in metastasizing tumors compared to non-metastasizing tumors. Meta-analysis has been used to determine overrepresentation of pathways and transcription factors targets, concordant deregulated in metastasizing breast tumors, in several data sets. Results The major findings are up-regulation of cell cycle pathways and a metabolic shift towards glucose metabolism reflected in several pathways in metastasizing tumors. Growth factor pathways seem to play dual roles; EGF and PDGF pathways are decreased, while VEGF and sex-hormone pathways are increased in tumors that metastasize. Furthermore, migration, proteasome, immune system, angiogenesis, DNA repair and several signal transduction pathways are associated to metastasis. Finally several transcription factors e.g. E2F, NFY, and YY1 are identified as being involved in metastasis. Conclusion By pathway meta-analysis many biological mechanisms beyond major characteristics such as proliferation are identified. Transcription factor analysis identifies a number of key factors that support central pathways. Several previously proposed treatment targets are identified and several new pathways that may constitute new targets are identified.

  2. Consistent Differential Expression Pattern (CDEP on microarray to identify genes related to metastatic behavior

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    Tsoi Lam C

    2011-11-01

    Full Text Available Abstract Background To utilize the large volume of gene expression information generated from different microarray experiments, several meta-analysis techniques have been developed. Despite these efforts, there remain significant challenges to effectively increasing the statistical power and decreasing the Type I error rate while pooling the heterogeneous datasets from public resources. The objective of this study is to develop a novel meta-analysis approach, Consistent Differential Expression Pattern (CDEP, to identify genes with common differential expression patterns across different datasets. Results We combined False Discovery Rate (FDR estimation and the non-parametric RankProd approach to estimate the Type I error rate in each microarray dataset of the meta-analysis. These Type I error rates from all datasets were then used to identify genes with common differential expression patterns. Our simulation study showed that CDEP achieved higher statistical power and maintained low Type I error rate when compared with two recently proposed meta-analysis approaches. We applied CDEP to analyze microarray data from different laboratories that compared transcription profiles between metastatic and primary cancer of different types. Many genes identified as differentially expressed consistently across different cancer types are in pathways related to metastatic behavior, such as ECM-receptor interaction, focal adhesion, and blood vessel development. We also identified novel genes such as AMIGO2, Gem, and CXCL11 that have not been shown to associate with, but may play roles in, metastasis. Conclusions CDEP is a flexible approach that borrows information from each dataset in a meta-analysis in order to identify genes being differentially expressed consistently. We have shown that CDEP can gain higher statistical power than other existing approaches under a variety of settings considered in the simulation study, suggesting its robustness and insensitivity to data variation commonly associated with microarray experiments. Availability: CDEP is implemented in R and freely available at: http://genomebioinfo.musc.edu/CDEP/ Contact: zhengw@musc.edu

  3. Integrated Model of De Novo and Inherited Genetic Variants Yields Greater Power to Identify Risk Genes

    Science.gov (United States)

    He, Xin; Sanders, Stephan J.; Liu, Li; De Rubeis, Silvia; Lim, Elaine T.; Sutcliffe, James S.; Schellenberg, Gerard D.; Gibbs, Richard A.; Daly, Mark J.; Buxbaum, Joseph D.; State, Matthew W.; Devlin, Bernie; Roeder, Kathryn

    2013-01-01

    De novo mutations affect risk for many diseases and disorders, especially those with early-onset. An example is autism spectrum disorders (ASD). Four recent whole-exome sequencing (WES) studies of ASD families revealed a handful of novel risk genes, based on independent de novo loss-of-function (LoF) mutations falling in the same gene, and found that de novo LoF mutations occurred at a twofold higher rate than expected by chance. However successful these studies were, they used only a small fraction of the data, excluding other types of de novo mutations and inherited rare variants. Moreover, such analyses cannot readily incorporate data from case-control studies. An important research challenge in gene discovery, therefore, is to develop statistical methods that accommodate a broader class of rare variation. We develop methods that can incorporate WES data regarding de novo mutations, inherited variants present, and variants identified within cases and controls. TADA, for Transmission And De novo Association, integrates these data by a gene-based likelihood model involving parameters for allele frequencies and gene-specific penetrances. Inference is based on a Hierarchical Bayes strategy that borrows information across all genes to infer parameters that would be difficult to estimate for individual genes. In addition to theoretical development we validated TADA using realistic simulations mimicking rare, large-effect mutations affecting risk for ASD and show it has dramatically better power than other common methods of analysis. Thus TADA's integration of various kinds of WES data can be a highly effective means of identifying novel risk genes. Indeed, application of TADA to WES data from subjects with ASD and their families, as well as from a study of ASD subjects and controls, revealed several novel and promising ASD candidate genes with strong statistical support. PMID:23966865

  4. Cross-study analysis of gene expression data for intermediate neuroblastoma identifies two biological subtypes

    International Nuclear Information System (INIS)

    Neuroblastoma patients show heterogeneous clinical courses ranging from life-threatening progression to spontaneous regression. Recently, gene expression profiles of neuroblastoma tumours were associated with clinically different phenotypes. However, such data is still rare for important patient subgroups, such as patients with MYCN non-amplified advanced stage disease. Prediction of the individual course of disease and optimal therapy selection in this cohort is challenging. Additional research effort is needed to describe the patterns of gene expression in this cohort and to identify reliable prognostic markers for this subset of patients. We combined gene expression data from two studies in a meta-analysis in order to investigate differences in gene expression of advanced stage (3 or 4) tumours without MYCN amplification that show contrasting outcomes (alive or dead) at five years after initial diagnosis. In addition, a predictive model for outcome was generated. Gene expression profiles from 66 patients were included from two studies using different microarray platforms. In the combined data set, 72 genes were identified as differentially expressed by meta-analysis at a false discovery rate (FDR) of 8.33%. Meta-analysis detected 34 differentially expressed genes that were not found as significant in either single study. Outcome prediction based on data of both studies resulted in a predictive accuracy of 77%. Moreover, the genes that were differentially expressed in subgroups of advanced stage patients without MYCN amplification accurately separated MYCN amplified tumours from low stage tumours without MYCN amplification. Our findings support the hypothesis that neuroblastoma consists of two biologically distinct subgroups that differ by characteristic gene expression patterns, which are associated with divergent clinical outcome

  5. Gene Expression Profiling Identifies Important Genes Affected by R2 Compound Disrupting FAK and P53 Complex

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    Vita M. Golubovskaya

    2014-01-01

    Full Text Available Focal Adhesion Kinase (FAK is a non-receptor kinase that plays an important role in many cellular processes: adhesion, proliferation, invasion, angiogenesis, metastasis and survival. Recently, we have shown that Roslin 2 or R2 (1-benzyl-15,3,5,7-tetraazatricyclo[3.3.1.1~3,7~]decane compound disrupts FAK and p53 proteins, activates p53 transcriptional activity, and blocks tumor growth. In this report we performed a microarray gene expression analysis of R2-treated HCT116 p53+/+ and p53−/− cells and detected 1484 genes that were significantly up- or down-regulated (p < 0.05 in HCT116 p53+/+ cells but not in p53−/− cells. Among up-regulated genes in HCT p53+/+ cells we detected critical p53 targets: Mdm-2, Noxa-1, and RIP1. Among down-regulated genes, Met, PLK2, KIF14, BIRC2 and other genes were identified. In addition, a combination of R2 compound with M13 compound that disrupts FAK and Mmd-2 complex or R2 and Nutlin-1 that disrupts Mdm-2 and p53 decreased clonogenicity of HCT116 p53+/+ colon cancer cells more significantly than each agent alone in a p53-dependent manner. Thus, the report detects gene expression profile in response to R2 treatment and demonstrates that the combination of drugs targeting FAK, Mdm-2, and p53 can be a novel therapy approach.

  6. A meta-analysis of lung cancer gene expression identifies PTK7 as a survival gene in lung adenocarcinoma.

    Science.gov (United States)

    Chen, Ron; Khatri, Purvesh; Mazur, Pawel K; Polin, Melanie; Zheng, Yanyan; Vaka, Dedeepya; Hoang, Chuong D; Shrager, Joseph; Xu, Yue; Vicent, Silvestre; Butte, Atul J; Sweet-Cordero, E Alejandro

    2014-05-15

    Lung cancer remains the most common cause of cancer-related death worldwide and it continues to lack effective treatment. The increasingly large and diverse public databases of lung cancer gene expression constitute a rich source of candidate oncogenic drivers and therapeutic targets. To define novel targets for lung adenocarcinoma, we conducted a large-scale meta-analysis of genes specifically overexpressed in adenocarcinoma. We identified an 11-gene signature that was overexpressed consistently in adenocarcinoma specimens relative to normal lung tissue. Six genes in this signature were specifically overexpressed in adenocarcinoma relative to other subtypes of non-small cell lung cancer (NSCLC). Among these genes was the little studied protein tyrosine kinase PTK7. Immunohistochemical analysis confirmed that PTK7 is highly expressed in primary adenocarcinoma patient samples. RNA interference-mediated attenuation of PTK7 decreased cell viability and increased apoptosis in a subset of adenocarcinoma cell lines. Further, loss of PTK7 activated the MKK7-JNK stress response pathway and impaired tumor growth in xenotransplantation assays. Our work defines PTK7 as a highly and specifically expressed gene in adenocarcinoma and a potential therapeutic target in this subset of NSCLC. PMID:24654231

  7. Gene Expression Profiling Identifies Important Genes Affected by R2 Compound Disrupting FAK and P53 Complex

    International Nuclear Information System (INIS)

    Focal Adhesion Kinase (FAK) is a non-receptor kinase that plays an important role in many cellular processes: adhesion, proliferation, invasion, angiogenesis, metastasis and survival. Recently, we have shown that Roslin 2 or R2 (1-benzyl-15,3,5,7-tetraazatricyclo[3.3.1.1~3,7~]decane) compound disrupts FAK and p53 proteins, activates p53 transcriptional activity, and blocks tumor growth. In this report we performed a microarray gene expression analysis of R2-treated HCT116 p53+/+ and p53−/− cells and detected 1484 genes that were significantly up- or down-regulated (p < 0.05) in HCT116 p53+/+ cells but not in p53−/− cells. Among up-regulated genes in HCT p53+/+ cells we detected critical p53 targets: Mdm-2, Noxa-1, and RIP1. Among down-regulated genes, Met, PLK2, KIF14, BIRC2 and other genes were identified. In addition, a combination of R2 compound with M13 compound that disrupts FAK and Mmd-2 complex or R2 and Nutlin-1 that disrupts Mdm-2 and p53 decreased clonogenicity of HCT116 p53+/+ colon cancer cells more significantly than each agent alone in a p53-dependent manner. Thus, the report detects gene expression profile in response to R2 treatment and demonstrates that the combination of drugs targeting FAK, Mdm-2, and p53 can be a novel therapy approach

  8. Methods for simultaneously identifying coherent local clusters with smooth global patterns in gene expression profiles

    Directory of Open Access Journals (Sweden)

    Lee Yun-Shien

    2008-03-01

    Full Text Available Abstract Background The hierarchical clustering tree (HCT with a dendrogram 1 and the singular value decomposition (SVD with a dimension-reduced representative map 2 are popular methods for two-way sorting the gene-by-array matrix map employed in gene expression profiling. While HCT dendrograms tend to optimize local coherent clustering patterns, SVD leading eigenvectors usually identify better global grouping and transitional structures. Results This study proposes a flipping mechanism for a conventional agglomerative HCT using a rank-two ellipse (R2E, an improved SVD algorithm for sorting purpose seriation by Chen 3 as an external reference. While HCTs always produce permutations with good local behaviour, the rank-two ellipse seriation gives the best global grouping patterns and smooth transitional trends. The resulting algorithm automatically integrates the desirable properties of each method so that users have access to a clustering and visualization environment for gene expression profiles that preserves coherent local clusters and identifies global grouping trends. Conclusion We demonstrate, through four examples, that the proposed method not only possesses better numerical and statistical properties, it also provides more meaningful biomedical insights than other sorting algorithms. We suggest that sorted proximity matrices for genes and arrays, in addition to the gene-by-array expression matrix, can greatly aid in the search for comprehensive understanding of gene expression structures. Software for the proposed methods can be obtained at http://gap.stat.sinica.edu.tw/Software/GAP.

  9. Global Gene-Expression Analysis to Identify Differentially Expressed Genes Critical for the Heat Stress Response in Brassica rapa.

    Science.gov (United States)

    Dong, Xiangshu; Yi, Hankuil; Lee, Jeongyeo; Nou, Ill-Sup; Han, Ching-Tack; Hur, Yoonkang

    2015-01-01

    Genome-wide dissection of the heat stress response (HSR) is necessary to overcome problems in crop production caused by global warming. To identify HSR genes, we profiled gene expression in two Chinese cabbage inbred lines with different thermotolerances, Chiifu and Kenshin. Many genes exhibited >2-fold changes in expression upon exposure to 0.5- 4 h at 45C (high temperature, HT): 5.2% (2,142 genes) in Chiifu and 3.7% (1,535 genes) in Kenshin. The most enriched GO (Gene Ontology) items included 'response to heat', 'response to reactive oxygen species (ROS)', 'response to temperature stimulus', 'response to abiotic stimulus', and 'MAPKKK cascade'. In both lines, the genes most highly induced by HT encoded small heat shock proteins (Hsps) and heat shock factor (Hsf)-like proteins such as HsfB2A (Bra029292), whereas high-molecular weight Hsps were constitutively expressed. Other upstream HSR components were also up-regulated: ROS-scavenging genes like glutathione peroxidase 2 (BrGPX2, Bra022853), protein kinases, and phosphatases. Among heat stress (HS) marker genes in Arabidopsis, only exportin 1A (XPO1A) (Bra008580, Bra006382) can be applied to B. rapa for basal thermotolerance (BT) and short-term acquired thermotolerance (SAT) gene. CYP707A3 (Bra025083, Bra021965), which is involved in the dehydration response in Arabidopsis, was associated with membrane leakage in both lines following HS. Although many transcription factors (TF) genes, including DREB2A (Bra005852), were involved in HS tolerance in both lines, Bra024224 (MYB41) and Bra021735 (a bZIP/AIR1 [Anthocyanin-Impaired-Response-1]) were specific to Kenshin. Several candidate TFs involved in thermotolerance were confirmed as HSR genes by real-time PCR, and these assignments were further supported by promoter analysis. Although some of our findings are similar to those obtained using other plant species, clear differences in Brassica rapa reveal a distinct HSR in this species. Our data could also provide a springboard for developing molecular markers of HS and for engineering HS tolerant B. rapa. PMID:26102990

  10. Transcriptional Profiling of Whole Blood Identifies a Unique 5-Gene Signature for Myelofibrosis and Imminent Myelofibrosis Transformation

    DEFF Research Database (Denmark)

    Hasselbalch, Hans Carl; Skov, Vibe; Stauffer Larsen, Thomas; Thomassen, Mads; Hasselbalch Riley, Caroline; Jensen, Morten K; Bjerrum, Ole Weis; Kruse, Torben A

    2014-01-01

    Identifying a distinct gene signature for myelofibrosis may yield novel information of the genes, which are responsible for progression of essential thrombocythemia and polycythemia vera towards myelofibrosis. We aimed at identifying a simple gene signature - composed of a few genes - which were...... considered to be responsible for the derangement of bone marrow stroma in myelofibrosis. Accordingly, this gene-signature may reflect key processes in the pathogenesis and pathophysiology of myelofibrosis development....

  11. Use of Persistent Identifiers to link Heterogeneous Data Systems in the Integrated Earth Data Applications (IEDA) Facility

    Science.gov (United States)

    Hsu, L.; Lehnert, K. A.; Carbotte, S. M.; Arko, R. A.; Ferrini, V.; O'hara, S. H.; Walker, J. D.

    2012-12-01

    The Integrated Earth Data Applications (IEDA) facility maintains multiple data systems with a wide range of solid earth data types from the marine, terrestrial, and polar environments. Examples of the different data types include syntheses of ultra-high resolution seafloor bathymetry collected on large collaborative cruises and analytical geochemistry measurements collected by single investigators in small, unique projects. These different data types have historically been channeled into separate, discipline-specific databases with search and retrieval tailored for the specific data type. However, a current major goal is to integrate data from different systems to allow interdisciplinary data discovery and scientific analysis. To increase discovery and access across these heterogeneous systems, IEDA employs several unique IDs, including sample IDs (International Geo Sample Number, IGSN), person IDs (GeoPass ID), funding award IDs (NSF Award Number), cruise IDs (from the Marine Geoscience Data System Expedition Metadata Catalog), dataset IDs (DOIs), and publication IDs (DOIs). These IDs allow linking of a sample registry (System for Earth SAmple Registration), data libraries and repositories (e.g. Geochemical Research Library, Marine Geoscience Data System), integrated synthesis databases (e.g. EarthChem Portal, PetDB), and investigator services (IEDA Data Compliance Tool). The linked systems allow efficient discovery of related data across different levels of granularity. In addition, IEDA data systems maintain links with several external data systems, including digital journal publishers. Links have been established between the EarthChem Portal and ScienceDirect through publication DOIs, returning sample-level objects and geochemical analyses for a particular publication. Linking IEDA-hosted data to digital publications with IGSNs at the sample level and with IEDA-allocated dataset DOIs are under development. As an example, an individual investigator could sign up for a GeoPass account ID, write a proposal to NSF and create a data plan using the IEDA Data Management Plan Tool. Having received the grant, the investigator then collects rock samples on a scientific cruise from dredges and registers the samples with IGSNs. The investigator then performs analytical geochemistry on the samples, and submits the full dataset to the Geochemical Resource Library for a dataset DOI. Finally, the investigator writes an article that is published in Science Direct. Knowing any of the following IDs: Investigator GeoPass ID, NSF Award Number, Cruise ID, Sample IGSNs, dataset DOI, or publication DOI, a user would be able to navigate to all samples, datasets, and publications in IEDA and external systems. Use of persistent identifiers to link heterogeneous data systems in IEDA thus increases access, discovery, and proper citation of hard-earned investigator datasets.

  12. A phase synchronization clustering algorithm for identifying interesting groups of genes from cell cycle expression data

    Directory of Open Access Journals (Sweden)

    Tcha Hong

    2008-01-01

    Full Text Available Abstract Background The previous studies of genome-wide expression patterns show that a certain percentage of genes are cell cycle regulated. The expression data has been analyzed in a number of different ways to identify cell cycle dependent genes. In this study, we pose the hypothesis that cell cycle dependent genes are considered as oscillating systems with a rhythm, i.e. systems producing response signals with period and frequency. Therefore, we are motivated to apply the theory of multivariate phase synchronization for clustering cell cycle specific genome-wide expression data. Results We propose the strategy to find groups of genes according to the specific biological process by analyzing cell cycle specific gene expression data. To evaluate the propose method, we use the modified Kuramoto model, which is a phase governing equation that provides the long-term dynamics of globally coupled oscillators. With this equation, we simulate two groups of expression signals, and the simulated signals from each group shares their own common rhythm. Then, the simulated expression data are mixed with randomly generated expression data to be used as input data set to the algorithm. Using these simulated expression data, it is shown that the algorithm is able to identify expression signals that are involved in the same oscillating process. We also evaluate the method with yeast cell cycle expression data. It is shown that the output clusters by the proposed algorithm include genes, which are closely associated with each other by sharing significant Gene Ontology terms of biological process and/or having relatively many known biological interactions. Therefore, the evaluation analysis indicates that the method is able to identify expression signals according to the specific biological process. Our evaluation analysis also indicates that some portion of output by the proposed algorithm is not obtainable by the traditional clustering algorithm with Euclidean distance or linear correlation. Conclusion Based on the evaluation experiments, we draw the conclusion as follows: 1 Based on the theory of multivariate phase synchronization, it is feasible to find groups of genes, which have relevant biological interactions and/or significantly shared GO slim terms of biological process, using cell cycle specific gene expression signals. 2 Among all the output clusters by the proposed algorithm, the cluster with relatively large size has a tendency to include more known interactions than the one with relatively small size. 3 It is feasible to understand the cell cycle specific gene expression patterns as the phenomenon of collective synchronization. 4 The proposed algorithm is able to find prominent groups of genes, which are not obtainable by traditional clustering algorithm.

  13. Genetic screens to identify pathogenic gene variants in the common cancer predisposition Lynch syndrome

    DEFF Research Database (Denmark)

    Drost, Mark; Lützen, Anne; van Hees, Sandrine; Ferreira, Daniel; Calléja, Fabienne; Zonneveld, José B M; Nielsen, Finn Cilius; Rasmussen, Lene Juel; de Wind, Niels

    2013-01-01

    In many individuals suspected of the common cancer predisposition Lynch syndrome, variants of unclear significance (VUS), rather than an obviously pathogenic mutations, are identified in one of the DNA mismatch repair (MMR) genes. The uncertainty of whether such VUS inactivate MMR, and therefore...... are pathogenic, precludes targeted healthcare for both carriers and their relatives. To facilitate the identification of pathogenic VUS, we have developed an in cellulo genetic screen-based procedure for the large-scale mutagenization, identification, and cataloging of residues of MMR genes critical...... for MMR gene function. When a residue identified as mutated in an individual suspected of Lynch syndrome is listed as critical in such a reverse diagnosis catalog, there is a high probability that the corresponding human VUS is pathogenic. To investigate the applicability of this approach, we have...

  14. Identifying glycoside hydrolase family 18 genes in the mycoparasitic fungal species Clonostachys rosea.

    Science.gov (United States)

    Tzelepis, Georgios; Dubey, Mukesh; Jensen, Dan Funck; Karlsson, Magnus

    2015-07-01

    Clonostachysrosea is a mycoparasitic fungal species that is an efficient biocontrol agent against many plant diseases. During mycoparasitic interactions, one of the most crucial steps is the hydrolysis of the prey's fungal cell wall, which mainly consists of glucans, glycoproteins and chitin. Chitinases are hydrolytic enzymes responsible for chitin degradation and it is suggested that they play an important role in fungal-fungal interactions. Fungal chitinases belong exclusively to the glycoside hydrolase (GH) family 18.These GH18 proteins are categorized into three distinct phylogenetic groups (A, B and C), subdivided into several subgroups. In this study, we identified 14 GH18 genes in the C. rosea genome, which is remarkably low compared with the high numbers found in mycoparasitic Trichoderma species. Phylogenetic analysis revealed that C. rosea contains eight genes in group A, two genes in group B, two genes in group C, one gene encoding a putative ENGase (endo-β-N-acetylglucosaminidase) and the ech37 gene, which is of bacterial origin. Gene expression analysis showed that only two genes had higher transcription levels during fungal-fungal interactions, while eight out of 14 GH18 genes were triggered by chitin. Furthermore, deletion of the C group chiC2 gene decreased the growth inhibitory activity of C. rosea culture filtrates against Botrytis cinerea and Rhizoctonia solani, although the biocontrol ability of C. rosea against B. cinerea was not affected. In addition, a potential role of the CHIC2 chitinase in the sporulation process was revealed. These results provide new information about the role of GH18 proteins in mycoparasitic interactions. PMID:25881898

  15. Systems Biology in Animal Breeding: Identifying relationships among markers, genes, and phenotypes

    Science.gov (United States)

    The Breeding and Genetics Symposium titled “Systems Biology in Animal Breeding: Identifying relationships among markers, genes, and phenotypes” was held at the Joint Annual Meeting of the American Dairy Science Association and the American Society of Animal Science in Phoenix, AZ, July 15 to 19, 201...

  16. Multiple gene mutations identified in patients infected with influenza A (H7N9) virus.

    Science.gov (United States)

    Chen, Cuicui; Wang, Mingbang; Zhu, Zhaoqin; Qu, Jieming; Xi, Xiuhong; Tang, Xinjun; Lao, Xiangda; Seeley, Eric; Li, Tao; Fan, Xiaomei; Du, Chunling; Wang, Qin; Yang, Lin; Hu, Yunwen; Bai, Chunxue; Zhang, Zhiyong; Lu, Shuihua; Song, Yuanlin; Zhou, Wenhao

    2016-01-01

    Influenza A (H7N9) virus induced high mortality since 2013. It is important to elucidate the potential genetic variations that contribute to virus infection susceptibilities. In order to identify genetic mutations that might increase host susceptibility to infection, we performed exon sequencing and validated the SNPS by Sanger sequencing on 18 H7N9 patients. Blood samples were collected from 18 confirmed H7N9 patients. The genomic DNA was captured with the Agilent SureSelect Human All Exon kit, sequenced on the Illumina Hiseq 2000, and the resulting data processed and annotated with Genome analysis Tool. SNPs were verified by independent Sanger sequencing. The DAVID database and the DAPPLE database were used to do bioinformatics analysis. Through exon sequencing and Sanger sequencing, we identified 21 genes that were highly associated with H7N9 influenza infection. Protein-protein interaction analysis showed that direct interactions among genetic products were significantly higher than expected (p = 0.004), and DAVID analysis confirmed the defense-related functions of these genes. Gene mutation profiles of survived and non-survived patients were similar, suggesting some of genes identified in this study may be associated with H7N9 influenza susceptibility. Host specific genetic determinants of disease severity identified by this approach may provide new targets for the treatment of H7N9 influenza. PMID:27156515

  17. Candidate fire blight resistance genes in Malus identified with the use of genomic tools and approaches

    Science.gov (United States)

    The goal of this research is to utilize current advances in Rosaceae genomics to identify DNA markers for use in marker-assisted selection of durable resistance to fire blight. Candidate fire blight resistance genes were selected and ranked based upon differential expression after inoculation with ...

  18. Evaluation of potential regulatory elements identified as DNase I hypersensitive sites in the CFTR gene

    DEFF Research Database (Denmark)

    Phylactides, M.; Rowntree, R.; Nuthall, H.; Ussery, David; Wheeler, A.; Harris, A.

    2002-01-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) gene shows a complex pattern of expression, with temporal and spatial regulation that is not accounted for by elements in the promoter. One approach to identifying the regulatory elements for CFTR is the mapping of DNase I hypersensit...

  19. Resequencing 50 accessions of cultivated and wild rice yields markers for identifying agronomically important genes

    DEFF Research Database (Denmark)

    Xu, Xun; Liu, Xin; Ge, Song; Jensen, Jeffrey D.; Hu, Fengyi; Li, Xin; Dong, Yang; Gutenkunst, Ryan N.; Fang, Lin; Huang, Lei; Li, Jingxiang; He, Weiming; Zhang, Guojie; Zheng, Xiaoming; Zhang, Fumin; Li, Yingrui; Yu, Chang; Kristiansen, Karsten; Zhang, Xiuqing; Wang, Jian; Wright, Mark; McCouch, Susan; Nielsen, Rasmus; Wang, Jun; Wang, Wen

    2012-01-01

    raw data coverage. We investigated genome-wide variation patterns in rice and obtained 6.5 million high-quality single nucleotide polymorphisms (SNPs) after excluding sites with missing data in any accession. Using these population SNP data, we identified thousands of genes with significantly lower...

  20. Chicken ovalbumin gene fused to a herpes simplex virus. cap alpha. promoter and linked to a thymidine kinase gene is regulated like a viral gene

    Energy Technology Data Exchange (ETDEWEB)

    Post, L.E.; Norrild, B.; Simpson, T.; Roizman, B.

    1982-03-01

    The authors describe a system for the introduction, selection, and expression of eucaryotic genes in higher eucaryotic cells. The carrier consisted of the herpes simplex virus 1 (HSV-1) tk gene covalently linked to an HSV-1 ..cap alpha.. promoter directed away from the tk gene. In this study they fused to the ..cap alpha.. promoter the 5' transcribed noncoding sequences and the coding sequences of the chicken oviduct ovalbumin gene. Cells converted to the TK/sup +/ phenotype with this chimeric fragment produced an ovalbumin precursor which was processed and secreted into the extracellular fluid. The ovalbumin gene utilized the HSV-1 ..cap alpha.. promoter and was regulated as a viral gene inasmuch as inversion of the genomic DNA relative to the ..cap alpha.. promoter resulted in no ovalbumin synthesis, and production of ovalbumin was enhanced after superinfection with HSV-1. Synthesis of ovalbumin was not detected when cDNA was linked to the HSV-1 ..cap alpha.. promoter. The carrier system described in this study is suitable for introduction, selection, and expression of eucaryotic genes whose natural promoter is either weak or requires the presence of regulatory elements which may be absent from undifferentiated cells in culture.

  1. Gene expression meta-analysis identifies chromosomal regions involved in ovarian cancer survival

    DEFF Research Database (Denmark)

    Thomassen, Mads; Jochumsen, Kirsten M; Mogensen, Ole; Tan, Qihua; Kruse, Torben A

    2009-01-01

    summarized mutation load in these regions by a combined mutation score that is statistical significantly associated to survival by analysis in the data sets used for identification of the regions. Furthermore, the prognostic value of the combined mutation score was validated in an independent large data set......Ovarian cancer cells exhibit complex karyotypic alterations causing deregulation of numerous genes. Some of these genes are probably causal for cancer formation and local growth, whereas others are causal for metastasis and recurrence. By using publicly available data sets, we have investigated the...... relation of gene expression and chromosomal position to identify chromosomal regions of importance for early recurrence of ovarian cancer. By use of *Gene Set Enrichment Analysis*, we have ranked chromosomal regions according to their association to survival. Over-representation analysis including 1...

  2. Screening of a Leptospira biflexa Mutant Library To Identify Genes Involved in Ethidium Bromide Tolerance

    Science.gov (United States)

    P?troov, Helena

    2014-01-01

    Leptospira spp. are spirochete bacteria comprising both pathogenic and free-living species. The saprophyte L. biflexa is a model bacterium for studying leptospiral biology due to relative ease of culturing and genetic manipulation. In this study, we constructed a library of 4,996 random transposon mutants in L. biflexa. We screened the library for increased susceptibility to the DNA intercalating agent, ethidium bromide (EtBr), in order to identify genetic determinants that reduce L. biflexa susceptibility to antimicrobial agents. By phenotypic screening, using subinhibitory EtBr concentrations, we identified 29 genes that, when disrupted via transposon insertion, led to increased sensitivity of the bacteria to EtBr. At the functional level, these genes could be categorized by function as follows: regulation and signaling (n = 11), transport (n = 6), membrane structure (n = 5), stress response (n = 2), DNA damage repair (n = 1), and other processes (n = 3), while 1 gene had no predicted function. Genes involved in transport (including efflux pumps) and regulation (two-component systems, anti-sigma factor antagonists, etc.) were overrepresented, demonstrating that these genes are major contributors to EtBr tolerance. This finding suggests that transport genes which would prevent EtBr to enter the cell cytoplasm are critical for EtBr resistance. We identified genes required for the growth of L. biflexa in the presence of sublethal EtBr concentration and characterized their potential as antibiotic resistance determinants. This study will help to delineate mechanisms of adaptation to toxic compounds, as well as potential mechanisms of antibiotic resistance development in pathogenic L. interrogans. PMID:25063661

  3. Transcriptome profiling of bacterial responses to root exudates identifies genes involved in microbe-plant interactions.

    Science.gov (United States)

    Mark, G Louise; Dow, J Maxwell; Kiely, Patrick D; Higgins, Hazel; Haynes, Jill; Baysse, Christine; Abbas, Abdelhamid; Foley, Tara; Franks, Ashley; Morrissey, John; O'Gara, Fergal

    2005-11-29

    Molecules exuded by plant roots are thought to act as signals to influence the ability of microbial strains to colonize the roots and to survive in the rhizosphere. Differential bacterial responses to signals from different plant species may mediate the selection of specific rhizosphere populations. Very little, however, is known about the effects of plant exudates on patterns of bacterial gene expression. Here, we have tested the concept that plant root exudates modulate expression of bacterial genes involved in establishing microbe-plant interactions. We have examined the influence on the Pseudomonas aeruginosa PA01 transcriptome of exudates from two varieties of sugarbeet that select for genetically distinct pseudomonad populations in the rhizosphere. The response to the two exudates showed only a partial overlap; the majority of those genes with altered expression was regulated in response to only one of the two exudates. Genes with altered expression included those with functions previously implicated in microbe-plant interactions, such as aspects of metabolism, chemotaxis and type III secretion, and a subset with putative or unknown function. Use of a panel of mutants with targeted disruptions allowed us to identify previously uncharacterized genes with roles in the competitive ability of P. aeruginosa in the rhizosphere within this subset. No genes with host-specific effects were identified. Homologues of the genes identified occur in the genomes of both beneficial and pathogenic root-associated bacteria, suggesting that this strategy may help to elucidate molecular interactions that are important for biocontrol, plant growth promotion, and plant pathogenesis. PMID:16301542

  4. Identifying and assessing the impact of wine acid-related genes in yeast.

    Science.gov (United States)

    Chidi, Boredi S; Rossouw, Debra; Bauer, Florian F

    2016-02-01

    Saccharomyces cerevisiae strains used for winemaking show a wide range of fermentation phenotypes, and the genetic background of individual strains contributes significantly to the organoleptic properties of wine. This strain-dependent impact extends to the organic acid composition of the wine, an important quality parameter. However, little is known about the genes which may impact on organic acids during grape must fermentation. To generate novel insights into the genetic regulation of this metabolic network, a subset of genes was identified based on a comparative analysis of the transcriptomes and organic acid profiles of different yeast strains showing different production levels of organic acids. These genes showed significant inter-strain differences in their transcription levels at one or more stages of fermentation and were also considered likely to influence organic acid metabolism based on existing functional annotations. Genes selected in this manner were ADH3, AAD6, SER33, ICL1, GLY1, SFC1, SER1, KGD1, AGX1, OSM1 and GPD2. Yeast strains carrying deletions for these genes were used to conduct fermentations and determine organic acid levels at various stages of alcoholic fermentation in synthetic grape must. The impact of these deletions on organic acid profiles was quantified, leading to novel insights and hypothesis generation regarding the role/s of these genes in wine yeast acid metabolism under fermentative conditions. Overall, the data contribute to our understanding of the roles of selected genes in yeast metabolism in general and of organic acid metabolism in particular. PMID:26040556

  5. A graph-search framework for associating gene identifiers with documents

    Directory of Open Access Journals (Sweden)

    Cohen William W

    2006-10-01

    Full Text Available Abstract Background One step in the model organism database curation process is to find, for each article, the identifier of every gene discussed in the article. We consider a relaxation of this problem suitable for semi-automated systems, in which each article is associated with a ranked list of possible gene identifiers, and experimentally compare methods for solving this geneId ranking problem. In addition to baseline approaches based on combining named entity recognition (NER systems with a "soft dictionary" of gene synonyms, we evaluate a graph-based method which combines the outputs of multiple NER systems, as well as other sources of information, and a learning method for reranking the output of the graph-based method. Results We show that named entity recognition (NER systems with similar F-measure performance can have significantly different performance when used with a soft dictionary for geneId-ranking. The graph-based approach can outperform any of its component NER systems, even without learning, and learning can further improve the performance of the graph-based ranking approach. Conclusion The utility of a named entity recognition (NER system for geneId-finding may not be accurately predicted by its entity-level F1 performance, the most common performance measure. GeneId-ranking systems are best implemented by combining several NER systems. With appropriate combination methods, usefully accurate geneId-ranking systems can be constructed based on easily-available resources, without resorting to problem-specific, engineered components.

  6. Global gene analysis identifying genes commonly regulated by the Ras/Raf/MEK and type I IFN pathways

    Directory of Open Access Journals (Sweden)

    Y. Komatsu

    2015-06-01

    Full Text Available Oncolytic viruses exploit alterations in cancer cells to specifically infect cancer cells but not normal healthy cells. Previous work has shown that oncogenic Ras interferes with interferon (IFN signaling to promote viral replication. Furthermore, inhibition of the Ras/Raf/MEK/ERK pathway at the level of Ras, MEK, or ERK was sufficient to restore IFN signaling. In order to identify genes that were commonly regulated by the inhibition of the Ras pathway and the IFN pathway, we treated NIH/3T3 cells that overexpress oncogenic Ras with the MEK inhibitor, U0126, or IFN-α for 6 h, and performed DNA microarray analysis (Gene Expression Omnibus accession number GSE49469. Here, we also provide additional information on the experimental and functional analysis of the genes responsive to U0126 and IFN.

  7. Identifying new sex-linked genes through BAC sequencing in the dioecious plant Silene latifolia

    Czech Academy of Sciences Publication Activity Database

    Blavet, N.; Blavet, Hana; Muyle, A.; Kaefer, J.; Čegan, Radim; Deschamps, C.; Zemp, N.; Mousset, S.; Aubourg, S.; Bergero, R.; Charlesworth, D.; Hobza, Roman; Widmer, A.; Marais, G.A.B.

    2015-01-01

    Roč. 16, JUL 2015 (2015). ISSN 1471-2164 R&D Projects: GA ČR(CZ) GAP501/12/2220 Institutional support: RVO:68081707 Keywords : Y-CHROMOSOME * EVOLUTION * REARRANGEMENTS Subject RIV: BO - Biophysics Impact factor: 3.986, year: 2014

  8. Return to the fetal gene program: A suggested metabolic link to gene expression in the heart

    OpenAIRE

    Taegtmeyer, Heinrich; Sen, Shiraj; Vela, Deborah

    2010-01-01

    A hallmark of cardiac metabolism before birth is the predominance of carbohydrate use for energy provision. After birth, energy substrate metabolism rapidly switches to the oxidation of fatty acids. This switch accompanies the expression of “adult” isoforms of metabolic enzymes and other proteins. However, in a variety of pathophysiologic conditions, including hypoxia, ischemia, hypertrophy, atrophy, diabetes, and hypothyroidism, the postnatal heart returns to the “fetal” gene program. These ...

  9. Missing Links in Genes to Traits: Toward Teaching for an Integrated Framework of Genetics

    Science.gov (United States)

    Pavlova, Iglika V.; Kreher, Scott A.

    2013-01-01

    Genetics, one of the most influential fields, underlies all of biology and produces discoveries that are in the news daily. However, many students leave introductory biology and genetics courses lacking a coherent framework of knowledge to use in their daily lives. We identify substantial "missing links" in the teaching of foundational…

  10. Transcriptome analysis of recurrently deregulated genes across multiple cancers identifies new pan-cancer biomarkers

    DEFF Research Database (Denmark)

    Kaczkowski, Bogumil; Tanaka, Yuji; Kawaji, Hideya; Sandelin, Albin; Andersson, Robin; Itoh, Masayoshi; Lassmann, Timo; Hayashizaki, Yoshihide; Carninci, Piero; Forrest, Alistair R

    2015-01-01

    Genes that are commonly deregulated in cancer are clinically attractive as candidate pan-diagnostic markers and therapeutic targets. To globally identify such targets, we compared Cap Analysis of Gene Expression (CAGE) profiles from 225 different cancer cell lines and 339 corresponding primary cell...... samples to identify transcripts that are deregulated recurrently in a broad range of cancer types. Comparing RNA-seq data from 4,055 tumors and 563 normal tissues profiled in the TCGA and FANTOM5 datasets, we identified a core transcript set with theranostic potential. Our analyses also revealed enhancer...... RNAs which are upregulated in cancer, defining promoters which overlap with repetitive elements (especially SINE/Alu and LTR/ERV1 elements) that are often upregulated in cancer. Lastly, we documented for the first time upregulation of multiple copies of the REP522 interspersed repeat in cancer. Overall...

  11. Global gene analysis identifying genes commonly regulated by the Ras/Raf/MEK and type I IFN pathways

    OpenAIRE

    Komatsu, Y.; Hirasawa, K.; Christian, S.L.

    2015-01-01

    Oncolytic viruses exploit alterations in cancer cells to specifically infect cancer cells but not normal healthy cells. Previous work has shown that oncogenic Ras interferes with interferon (IFN) signaling to promote viral replication. Furthermore, inhibition of the Ras/Raf/MEK/ERK pathway at the level of Ras, MEK, or ERK was sufficient to restore IFN signaling. In order to identify genes that were commonly regulated by the inhibition of the Ras pathway and the IFN pathway, we treated NIH/3T3...

  12. Microcephaly gene links Trithorax and REST/NRSF to control neural stem cell proliferation and differentiation

    OpenAIRE

    Yang, Yawei J.; Baltus, Andrew E.; Mathew, Rebecca S.; Murphy, Elisabeth A.; Evrony, Gilad D.; Gonzalez, Dilenny M.; Wang, Estee P.; Marshall-Walker, Christine A.; Barry, Brenda J.; Murn, Jernej; Tatarakis, Antonis; Mahajan, Muktar A; Samuels, Herbert H; Shi, Yang; Golden, Jeffrey A

    2012-01-01

    Microcephaly is a neurodevelopmental disorder causing significantly reduced cerebral cortex size. Many known microcephaly gene products localize to centrosomes, regulating cell fate and proliferation. Here, we identify and characterize a nuclear zinc finger protein, ZNF335/NIF-1, as a causative gene for severe microcephaly, small somatic size, and neonatal death. Znf335-null mice are embryonically lethal and conditional knockout leads to severely reduced cortical size. RNA-interference and po...

  13. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production

    OpenAIRE

    Michelucci, Alessandro; Cordes, Thekla; Ghelfi, Jenny; Pailot, Arnaud; Reiling, Norbert; Goldmann, Oliver; Binz, Tina; Wegner, Andr; Tallam, Aravind; Rausell, Antonio; Buttini, Manuel; Linster, Carole L.; Medina, Eva; Balling, Rudi; Hiller, Karsten

    2013-01-01

    Immunoresponsive gene 1 (Irg1) is highly expressed in mammalian macrophages during inflammation, but its biological function has not yet been elucidated. Here, we identify Irg1 as the gene coding for an enzyme producing itaconic acid (also known as methylenesuccinic acid) through the decarboxylation of cis-aconitate, a tricarboxylic acid cycle intermediate. Using a gain-and-loss-of-function approach in both mouse and human immune cells, we found Irg1 expression levels correlating with the amo...

  14. GPR143 Gene Mutations in Five Chinese Families with X-linked Congenital Nystagmus.

    Science.gov (United States)

    Han, Ruifang; Wang, Xiaojuan; Wang, Dongjie; Wang, Liming; Yuan, Zhongfang; Ying, Ming; Li, Ningdong

    2015-01-01

    The ocular albinism type I (OA1) is clinically characterized by impaired visual acuity, nystagmus, iris hypopigmentation with translucency, albinotic fundus, and macular hypoplasia together with normally pigmented skin and hair. However, it is easily misdiagnosed as congenital idiopathic nystagmus in some Chinese patients with OA1 caused by the G-protein coupled receptor 143 (GPR143) gene mutations. Mutations in the FERM domain-containing 7 (FRMD7) gene are responsible for the X-linked congenital idiopathic nystagmus. In this study, five Chinese families initially diagnosed as X-linked congenital nystagmus were recruited and patients underwent ophthalmological examinations. After direct sequencing of the FRMD7 and GPR143 genes, five mutations in GPR143 gene were detected in each of the five families, including a novel nonsense mutation of c.333G>A (p.W111X), two novel splicing mutations of c.360+1G>C and c.659-1G>A, a novel small deletion mutation of c.43_50dupGACGCAGC (p.L20PfsX25), and a previously reported missense mutation of c.703G>A (p.E235K). Optical coherence tomography (OCT) examination showed foveal hypoplasia in all the affected patients with nystagmus. Our study further expands the GPR143 mutation spectrum and contributes to the study of GPR143 molecular pathogenesis. Molecular diagnosis and optical coherence tomography (OCT) are two useful tools for differential diagnosis. PMID:26160353

  15. Principal components analysis based methodology to identify differentially expressed genes in time-course microarray data

    Directory of Open Access Journals (Sweden)

    Srinivasan Rajagopalan

    2008-06-01

    Full Text Available Abstract Background Time-course microarray experiments are being increasingly used to characterize dynamic biological processes. In these experiments, the goal is to identify genes differentially expressed in time-course data, measured between different biological conditions. These differentially expressed genes can reveal the changes in biological process due to the change in condition which is essential to understand differences in dynamics. Results In this paper, we propose a novel method for finding differentially expressed genes in time-course data and across biological conditions (say C1 and C2. We model the expression at C1 using Principal Component Analysis and represent the expression profile of each gene as a linear combination of the dominant Principal Components (PCs. Then the expression data from C2 is projected on the developed PCA model and scores are extracted. The difference between the scores is evaluated using a hypothesis test to quantify the significance of differential expression. We evaluate the proposed method to understand differences in two case studies (1 the heat shock response of wild-type and HSF1 knockout mice, and (2 cell-cycle between wild-type and Fkh1/Fkh2 knockout Yeast strains. Conclusion In both cases, the proposed method identified biologically significant genes.

  16. Expressed sequences tags of the anther smut fungus, Microbotryum violaceum, identify mating and pathogenicity genes

    Directory of Open Access Journals (Sweden)

    Devier Benjamin

    2007-08-01

    Full Text Available Abstract Background The basidiomycete fungus Microbotryum violaceum is responsible for the anther-smut disease in many plants of the Caryophyllaceae family and is a model in genetics and evolutionary biology. Infection is initiated by dikaryotic hyphae produced after the conjugation of two haploid sporidia of opposite mating type. This study describes M. violaceum ESTs corresponding to nuclear genes expressed during conjugation and early hyphal production. Results A normalized cDNA library generated 24,128 sequences, which were assembled into 7,765 unique genes; 25.2% of them displayed significant similarity to annotated proteins from other organisms, 74.3% a weak similarity to the same set of known proteins, and 0.5% were orphans. We identified putative pheromone receptors and genes that in other fungi are involved in the mating process. We also identified many sequences similar to genes known to be involved in pathogenicity in other fungi. The M. violaceum EST database, MICROBASE, is available on the Web and provides access to the sequences, assembled contigs, annotations and programs to compare similarities against MICROBASE. Conclusion This study provides a basis for cloning the mating type locus, for further investigation of pathogenicity genes in the anther smut fungi, and for comparative genomics.

  17. Variants in candidate ALS modifier genes linked to Cu/Zn superoxide dismutase do not explain divergent survival phenotypes.

    Science.gov (United States)

    Broom, Wendy J; Russ, Carsten; Sapp, Peter C; McKenna-Yasek, Diane; Hosler, Betsy A; Andersen, Peter M; Brown, Robert H

    2006-01-01

    Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS cases; approximately 25% are due to mutations in the Cu/Zn superoxide dismutase gene (SOD1). In North America, SOD1(A4V) is the most common SOD1 mutation. A4V ALS cases typically have a very short survival (1-1.5 years versus 3-5 years for other dominant SOD1 mutations). A recent study of A4V carriers identified a common haplotype around the SOD1 locus, suggesting the hypothesis that genetic variations within the haplotypic region might accelerate the course of A4V cases. By contrast, SOD1(D90A/D90A) ALS cases have a very slow progression (>10 years), raising the reciprocal hypothesis that modifier genes linked to SOD1 ameliorate the phenotype of recessively inherited SOD1(D90A/D90A) mutations. In the present study, DNA sequencing of four genes within the haplotypic region shared in A4V and D90A ALS patients revealed 15 novel variants, but none result in changes in amino acid sequences specifically associated with SOD1(D90A/D90A) or SOD1(A4V) ALS. We conclude that mutations within coding regions of genes around the SOD1 locus are not responsible for the more aggressive and more benign natures of the SOD1(A4V) and SOD1(D90A/D90A) mutations, respectively. PMID:16174551

  18. Linking Advanced Visualization and MATLAB for the Analysis of 3D Gene Expression Data

    Energy Technology Data Exchange (ETDEWEB)

    Ruebel, Oliver; Keranen, Soile V.E.; Biggin, Mark; Knowles, David W.; Weber, Gunther H.; Hagen, Hans; Hamann, Bernd; Bethel, E. Wes

    2011-03-30

    Three-dimensional gene expression PointCloud data generated by the Berkeley Drosophila Transcription Network Project (BDTNP) provides quantitative information about the spatial and temporal expression of genes in early Drosophila embryos at cellular resolution. The BDTNP team visualizes and analyzes Point-Cloud data using the software application PointCloudXplore (PCX). To maximize the impact of novel, complex data sets, such as PointClouds, the data needs to be accessible to biologists and comprehensible to developers of analysis functions. We address this challenge by linking PCX and Matlab via a dedicated interface, thereby providing biologists seamless access to advanced data analysis functions and giving bioinformatics researchers the opportunity to integrate their analysis directly into the visualization application. To demonstrate the usefulness of this approach, we computationally model parts of the expression pattern of the gene even skipped using a genetic algorithm implemented in Matlab and integrated into PCX via our Matlab interface.

  19. Non-linked inhibitory gene controls a disease mimicking mutant in rice [Oryza sativa L.

    International Nuclear Information System (INIS)

    A gamma ray induced disease mimicking mutant called luchai lesion was isolated in the rice variety White Luchai 112. The appearance of small light red lesions and their development continued from seedling to flowering. The lesions appeared gradually on older leaves and their uncontrolled spread eventually lead to leaf senescence. They resembled the disease spots caused by Magnaporthe grisea. However, pathological studies ruled out the possibility of pathogen mediated disease symptoms. Genetic studies revealed that lesions were governed by a dominant gene; however, their expression was suppressed in presence of a non-linked inhibitory gene. It is hypothesised that the plant cells of the mutant are able to sense inbuilt spontaneous signals leading to lesion development, but in presence of an inhibitory gene the signals are suppressed by perturbation in the signal transduction pathway

  20. Behavioral and cerebellar transmission deficits in mice lacking the autism-linked gene islet brain-2.

    Science.gov (United States)

    Giza, Joanna; Urbanski, Michael J; Prestori, Francesca; Bandyopadhyay, Bhaswati; Yam, Annie; Friedrich, Victor; Kelley, Kevin; D'Angelo, Egidio; Goldfarb, Mitchell

    2010-11-01

    Deletion of the human SHANK3 gene near the terminus of chromosome 22q is associated with Phelan-McDermid syndrome and autism spectrum disorders. Nearly all such deletions also span the tightly linked IB2 gene. We show here that IB2 protein is broadly expressed in the brain and is highly enriched within postsynaptic densities. Experimental disruption of the IB2 gene in mice reduces AMPA and enhances NMDA receptor-mediated glutamatergic transmission in cerebellum, changes the morphology of Purkinje cell dendritic arbors, and induces motor and cognitive deficits suggesting an autism phenotype. These findings support a role for human IB2 mutation as a contributing genetic factor in Chr22qter-associated cognitive disorders. PMID:21048139

  1. Gene Expression Profiling in Hereditary, BRCA1-linked Breast Cancer: Preliminary Report

    Directory of Open Access Journals (Sweden)

    Dudaladava Volha

    2006-01-01

    Full Text Available Abstract Global analysis of gene expression by DNA microarrays is nowadays a widely used tool, especially relevant for cancer research. It helps the understanding of complex biology of cancer tissue, allows identification of novel molecular markers, reveals previously unknown molecular subtypes of cancer that differ by clinical features like drug susceptibility or general prognosis. Our aim was to compare gene expression profiles in breast cancer that develop against a background of inherited predisposing mutations versus sporadic breast cancer. In this preliminary study we analysed seven hereditary, BRCA1 mutation-linked breast cancer tissues and seven sporadic cases that were carefully matched by histopathology and ER status. Additionally, we analysed 6 samples of normal breast tissue. We found that while the difference in gene expression profiles between tumour tissue and normal breast can be easily recognized by unsupervised algorithms, the difference between those two types of tumours is more discrete. However, by supervised methods of data analysis, we were able to select a set of genes that may differentiate between hereditary and sporadic tumours. The most significant difference concerns genes that code for proteins engaged in regulation of transcription, cellular metabolism, signalling, proliferation and cell death. Microarray results for chosen genes (TOB1, SEPHS2 were validated by real-time RT-PCR.

  2. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency.

    Science.gov (United States)

    De Ravin, Suk See; Wu, Xiaolin; Moir, Susan; Anaya-O'Brien, Sandra; Kwatemaa, Nana; Littel, Patricia; Theobald, Narda; Choi, Uimook; Su, Ling; Marquesen, Martha; Hilligoss, Dianne; Lee, Janet; Buckner, Clarissa M; Zarember, Kol A; O'Connor, Geraldine; McVicar, Daniel; Kuhns, Douglas; Throm, Robert E; Zhou, Sheng; Notarangelo, Luigi D; Hanson, I Celine; Cowan, Mort J; Kang, Elizabeth; Hadigan, Coleen; Meagher, Michael; Gray, John T; Sorrentino, Brian P; Malech, Harry L

    2016-04-20

    X-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations inIL2RGencoding the common chain (γc) of several interleukin receptors. Gamma-retroviral (γRV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy. Follow-up data from two older patients demonstrate that lentiviral vector γc transduced autologous HSC gene therapy after nonmyeloablative busulfan conditioning achieves selective expansion of gene-marked T, NK, and B cells, which is associated with sustained restoration of humoral responses to immunization and clinical improvement at 2 to 3 years after treatment. Similar gene marking levels have been achieved in three younger patients, albeit with only 6 to 9 months of follow-up. Lentiviral gene therapy with reduced-intensity conditioning appears safe and can restore humoral immune function to posthaploidentical transplant older patients with SCID-X1. PMID:27099176

  3. Identifying candidate genes affecting developmental time in Drosophila melanogaster: pervasive pleiotropy and gene-by-environment interaction

    Directory of Open Access Journals (Sweden)

    Hasson Esteban

    2008-08-01

    Full Text Available Abstract Background Understanding the genetic architecture of ecologically relevant adaptive traits requires the contribution of developmental and evolutionary biology. The time to reach the age of reproduction is a complex life history trait commonly known as developmental time. In particular, in holometabolous insects that occupy ephemeral habitats, like fruit flies, the impact of developmental time on fitness is further exaggerated. The present work is one of the first systematic studies of the genetic basis of developmental time, in which we also evaluate the impact of environmental variation on the expression of the trait. Results We analyzed 179 co-isogenic single P[GT1]-element insertion lines of Drosophila melanogaster to identify novel genes affecting developmental time in flies reared at 25°C. Sixty percent of the lines showed a heterochronic phenotype, suggesting that a large number of genes affect this trait. Mutant lines for the genes Merlin and Karl showed the most extreme phenotypes exhibiting a developmental time reduction and increase, respectively, of over 2 days and 4 days relative to the control (a co-isogenic P-element insertion free line. In addition, a subset of 42 lines selected at random from the initial set of 179 lines was screened at 17°C. Interestingly, the gene-by-environment interaction accounted for 52% of total phenotypic variance. Plastic reaction norms were found for a large number of developmental time candidate genes. Conclusion We identified components of several integrated time-dependent pathways affecting egg-to-adult developmental time in Drosophila. At the same time, we also show that many heterochronic phenotypes may arise from changes in genes involved in several developmental mechanisms that do not explicitly control the timing of specific events. We also demonstrate that many developmental time genes have pleiotropic effects on several adult traits and that the action of most of them is sensitive to temperature during development. Taken together, our results stress the need to take into account the effect of environmental variation and the dynamics of gene interactions on the genetic architecture of this complex life-history trait.

  4. Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome.

    Science.gov (United States)

    Albers, Cornelis A; Cvejic, Ana; Favier, Rémi; Bouwmans, Evelien E; Alessi, Marie-Christine; Bertone, Paul; Jordan, Gregory; Kettleborough, Ross N W; Kiddle, Graham; Kostadima, Myrto; Read, Randy J; Sipos, Botond; Sivapalaratnam, Suthesh; Smethurst, Peter A; Stephens, Jonathan; Voss, Katrin; Nurden, Alan; Rendon, Augusto; Nurden, Paquita; Ouwehand, Willem H

    2011-08-01

    Gray platelet syndrome (GPS) is a predominantly recessive platelet disorder that is characterized by mild thrombocytopenia with large platelets and a paucity of α-granules; these abnormalities cause mostly moderate but in rare cases severe bleeding. We sequenced the exomes of four unrelated individuals and identified NBEAL2 as the causative gene; it has no previously known function but is a member of a gene family that is involved in granule development. Silencing of nbeal2 in zebrafish abrogated thrombocyte formation. PMID:21765411

  5. Back to the sea twice: identifying candidate plant genes for molecular evolution to marine life

    Directory of Open Access Journals (Sweden)

    Reusch Thorsten BH

    2011-01-01

    Full Text Available Abstract Background Seagrasses are a polyphyletic group of monocotyledonous angiosperms that have adapted to a completely submerged lifestyle in marine waters. Here, we exploit two collections of expressed sequence tags (ESTs of two wide-spread and ecologically important seagrass species, the Mediterranean seagrass Posidonia oceanica (L. Delile and the eelgrass Zostera marina L., which have independently evolved from aquatic ancestors. This replicated, yet independent evolutionary history facilitates the identification of traits that may have evolved in parallel and are possible instrumental candidates for adaptation to a marine habitat. Results In our study, we provide the first quantitative perspective on molecular adaptations in two seagrass species. By constructing orthologous gene clusters shared between two seagrasses (Z. marina and P. oceanica and eight distantly related terrestrial angiosperm species, 51 genes could be identified with detection of positive selection along the seagrass branches of the phylogenetic tree. Characterization of these positively selected genes using KEGG pathways and the Gene Ontology uncovered that these genes are mostly involved in translation, metabolism, and photosynthesis. Conclusions These results provide first insights into which seagrass genes have diverged from their terrestrial counterparts via an initial aquatic stage characteristic of the order and to the derived fully-marine stage characteristic of seagrasses. We discuss how adaptive changes in these processes may have contributed to the evolution towards an aquatic and marine existence.

  6. Transcriptome profiling to identify genes involved in pathogenicity of Valsa mali on apple tree.

    Science.gov (United States)

    Ke, Xiwang; Yin, Zhiyuan; Song, Na; Dai, Qingqing; Voegele, Ralf T; Liu, Yangyang; Wang, Haiying; Gao, Xiaoning; Kang, Zhensheng; Huang, Lili

    2014-07-01

    Apple Valsa canker, caused by the fungus Valsa mali (Vm), is one of the most destructive diseases of apple in China. A better understanding of this host-pathogen interaction is urgently needed to improve management strategies. In the current study we sequenced the transcriptomes of Vm during infection of apple bark and mycelium grown in axenic culture using Illumina RNA-Seq technology. We identified 437 genes that were differentially expressed during fungal infection compared to fungal mycelium grown in axenic culture. One hundred and thirty nine of these 437 genes showed more than two fold higher transcript abundance during infection. GO and KEGG enrichment analyses of the up-regulated genes suggest prevalence of genes associated with pectin catabolic, hydrolase activity and secondary metabolite biosynthesis during fungal infection. Some of the up-regulated genes associated with loss of pathogenicity and reduced virulence annotated by host-pathogen interaction databases may also be involved in cell wall hydrolysis and secondary metabolite transport, including a glycoside hydrolase family 28 protein, a peptidase and two major facilitator superfamily proteins. This highlights the importance of secondary metabolites and cell wall hydrolases during establishment of apple Valsa canker. Functional verification of the genes involved in pathogenicity of Vm will allow us to better understand how the fungus interferes with the host machinery and assists in apple canker establishment. PMID:24747070

  7. On estimation and identifiability issues of sex-linked inheritance with a case study of pigmentation in Swiss barn owl (Tyto alba).

    Science.gov (United States)

    Larsen, Camilla T; Holand, Anna M; Jensen, Henrik; Steinsland, Ingelin; Roulin, Alexandre

    2014-05-01

    Genetic evaluation using animal models or pedigree-based models generally assume only autosomal inheritance. Bayesian animal models provide a flexible framework for genetic evaluation, and we show how the model readily can accommodate situations where the trait of interest is influenced by both autosomal and sex-linked inheritance. This allows for simultaneous calculation of autosomal and sex-chromosomal additive genetic effects. Inferences were performed using integrated nested Laplace approximations (INLA), a nonsampling-based Bayesian inference methodology. We provide a detailed description of how to calculate the inverse of the X- or Z-chromosomal additive genetic relationship matrix, needed for inference. The case study of eumelanic spot diameter in a Swiss barn owl (Tyto alba) population shows that this trait is substantially influenced by variation in genes on the Z-chromosome ([Formula: see text] and [Formula: see text]). Further, a simulation study for this study system shows that the animal model accounting for both autosomal and sex-chromosome-linked inheritance is identifiable, that is, the two effects can be distinguished, and provides accurate inference on the variance components. PMID:24967075

  8. Evaluation of voltage-dependent calcium channel γ gene families identified several novel potential susceptible genes to schizophrenia

    Science.gov (United States)

    Guan, Fanglin; Zhang, Tianxiao; Liu, Xinshe; Han, Wei; Lin, Huali; Li, Lu; Chen, Gang; Li, Tao

    2016-01-01

    Voltage-gated L-type calcium channels (VLCC) are distributed widely throughout the brain. Among the genes involved in schizophrenia (SCZ), genes encoding VLCC subunits have attracted widespread attention. Among the four subunits comprising the VLCC (α − 1, α −2/δ, β, and γ), the γ subunit that comprises an eight-member protein family is the least well understood. In our study, to further investigate the risk susceptibility by the γ subunit gene family to SCZ, we conducted a large-scale association study in Han Chinese individuals. The SNP rs17645023 located in the intergenic region of CACNG4 and CACNG5 was identified to be significantly associated with SCZ (OR = 0.856, P = 5.43 × 10−5). Similar results were obtained in the meta-analysis with the current SCZ PGC data (OR = 0.8853). We also identified a two-SNP haplotype (rs10420331-rs11084307, P = 1.4 × 10−6) covering the intronic region of CACNG8 to be significantly associated with SCZ. Epistasis analyses were conducted, and significant statistical interaction (OR = 0.622, P = 2.93 × 10−6, Pperm < 0.001) was observed between rs192808 (CACNG6) and rs2048137 (CACNG5). Our results indicate that CACNG4, CACNG5, CACNG6 and CACNG8 may contribute to the risk of SCZ. The statistical epistasis identified between CACNG5 and CACNG6 suggests that there may be an underlying biological interaction between the two genes. PMID:27102562

  9. Transcriptomic and genetic studies identify NFAT5 as a candidate gene for cocaine dependence.

    Science.gov (United States)

    Fernàndez-Castillo, N; Cabana-Domínguez, J; Soriano, J; Sànchez-Mora, C; Roncero, C; Grau-López, L; Ros-Cucurull, E; Daigre, C; van Donkelaar, M M J; Franke, B; Casas, M; Ribasés, M; Cormand, B

    2015-01-01

    Cocaine reward and reinforcing effects are mediated mainly by dopaminergic neurotransmission. In this study, we aimed at evaluating gene expression changes induced by acute cocaine exposure on SH-SY5Y-differentiated cells, which have been widely used as a dopaminergic neuronal model. Expression changes and a concomitant increase in neuronal activity were observed after a 5 μM cocaine exposure, whereas no changes in gene expression or in neuronal activity took place at 1 μM cocaine. Changes in gene expression were identified in a total of 756 genes, mainly related to regulation of transcription and gene expression, cell cycle, adhesion and cell projection, as well as mitogen-activeated protein kinase (MAPK), CREB, neurotrophin and neuregulin signaling pathways. Some genes displaying altered expression were subsequently targeted with predicted functional single-nucleotide polymorphisms (SNPs) in a case-control association study in a sample of 806 cocaine-dependent patients and 817 controls. This study highlighted associations between cocaine dependence and five SNPs predicted to alter microRNA binding at the 3'-untranslated region of the NFAT5 gene. The association of SNP rs1437134 with cocaine dependence survived the Bonferroni correction for multiple testing. A functional effect was confirmed for this variant by a luciferase reporter assay, with lower expression observed for the rs1437134G allele, which was more pronounced in the presence of hsa-miR-509. However, brain volumes in regions of relevance to addiction, as assessed with magnetic resonance imaging, did not correlate with NFAT5 variation. These results suggest that the NFAT5 gene, which is upregulated a few hours after cocaine exposure, may be involved in the genetic predisposition to cocaine dependence. PMID:26506053

  10. PhiSiGns: an online tool to identify signature genes in phages and design PCR primers for examining phage diversity

    Directory of Open Access Journals (Sweden)

    Dwivedi Bhakti

    2012-03-01

    Full Text Available Abstract Background Phages (viruses that infect bacteria have gained significant attention because of their abundance, diversity and important ecological roles. However, the lack of a universal gene shared by all phages presents a challenge for phage identification and characterization, especially in environmental samples where it is difficult to culture phage-host systems. Homologous conserved genes (or "signature genes" present in groups of closely-related phages can be used to explore phage diversity and define evolutionary relationships amongst these phages. Bioinformatic approaches are needed to identify candidate signature genes and design PCR primers to amplify those genes from environmental samples; however, there is currently no existing computational tool that biologists can use for this purpose. Results Here we present PhiSiGns, a web-based and standalone application that performs a pairwise comparison of each gene present in user-selected phage genomes, identifies signature genes, generates alignments of these genes, and designs potential PCR primer pairs. PhiSiGns is available at (http://www.phantome.org/phisigns/; http://phisigns.sourceforge.net/ with a link to the source code. Here we describe the specifications of PhiSiGns and demonstrate its application with a case study. Conclusions PhiSiGns provides phage biologists with a user-friendly tool to identify signature genes and design PCR primers to amplify related genes from uncultured phages in environmental samples. This bioinformatics tool will facilitate the development of novel signature genes for use as molecular markers in studies of phage diversity, phylogeny, and evolution.

  11. Gene Expression Profiling Identifies Important Genes Affected by R2 Compound Disrupting FAK and P53 Complex

    Energy Technology Data Exchange (ETDEWEB)

    Golubovskaya, Vita M., E-mail: Vita.Golubovskaya@roswellpark.org; Ho, Baotran [Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263 (United States); Conroy, Jeffrey [Genomics Shared Resource, Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263 (United States); Liu, Song; Wang, Dan [Bioinformatics Core Facility, Biostatistics, Roswell Park Cancer Institute, Buffalo, NY 14263 (United States); Cance, William G. [Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263 (United States)

    2014-01-21

    Focal Adhesion Kinase (FAK) is a non-receptor kinase that plays an important role in many cellular processes: adhesion, proliferation, invasion, angiogenesis, metastasis and survival. Recently, we have shown that Roslin 2 or R2 (1-benzyl-15,3,5,7-tetraazatricyclo[3.3.1.1~3,7~]decane) compound disrupts FAK and p53 proteins, activates p53 transcriptional activity, and blocks tumor growth. In this report we performed a microarray gene expression analysis of R2-treated HCT116 p53{sup +/+} and p53{sup −/−} cells and detected 1484 genes that were significantly up- or down-regulated (p < 0.05) in HCT116 p53{sup +/+} cells but not in p53{sup −/−} cells. Among up-regulated genes in HCT p53{sup +/+} cells we detected critical p53 targets: Mdm-2, Noxa-1, and RIP1. Among down-regulated genes, Met, PLK2, KIF14, BIRC2 and other genes were identified. In addition, a combination of R2 compound with M13 compound that disrupts FAK and Mmd-2 complex or R2 and Nutlin-1 that disrupts Mdm-2 and p53 decreased clonogenicity of HCT116 p53{sup +/+} colon cancer cells more significantly than each agent alone in a p53-dependent manner. Thus, the report detects gene expression profile in response to R2 treatment and demonstrates that the combination of drugs targeting FAK, Mdm-2, and p53 can be a novel therapy approach.

  12. Mutual or Unrequited Love: Identifying Stable Clusters in Social Networks with Uni- and Bi-directional Links

    CERN Document Server

    Li, Yanhua; Bao, Jie

    2012-01-01

    Many social networks, e.g., Slashdot and Twitter, can be represented as directed graphs (digraphs) with two types of links between entities: mutual (bi-directional) and one-way (uni-directional) connections. Social science theories reveal that mutual connections are more stable than one-way connections, and one-way connections exhibit various tendencies to become mutual connections. It is therefore important to take such tendencies into account when performing clustering of social networks with both mutual and one-way connections. In this paper, we utilize the dyadic methods to analyze social networks, and develop a generalized mutuality tendency theory to capture the tendencies of those node pairs which tend to establish mutual connections more frequently than those occur by chance. Using these results, we develop a mutuality-tendency-aware spectral clustering algorithm to identify more stable clusters by maximizing the within-cluster mutuality tendency and minimizing the cross-cluster mutuality tendency. Ex...

  13. Identifying the Viral Genes Encoding Envelope Glycoproteins for Differentiation of Cyprinid herpesvirus 3 Isolates

    Directory of Open Access Journals (Sweden)

    Se Chang Park

    2013-01-01

    Full Text Available Cyprinid herpes virus 3 (CyHV-3 diseases have been reported around the world and are associated with high mortalities of koi (Cyprinus carpio. Although little work has been conducted on the molecular analysis of this virus, glycoprotein genes identified in the present study seem to be valuable targets for genetic comparison of this virus. Three envelope glycoprotein genes (ORF25, 65 and 116 of the CyHV-3 isolates from the USA, Israel, Japan and Korea were compared, and interestingly, sequence insertions or deletions were observed in these target regions. In addition, polymorphisms were presented in microsatellite zones from two glycoprotein genes (ORF65 and 116. In phylogenetic tree analysis, the Korean isolate was remarkably distinguished from USA, Israel, Japan isolates. These findings may be suitable for many applications including isolates differentiation and phylogeny studies.

  14. An EST-based analysis identifies new genes and reveals distinctive gene expression features of Coffea arabica and Coffea canephora

    Directory of Open Access Journals (Sweden)

    Colombo Carlos A

    2011-02-01

    Full Text Available Abstract Background Coffee is one of the world's most important crops; it is consumed worldwide and plays a significant role in the economy of producing countries. Coffea arabica and C. canephora are responsible for 70 and 30% of commercial production, respectively. C. arabica is an allotetraploid from a recent hybridization of the diploid species, C. canephora and C. eugenioides. C. arabica has lower genetic diversity and results in a higher quality beverage than C. canephora. Research initiatives have been launched to produce genomic and transcriptomic data about Coffea spp. as a strategy to improve breeding efficiency. Results Assembling the expressed sequence tags (ESTs of C. arabica and C. canephora produced by the Brazilian Coffee Genome Project and the Nestlé-Cornell Consortium revealed 32,007 clusters of C. arabica and 16,665 clusters of C. canephora. We detected different GC3 profiles between these species that are related to their genome structure and mating system. BLAST analysis revealed similarities between coffee and grape (Vitis vinifera genes. Using KA/KS analysis, we identified coffee genes under purifying and positive selection. Protein domain and gene ontology analyses suggested differences between Coffea spp. data, mainly in relation to complex sugar synthases and nucleotide binding proteins. OrthoMCL was used to identify specific and prevalent coffee protein families when compared to five other plant species. Among the interesting families annotated are new cystatins, glycine-rich proteins and RALF-like peptides. Hierarchical clustering was used to independently group C. arabica and C. canephora expression clusters according to expression data extracted from EST libraries, resulting in the identification of differentially expressed genes. Based on these results, we emphasize gene annotation and discuss plant defenses, abiotic stress and cup quality-related functional categories. Conclusion We present the first comprehensive genome-wide transcript profile study of C. arabica and C. canephora, which can be freely assessed by the scientific community at http://www.lge.ibi.unicamp.br/coffea. Our data reveal the presence of species-specific/prevalent genes in coffee that may help to explain particular characteristics of these two crops. The identification of differentially expressed transcripts offers a starting point for the correlation between gene expression profiles and Coffea spp. developmental traits, providing valuable insights for coffee breeding and biotechnology, especially concerning sugar metabolism and stress tolerance.

  15. Novel ?-catenin target genes identified in thalamic neurons encode modulators of neuronal excitability

    Directory of Open Access Journals (Sweden)

    Wisniewska Marta B

    2012-11-01

    Full Text Available Abstract Background LEF1/TCF transcription factors and their activator ?-catenin are effectors of the canonical Wnt pathway. Although Wnt/?-catenin signaling has been implicated in neurodegenerative and psychiatric disorders, its possible role in the adult brain remains enigmatic. To address this issue, we sought to identify the genetic program activated by ?-catenin in neurons. We recently showed that ?-catenin accumulates specifically in thalamic neurons where it activates Cacna1g gene expression. In the present study, we combined bioinformatics and experimental approaches to find new ?-catenin targets in the adult thalamus. Results We first selected the genes with at least two conserved LEF/TCF motifs within the regulatory elements. The resulting list of 428 putative LEF1/TCF targets was significantly enriched in known Wnt targets, validating our approach. Functional annotation of the presumed targets also revealed a group of 41 genes, heretofore not associated with Wnt pathway activity, that encode proteins involved in neuronal signal transmission. Using custom polymerase chain reaction arrays, we profiled the expression of these genes in the rat forebrain. We found that nine of the analyzed genes were highly expressed in the thalamus compared with the cortex and hippocampus. Removal of nuclear ?-catenin from thalamic neurons in vitro by introducing its negative regulator Axin2 reduced the expression of six of the nine genes. Immunoprecipitation of chromatin from the brain tissues confirmed the interaction between ?-catenin and some of the predicted LEF1/TCF motifs. The results of these experiments validated four genes as authentic and direct targets of ?-catenin: Gabra3 for the receptor of GABA neurotransmitter, Calb2 for the Ca2+-binding protein calretinin, and the Cacna1g and Kcna6 genes for voltage-gated ion channels. Two other genes from the latter cluster, Cacna2d2 and Kcnh8, appeared to be regulated by ?-catenin, although the binding of ?-catenin to the regulatory sequences of these genes could not be confirmed. Conclusions In the thalamus, ?-catenin regulates the expression of a novel group of genes that encode proteins involved in neuronal excitation. This implies that the transcriptional activity of ?-catenin is necessary for the proper excitability of thalamic neurons, may influence activity in the thalamocortical circuit, and may contribute to thalamic pathologies.

  16. Effect prediction of identified SNPs linked to fruit quality and chilling injury in peach [Prunus persica (L.) Batsch].

    Science.gov (United States)

    Martínez-García, Pedro J; Fresnedo-Ramírez, Jonathan; Parfitt, Dan E; Gradziel, Thomas M; Crisosto, Carlos H

    2013-01-01

    Single nucleotide polymorphisms (SNPs) are a fundamental source of genomic variation. Large SNP panels have been developed for Prunus species. Fruit quality traits are essential peach breeding program objectives since they determine consumer acceptance, fruit consumption, industry trends and cultivar adoption. For many cultivars, these traits are negatively impacted by cold storage, used to extend fruit market life. The major symptoms of chilling injury are lack of flavor, off flavor, mealiness, flesh browning, and flesh bleeding. A set of 1,109 SNPs was mapped previously and 67 were linked with these complex traits. The prediction of the effects associated with these SNPs on downstream products from the 'peach v1.0' genome sequence was carried out. A total of 2,163 effects were detected, 282 effects (non-synonymous, synonymous or stop codon gained) were located in exonic regions (13.04 %) and 294 placed in intronic regions (13.59 %). An extended list of genes and proteins that could be related to these traits was developed. Two SNP markers that explain a high percentage of the observed phenotypic variance, UCD_SNP_1084 and UCD_SNP_46, are associated with zinc finger (C3HC4-type RING finger) family protein and AOX1A (alternative oxidase 1a) protein groups, respectively. In addition, phenotypic variation suggests that the observed polymorphism for SNP UCD_SNP_1084 [A/G] mutation could be a candidate quantitative trait nucleotide affecting quantitative trait loci for mealiness. The interaction and expression of affected proteins could explain the variation observed in each individual and facilitate understanding of gene regulatory networks for fruit quality traits in peach. PMID:23184287

  17. Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci.

    Science.gov (United States)

    Asselbergs, Folkert W; Guo, Yiran; van Iperen, Erik P A; Sivapalaratnam, Suthesh; Tragante, Vinicius; Lanktree, Matthew B; Lange, Leslie A; Almoguera, Berta; Appelman, Yolande E; Barnard, John; Baumert, Jens; Beitelshees, Amber L; Bhangale, Tushar R; Chen, Yii-Der Ida; Gaunt, Tom R; Gong, Yan; Hopewell, Jemma C; Johnson, Toby; Kleber, Marcus E; Langaee, Taimour Y; Li, Mingyao; Li, Yun R; Liu, Kiang; McDonough, Caitrin W; Meijs, Matthijs F L; Middelberg, Rita P S; Musunuru, Kiran; Nelson, Christopher P; O'Connell, Jeffery R; Padmanabhan, Sandosh; Pankow, James S; Pankratz, Nathan; Rafelt, Suzanne; Rajagopalan, Ramakrishnan; Romaine, Simon P R; Schork, Nicholas J; Shaffer, Jonathan; Shen, Haiqing; Smith, Erin N; Tischfield, Sam E; van der Most, Peter J; van Vliet-Ostaptchouk, Jana V; Verweij, Niek; Volcik, Kelly A; Zhang, Li; Bailey, Kent R; Bailey, Kristian M; Bauer, Florianne; Boer, Jolanda M A; Braund, Peter S; Burt, Amber; Burton, Paul R; Buxbaum, Sarah G; Chen, Wei; Cooper-Dehoff, Rhonda M; Cupples, L Adrienne; deJong, Jonas S; Delles, Christian; Duggan, David; Fornage, Myriam; Furlong, Clement E; Glazer, Nicole; Gums, John G; Hastie, Claire; Holmes, Michael V; Illig, Thomas; Kirkland, Susan A; Kivimaki, Mika; Klein, Ronald; Klein, Barbara E; Kooperberg, Charles; Kottke-Marchant, Kandice; Kumari, Meena; LaCroix, Andrea Z; Mallela, Laya; Murugesan, Gurunathan; Ordovas, Jose; Ouwehand, Willem H; Post, Wendy S; Saxena, Richa; Scharnagl, Hubert; Schreiner, Pamela J; Shah, Tina; Shields, Denis C; Shimbo, Daichi; Srinivasan, Sathanur R; Stolk, Ronald P; Swerdlow, Daniel I; Taylor, Herman A; Topol, Eric J; Toskala, Elina; van Pelt, Joost L; van Setten, Jessica; Yusuf, Salim; Whittaker, John C; Zwinderman, A H; Anand, Sonia S; Balmforth, Anthony J; Berenson, Gerald S; Bezzina, Connie R; Boehm, Bernhard O; Boerwinkle, Eric; Casas, Juan P; Caulfield, Mark J; Clarke, Robert; Connell, John M; Cruickshanks, Karen J; Davidson, Karina W; Day, Ian N M; de Bakker, Paul I W; Doevendans, Pieter A; Dominiczak, Anna F; Hall, Alistair S; Hartman, Catharina A; Hengstenberg, Christian; Hillege, Hans L; Hofker, Marten H; Humphries, Steve E; Jarvik, Gail P; Johnson, Julie A; Kaess, Bernhard M; Kathiresan, Sekar; Koenig, Wolfgang; Lawlor, Debbie A; März, Winfried; Melander, Olle; Mitchell, Braxton D; Montgomery, Grant W; Munroe, Patricia B; Murray, Sarah S; Newhouse, Stephen J; Onland-Moret, N Charlotte; Poulter, Neil; Psaty, Bruce; Redline, Susan; Rich, Stephen S; Rotter, Jerome I; Schunkert, Heribert; Sever, Peter; Shuldiner, Alan R; Silverstein, Roy L; Stanton, Alice; Thorand, Barbara; Trip, Mieke D; Tsai, Michael Y; van der Harst, Pim; van der Schoot, Ellen; van der Schouw, Yvonne T; Verschuren, W M Monique; Watkins, Hugh; Wilde, Arthur A M; Wolffenbuttel, Bruce H R; Whitfield, John B; Hovingh, G Kees; Ballantyne, Christie M; Wijmenga, Cisca; Reilly, Muredach P; Martin, Nicholas G; Wilson, James G; Rader, Daniel J; Samani, Nilesh J; Reiner, Alex P; Hegele, Robert A; Kastelein, John J P; Hingorani, Aroon D; Talmud, Philippa J; Hakonarson, Hakon; Elbers, Clara C; Keating, Brendan J; Drenos, Fotios

    2012-11-01

    Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids. PMID:23063622

  18. Single mitochondrial gene barcodes reliably identify sister-species in diverse clades of birds

    Directory of Open Access Journals (Sweden)

    Baker Allan J

    2008-03-01

    Full Text Available Abstract Background DNA barcoding of life using a standardized COI sequence was proposed as a species identification system, and as a method for detecting putative new species. Previous tests in birds showed that individuals can be correctly assigned to species in ~94% of the cases and suggested a threshold of 10× mean intraspecific difference to detect potential new species. However, these tests were criticized because they were based on a single maternally inherited gene rather than multiple nuclear genes, did not compare phylogenetically identified sister species, and thus likely overestimated the efficacy of DNA barcodes in identifying species. Results To test the efficacy of DNA barcodes we compared ~650 bp of COI in 60 sister-species pairs identified in multigene phylogenies from 10 orders of birds. In all pairs, individuals of each species were monophyletic in a neighbor-joining (NJ tree, and each species possessed fixed mutational differences distinguishing them from their sister species. Consequently, individuals were correctly assigned to species using a statistical coalescent framework. A coalescent test of taxonomic distinctiveness based on chance occurrence of reciprocal monophyly in two lineages was verified in known sister species, and used to identify recently separated lineages that represent putative species. This approach avoids the use of a universal distance cutoff which is invalidated by variation in times to common ancestry of sister species and in rates of evolution. Conclusion Closely related sister species of birds can be identified reliably by barcodes of fixed diagnostic substitutions in COI sequences, verifying coalescent-based statistical tests of reciprocal monophyly for taxonomic distinctiveness. Contrary to recent criticisms, a single DNA barcode is a rapid way to discover monophyletic lineages within a metapopulation that might represent undiscovered cryptic species, as envisaged in the unified species concept. This identifies a smaller set of lineages that can also be tested independently for species status with multiple nuclear gene approaches and other phenotypic characters.

  19. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci.

    Science.gov (United States)

    Shen, Changbing; Gao, Jing; Sheng, Yujun; Dou, Jinfa; Zhou, Fusheng; Zheng, Xiaodong; Ko, Randy; Tang, Xianfa; Zhu, Caihong; Yin, Xianyong; Sun, Liangdan; Cui, Yong; Zhang, Xuejun

    2016-01-01

    Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo. PMID:26870082

  20. Regulatory elements of the floral homeotic gene AGAMOUS identified by phylogenetic footprinting and shadowing.

    Energy Technology Data Exchange (ETDEWEB)

    Hong, R. L., Hamaguchi, L., Busch, M. A., and Weigel, D.

    2003-06-01

    OAK-B135 In Arabidopsis thaliana, cis-regulatory sequences of the floral homeotic gene AGAMOUS (AG) are located in the second intron. This 3 kb intron contains binding sites for two direct activators of AG, LEAFY (LFY) and WUSCHEL (WUS), along with other putative regulatory elements. We have used phylogenetic footprinting and the related technique of phylogenetic shadowing to identify putative cis-regulatory elements in this intron. Among 29 Brassicaceae, several other motifs, but not the LFY and WUS binding sites previously identified, are largely invariant. Using reporter gene analyses, we tested six of these motifs and found that they are all functionally important for activity of AG regulatory sequences in A. thaliana. Although there is little obvious sequence similarity outside the Brassicaceae, the intron from cucumber AG has at least partial activity in A. thaliana. Our studies underscore the value of the comparative approach as a tool that complements gene-by-gene promoter dissection, but also highlight that sequence-based studies alone are insufficient for a complete identification of cis-regulatory sites.

  1. AbMiner: A bioinformatic resource on available monoclonal antibodies and corresponding gene identifiers for genomic, proteomic, and immunologic studies

    Directory of Open Access Journals (Sweden)

    Shankavaram Uma

    2006-04-01

    Full Text Available Abstract Background Monoclonal antibodies are used extensively throughout the biomedical sciences for detection of antigens, either in vitro or in vivo. We, for example, have used them for quantitation of proteins on "reverse-phase" protein lysate arrays. For those studies, we quality-controlled > 600 available monoclonal antibodies and also needed to develop precise information on the genes that encode their antigens. Translation among the various protein and gene identifier types proved non-trivial because of one-to-many and many-to-one relationships. To organize the antibody, protein, and gene information, we initially developed a relational database in Filemaker for our own use. When it became apparent that the information would be useful to many other researchers faced with the need to choose or characterize antibodies, we developed it further as AbMiner, a fully relational web-based database under MySQL, programmed in Java. Description AbMiner is a user-friendly, web-based relational database of information on > 600 commercially available antibodies that we validated by Western blot for protein microarray studies. It includes many types of information on the antibody, the immunogen, the vendor, the antigen, and the antigen's gene. Multiple gene and protein identifier types provide links to corresponding entries in a variety of other public databases, including resources for phosphorylation-specific antibodies. AbMiner also includes our quality-control data against a pool of 60 diverse cancer cell types (the NCI-60 and also protein expression levels for the NCI-60 cells measured using our high-density "reverse-phase" protein lysate microarrays for a selection of the listed antibodies. Some other available database resources give information on antibody specificity for one or a couple of cell types. In contrast, the data in AbMiner indicate specificity with respect to the antigens in a pool of 60 diverse cell types from nine different tissues of origin. Conclusion AbMiner is a relational database that provides extensive information from our own laboratory and other sources on more than 600 available antibodies and the genes that encode the antibodies' antigens. The data will be made freely available at http://discover.nci.nih.gov/abminer

  2. Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci

    OpenAIRE

    Asselbergs, Folkert W.; Guo, Yiran; Van Iperen, Erik P.A.; Sivapalaratnam, Suthesh; Tragante, Vinicius; Lanktree, Matthew B.; Lange, Leslie A.; Almoguera, Berta; Appelman, Yolande E.; Barnard, John; Baumert, Jens; Beitelshees, Amber L.; Bhangale, Tushar R.; Chen, Yii-Der Ida; Gaunt, Tom R.

    2012-01-01

    Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SN...

  3. Linear normalised hash function for clustering gene sequences and identifying reference sequences from multiple sequence alignments

    Directory of Open Access Journals (Sweden)

    Helal Manal

    2012-01-01

    Full Text Available Abstract Background Comparative genomics has put additional demands on the assessment of similarity between sequences and their clustering as means for classification. However, defining the optimal number of clusters, cluster density and boundaries for sets of potentially related sequences of genes with variable degrees of polymorphism remains a significant challenge. The aim of this study was to develop a method that would identify the cluster centroids and the optimal number of clusters for a given sensitivity level and could work equally well for the different sequence datasets. Results A novel method that combines the linear mapping hash function and multiple sequence alignment (MSA was developed. This method takes advantage of the already sorted by similarity sequences from the MSA output, and identifies the optimal number of clusters, clusters cut-offs, and clusters centroids that can represent reference gene vouchers for the different species. The linear mapping hash function can map an already ordered by similarity distance matrix to indices to reveal gaps in the values around which the optimal cut-offs of the different clusters can be identified. The method was evaluated using sets of closely related (16S rRNA gene sequences of Nocardia species and highly variable (VP1 genomic region of Enterovirus 71 sequences and outperformed existing unsupervised machine learning clustering methods and dimensionality reduction methods. This method does not require prior knowledge of the number of clusters or the distance between clusters, handles clusters of different sizes and shapes, and scales linearly with the dataset. Conclusions The combination of MSA with the linear mapping hash function is a computationally efficient way of gene sequence clustering and can be a valuable tool for the assessment of similarity, clustering of different microbial genomes, identifying reference sequences, and for the study of evolution of bacteria and viruses.

  4. Haplotype Association Mapping Identifies a Candidate Gene Region in Mice Infected With Staphylococcus aureus

    OpenAIRE

    Johnson, Nicole V.; Ahn, Sun Hee; Deshmukh, Hitesh; Levin, Mikhail K.; Nelson, Charlotte L.; Scott, William K.; Allen, Andrew; Fowler, Vance G.; COWELL, LINDSAY G.

    2012-01-01

    Exposure to Staphylococcus aureus has a variety of outcomes, from asymptomatic colonization to fatal infection. Strong evidence suggests that host genetics play an important role in susceptibility, but the specific host genetic factors involved are not known. The availability of genome-wide single nucleotide polymorphism (SNP) data for inbred Mus musculus strains means that haplotype association mapping can be used to identify candidate susceptibility genes. We applied haplotype association m...

  5. Loci influencing blood pressure identified using a cardiovascular gene-centric array

    OpenAIRE

    Ganesh, S.K.; Tragante, V.; Guo, W.; Guo, Y.; Lanktree, M. B.; Smith, E N; Johnson, T; Castillo, B. A.; J Barnard; J. Baumert; Chang, Y.-P. C.; C.C. Elbers; Farrall, M; Fischer, M.E.; Franceschini, N.

    2013-01-01

    Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 ...

  6. Loci influencing blood pressure identified using a cardiovascular gene-centric array

    OpenAIRE

    Ganesh, Santhi K.; Tragante, Vinicius; Guo, Wei; Guo, Yiran; Lanktree, Matthew B; Smith, Erin N.; Johnson, Toby; Castillo, Berta Almoguera; Barnard, John; Baumert, Jens; Chang, Yen-Pei Christy; Elbers, Clara C.; Farrall, Martin; Fischer, Mary E; Franceschini, Nora

    2013-01-01

    Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped 50 000 single-nucleotide polymorphisms (SNPs) that capture variation in 2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 an...

  7. A Quantitative High-Throughput Screen Identifies Potential Epigenetic Modulators of Gene Expression

    OpenAIRE

    Johnson, Ronald L.; Huang, Wenwei; Jadhav, Ajit; Austin, Christopher P.; Inglese, James; Martinez, Elisabeth D.

    2007-01-01

    Epigenetic regulation of gene expression is essential in embryonic development and contributes to cancer pathology. We used a cell-based imaging assay that measures derepression of a silenced GFP reporter to identify novel classes of compounds involved in epigenetic regulation. This Locus Derepression (LDR) assay was screened against a 69,137-member chemical library using quantitative high-throughput screening (qHTS), a titration-response method that assays compounds at multiple concentration...

  8. An Efficient Genetic Screen in Drosophila to Identify Nuclear-Encoded Genes With Mitochondrial Function

    OpenAIRE

    Liao, T. S. Vivian; Gerald B. Call; Guptan, Preeta; Cespedes, Albert; Marshall, Jamie; Yackle, Kevin; Owusu-Ansah, Edward; Mandal, Sudip; Fang, Q. Angela; Goodstein, Gelsey L.; Kim, William; Banerjee, Utpal

    2006-01-01

    We conducted a screen for glossy-eye flies that fail to incorporate BrdU in the third larval instar eye disc but exhibit normal neuronal differentiation and isolated 23 complementation groups of mutants. These same phenotypes were previously seen in mutants for cytochrome c oxidase subunit Va. We have molecularly characterized six complementation groups and, surprisingly, each encodes a mitochondrial protein. Therefore, we believe our screen to be an efficient method for identifying genes wit...

  9. Transcriptome Analysis of Syringa oblata Lindl. Inflorescence Identifies Genes Associated with Pigment Biosynthesis and Scent Metabolism

    OpenAIRE

    Jian ZHENG; Hu, Zenghui; Guan, Xuelian; Dou, Dequan; Bai, Guo; Wang, Yu; Guo, Yingtian; Li, Wei; Leng, Pingsheng

    2015-01-01

    Syringa oblata Lindl. is a woody ornamental plant with high economic value and characteristics that include early flowering, multiple flower colors, and strong fragrance. Despite a long history of cultivation, the genetics and molecular biology of S. oblata are poorly understood. Transcriptome and expression profiling data are needed to identify genes and to better understand the biological mechanisms of floral pigments and scents in this species. Nine cDNA libraries were obtained from three ...

  10. Yeast functional screen to identify genes conferring salt stress tolerance in Salicornia europaea

    OpenAIRE

    Nakahara, Yoshiki; Sawabe, Shogo; Kainuma, Kenta; Katsuhara, Maki; Shibasaka, Mineo; SUZUKI, Masanori; Yamamoto, Kosuke; Oguri, Suguru; Sakamoto, Hikaru

    2015-01-01

    Salinity is a critical environmental factor that adversely affects crop productivity. Halophytes have evolved various mechanisms to adapt to saline environments. Salicornia europaea L. is one of the most salt-tolerant plant species. It does not have special salt-secreting structures like a salt gland or salt bladder, and is therefore a good model for studying the common mechanisms underlying plant salt tolerance. To identify candidate genes encoding key proteins in the mediation of salt toler...

  11. A functional siRNA screen identifies genes modulating angiotensin II-mediated EGFR transactivation

    OpenAIRE

    George, Amee J.; Purdue, Brooke W.; Gould, Cathryn M.; Thomas, Daniel W.; Handoko, Yanny; Qian, Hongwei; Quaife-Ryan, Gregory A.; Morgan, Kylie A.; Simpson, Kaylene J.; Walter G. Thomas; Ross D. Hannan

    2013-01-01

    The angiotensin type 1 receptor (AT1R) transactivates the epidermal growth factor receptor (EGFR) to mediate cellular growth, however, the molecular mechanisms involved have not yet been resolved. To address this, we performed a functional siRNA screen of the human kinome in human mammary epithelial cells that demonstrate a robust AT1R–EGFR transactivation. We identified a suite of genes encoding proteins that both positively and negatively regulate AT1R–EGFR transactivation. Many candidates ...

  12. Genome-wide transcriptome analysis identifies novel gene signatures implicated in human chronic liver disease

    OpenAIRE

    Smalling, Rana L.; Delker, Don A.; Zhang, Yuxia; Nieto, Natalia; Mcguiness, Michael S.; Liu, Shuanghu; Friedman, Scott L; HAGEDORN, CURT H.; Wang, Li

    2013-01-01

    The molecular mechanisms behind human liver disease progression to cirrhosis remain elusive. Nuclear receptor small heterodimer partner (SHP/Nr0b2) is a hepatic tumor suppressor and a critical regulator of liver function. SHP expression is diminished in human cirrhotic livers, suggesting a regulatory role in human liver diseases. The goal of this study was to identify novel SHP-regulated genes that are involved in the development and progression of chronic liver disease. To achieve this, we c...

  13. Filtering Gene Ontology semantic similarity for identifying protein complexes in large protein interaction networks

    OpenAIRE

    Wang Jian; Xie Dong; Lin Hongfei; Yang Zhihao; Zhang Yijia

    2012-01-01

    Abstract Background Many biological processes recognize in particular the importance of protein complexes, and various computational approaches have been developed to identify complexes from protein-protein interaction (PPI) networks. However, high false-positive rate of PPIs leads to challenging identification. Results A protein semantic similarity measure is proposed in this study, based on the ontology structure of Gene Ontology (GO) terms and GO annotations to estimate the reliability of ...

  14. Mutations in the X-Linked Retinitis Pigmentosa Genes RPGR and RP2 Found in 8.5% of Families with a Provisional Diagnosis of Autosomal Dominant Retinitis Pigmentosa

    OpenAIRE

    Churchill, Jennifer D.; BOWNE, SARA J.; Sullivan, Lori S.; Lewis, Richard Alan; Wheaton, Dianna K.; Birch, David G.; Branham, Kari E.; Heckenlively, John R.; Daiger, Stephen P.

    2013-01-01

    This study identifies the fraction of families in a well-characterized cohort with a provisional diagnosis of autosomal dominant retinitis pigmentosa (adRP) that have disease-causing mutations in the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene or the retinitis pigmentosa 2 (RP2) gene.

  15. Gene networks associated with conditional fear in mice identified using a systems genetics approach

    Directory of Open Access Journals (Sweden)

    Eskin Eleazar

    2011-03-01

    Full Text Available Abstract Background Our understanding of the genetic basis of learning and memory remains shrouded in mystery. To explore the genetic networks governing the biology of conditional fear, we used a systems genetics approach to analyze a hybrid mouse diversity panel (HMDP with high mapping resolution. Results A total of 27 behavioral quantitative trait loci were mapped with a false discovery rate of 5%. By integrating fear phenotypes, transcript profiling data from hippocampus and striatum and also genotype information, two gene co-expression networks correlated with context-dependent immobility were identified. We prioritized the key markers and genes in these pathways using intramodular connectivity measures and structural equation modeling. Highly connected genes in the context fear modules included Psmd6, Ube2a and Usp33, suggesting an important role for ubiquitination in learning and memory. In addition, we surveyed the architecture of brain transcript regulation and demonstrated preservation of gene co-expression modules in hippocampus and striatum, while also highlighting important differences. Rps15a, Kif3a, Stard7, 6330503K22RIK, and Plvap were among the individual genes whose transcript abundance were strongly associated with fear phenotypes. Conclusion Application of our multi-faceted mapping strategy permits an increasingly detailed characterization of the genetic networks underlying behavior.

  16. Transcriptional profiling identifies differentially expressed genes in developing turkey skeletal muscle

    Directory of Open Access Journals (Sweden)

    Velleman Sandra G

    2011-03-01

    Full Text Available Abstract Background Skeletal muscle growth and development from embryo to adult consists of a series of carefully regulated changes in gene expression. Understanding these developmental changes in agriculturally important species is essential to the production of high quality meat products. For example, consumer demand for lean, inexpensive meat products has driven the turkey industry to unprecedented production through intensive genetic selection. However, achievements of increased body weight and muscle mass have been countered by an increased incidence of myopathies and meat quality defects. In a previous study, we developed and validated a turkey skeletal muscle-specific microarray as a tool for functional genomics studies. The goals of the current study were to utilize this microarray to elucidate functional pathways of genes responsible for key events in turkey skeletal muscle development and to compare differences in gene expression between two genetic lines of turkeys. To achieve these goals, skeletal muscle samples were collected at three critical stages in muscle development: 18d embryo (hyperplasia, 1d post-hatch (shift from myoblast-mediated growth to satellite cell-modulated growth by hypertrophy, and 16wk (market age from two genetic lines: a randombred control line (RBC2 maintained without selection pressure, and a line (F selected from the RBC2 line for increased 16wk body weight. Array hybridizations were performed in two experiments: Experiment 1 directly compared the developmental stages within genetic line, while Experiment 2 directly compared the two lines within each developmental stage. Results A total of 3474 genes were differentially expressed (false discovery rate; FDR Conclusions The current study identified gene pathways and uncovered novel genes important in turkey muscle growth and development. Future experiments will focus further on several of these candidate genes and the expression and mechanism of action of their protein products.

  17. Differential display identifies overexpression of the USP36 gene, encoding a deubiquitinating enzyme, in ovarian cancer

    Directory of Open Access Journals (Sweden)

    Jianduan Li, Lisa M. Olson, Zhengyan Zhang, Lina Li, Miri Bidder, Loan Nguyen, John Pfeifer, Janet S. Rader

    2008-01-01

    Full Text Available Objectives. To find potential diagnostic markers or therapeutic targets, we used differential display technique to identify genes that are over or under expressed in human ovarian cancer. Methods. Genes were initially identified by differential display between two human ovarian surface epithelium cultures and two ovarian cancer cell lines, A2780 and Caov-3. Genes were validated by relative quantitative RT-PCR and RNA in situ hybridization. Results. Twenty-eight non-redundant sequences were expressed differentially in the normal ovarian epithelium and ovarian cancer cell lines. Seven of the 28 sequences showed differential expression between normal ovary and ovarian cancer tissue by RT-PCR. USP36 was over-expressed in ovarian cancer cell lines and tissues by RT-PCR and RNA in situ hybridization. Northern blot analysis and RT-PCR revealed two transcripts for USP36 in ovarian tissue. The major transcript was more specific for ovarian cancer and was detected by RT-PCR in 9/9 ovarian cancer tissues, 3/3 cancerous ascites, 5/14 (36% sera from patients with ovarian cancer, and 0/7 sera from women without ovarian cancer. Conclusion. USP36 is overexpressed in ovarian cancer compared to normal ovary and its transcripts were identified in ascites and serum of ovarian cancer patients.

  18. Comparison of Expression Profiles in Ovarian Epithelium In Vivo and Ovarian Cancer Identifies Novel Candidate Genes Involved in Disease Pathogenesis

    OpenAIRE

    Emmanuel, Catherine; Gava, Natalie; Kennedy, Catherine; Balleine, Rosemary L.; Sharma, Raghwa; Wain, Gerard; Brand, Alison; Hogg, Russell; Etemadmoghadam, Dariush; George, Joshy; Birrer, Michael James; Clarke, Christine L.; Chenevix-Trench, Georgia; Bowtell, David D. L.; Harnett, Paul R.

    2011-01-01

    Molecular events leading to epithelial ovarian cancer are poorly understood but ovulatory hormones and a high number of life-time ovulations with concomitant proliferation, apoptosis, and inflammation, increases risk. We identified genes that are regulated during the estrous cycle in murine ovarian surface epithelium and analysed these profiles to identify genes dysregulated in human ovarian cancer, using publically available datasets. We identified 338 genes that are regulated in murine ovar...

  19. A missense mutation, p.V132G, in the X-linked spermine synthase gene (SMS) causes Snyder-Robinson syndrome

    Science.gov (United States)

    Becerra-Solano, L.E.; Butler, J.; Castañeda-Cisneros, G.; McCloskey, D.E.; Wang, X.; Pegg, A.E.; Schwartz, C.E.; Sánchez-Corona, J.; García-Ortiz, J.E.

    2009-01-01

    Snyder-Robinson syndrome (SRS, OMIM 309583) is a rare X-linked syndrome characterized by mental retardation, marfanoid habitus, skeletal defects, osteoporosis and facial asymmetry. Linkage analysis localized the related gene to Xp21.3-p22.12, and a G-to-A transition at point +5 of intron 4 of the spermine synthase gene, which caused truncation of the SMS protein and loss of enzyme activity, was identified in the original family. Here we describe another family with Snyder-Robinson syndrome in two Mexican brothers and a novel mutation (c.496T>G) in the exon 5 of the SMS gene confirming its involvement in this rare X-linked mental retardation syndrome. PMID:19206178

  20. Microarray analysis identifies a common set of cellular genes modulated by different HCV replicon clones

    Directory of Open Access Journals (Sweden)

    Gerosolimo Germano

    2008-06-01

    Full Text Available Abstract Background Hepatitis C virus (HCV RNA synthesis and protein expression affect cell homeostasis by modulation of gene expression. The impact of HCV replication on global cell transcription has not been fully evaluated. Thus, we analysed the expression profiles of different clones of human hepatoma-derived Huh-7 cells carrying a self-replicating HCV RNA which express all viral proteins (HCV replicon system. Results First, we compared the expression profile of HCV replicon clone 21-5 with both the Huh-7 parental cells and the 21-5 cured (21-5c cells. In these latter, the HCV RNA has been eliminated by IFN-α treatment. To confirm data, we also analyzed microarray results from both the 21-5 and two other HCV replicon clones, 22-6 and 21-7, compared to the Huh-7 cells. The study was carried out by using the Applied Biosystems (AB Human Genome Survey Microarray v1.0 which provides 31,700 probes that correspond to 27,868 human genes. Microarray analysis revealed a specific transcriptional program induced by HCV in replicon cells respect to both IFN-α-cured and Huh-7 cells. From the original datasets of differentially expressed genes, we selected by Venn diagrams a final list of 38 genes modulated by HCV in all clones. Most of the 38 genes have never been described before and showed high fold-change associated with significant p-value, strongly supporting data reliability. Classification of the 38 genes by Panther System identified functional categories that were significantly enriched in this gene set, such as histones and ribosomal proteins as well as extracellular matrix and intracellular protein traffic. The dataset also included new genes involved in lipid metabolism, extracellular matrix and cytoskeletal network, which may be critical for HCV replication and pathogenesis. Conclusion Our data provide a comprehensive analysis of alterations in gene expression induced by HCV replication and reveal modulation of new genes potentially useful for selection of antiviral targets.

  1. Heterogeneous activation of the TGFβ pathway in glioblastomas identified by gene expression-based classification using TGFβ-responsive genes

    Directory of Open Access Journals (Sweden)

    Xu Xie L

    2009-02-01

    Full Text Available Abstract Background TGFβ has emerged as an attractive target for the therapeutic intervention of glioblastomas. Aberrant TGFβ overproduction in glioblastoma and other high-grade gliomas has been reported, however, to date, none of these reports has systematically examined the components of TGFβ signaling to gain a comprehensive view of TGFβ activation in large cohorts of human glioma patients. Methods TGFβ activation in mammalian cells leads to a transcriptional program that typically affects 5–10% of the genes in the genome. To systematically examine the status of TGFβ activation in high-grade glial tumors, we compiled a gene set of transcriptional response to TGFβ stimulation from tissue culture and in vivo animal studies. These genes were used to examine the status of TGFβ activation in high-grade gliomas including a large cohort of glioblastomas. Unsupervised and supervised classification analysis was performed in two independent, publicly available glioma microarray datasets. Results Unsupervised and supervised classification using the TGFβ-responsive gene list in two independent glial tumor gene expression data sets revealed various levels of TGFβ activation in these tumors. Among glioblastomas, one of the most devastating human cancers, two subgroups were identified that showed distinct TGFβ activation patterns as measured from transcriptional responses. Approximately 62% of glioblastoma samples analyzed showed strong TGFβ activation, while the rest showed a weak TGFβ transcriptional response. Conclusion Our findings suggest heterogeneous TGFβ activation in glioblastomas, which may cause potential differences in responses to anti-TGFβ therapies in these two distinct subgroups of glioblastomas patients.

  2. Microarray Analysis in a Cell Death Resistant Glioma Cell Line to Identify Signaling Pathways and Novel Genes Controlling Resistance and Malignancy

    Energy Technology Data Exchange (ETDEWEB)

    Seznec, Janina; Naumann, Ulrike, E-mail: ulrike.naumann@uni-tuebingen.de [Laboratory of Molecular Neuro-Oncology, Department of General Neurology, Hertie-Institute for Clinical Brain Research and Center Neurology, University of Tuebingen, Otfried-Mueller-Str. 27, Tuebingen 72076 (Germany)

    2011-06-27

    Glioblastoma multiforme (GBM) is a lethal type of cancer mainly resistant to radio- and chemotherapy. Since the tumor suppressor p53 functions as a transcription factor regulating the expression of genes involved in growth inhibition, DNA repair and apoptosis, we previously assessed whether specific differences in the modulation of gene expression are responsible for the anti-tumor properties of a dominant positive p53, chimeric tumor suppressor (CTS)-1. CTS-1 is based on the sequence of p53 and designed to resist various mechanisms of inactivation which limit the activity of p53. To identify CTS-1-regulated cell death-inducing genes, we generated a CTS-1-resistant glioma cell line (229R). We used Affymetrix whole-genome microarray expression analysis to analyze alterations in gene expression and identified a variety of CTS-1 regulated genes involved in cancer-linked processes. 313 genes were differentially expressed in Adeno-CTS-1 (Ad-CTS-1)-infected and 700 genes in uninfected 229R cells compared to matching parental cells. Ingenuity Pathway Analysis (IPA) determined a variety of differentially expressed genes in Ad-CTS-1-infected cells that were members of the intracellular networks with central tumor-involved players such as nuclear factor kappa B (NF-?B), protein kinase B (PKB/AKT) or transforming growth factor beta (TGF-?). Differentially regulated genes include secreted factors as well as intracellular proteins and transcription factors regulating not only cell death, but also processes such as tumor cell motility and immunity. This work gives an overview of the pathways differentially regulated in the resistant versus parental glioma cells and might be helpful to identify candidate genes which could serve as targets to develop novel glioma specific therapy strategies.

  3. Microarray analysis in a cell death resistant glioma cell line to identify signaling pathways and novel genes controlling resistance and malignancy.

    Science.gov (United States)

    Seznec, Janina; Naumann, Ulrike

    2011-01-01

    Glioblastoma multiforme (GBM) is a lethal type of cancer mainly resistant to radio- and chemotherapy. Since the tumor suppressor p53 functions as a transcription factor regulating the expression of genes involved in growth inhibition, DNA repair and apoptosis, we previously assessed whether specific differences in the modulation of gene expression are responsible for the anti-tumor properties of a dominant positive p53, chimeric tumor suppressor (CTS)-1. CTS-1 is based on the sequence of p53 and designed to resist various mechanisms of inactivation which limit the activity of p53. To identify CTS-1-regulated cell death-inducing genes, we generated a CTS-1-resistant glioma cell line (229R). We used Affymetrix whole-genome microarray expression analysis to analyze alterations in gene expression and identified a variety of CTS-1 regulated genes involved in cancer-linked processes. 313 genes were differentially expressed in Adeno-CTS-1 (Ad-CTS-1)-infected and 700 genes in uninfected 229R cells compared to matching parental cells. Ingenuity Pathway Analysis (IPA) determined a variety of differentially expressed genes in Ad-CTS-1-infected cells that were members of the intracellular networks with central tumor-involved players such as nuclear factor kappa B (NF-?B), protein kinase B (PKB/AKT) or transforming growth factor beta (TGF-?). Differentially regulated genes include secreted factors as well as intracellular proteins and transcription factors regulating not only cell death, but also processes such as tumor cell motility and immunity. This work gives an overview of the pathways differentially regulated in the resistant versus parental glioma cells and might be helpful to identify candidate genes which could serve as targets to develop novel glioma specific therapy strategies. PMID:24212935

  4. Microarray Analysis in a Cell Death Resistant Glioma Cell Line to Identify Signaling Pathways and Novel Genes Controlling Resistance and Malignancy

    Directory of Open Access Journals (Sweden)

    Janina Seznec

    2011-06-01

    Full Text Available Glioblastoma multiforme (GBM is a lethal type of cancer mainly resistant to radio- and chemotherapy. Since the tumor suppressor p53 functions as a transcription factor regulating the expression of genes involved in growth inhibition, DNA repair and apoptosis, we previously assessed whether specific differences in the modulation of gene expression are responsible for the anti-tumor properties of a dominant positive p53, chimeric tumor suppressor (CTS-1. CTS-1 is based on the sequence of p53 and designed to resist various mechanisms of inactivation which limit the activity of p53. To identify CTS-1-regulated cell death-inducing genes, we generated a CTS-1-resistant glioma cell line (229R. We used Affymetrix whole-genome microarray expression analysis to analyze alterations in gene expression and identified a variety of CTS-1 regulated genes involved in cancer-linked processes. 313 genes were differentially expressed in Adeno-CTS-1 (Ad-CTS-1-infected and 700 genes in uninfected 229R cells compared to matching parental cells. Ingenuity Pathway Analysis (IPA determined a variety of differentially expressed genes in Ad-CTS-1-infected cells that were members of the intracellular networks with central tumor-involved players such as nuclear factor kappa B (NF-?B, protein kinase B (PKB/AKT or transforming growth factor beta (TGF-?. Differentially regulated genes include secreted factors as well as intracellular proteins and transcription factors regulating not only cell death, but also processes such as tumor cell motility and immunity. This work gives an overview of the pathways differentially regulated in the resistant versus parental glioma cells and might be helpful to identify candidate genes which could serve as targets to develop novel glioma specific therapy strategies.

  5. Microarray Analysis in a Cell Death Resistant Glioma Cell Line to Identify Signaling Pathways and Novel Genes Controlling Resistance and Malignancy

    International Nuclear Information System (INIS)

    Glioblastoma multiforme (GBM) is a lethal type of cancer mainly resistant to radio- and chemotherapy. Since the tumor suppressor p53 functions as a transcription factor regulating the expression of genes involved in growth inhibition, DNA repair and apoptosis, we previously assessed whether specific differences in the modulation of gene expression are responsible for the anti-tumor properties of a dominant positive p53, chimeric tumor suppressor (CTS)-1. CTS-1 is based on the sequence of p53 and designed to resist various mechanisms of inactivation which limit the activity of p53. To identify CTS-1-regulated cell death-inducing genes, we generated a CTS-1-resistant glioma cell line (229R). We used Affymetrix whole-genome microarray expression analysis to analyze alterations in gene expression and identified a variety of CTS-1 regulated genes involved in cancer-linked processes. 313 genes were differentially expressed in Adeno-CTS-1 (Ad-CTS-1)-infected and 700 genes in uninfected 229R cells compared to matching parental cells. Ingenuity Pathway Analysis (IPA) determined a variety of differentially expressed genes in Ad-CTS-1-infected cells that were members of the intracellular networks with central tumor-involved players such as nuclear factor kappa B (NF-κB), protein kinase B (PKB/AKT) or transforming growth factor beta (TGF-β). Differentially regulated genes include secreted factors as well as intracellular proteins and transcription factors regulating not only cell death, but also processes such as tumor cell motility and immunity. This work gives an overview of the pathways differentially regulated in the resistant versus parental glioma cells and might be helpful to identify candidate genes which could serve as targets to develop novel glioma specific therapy strategies

  6. Analysis of genomic aberrations and gene expression profiling identifies novel lesions and pathways in myeloproliferative neoplasms

    International Nuclear Information System (INIS)

    Polycythemia vera (PV), essential thrombocythemia and primary myelofibrosis, are myeloproliferative neoplasms (MPNs) with distinct clinical features and are associated with the JAK2V617F mutation. To identify genomic anomalies involved in the pathogenesis of these disorders, we profiled 87 MPN patients using Affymetrix 250K single-nucleotide polymorphism (SNP) arrays. Aberrations affecting chr9 were the most frequently observed and included 9pLOH (n=16), trisomy 9 (n=6) and amplifications of 9p13.3–23.3 (n=1), 9q33.1–34.13 (n=1) and 9q34.13 (n=6). Patients with trisomy 9 were associated with elevated JAK2V617F mutant allele burden, suggesting that gain of chr9 represents an alternative mechanism for increasing JAK2V617F dosage. Gene expression profiling of patients with and without chr9 abnormalities (+9, 9pLOH), identified genes potentially involved in disease pathogenesis including JAK2, STAT5B and MAPK14. We also observed recurrent gains of 1p36.31–36.33 (n=6), 17q21.2–q21.31 (n=5) and 17q25.1–25.3 (n=5) and deletions affecting 18p11.31–11.32 (n=8). Combined SNP and gene expression analysis identified aberrations affecting components of a non-canonical PRC2 complex (EZH1, SUZ12 and JARID2) and genes comprising a ‘HSC signature' (MLLT3, SMARCA2 and PBX1). We show that NFIB, which is amplified in 7/87 MPN patients and upregulated in PV CD34+ cells, protects cells from apoptosis induced by cytokine withdrawal

  7. Identifying Paracoccidioides phylogenetic species by PCR-RFLP of the alpha-tubulin gene.

    Science.gov (United States)

    Roberto, Thiago Nunes; Rodrigues, Anderson Messias; Hahn, Rosane Christine; de Camargo, Zoilo Pires

    2016-03-01

    Paracoccidioidomycosis is an important systemic fungal infection that occurs throughout Latin America. The etiological agents comprise a species complex that includes two major groups: P. brasiliensis (including subgroups S1, PS2, and PS3) and P. lutzii. A great number of phenotypes may overlap, especially among closely related groups, discouraging the use of morphology alone for species recognition. To overcome this problem, here we propose identifying cryptic Paracoccidioides spp. using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) of the alpha-tubulin (TUB1) gene. In silico analysis of 90 TUB1 sequences led to the identification of two restriction enzymes with the potential to identify Paracoccidioides: Bcl I and Msp I. A portion of the TUB1 gene was amplified and double digested in vitro with the Bcl I and Msp I endonucleases, which generated four different electrophoretic patterns corresponding to the four main genetic groups: S1, PS2, and PS3 of P. brasiliensis and P. lutzii. The major P. brasiliensis group recognized was S1 (n = 17; 42.5%), followed by PS2 (n = 9; 22.5%) and PS3 (n = 6; 15%). A total of eight (20%) P. lutzii isolates were identified, mainly from midwestern Brazil. Our data revealed that TUB1-RFLP is an efficient, fast, and inexpensive tool for identifying Paracoccidioides spp., which may be directly applied to the molecular epidemiological studies of paracoccidioidomycosis. PMID:26667263

  8. Dorsal horn-enriched genes identified by DNA microarray, in situ hybridization and immunohistochemistry

    Directory of Open Access Journals (Sweden)

    Koblan Kenneth S

    2002-08-01

    Full Text Available Abstract Background Neurons in the dorsal spinal cord play important roles in nociception and pain. These neurons receive input from peripheral sensory neurons and then transmit the signals to the brain, as well as receive and integrate descending control signals from the brain. Many molecules important for pain transmission have been demonstrated to be localized to the dorsal horn of the spinal cord. Further understanding of the molecular interactions and signaling pathways in the dorsal horn neurons will require a better knowledge of the molecular neuroanatomy in the dorsal spinal cord. Results A large scale screening was conducted for genes with enriched expression in the dorsal spinal cord using DNA microarray and quantitative real-time PCR. In addition to genes known to be specifically expressed in the dorsal spinal cord, other neuropeptides, receptors, ion channels, and signaling molecules were also found enriched in the dorsal spinal cord. In situ hybridization and immunohistochemistry revealed the cellular expression of a subset of these genes. The regulation of a subset of the genes was also studied in the spinal nerve ligation (SNL neuropathic pain model. In general, we found that the genes that are enriched in the dorsal spinal cord were not among those found to be up-regulated in the spinal nerve ligation model of neuropathic pain. This study also provides a level of validation of the use of DNA microarrays in conjunction with our novel analysis algorithm (SAFER for the identification of differences in gene expression. Conclusion This study identified molecules that are enriched in the dorsal horn of the spinal cord and provided a molecular neuroanatomy in the spinal cord, which will aid in the understanding of the molecular mechanisms important in nociception and pain.

  9. Gene Therapy for X-Linked Severe Combined Immunodeficiency: Where Do We Stand?

    Science.gov (United States)

    Cavazzana, Marina; Six, Emmanuelle; Lagresle-Peyrou, Chantal; Andr-Schmutz, Isabelle; Hacein-Bey-Abina, Salima

    2016-02-01

    More than 20 years ago, X-linked severe combined immunodeficiency (SCID-X1) appeared to be the best condition to test the feasibility of hematopoietic stem cell gene therapy. The seminal SCID-X1 clinical studies, based on first-generation gammaretroviral vectors, demonstrated good long-term immune reconstitution in most treated patients despite the occurrence of vector-related leukemia in a few of them. This gene therapy has successfully enabled correction of the T cell defect. Natural killer and B cell defects were only partially restored, most likely due to the absence of a conditioning regimen. The success of these pioneering trials paved the way for the extension of gene-based treatment to many other diseases of the hematopoietic system, but the unfortunate serious adverse events led to extensive investigations to define the retrovirus integration profiles. This review puts into perspective the clinical experience of gene therapy for SCID-X1, with the development and implementation of new generations of safer vectors such as self-inactivating gammaretroviral or lentiviral vectors as well as major advances in integrome knowledge. PMID:26790362

  10. Towards isolation of the gene for X-linked retinitis pigmentosa (RP3)

    Energy Technology Data Exchange (ETDEWEB)

    Dry, K.L.; Aldred, M.A.; Hardwick, L.J. [MRC Human Genetics Unit, Scotland (United Kingdom)] [and others

    1994-09-01

    Until recently the region of interest containing the gene for X-linked retinitis pigmentosa (RP3) was thought to lie between CYBB (Xp21.1) and the proximal end of the deletion in patient BB (JBBprox). This region was thought to span 100-150 kb. Here we present new mapping data to show that the distance between the 5{prime} (most proximal) end of CYBB and JBBprox is only 50 kb. Recently Roux et al. (1994) have described the isolation of a gene within this region but this showed no disease-associated changes. Further evidence from mapping the deletion in patient NF (who suffered from McLead`s syndrome and CGD but not RP) and from linkage analysis of our RP3 families with a new dinucleotide repeat suggests that the gene must extend proximally from JBBprox. In order to extend the region of search we have constructed a YAC contig spanning 800 kb to OTC. We are continuing our search for the RP3 gene using a variety of strategies including exon trapping and cDNA enrichment as well as direct screening of cDNA libraries with subclones from this region.

  11. Gene expression profiling to identify eggshell proteins involved in physical defense of the chicken egg

    Directory of Open Access Journals (Sweden)

    Sibut Vonick

    2010-01-01

    Full Text Available Abstract Background As uricoletic animals, chickens produce cleidoic eggs, which are self-contained bacteria-resistant biological packages for extra-uterine development of the chick embryo. The eggshell constitutes a natural physical barrier against bacterial penetration if it forms correctly and remains intact. The eggshell's remarkable mechanical properties are due to interactions among mineral components and the organic matrix proteins. The purpose of our study was to identify novel eggshell proteins by examining the transcriptome of the uterus during calcification of the eggshell. An extensive bioinformatic analysis on genes over-expressed in the uterus allowed us to identify novel eggshell proteins that contribute to the egg's natural defenses. Results Our 14 K Del-Mar Chicken Integrated Systems microarray was used for transcriptional profiling in the hen's uterus during eggshell deposition. A total of 605 transcripts were over-expressed in the uterus compared with the magnum or white isthmus across a wide range of abundance (1.1- to 79.4-fold difference. The 605 highly-expressed uterine transcripts correspond to 469 unique genes, which encode 437 different proteins. Gene Ontology (GO analysis was used for interpretation of protein function. The most over-represented GO terms are related to genes encoding ion transport proteins, which provide eggshell mineral precursors. Signal peptide sequence was found for 54 putative proteins secreted by the uterus during eggshell formation. Many functional proteins are involved in calcium binding or biomineralization--prerequisites for interacting with the mineral phase during eggshell fabrication. While another large group of proteins could be involved in proper folding of the eggshell matrix. Many secreted uterine proteins possess antibacterial properties, which would protect the egg against microbial invasion. A final group includes proteases and protease inhibitors that regulate protein activity in the acellular uterine fluid where eggshell formation takes place. Conclusions Our original study provides the first detailed description of the chicken uterus transcriptome during formation of the eggshell. We have discovered a cache of about 600 functional genes and identified a large number of encoded proteins secreted into uterine fluid for fabrication of the eggshell and chemical protection of the egg. Some of these uterine genes could prove useful as biological markers for genetic improvement of phenotypic traits (i.e., egg and eggshell quality.

  12. ZCURVE 3.0: identify prokaryotic genes with higher accuracy as well as automatically and accurately select essential genes.

    Science.gov (United States)

    Hua, Zhi-Gang; Lin, Yan; Yuan, Ya-Zhou; Yang, De-Chang; Wei, Wen; Guo, Feng-Biao

    2015-07-01

    In 2003, we developed an ab initio program, ZCURVE 1.0, to find genes in bacterial and archaeal genomes. In this work, we present the updated version (i.e. ZCURVE 3.0). Using 422 prokaryotic genomes, the average accuracy was 93.7% with the updated version, compared with 88.7% with the original version. Such results also demonstrate that ZCURVE 3.0 is comparable with Glimmer 3.02 and may provide complementary predictions to it. In fact, the joint application of the two programs generated better results by correctly finding more annotated genes while also containing fewer false-positive predictions. As the exclusive function, ZCURVE 3.0 contains one post-processing program that can identify essential genes with high accuracy (generally >90%). We hope ZCURVE 3.0 will receive wide use with the web-based running mode. The updated ZCURVE can be freely accessed from http://cefg.uestc.edu.cn/zcurve/ or http://tubic.tju.edu.cn/zcurveb/ without any restrictions. PMID:25977299

  13. Identifying differential expression genes and single nucleotide variations using RNA-seq in metastatic melanoma.

    Science.gov (United States)

    Liu, D; Zhao, Z G; Jiao, Z L; Li, H J

    2014-01-01

    Melanoma is a malignant tumor and one of the most frequent metastatic cancers. This study was conducted to identify differential expression genes (DEGs) and single nucleotide variations (SNVs) in metastatic melanoma. We analyzed microarray data of GSE23056 downloaded from the Gene Expression Omnibus, including two normal samples (skinN1 and skinN2) and 2 metastatic melanoma samples (skinT and lymphT). We not only compared DEGs in metastatic melanoma samples with normal samples (lymphT_skinN and skinT_skinN), but also compared DEGs between two metastatic melanoma types (lymphT_skinT). SNVs were identified by using Burrows-Wheeler Aligner and Cufflinks in metastatic melanoma samples using RNA-seq. Sequence Alignment/Map tools and the ANNOVAR software were used to analyze and annotate SNVs. We identified 18 significantly common DEGs in lymphT_skinN and skinT_skinN and one common gene, YBX1, in lymphT_skinN, skinT_skinN, and lymphT_skinT. We identified 49,534, 48,118, 63,812, and 33,096 SNVs in skinN1, skinN2, skinT, and lymphT, respectively. Twenty-nine SNVs were located in exonic regions of two DEGs, HLA-B and TSPAN10. SNVs that exist only in tumors were located in MARVELD1, SLC16A3, and VAV3. The DEGs screened in our study are potential biomarkers for metastatic melanoma therapy. PMID:25299200

  14. High Throughput Sequencing Identifies Misregulated Genes in the Drosophila Polypyrimidine Tract-Binding Protein (hephaestus) Mutant Defective in Spermatogenesis

    Science.gov (United States)

    Sridharan, Vinod; Heimiller, Joseph; Robida, Mark D.; Singh, Ravinder

    2016-01-01

    The Drosophila polypyrimidine tract-binding protein (dmPTB or hephaestus) plays an important role during spermatogenesis. The heph2 mutation in this gene results in a specific defect in spermatogenesis, causing aberrant spermatid individualization and male sterility. However, the array of molecular defects in the mutant remains uncharacterized. Using an unbiased high throughput sequencing approach, we have identified transcripts that are misregulated in this mutant. Aberrant transcripts show altered expression levels, exon skipping, and alternative 5’ ends. We independently verified these findings by reverse-transcription and polymerase chain reaction (RT-PCR) analysis. Our analysis shows misregulation of transcripts that have been connected to spermatogenesis, including components of the actomyosin cytoskeletal apparatus. We show, for example, that the Myosin light chain 1 (Mlc1) transcript is aberrantly spliced. Furthermore, bioinformatics analysis reveals that Mlc1 contains a high affinity binding site(s) for dmPTB and that the site is conserved in many Drosophila species. We discuss that Mlc1 and other components of the actomyosin cytoskeletal apparatus offer important molecular links between the loss of dmPTB function and the observed developmental defect in spermatogenesis. This study provides the first comprehensive list of genes misregulated in vivo in the heph2 mutant in Drosophila and offers insight into the role of dmPTB during spermatogenesis. PMID:26942929

  15. SERPINA1 Full-Gene Sequencing Identifies Rare Mutations Not Detected in Targeted Mutation Analysis.

    Science.gov (United States)

    Graham, Rondell P; Dina, Michelle A; Howe, Sarah C; Butz, Malinda L; Willkomm, Kurt S; Murray, David L; Snyder, Melissa R; Rumilla, Kandelaria M; Halling, Kevin C; Highsmith, W Edward

    2015-11-01

    Genetic α-1 antitrypsin (AAT) deficiency is characterized by low serum AAT levels and the identification of causal mutations or an abnormal protein. It needs to be distinguished from deficiency because of nongenetic causes, and diagnostic delay may contribute to worse patient outcome. Current routine clinical testing assesses for only the most common mutations. We wanted to determine the proportion of unexplained cases of AAT deficiency that harbor causal mutations not identified through current standard allele-specific genotyping and isoelectric focusing (IEF). All prospective cases from December 1, 2013, to October 1, 2014, with a low serum AAT level not explained by allele-specific genotyping and IEF were assessed through full-gene sequencing with a direct sequencing method for pathogenic mutations. We reviewed the results using American Council of Medical Genetics criteria. Of 3523 cases, 42 (1.2%) met study inclusion criteria. Pathogenic or likely pathogenic mutations not identified through clinical testing were detected through full-gene sequencing in 16 (38%) of the 42 cases. Rare mutations not detected with current allele-specific testing and IEF underlie a substantial proportion of genetic AAT deficiency. Full-gene sequencing, therefore, has the ability to improve accuracy in the diagnosis of AAT deficiency. PMID:26321041

  16. Expression profiling identifies genes involved in neoplastic transformation of serous ovarian cancer

    International Nuclear Information System (INIS)

    The malignant potential of serous ovarian tumors, the most common ovarian tumor subtype, varies from benign to low malignant potential (LMP) tumors to frankly invasive cancers. Given the uncertainty about the relationship between these different forms, we compared their patterns of gene expression. Expression profiling was carried out on samples of 7 benign, 7 LMP and 28 invasive (moderate and poorly differentiated) serous tumors and four whole normal ovaries using oligonucleotide microarrays representing over 21,000 genes. We identified 311 transcripts that distinguished invasive from benign tumors, and 20 transcripts that were significantly differentially expressed between invasive and LMP tumors at p < 0.01 (with multiple testing correction). Five genes that were differentially expressed between invasive and either benign or normal tissues were validated by real time PCR in an independent panel of 46 serous tumors (4 benign, 7 LMP, 35 invasive). Overexpression of SLPI and WNT7A and down-regulation of C6orf31, PDGFRA and GLTSCR2 were measured in invasive and LMP compared with benign and normal tissues. Over-expression of WNT7A in an ovarian cancer cell line led to increased migration and invasive capacity. These results highlight several genes that may play an important role across the spectrum of serous ovarian tumorigenesis

  17. Phencyclidine-induced changes in rat cortical gene expression identified by microarray analysis: implications for schizophrenia.

    Science.gov (United States)

    Kaiser, Sergio; Foltz, Lisa A; George, Carolyn A; Kirkwood, Sandra C; Bemis, Kerry G; Lin, Xi; Gelbert, Lawrence M; Nisenbaum, Laura K

    2004-06-01

    Acute phencyclidine induces schizophrenia-like symptoms in healthy humans and psychotic episodes in schizophrenics. Although phencyclidine is known as a N-methyl d-aspartate receptor antagonist (NMDA-R), the molecular events underlying the behavioral symptoms remain largely unknown. Statistical analysis of oligonucleotide microarray data was used to identify phencyclidine-induced alterations in rat cortical gene expression. Acute phencyclidine produced a statistically significant change in 477 genes in rat prefrontal cortex (PFC), a brain area associated with cognitive dysfunction in schizophrenics. Real-time quantitative PCR (RTQ-PCR) confirmed a subset of these changes ranging from -59% to 255% (smallest confirmation: -19%). Subsequent time-course and dose-response studies using RTQ-PCR confirmed and extended the original microarray results. At the molecular level, genes altered by phencyclidine are related to diverse biological processes including stress, inflammatory response, growth and development, neural plasticity and signal transduction. Further analysis, aimed at assessing the relevance of our results to schizophrenia, revealed dysregulation of genes related to: (i) thalamocortical projections, (ii) neurotransmission and neuromodulation, (iii) thyroid hormone activity, (iv) oligodendrocyte linage, (v) brain lipid metabolism, (vi) sleep architecture and (viii) the velocardiofacial syndrome. PMID:15207279

  18. Analysis of multiple transcriptomes of the African oil palm (Elaeis guineensis) to identify reference genes for RT-qPCR.

    Science.gov (United States)

    Xia, Wei; Mason, Annaliese S; Xiao, Yong; Liu, Zheng; Yang, Yaodong; Lei, Xintao; Wu, Xiaoming; Ma, Zilong; Peng, Ming

    2014-08-20

    The African oil palm (Elaeis guineensis), which is grown in tropical and subtropical regions, is a highly productive oil-bearing crop. For gene expression-based analyses such as reverse transcription-quantitative real time PCR (RT-qPCR), reference genes are essential to provide a baseline with which to quantify relative gene expression. Normalization using reliable reference genes is critical in correctly interpreting expression data from RT-qPCR. In order to identify suitable reference genes in African oil palm, 17 transcriptomes of different tissues obtained from NCBI were systematically assessed for gene expression variation. In total, 53 putative candidate reference genes with coefficient of variation values <3.0 were identified: 18 in reproductive tissue and 35 in vegetative tissue. Analysis for enriched functions showed that approximately 90% of identified genes were clustered in cell component gene functions, and 12 out of 53 genes were traditional housekeeping genes. We selected and validated 16 reference genes chosen from leaf tissue transcriptomes by using RT-qPCR in sets of cold, drought and high salinity treated samples, and ranked expression stability using statistical algorithms geNorm, Normfinder and Bestkeeper. Genes encoding actin, adenine phosphoribosyltransferase and eukaryotic initiation factor 4A genes were the most stable genes over the cold, drought and high salinity stresses. Identification of stably expressed genes as reference gene candidates from multiple transcriptome datasets was found to be reliable and efficient, and some traditional housekeeping genes were more stably expressed than others. We provide a useful molecular genetic resource for future gene expression studies in African oil palm, facilitating molecular genetics approaches for crop improvement in this species. PMID:24862192

  19. Misregulation of Gene Expression and Sterility in Interspecies Hybrids: Causal Links and Alternative Hypotheses.

    Science.gov (United States)

    Civetta, Alberto

    2016-05-01

    Understanding the origin of species is of interest to biologist in general and evolutionary biologist in particular. Hybrid male sterility (HMS) has been a focus in studies of speciation because sterility imposes a barrier to free gene flow between organisms, thus effectively isolating them as distinct species. In this review, I focus on the role of differential gene expression in HMS and speciation. Microarray and qPCR assays have established associations between misregulation of gene expression and sterility in hybrids between closely related species. These studies originally proposed disrupted expression of spermatogenesis genes as a causative of sterility. Alternatively, rapid genetic divergence of regulatory elements, particularly as they relate to the male sex (fast-male evolution), can drive the misregulation of sperm developmental genes in the absence of sterility. The use of fertile hybrids (both backcross and F1 progeny) as controls has lent support to this alternative explanation. Differences in gene expression between fertile and sterile hybrids can also be influenced by a pattern of faster evolution of the sex chromosome (fast-X evolution) than autosomes. In particular, it would be desirable to establish whether known X-chromosome sterility factors can act as trans-regulatory drivers of genome-wide patterns of misregulation. Genome-wide expression studies coupled with assays of proxies of sterility in F1 and BC progeny have identified candidate HMS genes but functional assays, and a better phenotypic characterization of sterility phenotypes, are needed to rigorously test how these genes might contribute to HMS. PMID:27025762

  20. HindIII identifies a two allele DNA polymorphism of the human cannabinoid receptor gene (CNR)

    Energy Technology Data Exchange (ETDEWEB)

    Caenazzo, L.; Hoehe, M.R.; Hsieh, W.T.; Berrettini, W.H.; Bonner, T.I.; Gershon, E.S. (National Inst. of Health, Bethesda, MD (United States))

    1991-09-11

    HCNR p5, a 0.9 kb BamHI/EcoRI fragment from the human cannabinoid receptor gene inserted into pUC19, was used as probe. The fragment is located in an intron approximately 14 kb 5{prime} of the initiation codon. This fragment is a clean single copy sequence by genomic blotting. Hybridization of human genomic DNA digested with HindIII identified a two allele RFLP with bands at 5.5 (A1) and 3.3 kb (A2). The human cannabinoid receptor gene has been genetically mapped in CEPH reference pedigrees to the centromeric/q region of chromosome 6. In situ hybridization localizes it to 6q14-q15. Codominant segregation has been observed in 26 informative two- and three-generation CEPH pedigrees and in 14 medium-sized disease families.

  1. Statistical methods for identifying differentially expressed genes in RNA-Seq experiments

    Directory of Open Access Journals (Sweden)

    Fang Zhide

    2012-07-01

    Full Text Available Abstract RNA sequencing (RNA-Seq is rapidly replacing microarrays for profiling gene expression with much improved accuracy and sensitivity. One of the most common questions in a typical gene profiling experiment is how to identify a set of transcripts that are differentially expressed between different experimental conditions. Some of the statistical methods developed for microarray data analysis can be applied to RNA-Seq data with or without modifications. Recently several additional methods have been developed specifically for RNA-Seq data sets. This review attempts to give an in-depth review of these statistical methods, with the goal of providing a comprehensive guide when choosing appropriate metrics for RNA-Seq statistical analyses.

  2. A Complementary Bioinformatics Approach to Identify Potential Plant Cell Wall Glycosyltransferase-Encoding Genes

    DEFF Research Database (Denmark)

    Egelund, Jack; Skjøt, Michael; Geshi, Naomi; Ulvskov, Peter; Petersen, Bent Larsen

    2004-01-01

    participate in the synthesis of hemicellulose, pectin, mannans, and various glycoproteins. At the Carbohydrate-Active enZYmes (CAZy) database where e.g. glucoside hydrolases and GTs are classified into gene families primarily based on amino acid sequence similarities, 415 Arabidopsis GTs have been classified....... Although much is known with regard to composition and fine structures of the plant CW, only a handful of CW biosynthetic GT genes-all classified in the CAZy system-have been characterized. In an effort to identify CW GTs that have not yet been classified in the CAZy database, a simple bioinformatics...... classified in CAZy were discarded. The resulting 139 sequences were then analyzed using the Three-Dimensional-Position-Specific Scoring Matrix and mGenTHREADER servers, and 27 sequences with similarity to either the GT-A or the GT-B fold were obtained. Proof of concept of the present approach has to some...

  3. Carbamate-linked cationic lipids with different hydrocarbon chains for gene delivery.

    Science.gov (United States)

    Shi, Jia; Yu, Shijun; Zhu, Jie; Zhi, Defu; Zhao, Yinan; Cui, Shaohui; Zhang, Shubiao

    2016-05-01

    A series of carbamate-linked cationic lipids containing saturated or unsaturated hydrocarbon chains and quaternary ammonium head were designed and synthesized. After recrystallization, carbamate-linked cationic lipids with high purity (over 95%) were obtained. The structures of these lipids were proved by IR spectrum, HR-ESI-MS, HPLC, (1)H NMR and (13)C NMR. The liposomes were prepared by using these cationic lipids and neutral lipid DOPE. Particle size and zeta-potential were studied to show that they were suitable for gene transfection. The DNA-bonding ability of C12:0, C14:0 and C18:1 cationic liposomes was much better than others. The results of transfection showed that hydrophobic chains of these lipids have great effects on their transfection activity. The lipids bearing C12:0, C14:0 saturated chains or C18:1 unsaturated chain showed relatively higher transfection efficiency and lower cytotoxicity. So these cationic lipids could be used as non-viral gene carriers for further studies. PMID:26895503

  4. Transcript and protein profiling identify candidate gene sets of potential adaptive significance in New Zealand Pachycladon

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    Schmidt Silvia

    2010-05-01

    Full Text Available Abstract Background Transcript profiling of closely related species provides a means for identifying genes potentially important in species diversification. However, the predictive value of transcript profiling for inferring downstream-physiological processes has been unclear. In the present study we use shotgun proteomics to validate inferences from microarray studies regarding physiological differences in three Pachycladon species. We compare transcript and protein profiling and evaluate their predictive value for inferring glucosinolate chemotypes characteristic of these species. Results Evidence from heterologous microarrays and shotgun proteomics revealed differential expression of genes involved in glucosinolate hydrolysis (myrosinase-associated proteins and biosynthesis (methylthioalkylmalate isomerase and dehydrogenase, the interconversion of carbon dioxide and bicarbonate (carbonic anhydrases, water use efficiency (ascorbate peroxidase, 2 cys peroxiredoxin, 20 kDa chloroplastic chaperonin, mitochondrial succinyl CoA ligase and others (glutathione-S-transferase, serine racemase, vegetative storage proteins, genes related to translation and photosynthesis. Differences in glucosinolate hydrolysis products were directly confirmed. Overall, prediction of protein abundances from transcript profiles was stronger than prediction of transcript abundance from protein profiles. Protein profiles also proved to be more accurate predictors of glucosinolate profiles than transcript profiles. The similarity of species profiles for both transcripts and proteins reflected previously inferred phylogenetic relationships while glucosinolate chemotypes did not. Conclusions We have used transcript and protein profiling to predict physiological processes that evolved differently during diversification of three Pachycladon species. This approach has also identified candidate genes potentially important in adaptation, which are now the focus of ongoing study. Our results indicate that protein profiling provides a valuable tool for validating transcript profiles in studies of adaptive divergence.

  5. Using Transcriptomics to Identify Differential Gene Expression in Response to Salinity among Australian Phragmites australis Clones

    Science.gov (United States)

    Holmes, Gareth D.; Hall, Nathan E.; Gendall, Anthony R.; Boon, Paul I.; James, Elizabeth A.

    2016-01-01

    Common Reed (Phragmites australis) is a frequent component of inland and coastal wetlands in temperate zones worldwide. Ongoing environmental changes have resulted in the decline of this species in many areas and invasive expansion in others. In the Gippsland Lakes coastal waterway system in south-eastern Australia, increasing salinity is thought to have contributed to the loss of fringing P. australis reed beds leading to increased shoreline erosion. A major goal of restoration in this waterway is to address the effect of salinity by planting a genetically diverse range of salt-tolerant P. australis plants. This has prompted an interest in examining the variation in salinity tolerance among clones and the underlying basis of this variation. Transcriptomics is an approach for identifying variation in genes and their expression levels associated with the exposure of plants to environmental stressors. In this paper we present initial results of the first comparative culm transcriptome analysis of P. australis clones. After sampling plants from sites of varied surface water salinity across the Gippsland Lakes, replicates from three clones from highly saline sites (>18 g L-1 TDS) and three from low salinity sites (<6 g L-1) were grown in containers irrigated with either fresh (<0.1 g L-1) or saline water (16 g L-1). An RNA-Seq protocol was used to generate sequence data from culm tissues from the 12 samples allowing an analysis of differential gene expression. Among the key findings, we identified several genes uniquely up- or down-regulated in clones from highly saline sites when irrigated with saline water relative to clones from low salinity sites. These included the higher relative expression levels of genes associated with photosynthesis and lignan biosynthesis indicative of a greater ability of these clones to maintain growth under saline conditions. Combined with growth data from a parallel study, our data suggests local adaptation of certain clones to salinity and provides a basis for more detailed studies. PMID:27148279

  6. Using Transcriptomics to Identify Differential Gene Expression in Response to Salinity among Australian Phragmites australis Clones.

    Science.gov (United States)

    Holmes, Gareth D; Hall, Nathan E; Gendall, Anthony R; Boon, Paul I; James, Elizabeth A

    2016-01-01

    Common Reed (Phragmites australis) is a frequent component of inland and coastal wetlands in temperate zones worldwide. Ongoing environmental changes have resulted in the decline of this species in many areas and invasive expansion in others. In the Gippsland Lakes coastal waterway system in south-eastern Australia, increasing salinity is thought to have contributed to the loss of fringing P. australis reed beds leading to increased shoreline erosion. A major goal of restoration in this waterway is to address the effect of salinity by planting a genetically diverse range of salt-tolerant P. australis plants. This has prompted an interest in examining the variation in salinity tolerance among clones and the underlying basis of this variation. Transcriptomics is an approach for identifying variation in genes and their expression levels associated with the exposure of plants to environmental stressors. In this paper we present initial results of the first comparative culm transcriptome analysis of P. australis clones. After sampling plants from sites of varied surface water salinity across the Gippsland Lakes, replicates from three clones from highly saline sites (>18 g L(-1) TDS) and three from low salinity sites (water (16 g L(-1)). An RNA-Seq protocol was used to generate sequence data from culm tissues from the 12 samples allowing an analysis of differential gene expression. Among the key findings, we identified several genes uniquely up- or down-regulated in clones from highly saline sites when irrigated with saline water relative to clones from low salinity sites. These included the higher relative expression levels of genes associated with photosynthesis and lignan biosynthesis indicative of a greater ability of these clones to maintain growth under saline conditions. Combined with growth data from a parallel study, our data suggests local adaptation of certain clones to salinity and provides a basis for more detailed studies. PMID:27148279

  7. Gene Expression Profiling Identifies Interferon Signalling Molecules and IGFBP3 in Human Degenerative Annulus Fibrosus.

    Science.gov (United States)

    Kazezian, Zepur; Gawri, Rahul; Haglund, Lisbet; Ouellet, Jean; Mwale, Fackson; Tarrant, Finbarr; O'Gaora, Peadar; Pandit, Abhay; Alini, Mauro; Grad, Sibylle

    2015-01-01

    Low back pain is a major cause of disability especially for people between 20 and 50 years of age. As a costly healthcare problem, it imposes a serious socio-economic burden. Current surgical therapies fail to replace the normal disc in facilitating spinal movements and absorbing load. The focus of regenerative medicine is on identifying biomarkers and signalling pathways to improve our understanding about cascades of disc degeneration and allow for the design of specific therapies. We hypothesized that comparing microarray profiles from degenerative and non-degenerative discs will lead to the identification of dysregulated signalling and pathophysiological targets. Microarray data sets were generated from human annulus fibrosus cells and analysed using IPA ingenuity pathway analysis. Gene expression values were validated by qRT-PCR, and respective proteins were identified by immunohistochemistry. Microarray analysis revealed 238 differentially expressed genes in the degenerative annulus fibrosus. Seventeen of the dysregulated molecular markers showed log2-fold changes greater than ±1.5. Various dysregulated cellular functions, including cell proliferation and inflammatory response, were identified. The most significant canonical pathway induced in degenerative annulus fibrosus was found to be the interferon pathway. This study indicates interferon-alpha signalling pathway activation with IFIT3 and IGFBP3 up-regulation, which may affect cellular function in human degenerative disc. PMID:26489762

  8. Targeted next-generation sequencing of 22 mismatch repair genes identifies Lynch syndrome families.

    Science.gov (United States)

    Talseth-Palmer, Bente A; Bauer, Denis C; Sjursen, Wenche; Evans, Tiffany J; McPhillips, Mary; Proietto, Anthony; Otton, Geoffrey; Spigelman, Allan D; Scott, Rodney J

    2016-05-01

    Causative germline mutations in mismatch repair (MMR) genes can only be identified in ~50% of families with a clinical diagnosis of the inherited colorectal cancer (CRC) syndrome hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome (LS). Identification of these patients are critical as they are at substantially increased risk of developing multiple primary tumors, mainly colorectal and endometrial cancer (EC), occurring at a young age. This demonstrates the need to develop new and/or more thorough mutation detection approaches. Next-generation sequencing (NGS) was used to screen 22 genes involved in the DNA MMR pathway in constitutional DNA from 14 HNPCC and 12 sporadic EC patients, plus 2 positive controls. Several softwares were used for analysis and functional annotation. We identified 5 exonic indel variants, 42 exonic nonsynonymous single-nucleotide variants (SNVs) and 1 intronic variant of significance. Three of these variants were class 5 (pathogenic) or class 4 (likely pathogenic), 5 were class 3 (uncertain clinical relevance) and 40 were classified as variants of unknown clinical significance. In conclusion, we have identified two LS families from the sporadic EC patients, one without a family history of cancer, supporting the notion for universal MMR screening of EC patients. In addition, we have detected three novel class 3 variants in EC cases. We have, in addition discovered a polygenic interaction which is the most likely cause of cancer development in a HNPCC patient that could explain previous inconsistent results reported on an intronic EXO1 variant. PMID:26811195

  9. Detection of mutations in the COL4A5 gene by SSCP in X-linked Alport syndrome

    DEFF Research Database (Denmark)

    Hertz, Jens Michael; Juncker, I; Persson, U; Matthijs, G; Schmidtke, J; Petersen, M B; Kjeldsen, M; Gregersen, N

    2001-01-01

    Alport syndrome is a progressive renal disease leading to chronic renal failure, which often is accompanied by sensorineural deafness and ophthalmological signs in the form of anterior lenticonus. The X-linked form of the disease is caused by mutations in the COL4A5 gene encoding the alpha5-chain...... of type IV-collagen. We performed mutation analysis of the COL4A5 gene by PCR-SSCP analysis of each of the 51 exons with flanking intronic sequences in 81 patients suspected of X-linked Alport syndrome including 29 clear X-linked cases, 37 cases from families with a pedigree compatible with X...

  10. Oil palm (Elaeis guineensis Jacq. tissue culture ESTs: Identifying genes associated with callogenesis and embryogenesis

    Directory of Open Access Journals (Sweden)

    Ooi Leslie CL

    2008-05-01

    Full Text Available Abstract Background Oil palm (Elaeis guineensis Jacq. is one of the most important oil bearing crops in the world. However, genetic improvement of oil palm through conventional breeding is extremely slow and costly, as the breeding cycle can take up to 10 years. This has brought about interest in vegetative propagation of oil palm. Since the introduction of oil palm tissue culture in the 1970s, clonal propagation has proven to be useful, not only in producing uniform planting materials, but also in the development of the genetic engineering programme. Despite considerable progress in improving the tissue culture techniques, the callusing and embryogenesis rates from proliferating callus cultures remain very low. Thus, understanding the gene diversity and expression profiles in oil palm tissue culture is critical in increasing the efficiency of these processes. Results A total of 12 standard cDNA libraries, representing three main developmental stages in oil palm tissue culture, were generated in this study. Random sequencing of clones from these cDNA libraries generated 17,599 expressed sequence tags (ESTs. The ESTs were analysed, annotated and assembled to generate 9,584 putative unigenes distributed in 3,268 consensi and 6,316 singletons. These unigenes were assigned putative functions based on similarity and gene ontology annotations. Cluster analysis, which surveyed the relatedness of each library based on the abundance of ESTs in each consensus, revealed that lipid transfer proteins were highly expressed in embryogenic tissues. A glutathione S-transferase was found to be highly expressed in non-embryogenic callus. Further analysis of the unigenes identified 648 non-redundant simple sequence repeats and 211 putative full-length open reading frames. Conclusion This study has provided an overview of genes expressed during oil palm tissue culture. Candidate genes with expression that are modulated during tissue culture were identified. However, in order to confirm whether these genes are suitable as early markers for embryogenesis, the genes need to be tested on earlier stages of tissue culture and a wider range of genotypes. This collection of ESTs is an important resource for genetic and genome analyses of the oil palm, particularly during tissue culture development.

  11. Exploiting CpG hypermutability to identify phenotypically significant variation within human protein-coding genes.

    Science.gov (United States)

    Ying, Hua; Huttley, Gavin

    2011-01-01

    The CpG dinucleotide is disproportionately represented in human genetic variation due to the hypermutability of 5-methyl-cytosine (5mC). We exploit this hypermutability and a novel codon substitution model to identify candidate functionally important exonic nucleotides. Population genetic theory suggests that codon positions with high cross-species CpG frequency will derive from stronger purifying selection. Using the phylogeny-based maximum likelihood inference framework, we applied codon substitution models with context-dependent parameters to measure the mutagenic and selective processes affecting CpG dinucleotides within exonic sequence. The suitability of these models was validated on >2,000 protein coding genes from a naturally occurring biological control, four yeast species that do not methylate their DNA. As expected, our analyses of yeast revealed no evidence for an elevated CpG transition rate or for substitution suppression affecting CpG-containing codons. Our analyses of >12,000 protein-coding genes from four primate lineages confirm the systemic influence of 5mC hypermutability on the divergence of these genes. After adjusting for confounding influences of mutation and the properties of the encoded amino acids, we confirmed that CpG-containing codons are under greater purifying selection in primates. Genes with significant evidence of enhanced suppression of nonsynonymous CpG changes were also shown to be significantly enriched in Online Mendelian Inheritance in Man. We developed a method for ranking candidate phenotypically influential CpG positions in human genes. Application of this method indicates that of the ∼1 million exonic CpG dinucleotides within humans, ∼20% are strong candidates for both hypermutability and disease association. PMID:21398426

  12. Microarray Expression Data Identify DCC as a Candidate Gene for Early Meningioma Progression

    Science.gov (United States)

    Schulten, Hans-Juergen; Hussein, Deema; Al-Adwani, Fatima; Karim, Sajjad; Al-Maghrabi, Jaudah; Al-Sharif, Mona; Jamal, Awatif; Al-Ghamdi, Fahad; Baeesa, Saleh S.; Bangash, Mohammed; Chaudhary, Adeel; Al-Qahtani, Mohammed

    2016-01-01

    Meningiomas are the most common primary brain tumors bearing in a minority of cases an aggressive phenotype. Although meningiomas are stratified according to their histology and clinical behavior, the underlying molecular genetics predicting aggressiveness are not thoroughly understood. We performed whole transcript expression profiling in 10 grade I and four grade II meningiomas, three of which invaded the brain. Microarray expression analysis identified deleted in colorectal cancer (DCC) as a differentially expressed gene (DEG) enabling us to cluster meningiomas into DCC low expression (3 grade I and 3 grade II tumors), DCC medium expression (2 grade I and 1 grade II tumors), and DCC high expression (5 grade I tumors) groups. Comparison between the DCC low expression and DCC high expression groups resulted in 416 DEGs (p-value 2). The most significantly downregulated genes in the DCC low expression group comprised DCC, phosphodiesterase 1C (PDE1C), calmodulin-dependent 70kDa olfactomedin 2 (OLFM2), glutathione S-transferase mu 5 (GSTM5), phosphotyrosine interaction domain containing 1 (PID1), sema domain, transmembrane domain (TM) and cytoplasmic domain, (semaphorin) 6D (SEMA6D), and indolethylamine N-methyltransferase (INMT). The most significantly upregulated genes comprised chromosome 5 open reading frame 63 (C5orf63), homeodomain interacting protein kinase 2 (HIPK2), and basic helix-loop-helix family, member e40 (BHLHE40). Biofunctional analysis identified as predicted top upstream regulators beta-estradiol, TGFB1, Tgf beta complex, LY294002, and dexamethasone and as predicted top regulator effectors NFkB, PIK3R1, and CREBBP. The microarray expression data served also for a comparison between meningiomas from female and male patients and for a comparison between brain invasive and non-invasive meningiomas resulting in a number of significant DEGs and related biofunctions. In conclusion, based on its expression levels, DCC may constitute a valid biomarker to identify those benign meningiomas at risk for progression. PMID:27096627

  13. The BridgeDb framework: standardized access to gene, protein and metabolite identifier mapping services

    Directory of Open Access Journals (Sweden)

    Hanspers Kristina

    2010-01-01

    Full Text Available Abstract Background Many complementary solutions are available for the identifier mapping problem. This creates an opportunity for bioinformatics tool developers. Tools can be made to flexibly support multiple mapping services or mapping services could be combined to get broader coverage. This approach requires an interface layer between tools and mapping services. Results Here we present BridgeDb, a software framework for gene, protein and metabolite identifier mapping. This framework provides a standardized interface layer through which bioinformatics tools can be connected to different identifier mapping services. This approach makes it easier for tool developers to support identifier mapping. Mapping services can be combined or merged to support multi-omics experiments or to integrate custom microarray annotations. BridgeDb provides its own ready-to-go mapping services, both in webservice and local database forms. However, the framework is intended for customization and adaptation to any identifier mapping service. BridgeDb has already been integrated into several bioinformatics applications. Conclusion By uncoupling bioinformatics tools from mapping services, BridgeDb improves capability and flexibility of those tools. All described software is open source and available at http://www.bridgedb.org.

  14. Identification of 42 Genes Linked to Stage II Colorectal Cancer Metastatic Relapse

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    Rabeah A. Al-Temaimi

    2016-04-01

    Full Text Available Colorectal cancer (CRC is one of the leading causes of cancer mortality. Metastasis remains the primary cause of CRC death. Predicting the possibility of metastatic relapse in early-stage CRC is of paramount importance to target therapy for patients who really need it and spare those with low-potential of metastasis. Ninety-six stage II CRC cases were stratified using high-resolution array comparative genomic hybridization (aCGH data based on a predictive survival algorithm and supervised clustering. All genes included within the resultant copy number aberrations were each interrogated independently at mRNA level using CRC expression datasets available from public repositories, which included 1820 colon cancers, and 167 normal colon tissues. Reduced mRNA expression driven by copy number losses and increased expression driven by copy number gains revealed 42 altered transcripts (29 reduced and 13 increased transcripts associated with metastatic relapse, short disease-free or overall survival, and/or epithelial to mesenchymal transition (EMT. Resultant genes were classified based on gene ontology (GO, which identified four functional enrichment groups involved in growth regulation, genomic integrity, metabolism, and signal transduction pathways. The identified 42 genes may be useful for predicting metastatic relapse in stage II CRC. Further studies are necessary to validate these findings.

  15. Expression profiling of Crambe abyssinica under arsenate stress identifies genes and gene networks involved in arsenic metabolism and detoxification

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    Kandasamy Suganthi

    2010-06-01

    Full Text Available Abstract Background Arsenic contamination is widespread throughout the world and this toxic metalloid is known to cause cancers of organs such as liver, kidney, skin, and lung in human. In spite of a recent surge in arsenic related studies, we are still far from a comprehensive understanding of arsenic uptake, detoxification, and sequestration in plants. Crambe abyssinica, commonly known as 'abyssinian mustard', is a non-food, high biomass oil seed crop that is naturally tolerant to heavy metals. Moreover, it accumulates significantly higher levels of arsenic as compared to other species of the Brassicaceae family. Thus, C. abyssinica has great potential to be utilized as an ideal inedible crop for phytoremediation of heavy metals and metalloids. However, the mechanism of arsenic metabolism in higher plants, including C. abyssinica, remains elusive. Results To identify the differentially expressed transcripts and the pathways involved in arsenic metabolism and detoxification, C. abyssinica plants were subjected to arsenate stress and a PCR-Select Suppression Subtraction Hybridization (SSH approach was employed. A total of 105 differentially expressed subtracted cDNAs were sequenced which were found to represent 38 genes. Those genes encode proteins functioning as antioxidants, metal transporters, reductases, enzymes involved in the protein degradation pathway, and several novel uncharacterized proteins. The transcripts corresponding to the subtracted cDNAs showed strong upregulation by arsenate stress as confirmed by the semi-quantitative RT-PCR. Conclusions Our study revealed novel insights into the plant defense mechanisms and the regulation of genes and gene networks in response to arsenate toxicity. The differential expression of transcripts encoding glutathione-S-transferases, antioxidants, sulfur metabolism, heat-shock proteins, metal transporters, and enzymes in the ubiquitination pathway of protein degradation as well as several unknown novel proteins serve as molecular evidence for the physiological responses to arsenate stress in plants. Additionally, many of these cDNA clones showing strong upregulation due to arsenate stress could be used as valuable markers. Further characterization of these differentially expressed genes would be useful to develop novel strategies for efficient phytoremediation as well as for engineering arsenic tolerant crops with reduced arsenic translocation to the edible parts of plants.

  16. Computational modeling with forward and reverse engineering links signaling network and genomic regulatory responses: NF-?B signaling-induced gene expression responses in inflammation

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    Peng Chien

    2010-06-01

    Full Text Available Abstract Background Signal transduction is the major mechanism through which cells transmit external stimuli to evoke intracellular biochemical responses. Diverse cellular stimuli create a wide variety of transcription factor activities through signal transduction pathways, resulting in different gene expression patterns. Understanding the relationship between external stimuli and the corresponding cellular responses, as well as the subsequent effects on downstream genes, is a major challenge in systems biology. Thus, a systematic approach is needed to integrate experimental data and theoretical hypotheses to identify the physiological consequences of environmental stimuli. Results We proposed a systematic approach that combines forward and reverse engineering to link the signal transduction cascade with the gene responses. To demonstrate the feasibility of our strategy, we focused on linking the NF-?B signaling pathway with the inflammatory gene regulatory responses because NF-?B has long been recognized to play a crucial role in inflammation. We first utilized forward engineering (Hybrid Functional Petri Nets to construct the NF-?B signaling pathway and reverse engineering (Network Components Analysis to build a gene regulatory network (GRN. Then, we demonstrated that the corresponding IKK profiles can be identified in the GRN and are consistent with the experimental validation of the IKK kinase assay. We found that the time-lapse gene expression of several cytokines and chemokines (TNF-?, IL-1, IL-6, CXCL1, CXCL2 and CCL3 is concordant with the NF-?B activity profile, and these genes have stronger influence strength within the GRN. Such regulatory effects have highlighted the crucial roles of NF-?B signaling in the acute inflammatory response and enhance our understanding of the systemic inflammatory response syndrome. Conclusion We successfully identified and distinguished the corresponding signaling profiles among three microarray datasets with different stimuli strengths. In our model, the crucial genes of the NF-?B regulatory network were also identified to reflect the biological consequences of inflammation. With the experimental validation, our strategy is thus an effective solution to decipher cross-talk effects when attempting to integrate new kinetic parameters from other signal transduction pathways. The strategy also provides new insight for systems biology modeling to link any signal transduction pathways with the responses of downstream genes of interest.

  17. Mis-splicing of the ABCC2 gene linked with Bt toxin resistance in Helicoverpa armigera.

    Science.gov (United States)

    Xiao, Yutao; Zhang, Tao; Liu, Chenxi; Heckel, David G; Li, Xianchun; Tabashnik, Bruce E; Wu, Kongming

    2014-01-01

    Toxins from the bacterium Bacillus thuringiensis (Bt) are used widely for insect control in sprays and transgenic plants, but their efficacy is reduced when pests evolve resistance. Previous work showed that mutations in a gene encoding the transporter protein ABCC2 are linked with resistance to Bt toxins Cry1Ab, Cry1Ac or both in four species of Lepidoptera. Here we compared the ABCC2 gene of Helicoverpa armigera (HaABCC2) between susceptible strains and a laboratory-selected strain with >1,000-fold resistance to Cry1Ac relative its susceptible parent strain. We discovered a 73-base pair (bp) insertion in the cDNA of the resistant strain that generates a premature stop codon expected to yield a truncated ABCC2 protein. Sequencing of genomic DNA revealed that this insertion is an intron that is not spliced out because of a 6-bp deletion at its splicing site. Analysis of progeny from crosses revealed tight genetic linkage between HaABCC2 and resistance to Cry1Ac. These results provide the first evidence that mis-splicing of a gene encoding an ABCC2 protein confers resistance to a Bt toxin. PMID:25154974

  18. A novel missense mutation in the CLCN7 gene linked to benign autosomal dominant osteopetrosis: a case series

    Directory of Open Access Journals (Sweden)

    Rashid Ban Mousa

    2013-01-01

    Full Text Available Abstract Introduction Osteopetrosis is a rare inherited genetic disease characterized by sclerosis of the skeleton. The absence or malfunction of osteoclasts is found to be strongly associated with the disease evolution. Currently, four clinically distinct forms of the disease have been recognized: the infantile autosomal recessive osteopetrosis, the malignant and the intermediate forms, and autosomal dominant osteopetrosis, type I and type II forms. The autosomal recessive types are the most severe forms with symptoms in very early childhood, whereas the autosomal dominant classes exhibit a heterogeneous trait with milder symptoms, often at later childhood or adulthood. Case presentation Case 1 is the 12-year-old daughter (index patient of an Iraqi-Kurdish family who, at the age of eight years, was diagnosed clinically to have mild autosomal dominant osteopetrosis. Presently, at 12-years old, she has severe complications due to the disease progression. In addition, the same family previously experienced the death of a female child in her late childhood. The deceased child had been misdiagnosed, at that time, with thalassemia major. In this report, we extended our investigation to identify the type of the inheritance patterns of osteopetrosis using molecular techniques, because consanguineous marriages exist within the family history. We have detected one heterozygous mutation in exon 15 of the Chloride Channel 7 gene in the index patient (Case 1, whereas other mutations were not detected in the associated genes TCIRG1, OSTM1, RANK, and RANKL. The missense mutation (CGG>TGG located in exon 15 (c.1225C>T of the Chloride Channel 7 gene changed the amino acid position 409 from arginine to tryptophan (p.R409W, c.1225C>T. Case 2 is the 16-year-old son (brother of the index patient of the same family who was diagnosed clinically with mild autosomal dominant osteopetrosis. We have identified the same heterozygous mutation in exon 15 of the Chloride channel 7 gene in this patient (Case 2. The missense mutation (CGG>TGG located in exon 15 (c.1225C>T of the Chloride channel 7 gene changed the amino acid position 409 from arginine to tryptophan (p.R409W, c.1225C>T. In addition to the clinical diagnosis of both cases, the missense mutation we identified in one allele of the Chloride channel 7 gene could be linked to autosomal dominant osteopetrosis-II because the symptoms appear in late childhood or adolescence. Conclusion In this family, the molecular diagnosis was confirmed after identification of the same mutation in the older son (sibling. Furthermore, we detected that the father and his brother (the uncle are carriers of the same mutation, whereas the mother and her sister (the aunt do not carry any mutation of the Chloride channel 7 gene. Thus, the disease penetrance is at least 60% in the family. The mother and father are cousins and a further consanguineous marriage between the aunt and the uncle is not recommended because the dominant allele of the Chloride channel 7 gene will be transferred to the progeny. However, a similar risk is also expected following a marriage between the uncle and an unrelated woman. The p.R409W mutation in the Chloride channel 7 gene has not yet been described in the literature and it possibly has a dominant-negative impact on the protein.

  19. Next-generation sequencing identifies novel CACNA1A gene mutations in episodic ataxia type 2.

    Science.gov (United States)

    Maksemous, Neven; Roy, Bishakha; Smith, Robert A; Griffiths, Lyn R

    2016-03-01

    Episodic Ataxia type 2 (EA2) is a rare autosomal dominantly inherited neurological disorder characterized by recurrent disabling imbalance, vertigo, and episodes of ataxia lasting minutes to hours. EA2 is caused most often by loss of function mutations of the calcium channel gene CACNA1A. In addition to EA2, mutations in CACNA1A are responsible for two other allelic disorders: familial hemiplegic migraine type 1 (FHM1) and spinocerebellar ataxia type 6 (SCA6). Herein, we have utilized next-generation sequencing (NGS) to screen the coding sequence, exon-intron boundaries, and Untranslated Regions (UTRs) of five genes where mutation is known to produce symptoms related to EA2, including CACNA1A. We performed this screening in a group of 31 unrelated patients with EA2 symptoms. Both novel and known mutations were detected through NGS technology, and confirmed through Sanger sequencing. Genetic testing showed in total 15 mutation bearing patients (48%), of which nine were novel mutations (6 missense and 3 small frameshift deletion mutations) and six known mutations (4 missense and 2 nonsense).These results demonstrate the efficiency of our NGS-panel for detecting known and novel mutations for EA2 in the CACNA1A gene, also identifying a novel missense mutation in ATP1A2 which is not a normal target for EA2 screening. PMID:27066515

  20. Exploiting Genomics Resources to Identify Candidate Genes Underlying Antioxidants Content in Tomato Fruit

    Science.gov (United States)

    Calafiore, Roberta; Ruggieri, Valentino; Raiola, Assunta; Rigano, Maria M.; Sacco, Adriana; Hassan, Mohamed I.; Frusciante, Luigi; Barone, Amalia

    2016-01-01

    The tomato is a model species for fleshy fruit development and ripening, as well as for genomics studies of others Solanaceae. Many genetic and genomics resources, including databases for sequencing, transcriptomics and metabolomics data, have been developed and are today available. The purpose of the present work was to uncover new genes and/or alleles that determine ascorbic acid and carotenoids accumulation, by exploiting one Solanum pennellii introgression lines (IL7-3) harboring quantitative trait loci (QTL) that increase the content of these metabolites in the fruit. The higher ascorbic acid and carotenoids content in IL7-3 was confirmed at three fruit developmental stages. The tomato genome reference sequence and the recently released S. pennellii genome sequence were investigated to identify candidate genes (CGs) that might control ascorbic acid and carotenoids accumulation. First of all, a refinement of the wild region borders in the IL7-3 was achieved by analyzing CAPS markers designed in our laboratory. Afterward, six CGs associated to ascorbic acid and one with carotenoids metabolism were identified exploring the annotation and the Gene Ontology terms of genes included in the region. Variants between the sequence of the wild and the cultivated alleles of these genes were investigated for their functional relevance and their potential effects on the protein sequences were predicted. Transcriptional levels of CGs in the introgression region were extracted from RNA-Seq data available for the entire S. pennellii introgression lines collection and verified by Real-Time qPCR. Finally, seven IL7-3 sub-lines were genotyped using 28 species-specific markers and then were evaluated for metabolites content. These analyses evidenced a significant decrease in transcript abundance for one 9-cis-epoxycarotenoid dioxygenase and one L-ascorbate oxidase homolog, whose role in the accumulation of carotenoids and ascorbic acid is discussed. Comprehensively, the reported results demonstrated that combining genetic and genomic resources in tomato, including bioinformatics tools, was a successful strategy to dissect one QTL for the increase of ascorbic acid and carotenoids in tomato fruit. PMID:27092148

  1. B.E.A.R. GeneInfo: A tool for identifying gene-related biomedical publications through user modifiable queries

    Directory of Open Access Journals (Sweden)

    Zhou Guohui

    2004-04-01

    Full Text Available Abstract Background Once specific genes are identified through high throughput genomics technologies there is a need to sort the final gene list to a manageable size for validation studies. The triaging and sorting of genes often relies on the use of supplemental information related to gene structure, metabolic pathways, and chromosomal location. Yet in disease states where the genes may not have identifiable structural elements, poorly defined metabolic pathways, or limited chromosomal data, flexible systems for obtaining additional data are necessary. In these situations having a tool for searching the biomedical literature using the list of identified genes while simultaneously defining additional search terms would be useful. Results We have built a tool, BEAR GeneInfo, that allows flexible searches based on the investigators knowledge of the biological process, thus allowing for data mining that is specific to the scientist's strengths and interests. This tool allows a user to upload a series of GenBank accession numbers, Unigene Ids, Locuslink Ids, or gene names. BEAR GeneInfo takes these IDs and identifies the associated gene names, and uses the lists of gene names to query PubMed. The investigator can add additional modifying search terms to the query. The subsequent output provides a list of publications, along with the associated reference hyperlinks, for reviewing the identified articles for relevance and interest. An example of the use of this tool in the study of human prostate cancer cells treated with Selenium is presented. Conclusions This tool can be used to further define a list of genes that have been identified through genomic or genetic studies. Through the use of targeted searches with additional search terms the investigator can limit the list to genes that match their specific research interests or needs. The tool is freely available on the web at http://prostategenomics.org1, and the authors will provide scripts and database components if requested mdatta@mcw.edu

  2. A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases.

    Science.gov (United States)

    Gustafsson, Mika; Gawel, Danuta R; Alfredsson, Lars; Baranzini, Sergio; Björkander, Janne; Blomgran, Robert; Hellberg, Sandra; Eklund, Daniel; Ernerudh, Jan; Kockum, Ingrid; Konstantinell, Aelita; Lahesmaa, Riita; Lentini, Antonio; Liljenström, H Robert I; Mattson, Lina; Matussek, Andreas; Mellergård, Johan; Mendez, Melissa; Olsson, Tomas; Pujana, Miguel A; Rasool, Omid; Serra-Musach, Jordi; Stenmarker, Margaretha; Tripathi, Subhash; Viitala, Miro; Wang, Hui; Zhang, Huan; Nestor, Colm E; Benson, Mikael

    2015-11-11

    Early regulators of disease may increase understanding of disease mechanisms and serve as markers for presymptomatic diagnosis and treatment. However, early regulators are difficult to identify because patients generally present after they are symptomatic. We hypothesized that early regulators of T cell-associated diseases could be found by identifying upstream transcription factors (TFs) in T cell differentiation and by prioritizing hub TFs that were enriched for disease-associated polymorphisms. A gene regulatory network (GRN) was constructed by time series profiling of the transcriptomes and methylomes of human CD4(+) T cells during in vitro differentiation into four helper T cell lineages, in combination with sequence-based TF binding predictions. The TFs GATA3, MAF, and MYB were identified as early regulators and validated by ChIP-seq (chromatin immunoprecipitation sequencing) and small interfering RNA knockdowns. Differential mRNA expression of the TFs and their targets in T cell-associated diseases supports their clinical relevance. To directly test if the TFs were altered early in disease, T cells from patients with two T cell-mediated diseases, multiple sclerosis and seasonal allergic rhinitis, were analyzed. Strikingly, the TFs were differentially expressed during asymptomatic stages of both diseases, whereas their targets showed altered expression during symptomatic stages. This analytical strategy to identify early regulators of disease by combining GRNs with genome-wide association studies may be generally applicable for functional and clinical studies of early disease development. PMID:26560356

  3. Common gene polymorphisms and nutrition: emerging links with pathogenesis of multifactorial chronic diseases (review).

    Science.gov (United States)

    Loktionov, Alexandre

    2003-08-01

    Rapid progress in human genome decoding has accelerated search for the role of gene polymorphisms in the pathogenesis of complex multifactorial diseases. This review summarizes the results of recent studies on the associations of common gene variants with multifactorial chronic conditions strongly affected by nutritional factors. Three main individual sections discuss genes related to energy homeostasis regulation and obesity, cardiovascular disease (CVD), and cancer. It is evident that several major chronic diseases are closely related (often through obesity) to deregulation of energy homeostasis. Multiple polymorphic genes encoding central and peripheral determinants of energy intake and expenditure have been revealed over the past decade. Food intake control may be affected by polymorphisms in the genes encoding taste receptors and a number of peripheral signaling peptides such as insulin, leptin, ghrelin, cholecystokinin, and corresponding receptors. Polymorphic central regulators of energy intake include hypothalamic neuropeptide Y, agouti-related protein, melanocortin pathway factors, CART (cocaine- and amphetamine-regulated transcript), some other neuropeptides, and receptors for these molecules. Potentially important polymorphisms in the genes encoding energy expenditure modulators (alpha- and beta- adrenoceptors, uncoupling proteins, and regulators of adipocyte growth and differentiation) are also discussed. CVD-related gene polymorphisms comprising those involved in the pathogenesis of atherosclerosis, blood pressure regulation, hemostasis control, and homocysteine metabolism are considered in a separate section with emphasis on multiple polymorphisms affecting lipid transport and metabolism and their interactions with diet. Cancer-associated polymorphisms are discussed for groups of genes encoding enzymes of xenobiotic metabolism, DNA repair enzymes, factors involved in the cell cycle control, hormonal regulation-associated proteins, enzymes related to DNA methylation through folate metabolism, and angiogenesis-related factors. There is an apparent progress in the field with hundreds of new gene polymorphisms discovered and characterized, however firm evidence consistently linking them with pathogenesis of complex chronic diseases is still limited. Ways of improving the efficiency of candidate gene approach-based studies are discussed in a short separate section. Successful unraveling of interaction between dietary factors, polymorphisms, and pathogenesis of several multifactorial diseases is exemplified by studies of folate metabolism in relation to CVD and cancer. It appears that several new directions emerge as targets of research on the role of genetic variation in relation to diet and complex chronic diseases. Regulation of energy homeostasis is a fundamental problem insufficiently investigated in this context so far. Impacts of genetic variation on systems controlling angiogenesis, inflammatory reactions, and cell growth and differentiation (comprising regulation of the cell cycle, DNA repair, and DNA methylation) are also largely unknown and need thorough analysis. These goals can be achieved by complex simultaneous analysis of multiple polymorphic genes controlling carefully defined and selected elements of relevant metabolic and regulatory pathways in meticulously designed large-scale studies. PMID:12948874

  4. Transposon Mutagenesis Identifies Novel Genes Associated with Staphylococcus aureus Persister Formation

    Science.gov (United States)

    Wang, Wenjie; Chen, Jiazhen; Chen, Gang; Du, Xin; Cui, Peng; Wu, Jing; Zhao, Jing; Wu, Nan; Zhang, Wenhong; Li, Min; Zhang, Ying

    2015-01-01

    Pathogenic bacterial persisters are responsible for the recalcitrance of chronic and persistent infections to antimicrobial therapy. Although the mechanisms of persister formation and survival have been widely studied in Escherichia coli, persistence mechanisms in Staphylococcus aureus remain largely unknown. Here, we screened a transposon mutant library of a clinical methicillin-resistant Staphylococcus aureus(MRSA)strain, USA500 (ST8), under antibiotic pressure and identified 13 genes whose insertion mutations resulted in a defect in persistence. These candidate genes were further confirmed by evaluating the survival of the mutants upon exposure to levofloxacin and several other stress conditions. We found 13 insertion mutants with significantly lower persister numbers under several stress conditions, including sdhA, sdhB, ureG, mnhG1, fbaA, ctaB, clpX, parE, HOU_0223, HOU_0587, HOU_2091, HOU_2315, and HOU_2346, which mapped into pathways of oxidative phosphorylation, TCA cycle, glycolysis, cell cycle, and ABC transporters, suggesting that these genes and pathways may play an important role in persister formation and survival. The newly constructed knockout strains of ureG, sdhA and sdhB and their complemented strains were also tested for defect in persisters following exposure to levofloxacin and several other stress conditions. The results from these experiments were consistent with the screening results, which indicated that deletion of these genes in MRSA USA500 leads to persister defect. These findings provide novel insights into the mechanisms of persister formation and survival in S. aureus and offer new targets for the development of persister-directed antibiotics for the improved treatment of chronic and persistent infections.

  5. Identifying regulational alterations in gene regulatory networks by state space representation of vector autoregressive models and variational annealing

    OpenAIRE

    Kojima Kaname; Imoto Seiya; Yamaguchi Rui; Fujita Andr; Yamauchi Mai; Gotoh Noriko; Miyano Satoru

    2012-01-01

    Abstract Background In the analysis of effects by cell treatment such as drug dosing, identifying changes on gene network structures between normal and treated cells is a key task. A possible way for identifying the changes is to compare structures of networks estimated from data on normal and treated cells separately. However, this approach usually fails to estimate accurate gene networks due to the limited length of time series data and measurement noise. Thus, approaches that identify chan...

  6. Integration of molecular biology tools for identifying promoters and genes abundantly expressed in flowers of Oncidium Gower Ramsey

    Directory of Open Access Journals (Sweden)

    Tung Shu-Yun

    2011-04-01

    Full Text Available Abstract Background Orchids comprise one of the largest families of flowering plants and generate commercially important flowers. However, model plants, such as Arabidopsis thaliana do not contain all plant genes, and agronomic and horticulturally important genera and species must be individually studied. Results Several molecular biology tools were used to isolate flower-specific gene promoters from Oncidium 'Gower Ramsey' (Onc. GR. A cDNA library of reproductive tissues was used to construct a microarray in order to compare gene expression in flowers and leaves. Five genes were highly expressed in flower tissues, and the subcellular locations of the corresponding proteins were identified using lip transient transformation with fluorescent protein-fusion constructs. BAC clones of the 5 genes, together with 7 previously published flower- and reproductive growth-specific genes in Onc. GR, were identified for cloning of their promoter regions. Interestingly, 3 of the 5 novel flower-abundant genes were putative trypsin inhibitor (TI genes (OnTI1, OnTI2 and OnTI3, which were tandemly duplicated in the same BAC clone. Their promoters were identified using transient GUS reporter gene transformation and stable A. thaliana transformation analyses. Conclusions By combining cDNA microarray, BAC library, and bombardment assay techniques, we successfully identified flower-directed orchid genes and promoters.

  7. Land use/cover changes in European mountain areas: identifying links between global driving forces and local consequences

    Science.gov (United States)

    Malek, iga; Schrter, Dagmar; Glade, Thomas

    2013-04-01

    Minor land use/cover changes in mountain areas can aggravate the consequences of hydro-meteorological hazards such as landslides, avalanches, rockfall and flash floods. What is more, they change the provisioning of ecosystem services; also as their recovery after anthropogenic induced changes in mountains are slower or not occurring at all due to harsh climate and soil conditions. Examples of these changes are urbanization in high risk areas or deforestation on slopes. To understand the driving forces behind land use/cover changes in European mountain areas, the focus is on the two case study areas: The Val Canale valley in the Italian Alps and the Buzau valley in the Romanian Carpathians. Land use/cover changes were analyzed in the recent decades applying various remote sensing techniques, such as satellite imagery classification and visual interpretation, as well as integration of various databases (e.g. forestry, spatial planning and cadaster plans). Instead of identifying the statistical significance of particular variables (e.g. population change), the links between different driving forces of global change (e.g. political and policy changes, infrastructural plans) and local socio-economic variables were investigated further through interviewing local and regional stakeholders. The results show how both areas differ in the consequences of global changes in terms of land use/cover change. The Italian area witnessed a trajectory from a commercially active and competitive area, to an area with a large portion of abandoned commercial, customs, industrial and mining zones. These processes were accompanied by the expansion of settlements comprised mostly of secondary housing on areas with high risk, resulting in catastrophic consequences in recent flash floods and debris flows events. The Romanian site also witnessed a breakdown of local commercial and industrial activities. Together with land ownership reforms, this has resulted in the emergence of subsistence farming and illegal logging. This intensification of activities has mostly affected land on slopes in an area where over 40 % of the area is subject to landslides. Relatively, the prevailing land use/cover change process in both areas, as usually in most European mountain areas, is reforestation. Small-scale changes however were most important in terms of negative consequences. Therefore we think it is necessary to focus on the local scale when identifying possible future negative consequences of land use/cover change. Acknowledgement This work is a part of the CHANGES project (Changing hydro-meteorological risks - as Analysed by a New Generation of European Scientists), a Marie Curie Initial Training Network, funded by the European Community's 7'th Framework Programme FP7/2007-2013 under Grant Agreement No. 263953.

  8. Identification of Three Novel Mutations in the FRMD7 Gene for X-linked Idiopathic Congenital Nystagmus

    Science.gov (United States)

    Zhang, Xiao; Ge, Xianglian; Yu, Ying; Zhang, Yilan; Wu, Yaming; Luan, Yin; Sun, Ji; Qu, Jia; Jin, Zi-Bing; Gu, Feng

    2014-01-01

    Idiopathic congenital nystagmus (ICN) consists of involuntary and periodic ocular motility, often with seriously reduced visual acuity. To identify the genetic defects associated with X-linked ICN, we performed PCR-based DNA direct sequencing of two candidate genes, FRMD7 and GPR143, in four families. Mutation analysis led to identification of three novel mutations, p.S260R, p.Q487X, and p.V549Y fsX554, in FRMD7 in three of the recruited families. Results from structural modeling indicated that the p.S260R may potentially disrupt FRMD7 function through loss of a phosphorylation site and/or interference with protein-protein interactions. Both p.Q487X, and p.V549Y fsX554 mutations were predicted to generate nonfunctional truncated proteins. Using a capture next generation sequencing method, we excluded CASK as the responsible gene for the remaining family. Combining sequence analysis and structural modeling, we report three novel mutations in FRMD7 in three independent families with XLICN, and provide molecular insights for future XLICN diagnosis and treatment.

  9. Quantitative variation in obesity-related traits and insulin precursors linked to the OB gene region on human chromosome 7

    Energy Technology Data Exchange (ETDEWEB)

    Duggirala, R.; Stern, M.P.; Reinhart, L.J. [Univ. of Texas Health Science Center, San Antonio, TX (United States)] [and others

    1996-09-01

    Despite the evidence that human obesity has strong genetic determinants, efforts at identifying specific genes that influence human obesity have largely been unsuccessful. Using the sibship data obtained from 32 low-income Mexican American pedigrees ascertained on a type II diabetic proband and a multipoint variance-components method, we tested for linkage between various obesity-related traits plus associated metabolic traits and 15 markers on human chromosome 7. We found evidence for linkage between markers in the OB gene region and various traits, as follows: D7S514 and extremity skinfolds (LOD = 3.1), human carboxypeptidase A1 (HCPA1) and 32,33-split proinsulin level (LOD = 4.2), and HCPA1 and proinsulin level (LOD = 3.2). A putative susceptibility locus linked to the marker D7S514 explained 56% of the total phenotypic variation in extremity skinfolds. Variation at the HCPA1 locus explained 64% of phenotypic variation in proinsulin level and {approximately}73% of phenotypic variation in split proinsulin concentration, respectively. Weaker evidence for linkage to several other obesity-related traits (e.g., waist circumference, body-mass index, fat mass by bioimpedance, etc.) was observed for a genetic location, which is {approximately}15 cM telomeric to OB. In conclusion, our study reveals that the OB region plays a significant role in determining the phenotypic variation of both insulin precursors and obesity-related traits, at least in Mexican Americans. 66 refs., 3 figs., 4 tabs.

  10. A nonsense mutation in the COL4A5 collagen gene in a family with X-linked juvenile Alport syndrome

    DEFF Research Database (Denmark)

    Hertz, Jens Michael; Heiskari, N; Zhou, J; Jensen, U B; Tryggvason, K

    1995-01-01

    47 of the COL4A5 gene in a patient with a juvenile form of X-linked Alport syndrome with deafness. This two base deletion caused a shift in the reading frame and introduced a premature stop codon which resulted in an alpha 5(IV)-chain shortened by 202 residues and lacking almost the entire NC1 domain......The X-linked form of Alport syndrome is associated with mutations in the COL4A5 gene encoding the alpha 5-chain of type IV collagen. By using PCR-amplification and direct sequencing we identified a novel mutation involving a deletion of the last two bases in the codon GGA for Glycine-1479 in exon...

  11. X-linked mental retardation with neonatal hypotonia in a French family (MRX15): Gene assignment to Xp11.22-Xp21.1

    Energy Technology Data Exchange (ETDEWEB)

    Raynaud, M.; Dessay, B.; Ayrault, A.D. [INSERM, Marseille (France)] [and others

    1996-07-12

    Linkage analysis was performed in a family with non-specific X-linked mental retardation (MRX 15). Hypotonia in infancy was the most remarkable physical manifestation. The severity of mental deficiency was variable among the patients, but all of them had poor or absent speech. Significant lod scores at a recombination fraction of zero were detected with the marker loci DXS1126, DXS255, and DXS573 (Zmax = 2.01) and recombination was observed with the two flanking loci DXS164 (Xp21.1) and DXS988 (Xp11.22), identifying a 17 cM interval. This result suggests a new gene localization in the proximal Xp region. In numerous families with non-specific X-linked mental retardation (MRX), the corresponding gene has been localized to the paracentromeric region in which a low recombination rate impairs the precision of mapping. 58 refs., 3 figs., 5 tabs.

  12. An X-linked homologue of the autosomal inprinted gene ZNF127 escapes X inactivation

    Energy Technology Data Exchange (ETDEWEB)

    Longstreet, M.; Nicholls, R.D.; Willard, H.F. [Case Western Reserve Univ., Cleveland, OH (United States)] [and others

    1994-09-01

    The ZNF127 gene has been shown to be subject to parental imprinting in both humans and the mouse and maps to within the Prader-Willi/Angelman Syndrome critical region on chromosome 15. We have cloned two X-linked related loci, one of which, ZNFXp is a transcribed gene while the other, ZNFXq, is an untranscribed pseudogene. ZNFXp is 83.6% identical to ZNFXq and 65.4% identical to ZNF127 over 1.4 kb of open reading frame they share in common, Like ZNF127, the predicted protein sequence of ZNFXp contains a C{sub 3}HC{sub 4} zinc finger domain and C{sub 3}H zinc finger-like motifs. Whereas ZNF127 has three C{sub 3}H motifs, ZNFXp has four. A strong CpG island is located within 1 kb 5{prime} of the predicted amino terminus of ZNFXp. Expression of ZNFXp has been detected from mouse/human somatic cell hybrids containing either an active (n=2) or an inactive (n=4) chromosome, and thus escapes X inactivation. Probes made from the 3{prime} UTR of ZNFXp detect a number of related loci in both human and murine DNA, none of which is the ZNF127 locus on chromosome 15. None of the detectable murine bands shows dosage differences between males and females as would be expected for X-linked loci. This raises the possibility that ZNFXp inserted into the human X chromosome after its divergence from a common ancestor with the murine X. We have mapped ZNFXp to Xp11.4 by Southern blotting and PCR of hybrid DNAs and by fluorescence in situ hybridization (FISH). ZNFXq maps within the X Inactivation Center (XIC) region on Xq13.2, approximately 300 kb distal to the XIST gene. We find it intriguing, and perhaps significant, that two members of this gene family are subject to epigenetic regulation -- one autosomal imprinting, and the other escape from X inactivation. These results could imply an evolutionary and mechanistic relationship between these two processes.

  13. Phenotypic Variability and Newly Identified Mutations of the IVD Gene in Japanese Patients with Isovaleric Acidemia.

    Science.gov (United States)

    Sakamoto, Osamu; Arai-Ichinoi, Natsuko; Mitsubuchi, Hiroshi; Chinen, Yasutsugu; Haruna, Hidenori; Maruyama, Hidehiko; Sugawara, Hidenori; Kure, Shigeo

    2015-01-01

    Isovaleric acidemia (IVA) is an autosomal recessive inborn error affecting leucine metabolism. It is caused by a deficiency in isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme that catalyzes the oxidation of isovaleryl-CoA to 3-methylcrotonyl-CoA. IVD is a FAD-containing enzyme, consisting of four identical subunits. Clinical features of IVA include poor feeding, vomiting, lethargy, developmental delay, metabolic acidosis, and a characteristic "sweaty foot" odor. IVA is one of the target disorders for newborn screening by tandem mass spectrometry (MS/MS). The human IVD gene is located on chromosome 15q. To date, over 50 disease-causing mutations have been reported worldwide. In this study, we searched for IVD mutations in five Japanese patients with IVA (neonatal type, two patients; chronic intermittent type, two patients; and mild biochemical type, one patient). The diagnosis of IVA was confirmed by urinary organic acid analysis using gas chromatography and mass spectrometry. All coding exons and the flanking introns in the IVD gene were amplified by PCR and were directly sequenced. We thus identified six hitherto unknown mutations (p.G94D, p.E116K, p.M167T, p.L243P, p.L246P, and c.696+1G>T) and four previously reported (p.R53P, p.R395C, p.Y403C, and p.E411K) pathogenic mutations. All patients were compound heterozygotes, and each mutation was identified in a single patient. Pathogenicity of newly identified mutations was validated using computational programs. Among them, the p.M167T is believed to influence FAD binding, as the position 167 is present in one of the FAD-binding sites. Our results have illustrated the heterogeneous mutation spectrum and clinical presentation of IVA in the Japanese patients. PMID:26018748

  14. Radiation sensitivity of human natural killer cell activity: control by X-linked genes

    International Nuclear Information System (INIS)

    The sensitivity of human natural killer cell activity after exposure of peripheral blood mononuclear cells to different doses of gamma irradiation was examined in a group of healthy adults and several families. Theee patterns of radiation sensitivity were observed: (1) loss of all NK activity after 3000 rads irradiation; (2) loss of approximately 50% of the NK activity; and (3) maintenance of activity after this dose of irradiation. Low dose irradiation (500 to 2000 rads) resulted in an enhancement of activity. The radiation dose giving low dose activation reflected the individual's sensitivity to 3000 rads. Population studies and the segregation in two informative families indicate that radiation sensitivity of NK activity is controlled by x-linked codominant genes

  15. Bridge DNA amplification of cancer-associated genes on cross-linked agarose microbeads

    International Nuclear Information System (INIS)

    A cross-linked agarose substrate was studied as a 3D support for bridge solid-phase DNA amplification (SPA). In this kind of SPA, primers are immobilized on agarose beads. Flow cell studies of SPA in real-time experiments showed that the amplification efficiency is strongly affected by (a) the presence of a linker between the primer and substrate, and (b) by the loading with primers. In fact, a high loading density may compromise SPA. The analysis of real time SPA curves using geometric growth model highlighted the advantage of 3D agarose support over the flat surfaces. The potential of bridge 3D SPA in DNA diagnostics was successfully demonstrated by on-chip analysis of mutations of the cancer-associated genes BRCA1/2 and CHEK2. (author)

  16. G-NEST: a gene neighborhood scoring tool to identify co-conserved, co-expressed genes

    Directory of Open Access Journals (Sweden)

    Lemay Danielle G

    2012-09-01

    Full Text Available Abstract Background In previous studies, gene neighborhoods—spatial clusters of co-expressed genes in the genome—have been defined using arbitrary rules such as requiring adjacency, a minimum number of genes, a fixed window size, or a minimum expression level. In the current study, we developed a Gene Neighborhood Scoring Tool (G-NEST which combines genomic location, gene expression, and evolutionary sequence conservation data to score putative gene neighborhoods across all possible window sizes simultaneously. Results Using G-NEST on atlases of mouse and human tissue expression data, we found that large neighborhoods of ten or more genes are extremely rare in mammalian genomes. When they do occur, neighborhoods are typically composed of families of related genes. Both the highest scoring and the largest neighborhoods in mammalian genomes are formed by tandem gene duplication. Mammalian gene neighborhoods contain highly and variably expressed genes. Co-localized noisy gene pairs exhibit lower evolutionary conservation of their adjacent genome locations, suggesting that their shared transcriptional background may be disadvantageous. Genes that are essential to mammalian survival and reproduction are less likely to occur in neighborhoods, although neighborhoods are enriched with genes that function in mitosis. We also found that gene orientation and protein-protein interactions are partially responsible for maintenance of gene neighborhoods. Conclusions Our experiments using G-NEST confirm that tandem gene duplication is the primary driver of non-random gene order in mammalian genomes. Non-essentiality, co-functionality, gene orientation, and protein-protein interactions are additional forces that maintain gene neighborhoods, especially those formed by tandem duplicates. We expect G-NEST to be useful for other applications such as the identification of core regulatory modules, common transcriptional backgrounds, and chromatin domains. The software is available at http://docpollard.org/software.html

  17. What is this link doing here? Beginning a fine-grained process of identifying reasons for academic hyperlink creation

    Directory of Open Access Journals (Sweden)

    Thelwall Mike

    2003-01-01

    Full Text Available The purpose of this paper is to begin a [fine-grained] process of differentiating between creation motivations for links in academic Web sites and citations in journals on the basis that they are very different phenomena.

  18. Whole-Genome Sequencing of Individuals from a Founder Population Identifies Candidate Genes for Asthma

    Science.gov (United States)

    Campbell, Catarina D.; Mohajeri, Kiana; Malig, Maika; Hormozdiari, Fereydoun; Nelson, Benjamin; Du, Gaixin; Patterson, Kristen M.; Eng, Celeste; Torgerson, Dara G.; Hu, Donglei; Herman, Catherine; Chong, Jessica X.; Ko, Arthur; O'Roak, Brian J.; Krumm, Niklas; Vives, Laura; Lee, Choli; Roth, Lindsey A.; Rodriguez-Cintron, William; Rodriguez-Santana, Jose; Brigino-Buenaventura, Emerita; Davis, Adam; Meade, Kelley; LeNoir, Michael A.; Thyne, Shannon; Jackson, Daniel J.; Gern, James E.; Lemanske, Robert F.; Shendure, Jay; Abney, Mark; Burchard, Esteban G.; Ober, Carole; Eichler, Evan E.

    2014-01-01

    Asthma is a complex genetic disease caused by a combination of genetic and environmental risk factors. We sought to test classes of genetic variants largely missed by genome-wide association studies (GWAS), including copy number variants (CNVs) and low-frequency variants, by performing whole-genome sequencing (WGS) on 16 individuals from asthma-enriched and asthma-depleted families. The samples were obtained from an extended 13-generation Hutterite pedigree with reduced genetic heterogeneity due to a small founding gene pool and reduced environmental heterogeneity as a result of a communal lifestyle. We sequenced each individual to an average depth of 13-fold, generated a comprehensive catalog of genetic variants, and tested the most severe mutations for association with asthma. We identified and validated 1960 CNVs, 19 nonsense or splice-site single nucleotide variants (SNVs), and 18 insertions or deletions that were out of frame. As follow-up, we performed targeted sequencing of 16 genes in 837 cases and 540 controls of Puerto Rican ancestry and found that controls carry a significantly higher burden of mutations in IL27RA (2.0% of controls; 0.23% of cases; nominal p?=?0.004; Bonferroni p?=?0.21). We also genotyped 593 CNVs in 1199 Hutterite individuals. We identified a nominally significant association (p?=?0.03; Odds ratio (OR)?=?3.13) between a 6 kbp deletion in an intron of NEDD4L and increased risk of asthma. We genotyped this deletion in an additional 4787 non-Hutterite individuals (nominal p?=?0.056; OR?=?1.69). NEDD4L is expressed in bronchial epithelial cells, and conditional knockout of this gene in the lung in mice leads to severe inflammation and mucus accumulation. Our study represents one of the early instances of applying WGS to complex disease with a large environmental component and demonstrates how WGS can identify risk variants, including CNVs and low-frequency variants, largely untested in GWAS. PMID:25116239

  19. A novel gammaretroviral shuttle vector insertional mutagenesis screen identifies SHARPIN as a breast cancer metastasis gene and prognostic biomarker.

    Science.gov (United States)

    Bii, Victor M; Rae, Dustin T; Trobridge, Grant D

    2015-11-24

    Breast cancer (BC) is the second leading cause of malignancy among U.S. women. Metastasis results in a poor prognosis and increased mortality, but the molecular mechanisms by which metastatic tumors occur are not well understood. Identifying the genes that drive the metastatic process could provide targets for improved therapy and biomarkers to improve BC patient outcomes. Using a forward mutagenesis screen, BC cells mutagenized with a replication-incompetent gammaretroviral vector (γRV) were xenotransplanted into the mammary fat pad of immunodeficient mice. In this approach the vector provirus dysregulates nearby genes, providing a selective advantage to transduced cells to form metastases. Metastatic tumors were analyzed for proviral integration sites to identify nearby candidate metastasis genes. The γRV has a transgene cassette that allows for rescue in bacteria and rapid identification of vector integration sites. Using this approach, we identified the previously described metastasis gene WWTR1 (TAZ), and three other novel candidate metastasis genes including SHARPIN. SHARPIN was independently validated in vivo as a BC metastasis gene. Analysis of patient data showed that SHARPIN expression predicts metastasis-free survival after adjuvant therapy. Our approach has broad potential to identify genes involved in oncogenic processes for BC and other cancers. We show here it can identify both known (WWTR1) and novel (SHARPIN) BC metastasis genes. PMID:26506596

  20. RNA-Sequencing Analysis of 5' Capped RNAs Identifies Many New Differentially Expressed Genes in Acute Hepatitis C Virus Infection

    Directory of Open Access Journals (Sweden)

    Bret S. E. Heale

    2012-04-01

    Full Text Available We describe the first report of RNA sequencing of 5' capped (Pol II RNAs isolated from acutely hepatitis C virus (HCV infected Huh 7.5 cells that provides a general approach to identifying differentially expressed annotated and unannotated genes that participate in viral-host interactions. We identified 100, 684, and 1,844 significantly differentially expressed annotated genes in acutely infected proliferative Huh 7.5 cells at 6, 48, and 72hours, respectively (fold change ? 1.5 and Bonferroni adjusted p-values < 0.05. Most of the differentially expressed genes (>80% and biological pathways (such as adipocytokine, Notch, Hedgehog and NOD-like receptor signaling were not identified by previous gene array studies. These genes are critical components of host immune, inflammatory and oncogenic pathways and provide new information regarding changes that may benefit the virus or mediate HCV induced pathology. RNAi knockdown studies of newly identified highly upregulated FUT1 and KLHDC7B genes provide evidence that their gene products regulate and facilitate HCV replication in hepatocytes. Our approach also identified novel Pol II unannotated transcripts that were upregulated. Results further identify new pathways that regulate HCV replication in hepatocytes and suggest that our approach will have general applications in studying viral-host interactions in model systems and clinical biospecimens.

  1. Candidate Genes Involved in the Biosynthesis of Triterpenoid Saponins in Platycodon grandiflorum Identified by Transcriptome Analysis

    Science.gov (United States)

    Ma, Chun-Hua; Gao, Zheng-Jie; Zhang, Jia-Jin; Zhang, Wei; Shao, Jian-Hui; Hai, Mei-Rong; Chen, Jun-Wen; Yang, Sheng-Chao; Zhang, Guang-Hui

    2016-01-01

    Background: Platycodon grandiflorum is the only species in the genus Platycodon of the family Campanulaceae, which has been traditionally used as a medicinal plant for its lung-heat-clearing, antitussive, and expectorant properties in China, Japanese, and Korean. Oleanane-type triterpenoid saponins were the main chemical components of P. grandiflorum and platycodin D was the abundant and main bioactive component, but little is known about their biosynthesis in plants. Hence, P. grandiflorum is an ideal medicinal plant for studying the biosynthesis of Oleanane-type saponins. In addition, the genomic information of this important herbal plant is unavailable. Principal findings: A total of 58,580,566 clean reads were obtained, which were assembled into 34,053 unigenes, with an average length of 936 bp and N50 of 1,661 bp by analyzing the transcriptome data of P. grandiflorum. Among these 34,053 unigenes, 22,409 unigenes (65.80%) were annotated based on the information available from public databases, including Nr, NCBI, Swiss-Prot, KOG, and KEGG. Furthermore, 21 candidate cytochrome P450 genes and 17 candidate UDP-glycosyltransferase genes most likely involved in triterpenoid saponins biosynthesis pathway were discovered from the transcriptome sequencing of P. grandiflorum. In addition, 10,626 SSRs were identified based on the transcriptome data, which would provide abundant candidates of molecular markers for genetic diversity and genetic map for this medicinal plant. Conclusion: The genomic data obtained from P. grandiflorum, especially the identification of putative genes involved in triterpenoid saponins biosynthesis pathway, will facilitate our understanding of the biosynthesis of triterpenoid saponins at molecular level.

  2. A novel splicing mutation of the FRMD7 gene in a Chinese family with X-linked congenital nystagmus

    Science.gov (United States)

    Hu, Ying; Shen, Jing; Zhang, Shuihua; Yang, Tao; Huang, Shangzhi

    2012-01-01

    Purpose To identify a potential pathogenic mutation in a four-generation Chinese family with X-linked congenital nystagmus (XLCN). Methods Routine clinical examination and ophthalmic evaluation were performed on normal controls, two patients and two healthy members of the family. Genomic DNA was prepared from the peripheral blood of members of the family and from 50 normal controls. All coding exons and the intronic boundaries of the four-point-one (4.1), ezrin,radixin, moesin(FERM) domain-containing7(FRMD7) gene were amplified using polymerase chain reaction (PCR) followed by direct sequencing. Results A previously unreported splicing mutation, c.1631 G?T transversion (c.1631 G>T), was detected preceding exon3 of FRMD7 in the patients but not in the unaffected family members and 50 unrelated healthy individuals. Conclusions We identified a novel mutation (c.1631 G?T) of FRMD7 in this Chinese family with XLCN. Our finding is the first report related to c.1631 G?T mutation in FRMD7. The result expands the mutation spectrum of FRMD7 in association with congenital nystagmus. PMID:22262942

  3. Genome-wide alterations in hippocampal 5-hydroxymethylcytosine links plasticity genes to acute stress.

    Science.gov (United States)

    Li, Sisi; Papale, Ligia A; Zhang, Qi; Madrid, Andy; Chen, Li; Chopra, Pankaj; Kele?, Sndz; Jin, Peng; Alisch, Reid S

    2016-02-01

    Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders, including anxiety and post-traumatic stress disorder. While even acute stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that is highly enriched in post-mitotic neurons and is associated with active transcription of neuronal genes. Recently, we found a hippocampal increase of 5hmC in the glucocorticoid receptor gene (Nr3c1) following acute stress, warranting a deeper investigation of stress-related 5hmC levels. Here we used an established chemical labeling and affinity purification method coupled with high-throughput sequencing technology to generate the first genome-wide profile of hippocampal 5hmC following exposure to acute restraint stress and a one-hour recovery. This approach found a genome-wide disruption in 5hmC associated with acute stress response, primarily in genic regions, and identified known and potentially novel stress-related targets that have a significant enrichment for neuronal ontological functions. Integration of these data with hippocampal gene expression data from these same mice found stress-related hydroxymethylation correlated to altered transcript levels and sequence motif predictions indicated that 5hmC may function by mediating transcription factor binding to these transcripts. Together, these data reveal an environmental impact on this newly discovered epigenetic mark in the brain and represent a critical step toward understanding stress-related epigenetic mechanisms that alter gene expression and can lead to the development of psychiatric disorders. PMID:26598390

  4. A dehydration-inducible gene in the truffle Tuber borchii identifies a novel group of dehydrins

    Directory of Open Access Journals (Sweden)

    Bonfante Paola

    2006-03-01

    Full Text Available Abstract Background The expressed sequence tag M6G10 was originally isolated from a screening for differentially expressed transcripts during the reproductive stage of the white truffle Tuber borchii. mRNA levels for M6G10 increased dramatically during fruiting body maturation compared to the vegetative mycelial stage. Results Bioinformatics tools, phylogenetic analysis and expression studies were used to support the hypothesis that this sequence, named TbDHN1, is the first dehydrin (DHN-like coding gene isolated in fungi. Homologs of this gene, all defined as "coding for hypothetical proteins" in public databases, were exclusively found in ascomycetous fungi and in plants. Although complete (or almost complete fungal genomes and EST collections of some Basidiomycota and Glomeromycota are already available, DHN-like proteins appear to be represented only in Ascomycota. A new and previously uncharacterized conserved signature pattern was identified and proposed to Uniprot database as the main distinguishing feature of this new group of DHNs. Expression studies provide experimental evidence of a transcript induction of TbDHN1 during cellular dehydration. Conclusion Expression pattern and sequence similarities to known plant DHNs indicate that TbDHN1 is the first characterized DHN-like protein in fungi. The high similarity of TbDHN1 with homolog coding sequences implies the existence of a novel fungal/plant group of LEA Class II proteins characterized by a previously undescribed signature pattern.

  5. Loci influencing blood pressure identified using a cardiovascular gene-centric array.

    Science.gov (United States)

    Ganesh, Santhi K; Tragante, Vinicius; Guo, Wei; Guo, Yiran; Lanktree, Matthew B; Smith, Erin N; Johnson, Toby; Castillo, Berta Almoguera; Barnard, John; Baumert, Jens; Chang, Yen-Pei Christy; Elbers, Clara C; Farrall, Martin; Fischer, Mary E; Franceschini, Nora; Gaunt, Tom R; Gho, Johannes M I H; Gieger, Christian; Gong, Yan; Isaacs, Aaron; Kleber, Marcus E; Mateo Leach, Irene; McDonough, Caitrin W; Meijs, Matthijs F L; Mellander, Olle; Molony, Cliona M; Nolte, Ilja M; Padmanabhan, Sandosh; Price, Tom S; Rajagopalan, Ramakrishnan; Shaffer, Jonathan; Shah, Sonia; Shen, Haiqing; Soranzo, Nicole; van der Most, Peter J; Van Iperen, Erik P A; Van Setten, Jessica; Van Setten, Jessic A; Vonk, Judith M; Zhang, Li; Beitelshees, Amber L; Berenson, Gerald S; Bhatt, Deepak L; Boer, Jolanda M A; Boerwinkle, Eric; Burkley, Ben; Burt, Amber; Chakravarti, Aravinda; Chen, Wei; Cooper-Dehoff, Rhonda M; Curtis, Sean P; Dreisbach, Albert; Duggan, David; Ehret, Georg B; Fabsitz, Richard R; Fornage, Myriam; Fox, Ervin; Furlong, Clement E; Gansevoort, Ron T; Hofker, Marten H; Hovingh, G Kees; Kirkland, Susan A; Kottke-Marchant, Kandice; Kutlar, Abdullah; Lacroix, Andrea Z; Langaee, Taimour Y; Li, Yun R; Lin, Honghuang; Liu, Kiang; Maiwald, Steffi; Malik, Rainer; Murugesan, Gurunathan; Newton-Cheh, Christopher; O'Connell, Jeffery R; Onland-Moret, N Charlotte; Ouwehand, Willem H; Palmas, Walter; Penninx, Brenda W; Pepine, Carl J; Pettinger, Mary; Polak, Joseph F; Ramachandran, Vasan S; Ranchalis, Jane; Redline, Susan; Ridker, Paul M; Rose, Lynda M; Scharnag, Hubert; Schork, Nicholas J; Shimbo, Daichi; Shuldiner, Alan R; Srinivasan, Sathanur R; Stolk, Ronald P; Taylor, Herman A; Thorand, Barbara; Trip, Mieke D; van Duijn, Cornelia M; Verschuren, W Monique; Wijmenga, Cisca; Winkelmann, Bernhard R; Wyatt, Sharon; Young, J Hunter; Boehm, Bernhard O; Caulfield, Mark J; Chasman, Daniel I; Davidson, Karina W; Doevendans, Pieter A; Fitzgerald, Garret A; Gums, John G; Hakonarson, Hakon; Hillege, Hans L; Illig, Thomas; Jarvik, Gail P; Johnson, Julie A; Kastelein, John J P; Koenig, Wolfgang; März, Winfried; Mitchell, Braxton D; Murray, Sarah S; Oldehinkel, Albertine J; Rader, Daniel J; Reilly, Muredach P; Reiner, Alex P; Schadt, Eric E; Silverstein, Roy L; Snieder, Harold; Stanton, Alice V; Uitterlinden, André G; van der Harst, Pim; van der Schouw, Yvonne T; Samani, Nilesh J; Johnson, Andrew D; Munroe, Patricia B; de Bakker, Paul I W; Zhu, Xiaofeng; Levy, Daniel; Keating, Brendan J; Asselbergs, Folkert W

    2013-04-15

    Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention. PMID:23303523

  6. Identifying functional gene sets from hierarchically clustered expression data: map of abiotic stress regulated genes in Arabidopsis thaliana

    OpenAIRE

    Kankainen, Matti; Brader, Günter; Törönen, Petri; Palva, E. Tapio; Holm, Liisa

    2006-01-01

    We present MultiGO, a web-enabled tool for the identification of biologically relevant gene sets from hierarchically clustered gene expression trees (). High-throughput gene expression measuring techniques, such as microarrays, are nowadays often used to monitor the expression of thousands of genes. Since these experiments can produce overwhelming amounts of data, computational methods that assist the data analysis and interpretation are essential. MultiGO is a tool that automatically extract...

  7. Orthologous genes identified by transcriptome sequencing in the spider genus Stegodyphus

    Directory of Open Access Journals (Sweden)

    Mattila Tiina M

    2012-02-01

    Full Text Available Abstract Background The evolution of sociality in spiders involves a transition from an outcrossing to a highly inbreeding mating system, a shift to a female biased sex ratio, and an increase in the reproductive skew among individuals. Taken together, these features are expected to result in a strong reduction in the effective population size. Such a decline in effective population size is expected to affect population genetic and molecular evolutionary processes, resulting in reduced genetic diversity and relaxed selective constraint across the genome. In the genus Stegodyphus, permanent sociality and regular inbreeding has evolved independently three times from periodic-social (outcrossing ancestors. This genus is therefore an ideal model for comparative studies of the molecular evolutionary and population genetic consequences of the transition to a regularly inbreeding mating system. However, no genetic resources are available for this genus. Results We present the analysis of high throughput transcriptome sequencing of three Stegodyphus species. Two of these are periodic-social (Stegodyphus lineatus and S.tentoriicola and one is permanently social (S. mimosarum. From non-normalized cDNA libraries, we obtained on average 7,000 putative uni-genes for each species. Three-way orthology, as predicted from reciprocal BLAST, identified 1,792 genes that could be used for cross-species comparison. Open reading frames (ORFs could be deduced from 1,345 of the three-way alignments. Preliminary molecular analyses suggest a five- to ten-fold reduction in heterozygosity in the social S. mimosarum compared with the periodic-social species. Furthermore, an increased ratio of non-synonymous to synonymous polymorphisms in the social species indicated relaxed efficiency of selection. However, there was no sign of relaxed selection on the phylogenetic branch leading to S. mimosarum. Conclusions The 1,792 three-way ortholog genes identified in this study provide a unique resource for comparative studies of the eco-genomics, population genetics and molecular evolution of repeated evolution of inbreeding sociality within the Stegodyphus genus. Preliminary analyses support theoretical expectations of depleted heterozygosity and relaxed selection in the social inbreeding species. Relaxed selection could not be detected in the S. mimosarum lineage, suggesting that there has been a recent transition to sociality in this species.

  8. Integrating genome annotation and QTL position to identify candidate genes for productivity, architecture and water-use efficiency in Populus spp

    Directory of Open Access Journals (Sweden)

    Monclus Romain

    2012-09-01

    Full Text Available Abstract Background Hybrid poplars species are candidates for biomass production but breeding efforts are needed to combine productivity and water use efficiency in improved cultivars. The understanding of the genetic architecture of growth in poplar by a Quantitative Trait Loci (QTL approach can help us to elucidate the molecular basis of such integrative traits but identifying candidate genes underlying these QTLs remains difficult. Nevertheless, the increase of genomic information together with the accessibility to a reference genome sequence (Populus trichocarpa Nisqually-1 allow to bridge QTL information on genetic maps and physical location of candidate genes on the genome. The objective of the study is to identify QTLs controlling productivity, architecture and leaf traits in a P. deltoides x P. trichocarpa F1 progeny and to identify candidate genes underlying QTLs based on the anchoring of genetic maps on the genome and the gene ontology information linked to genome annotation. The strategy to explore genome annotation was to use Gene Ontology enrichment tools to test if some functional categories are statistically over-represented in QTL regions. Results Four leaf traits and 7 growth traits were measured on 330 F1 P. deltoides x P. trichocarpa progeny. A total of 77 QTLs controlling 11 traits were identified explaining from 1.8 to 17.2% of the variation of traits. For 58 QTLs, confidence intervals could be projected on the genome. An extended functional annotation was built based on data retrieved from the plant genome database Phytozome and from an inference of function using homology between Populus and the model plant Arabidopsis. Genes located within QTL confidence intervals were retrieved and enrichments in gene ontology (GO terms were determined using different methods. Significant enrichments were found for all traits. Particularly relevant biological processes GO terms were identified for QTLs controlling number of sylleptic branches: intervals were enriched in GO terms of biological process like ‘ripening’ and ‘adventitious roots development’. Conclusion Beyond the simple identification of QTLs, this study is the first to use a global approach of GO terms enrichment analysis to fully explore gene function under QTLs confidence intervals in plants. This global approach may lead to identification of new candidate genes for traits of interest.

  9. Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy.

    Science.gov (United States)

    Stark, Klaus; Esslinger, Ulrike B; Reinhard, Wibke; Petrov, George; Winkler, Thomas; Komajda, Michel; Isnard, Richard; Charron, Philippe; Villard, Eric; Cambien, François; Tiret, Laurence; Aumont, Marie-Claude; Dubourg, Olivier; Trochu, Jean-Noël; Fauchier, Laurent; Degroote, Pascal; Richter, Anette; Maisch, Bernhard; Wichter, Thomas; Zollbrecht, Christa; Grassl, Martina; Schunkert, Heribert; Linsel-Nitschke, Patrick; Erdmann, Jeanette; Baumert, Jens; Illig, Thomas; Klopp, Norman; Wichmann, H-Erich; Meisinger, Christa; Koenig, Wolfgang; Lichtner, Peter; Meitinger, Thomas; Schillert, Arne; König, Inke R; Hetzer, Roland; Heid, Iris M; Regitz-Zagrosek, Vera; Hengstenberg, Christian

    2010-10-01

    Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06 × 10⁻⁶, OR  = 0.67 [95% CI 0.57-0.79] for the minor allele T). Three more SNPs showed p < 2.21 × 10⁻⁵. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n =564, n = 981 controls, p = 2.07 × 10⁻³, OR = 0.79 [95% CI 0.67-0.92]), France 1 (n = 433 cases, n = 395 controls, p =3.73 × 10⁻³, OR  = 0.74 [95% CI 0.60-0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26 × 10⁻⁴, OR  = 0.63 [95% CI 0.50-0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28 × 10⁻¹³, OR= 0.72 [95% CI 0.65-0.78]). None of the other three SNPs showed significant results in the replication stage.This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility. PMID:20975947

  10. Genetic Association Study Identifies HSPB7 as a Risk Gene for Idiopathic Dilated Cardiomyopathy

    Science.gov (United States)

    Stark, Klaus; Esslinger, Ulrike B.; Reinhard, Wibke; Petrov, George; Winkler, Thomas; Komajda, Michel; Isnard, Richard; Charron, Philippe; Villard, Eric; Cambien, François; Tiret, Laurence; Aumont, Marie-Claude; Dubourg, Olivier; Trochu, Jean-Noël; Fauchier, Laurent; DeGroote, Pascal; Richter, Anette; Maisch, Bernhard; Wichter, Thomas; Zollbrecht, Christa; Grassl, Martina; Schunkert, Heribert; Linsel-Nitschke, Patrick; Erdmann, Jeanette; Baumert, Jens; Illig, Thomas; Klopp, Norman; Wichmann, H.-Erich; Meisinger, Christa; Koenig, Wolfgang; Lichtner, Peter; Meitinger, Thomas; Schillert, Arne; König, Inke R.; Hetzer, Roland; Heid, Iris M.; Regitz-Zagrosek, Vera; Hengstenberg, Christian

    2010-01-01

    Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06×10−6, OR = 0.67 [95% CI 0.57–0.79] for the minor allele T). Three more SNPs showed p < 2.21×10−5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n = 564, n = 981 controls, p = 2.07×10−3, OR = 0.79 [95% CI 0.67–0.92]), France 1 (n = 433 cases, n = 395 controls, p = 3.73×10−3, OR = 0.74 [95% CI 0.60–0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26×10−4, OR = 0.63 [95% CI 0.50–0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28×10−13, OR = 0.72 [95% CI 0.65–0.78]). None of the other three SNPs showed significant results in the replication stage. This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility. PMID:20975947

  11. A framework to identify gene expression profiles in a model of inflammation induced by lipopolysaccharide after treatment with thalidomide

    Directory of Open Access Journals (Sweden)

    Paiva Renata T

    2012-06-01

    Full Text Available Abstract Background Thalidomide is an anti-inflammatory and anti-angiogenic drug currently used for the treatment of several diseases, including erythema nodosum leprosum, which occurs in patients with lepromatous leprosy. In this research, we use DNA microarray analysis to identify the impact of thalidomide on gene expression responses in human cells after lipopolysaccharide (LPS stimulation. We employed a two-stage framework. Initially, we identified 1584 altered genes in response to LPS. Modulation of this set of genes was then analyzed in the LPS stimulated cells treated with thalidomide. Results We identified 64 genes with altered expression induced by thalidomide using the rank product method. In addition, the lists of up-regulated and down-regulated genes were investigated by means of bioinformatics functional analysis, which allowed for the identification of biological processes affected by thalidomide. Confirmatory analysis was done in five of the identified genes using real time PCR. Conclusions The results showed some genes that can further our understanding of the biological mechanisms in the action of thalidomide. Of the five genes evaluated with real time PCR, three were down regulated and two were up regulated confirming the initial results of the microarray analysis.

  12. Estimating the False Discovery Rate Using Mixed Normal Distribution for Identifying Differentially Expressed Genes in Microarray Data Analysis

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    Chikuma Hamada

    2007-01-01

    Full Text Available The recent development of DNA microarray technology allows us to measure simultaneously the expression levels of thousands of genes and to identify truly correlated genes with anticancer drug response (differentially expressed genes from many candidate genes. Significance Analysis of Microarray (SAM is often used to estimate the false discovery rate (FDR, which is an index for optimizing the identifiability of differentially expressed genes, while the accuracy of the estimated FDR by SAM is not necessarily confirmed. We propose a new method for estimating the FDR assuming a mixed normal distribution on the test statistic and examine the performance of the proposed method and SAM using simulated data. The simulation results indicate that the accuracy of the estimated FDR by the proposed method and SAM, varied depending on the experimental conditions. We applied both methods to actual data comprised of expression levels of 12,625 genes of 10 responders and 14 non-responders to docetaxel for breast cancer. The proposed method identified 280 differentially expressed genes correlated with docetaxel response using a cut-off value for achieving FDR <0.01 to prevent false-positive genes, although 92 genes were previously thought to be correlated with docetaxel response ones.

  13. A framework to identify gene expression profiles in a model of inflammation induced by lipopolysaccharide after treatment with thalidomide

    OpenAIRE

    Paiva Renata T; Saliba Alessandra M; Fulco Tatiana O; de Souza Sales Jorgenilce; Serra de Carvalho Daniel; Sampaio Elizabeth P; Lopes Ulisses G; Sarno Euzenir N.; Nobre Flavio F

    2012-01-01

    Abstract Background Thalidomide is an anti-inflammatory and anti-angiogenic drug currently used for the treatment of several diseases, including erythema nodosum leprosum, which occurs in patients with lepromatous leprosy. In this research, we use DNA microarray analysis to identify the impact of thalidomide on gene expression responses in human cells after lipopolysaccharide (LPS) stimulation. We employed a two-stage framework. Initially, we identified 1584 altered genes in response to LPS. ...

  14. Integrating Transcriptome and Genome Re-Sequencing Data to Identify Key Genes and Mutations Affecting Chicken Eggshell Qualities

    OpenAIRE

    Zhang, Quan; Feng ZHU; Liu, Long; Zheng, Chuan Wei; Wang, He; Hou, Zhuo Cheng; Ning, Zhong Hua

    2015-01-01

    Eggshell damages lead to economic losses in the egg production industry and are a threat to human health. We examined 49-wk-old Rhode Island White hens (Gallus gallus) that laid eggs having shells with significantly different strengths and thicknesses. We used HiSeq 2000 (Illumina) sequencing to characterize the chicken transcriptome and whole genome to identify the key genes and genetic mutations associated with eggshell calcification. We identified a total of 14,234 genes expressed in the c...

  15. Identifying regulatory targets of cell cycle transcription factors using gene expression and ChIP-chip data

    OpenAIRE

    Li Wen-Hsiung; Wu Wei-Sheng; Chen Bor-Sen

    2007-01-01

    Abstract Background ChIP-chip data, which indicate binding of transcription factors (TFs) to DNA regions in vivo, are widely used to reconstruct transcriptional regulatory networks. However, the binding of a TF to a gene does not necessarily imply regulation. Thus, it is important to develop methods to identify regulatory targets of TFs from ChIP-chip data. Results We developed a method, called Temporal Relationship Identification Algorithm (TRIA), which uses gene expression data to identify ...

  16. Disruption of the Serine/Threonine Kinase 9 Gene Causes Severe X-Linked Infantile Spasms and Mental Retardation

    OpenAIRE

    Kalscheuer, Vera M; Tao, Jiong; Donnelly, Andrew; Hollway, Georgina; Schwinger, Eberhard; Kbart, Sabine; Menzel, Corinna; Hoeltzenbein, Maria; Tommerup, Niels; Eyre, Helen; Harbord, Michael; Haan, Eric; Sutherland, Grant R; Ropers, Hans-Hilger; Gcz, Jozef

    2003-01-01

    X-linked West syndrome, also called X-linked infantile spasms (ISSX), is characterized by early-onset generalized seizures, hypsarrhythmia, and mental retardation. Recently, we have shown that the majority of the X-linked families with infantile spasms carry mutations in the aristaless-related homeobox gene (ARX), which maps to the Xp21.3-p22.1 interval, and that the clinical picture in these patients can vary from mild mental retardation to severe ISSX with additional neurological abnormal...

  17. A highly conserved gene island of three genes on chromosome 3B of hexaploid wheat: diverse gene function and genomic structure maintained in a tightly linked block

    Directory of Open Access Journals (Sweden)

    Ma Wujun

    2010-05-01

    Full Text Available Abstract Background The complexity of the wheat genome has resulted from waves of retrotransposable element insertions. Gene deletions and disruptions generated by the fast replacement of repetitive elements in wheat have resulted in disruption of colinearity at a micro (sub-megabase level among the cereals. In view of genomic changes that are possible within a given time span, conservation of genes between species tends to imply an important functional or regional constraint that does not permit a change in genomic structure. The ctg1034 contig completed in this paper was initially studied because it was assigned to the Sr2 resistance locus region, but detailed mapping studies subsequently assigned it to the long arm of 3B and revealed its unusual features. Results BAC shotgun sequencing of the hexaploid wheat (Triticum aestivum cv. Chinese Spring genome has been used to assemble a group of 15 wheat BACs from the chromosome 3B physical map FPC contig ctg1034 into a 783,553 bp genomic sequence. This ctg1034 sequence was annotated for biological features such as genes and transposable elements. A three-gene island was identified among >80% repetitive DNA sequence. Using bioinformatics analysis there were no observable similarity in their gene functions. The ctg1034 gene island also displayed complete conservation of gene order and orientation with syntenic gene islands found in publicly available genome sequences of Brachypodium distachyon, Oryza sativa, Sorghum bicolor and Zea mays, even though the intergenic space and introns were divergent. Conclusion We propose that ctg1034 is located within the heterochromatic C-band region of deletion bin 3BL7 based on the identification of heterochromatic tandem repeats and presence of significant matches to chromodomain-containing gypsy LTR retrotransposable elements. We also speculate that this location, among other highly repetitive sequences, may account for the relative stability in gene order and orientation within the gene island. Sequence data from this article have been deposited with the GenBank Data Libraries under accession no. GQ422824

  18. Formaldehyde cross-linking and immunoprecipitation demonstrate developmental changes in H1 association with transcriptionally active genes.

    OpenAIRE

    Dedon, P.C.; Soults, J A; Allis, C. D.; Gorovsky, M A

    1991-01-01

    The in vivo association of histone H1 with specific genes in Tetrahymena thermophila was studied by using a simplified cross-linking and immunoprecipitation technique. Four genes were analyzed whose activities vary in three different developmental states (logarithmic growth, starvation, and conjugation). Hybridization of the immunoprecipitated DNA to cloned probes showed an inverse correlation between the level of immunoprecipitation with H1 antiserum and transcriptional activity. This repres...

  19. Towards a biophysical psychiatry: A modeling approach for studying effects of schizophrenia-linked genes on single-neuron excitability

    Directory of Open Access Journals (Sweden)

    Tuomo Mki-Marttunen

    2015-04-01

    Full Text Available Genome-wide association studies (GWAS employing large sample sizes and sophisticated statistical methods have recently yielded detailed information on the set of genes affected in various psychiatric disorders. This is especially important for polygenic, highly heritable disorders such as schizophrenia (SCZ [1]. The success lately witnessed in gene discovery brings up the next big challenge for psychiatric genetics translation of the genetic associations into biological insights [2]. In this study, we propose a computational approach for investigating the effects of a collection of excitability-related genes on various neuronal characteristics. As a proof of principle, we apply our approach for studying effects of SCZ-linked genes on firing behavior of a layer V pyramidal cell (L5PC. An L5PC extends throughout the cortical depth with the soma located in layer V and the apical dendrite branching into the apical tuft in layer I. The tuft serves as an integration hub for long-distance synaptic inputs, and is often considered a biological substrate for cortical associations providing high-level context for low-level (e.g., sensory inputs to the perisomatic compartment [3]. Therefore, the ability of L5PC to communicate the apical inputs to the soma has been proposed as one of the mechanisms that could be impaired in the mental disease [3]. In agreement with this hypothesis, recent psychiatric GWASs consistently reported association of genes coding for the subunits of voltage-gated Ca2+ channels as risk factors in SCZ and bipolar disorder [1,4]. A total of 108 genetic loci were recently confirmed to be associated with the risk of SCZ [5]. These loci span a wide set of protein-coding genes. The disorder is associated with genes affecting transmembrane currents of all major cationic species, Na+, K+, and Ca2+. In addition, some of the SCZ-linked genes are involved in regulation of the Ca2+ concentration in the intracellular medium, which is another great contributor to neuron excitability. All above aspects of electrophysiology are included in a recent multi-compartmental model of L5PC [6], which accurately describes the perisomatic firing behavior and its interplay with the generation of an apical Ca2+ spike. In this work, we rely on data from functional genomics studies that describe the effects of variants of certain ion channel or calcium transporter-encoding genes on the channel activation/inactivation properties or intracellular Ca2+ dynamics. We carry out our study by linking these effects to a change in the corresponding neuron model parameters, and observing the implication that these variants have on the information integration in an L5PC. These effects include e.g. shifts in channel activation or inactivation voltages, changes in time constants of channel activation and inactivation, as well as changes in resting level and decay time of intracellular Ca2+ concentration. It should be noted that information does not generally exist for the effect of single nucleotide polymorphism (SNP variants identified through GWASs on the biophysical parameters required for the computational models. We instead use information obtained from in vitro studies of more extreme genetic variations, including loss of function mutations. A central assumption of this approach is that the effects of SNP variants can be represented as scaled-down versions of those of the more extreme variants, and that the emergence of the full psychiatric disease phenotype results from the combined effect of a large number of subtle SNP effects. Our approach for variant implementation and downscaling is illustrated in Presentation 1. Our results show a multitude of alterations of the firing behavior and integration of inputs in neurons equipped with the considered gene variants. Most of the modeled effects of variants of CACNA1C, CACNB2, CACNA1D, CACNA1I, ATP2A2, ATP2B2, SCN1A, SCN9A, KCNS3, KCNB1, KCNN3, and HCN1 genes show a distinctive impact on the steady-state firing behavior of the L5PC. This can be observed as a gain o

  20. A gene controlling fetal hemoglobin expression in adults is not linked to the non-alpha globin cluster.

    Science.gov (United States)

    Gianni, A M; Bregni, M; Cappellini, M D; Fiorelli, G; Taramelli, R; Giglioni, B; Comi, P; Ottolenghi, S

    1983-01-01

    The possible linkage between a gene causing heterocellular hereditary persistence of fetal hemoglobin (HPFH) and human non-alpha globin loci has been studied in a large Sardinian family. In this family a homozygous beta o-thalassemic patient was found, with an unusually mild form of this disease, which was ascribed to the co-existence of a gene causing heterocellular HPFH. DNA polymorphisms in the non-alpha globin cluster were analyzed by restriction enzyme digestion with HincII, HindIII and BamHI and with epsilon-, gamma-and beta-globin probes; the pattern of inheritance of these polymorphisms indicates that the HPFH gene is transmitted with one beta o-thalassemic gene in a single instance, with the second beta o-thalassemic gene in three instances and with a normal beta-globin gene in two cases. These data indicate that this HPFH gene is not linked to the non-alpha globin gene cluster, in contrast to previous observations with different HPFH genes, and suggest that this gene might code for diffusible substances acting, directly or indirectly, on gamma-globin gene expression. Images Fig. 1. Fig. 2. Fig. 3. PMID:6196196

  1. New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism

    DEFF Research Database (Denmark)

    Horikoshi, Momoko; Yaghootkar, Hanieh; Mook-Kanamori, Dennis O; Sovio, Ulla; Taal, H Rob; Hennig, Branwen J; Bradfield, Jonathan P; St Pourcain, Beate; Evans, David M; Charoen, Pimphen; Kaakinen, Marika; Cousminer, Diana L; Lehtimäki, Terho; Kreiner-Møller, Eskil; Warrington, Nicole M; Bustamante, Mariona; Feenstra, Bjarke; Berry, Diane J; Thiering, Elisabeth; Pfab, Thiemo; Barton, Sheila J; Shields, Beverley M; Kerkhof, Marjan; van Leeuwen, Elisabeth M; Fulford, Anthony J; Kutalik, Zoltán; Zhao, Jing Hua; den Hoed, Marcel; Mahajan, Anubha; Lindi, Virpi; Goh, Liang-Kee; Hottenga, Jouke-Jan; Wu, Ying; Raitakari, Olli T; Harder, Marie N; Meirhaeghe, Aline; Ntalla, Ioanna; Salem, Rany M; Jameson, Karen A; Zhou, Kaixin; Monies, Dorota M; Lagou, Vasiliki; Kirin, Mirna; Heikkinen, Jani; Adair, Linda S; Alkuraya, Fowzan S; Al-Odaib, Ali; Amouyel, Philippe; Andersson, Ehm Astrid; Bennett, Amanda J; Blakemore, Alexandra I F; Buxton, Jessica L; Dallongeville, Jean; Das, Shikta; de Geus, Eco J C; Estivill, Xavier; Flexeder, Claudia; Froguel, Philippe; Geller, Frank; Godfrey, Keith M; Gottrand, Frédéric; Groves, Christopher J; Hansen, Torben; Hirschhorn, Joel N; Hofman, Albert; Hollegaard, Mads Vilhelm; Hougaard, David M; Hyppönen, Elina; Inskip, Hazel M; Isaacs, Aaron; Jørgensen, Torben; Kanaka-Gantenbein, Christina; Kemp, John P; Kiess, Wieland; Kilpeläinen, Tuomas O; Klopp, Norman; Knight, Bridget A; Kuzawa, Christopher W; McMahon, George; Newnham, John P; Niinikoski, Harri; Oostra, Ben A; Pedersen, Louise; Postma, Dirkje S; Ring, Susan M; Rivadeneira, Fernando; Robertson, Neil R; Sebert, Sylvain; Simell, Olli; Slowinski, Torsten; Tiesler, Carla M T; Tönjes, Anke; Vaag, Allan; Viikari, Jorma S; Vink, Jacqueline M; Vissing, Nadja Hawwa; Wareham, Nicholas J; Willemsen, Gonneke; Witte, Daniel R; Zhang, Haitao; Zhao, Jianhua; Wilson, James; Stumvoll, Michael; Prentice, Andrew M; Meyer, Brian F; Pearson, Ewan R; Boreham, Colin A G; Cooper, Cyrus; Gillman, Matthew W; Dedoussis, George V; Moreno, Luis A; Pedersen, Oluf; Saarinen, Maiju; Mohlke, Karen L; Boomsma, Dorret I; Saw, Seang-Mei; Lakka, Timo A; Körner, Antje; Loos, Ruth J F; Ong, Ken K; Vollenweider, Peter; van Duijn, Cornelia M; Koppelman, Gerard H; Hattersley, Andrew T; Holloway, John W; Hocher, Berthold; Heinrich, Joachim; Power, Chris; Melbye, Mads; Guxens, Mònica; Pennell, Craig E; Bønnelykke, Klaus; Bisgaard, Hans; Eriksson, Johan G; Widén, Elisabeth; Hakonarson, Hakon; Uitterlinden, André G; Pouta, Anneli; Lawlor, Debbie A; Smith, George Davey; Frayling, Timothy M; McCarthy, Mark I; Grant, Struan F A; Jaddoe, Vincent W V; Jarvelin, Marjo-Riitta; Timpson, Nicholas J; Prokopenko, Inga; Freathy, Rachel M

    2013-01-01

    -wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between...

  2. Identifying potential functional impact of mutations and polymorphisms: Linking heart failure, increased risk of arrhythmias and sudden cardiac death.

    Directory of Open Access Journals (Sweden)

    GILLESTOUMANIANTZ

    2013-09-01

    Full Text Available Researchers and clinicians have discovered several important concepts regarding the mechanisms responsible for increased risk of arrhythmias, heart failure and sudden cardiac death. One major step in defining the molecular basis of normal and abnormal cardiac electrical behaviour has been the identification of single mutations that greatly increase the risk for arrhythmias and sudden cardiac death by changing channel-gating characteristics. Indeed, mutations in several genes encoding ion channels, such as SCN5A, which encodes the major cardiac Na+ channel, have emerged as the basis for a variety of inherited cardiac arrhythmias such as long QT syndrome, Brugada syndrome, progressive cardiac conduction disorder, sinus node dysfunction or sudden infant death syndrome. In addition, genes encoding ion channel accessory proteins, like anchoring or chaperone proteins, which modify the expression, the regulation of endocytosis and the degradation of ion channel α-subunits have also been reported as susceptibility genes for arrhythmic syndromes. The regulation of ion channel protein expression also depends on a fine-tuned balance among different other mechanisms, such as gene transcription, RNA processing, post-transcriptional control of gene expression by miRNA, protein synthesis, assembly and post-translational modification and trafficking.

  3. LitMiner and WikiGene: identifying problem-related key players of gene regulation using publication abstracts

    OpenAIRE

    Maier, Holger; Döhr, Stefanie; Grote, Korbinian; O'Keeffe, Sean; Werner, Thomas; de Angelis, Martin Hrabé; Schneider, Ralf

    2005-01-01

    The LitMiner software is a literature data-mining tool that facilitates the identification of major gene regulation key players related to a user-defined field of interest in PubMed abstracts. The prediction of gene-regulatory relationships is based on co-occurrence analysis of key terms within the abstracts. LitMiner predicts relationships between key terms from the biomedical domain in four categories (genes, chemical compounds, diseases and tissues). Owing to the limitations (no direction,...

  4. Analysis of CATMA transcriptome data identifies hundreds of novel functional genes and improves gene models in the Arabidopsis genome

    Directory of Open Access Journals (Sweden)

    Schiex Thomas

    2007-11-01

    Full Text Available Abstract Background Since the finishing of the sequencing of the Arabidopsis thaliana genome, the Arabidopsis community and the annotator centers have been working on the improvement of gene annotation at the structural and functional levels. In this context, we have used the large CATMA resource on the Arabidopsis transcriptome to search for genes missed by different annotation processes. Probes on the CATMA microarrays are specific gene sequence tags (GSTs based on the CDS models predicted by the Eugene software. Among the 24 576 CATMA v2 GSTs, 677 are in regions considered as intergenic by the TAIR annotation. We analyzed the cognate transcriptome data in the CATMA resource and carried out data-mining to characterize novel genes and improve gene models. Results The statistical analysis of the results of more than 500 hybridized samples distributed among 12 organs provides an experimental validation for 465 novel genes. The hybridization evidence was confirmed by RT-PCR approaches for 88% of the 465 novel genes. Comparisons with the current annotation show that these novel genes often encode small proteins, with an average size of 137 aa. Our approach has also led to the improvement of pre-existing gene models through both the extension of 16 CDS and the identification of 13 gene models erroneously constituted of two merged CDS. Conclusion This work is a noticeable step forward in the improvement of the Arabidopsis genome annotation. We increased the number of Arabidopsis validated genes by 465 novel transcribed genes to which we associated several functional annotations such as expression profiles, sequence conservation in plants, cognate transcripts and protein motifs.

  5. Comparative transcriptome analysis of stylar canal cells identifies novel candidate genes implicated in the self-incompatibility response of Citrus clementina

    Directory of Open Access Journals (Sweden)

    Caruso Marco

    2012-02-01

    Full Text Available Abstract Background Reproductive biology in citrus is still poorly understood. Although in recent years several efforts have been made to study pollen-pistil interaction and self-incompatibility, little information is available about the molecular mechanisms regulating these processes. Here we report the identification of candidate genes involved in pollen-pistil interaction and self-incompatibility in clementine (Citrus clementina Hort. ex Tan.. These genes have been identified comparing the transcriptomes of laser-microdissected stylar canal cells (SCC isolated from two genotypes differing for self-incompatibility response ('Comune', a self-incompatible cultivar and 'Monreal', a self- compatible mutation of 'Comune'. Results The transcriptome profiling of SCC indicated that the differential regulation of few specific, mostly uncharacterized transcripts is associated with the breakdown of self-incompatibility in 'Monreal'. Among them, a novel F-box gene showed a drastic up-regulation both in laser microdissected stylar canal cells and in self-pollinated whole styles with stigmas of 'Comune' in concomitance with the arrest of pollen tube growth. Moreover, we identify a non-characterized gene family as closely associated to the self-incompatibility genetic program activated in 'Comune'. Three different aspartic-acid rich (Asp-rich protein genes, located in tandem in the clementine genome, were over-represented in the transcriptome of 'Comune'. These genes are tightly linked to a DELLA gene, previously found to be up-regulated in the self-incompatible genotype during pollen-pistil interaction. Conclusion The highly specific transcriptome survey of the stylar canal cells identified novel genes which have not been previously associated with self-pollen rejection in citrus and in other plant species. Bioinformatic and transcriptional analyses suggested that the mutation leading to self-compatibility in 'Monreal' affected the expression of non-homologous genes located in a restricted genome region. Also, we hypothesize that the Asp-rich protein genes may act as Ca2+ "entrapping" proteins, potentially regulating Ca2+ homeostasis during self-pollen recognition.

  6. Genetic link between Asians and native Americans: evidence from HLA genes and haplotypes.

    Science.gov (United States)

    Tokunaga, K; Ohashi, J; Bannai, M; Juji, T

    2001-09-01

    We have been studying polymorphisms of HLA class I and II genes in East Asians including Buryat in Siberia, Mongolian, Han Chinese, Man Chinese, Korean Chinese, South Korean, and Taiwan indigenous populations in collaboration with many Asian scientists. Regional populations in Japan, Hondo-Japanese, Ryukyuan, and Ainu, were also studied. HLA-A, -B, and -DRB1 gene frequencies were subjected to the correspondence analysis and calculation of DA distances. The correspondence analysis demonstrated several major clusters of human populations in the world. "Mongoloid" populations were highly diversified, in which several clusters such as Northeast Asians, Southeast Asians, Oceanians, and Native Americans were observed. Interestingly, an indigenous population in North Japan, Ainu, was placed relatively close to Native Americans in the correspondence analysis. Distribution of particular HLA-A, -B, -DRB1 alleles and haplotypes was also analyzed in relation to migration and dispersal routes of ancestral populations. A number of alleles and haplotypes showed characteristic patterns of regional distribution. For example, B39-HR5-DQ7 (B*3901-DRB1*1406-DQB1*0301) was shared by Ainu and Native Americans. A24-Cw8-B48 was commonly observed in Taiwan indigenous populations, Maori in New Zealand, Orochon in Northeast China, Inuit, and Tlingit. These findings further support the genetic link between East Asians and Native Americans. We have proposed that various ancestral populations in East Asia, marked by different HLA haplotypes, had migrated and dispersed through multiple routes. Moreover, relatively small genetic distances and the sharing of several HLA haplotypes between Ainu and Native Americans suggest that these populations are descendants of some Upper Paleolithic populations of East Asia. PMID:11543902

  7. Real-time qPCR identifies suitable reference genes for Borna disease virus-infected rat cortical neurons.

    Science.gov (United States)

    Zhang, Lujun; Liu, Siwen; Zhang, Liang; You, Hongmin; Huang, Rongzhong; Sun, Lin; He, Peng; Chen, Shigang; Zhang, Hong; Xie, Peng

    2014-01-01

    Quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR) is the most commonly-used technique to identify gene expression profiles. The selection of stably expressed reference genes is a prerequisite to properly evaluating gene expression. Here, the suitability of commonly-used reference genes in normalizing RT-qPCR assays of mRNA expression in cultured rat cortical neurons infected with Borna disease virus (BDV) was assessed. The expressions of eight commonly-used reference genes were comparatively analyzed in BDV-infected rat cortical neurons and non-infected control neurons mainly across 9 and 12 days post-infection. These reference genes were validated by RT-qPCR and separately ranked by four statistical algorithms: geNorm, NormFinder, BestKeeper and the comparative delta-Ct method. Then, the RankAggreg package was used to construct consensus rankings. ARBP was found to be the most stable internal control gene at Day 9, and ACTB at Day 12. As the assessment of the validity of the selected reference genes confirms the suitability of applying a combination of the two most stable references genes, combining the two most stable genes for normalization of RT-qPCR studies in BDV-infected rat cortical neurons is recommended at each time point. This study can contribute to improving BDV research by providing the means by which to obtain more reliable and accurate gene expression measurements. PMID:25431926

  8. Real-Time qPCR Identifies Suitable Reference Genes for Borna Disease Virus-Infected Rat Cortical Neurons

    Directory of Open Access Journals (Sweden)

    Lujun Zhang

    2014-11-01

    Full Text Available Quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR is the most commonly-used technique to identify gene expression profiles. The selection of stably expressed reference genes is a prerequisite to properly evaluating gene expression. Here, the suitability of commonly-used reference genes in normalizing RT-qPCR assays of mRNA expression in cultured rat cortical neurons infected with Borna disease virus (BDV was assessed. The expressions of eight commonly-used reference genes were comparatively analyzed in BDV-infected rat cortical neurons and non-infected control neurons mainly across 9 and 12 days post-infection. These reference genes were validated by RT-qPCR and separately ranked by four statistical algorithms: geNorm, NormFinder, BestKeeper and the comparative delta-Ct method. Then, the RankAggreg package was used to construct consensus rankings. ARBP was found to be the most stable internal control gene at Day 9, and ACTB at Day 12. As the assessment of the validity of the selected reference genes confirms the suitability of applying a combination of the two most stable references genes, combining the two most stable genes for normalization of RT-qPCR studies in BDV-infected rat cortical neurons is recommended at each time point. This study can contribute to improving BDV research by providing the means by which to obtain more reliable and accurate gene expression measurements.

  9. GtRNAdb 2.0: an expanded database of transfer RNA genes identified in complete and draft genomes.

    Science.gov (United States)

    Chan, Patricia P; Lowe, Todd M

    2016-01-01

    Transfer RNAs represent the largest, most ubiquitous class of non-protein coding RNA genes found in all living organisms. The tRNAscan-SE search tool has become the de facto standard for annotating tRNA genes in genomes, and the Genomic tRNA Database (GtRNAdb) was created as a portal for interactive exploration of these gene predictions. Since its published description in 2009, the GtRNAdb has steadily grown in content, and remains the most commonly cited web-based source of tRNA gene information. In this update, we describe not only a major increase in the number of tRNA predictions (>367000) and genomes analyzed (>4370), but more importantly, the integration of new analytic and functional data to improve the quality and biological context of tRNA gene predictions. New information drawn from other sources includes tRNA modification data, epigenetic data, single nucleotide polymorphisms, gene expression and evolutionary conservation. A richer set of analytic data is also presented, including better tRNA functional prediction, non-canonical features, predicted structural impacts from sequence variants and minimum free energy structural predictions. Views of tRNA genes in genomic context are provided via direct links to the UCSC genome browsers. The database can be searched by sequence or gene features, and is available at http://gtrnadb.ucsc.edu/. PMID:26673694

  10. Cloning and characterization of CLCN5, the human kidney chloride channel gene implicated in Dent disease (an X-linked hereditary nephrolithiasis)

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, S.E.; Van Bakel, I.; Craig, I.W. [Univ. of Oxford (United Kingdom)] [and others

    1995-10-10

    Dent disease, an X-linked familial renal tubular disorder, is a form of Fanconi syndrome associated with proteinuria, hypercalciuria, nephrocalcinosis, kidney stones, and eventual renal failure. We have previously used positional cloning to identify the 3{prime} part of a novel kidney-specific gene (initially termed hClC-K2, but now referred to as CLCN5), which is deleted in patients from one pedigree segregating Dent disease. Mutations that disrupt this gene have been identified in other patients with this disorder. Here we describe the isolation and characterization of the complete open reading frame of the human CLCN5 gene, which is predicted to encode a protein of 746 amino acids, with significant homology to all known members of the ClC family of voltage-gated chloride channels. CLCN5 belongs to a distinct branch of this family, which also includes the recently identified genes CLCN3 and CLCN4. We have shown that the coding region of CLCN5 is organized into 12 exons, spanning 25-30 kb of genomic DNA, and have determined the sequence of each exon-intron boundary. The elucidation of the coding sequence and exon-intron organization of CLCN5 will both expedite the evaluation of structure/function relationships of these ion channels and facilitate the screening of other patients with renal tubular dysfunction for mutations at this locus. 31 refs., 5 figs.

  11. Late blight resistance gene from Solanum ruiz-ceballosii is located on potato chromosome X and linked to violet flower colour

    Directory of Open Access Journals (Sweden)

    ?liwka Jadwiga

    2012-02-01

    Full Text Available Abstract Background Phytophthora infestans (Mont. de Bary, the causal organism of late blight, is economically the most important pathogen of potato and resistance against it has been one of the primary goals of potato breeding. Some potentially durable, broad-spectrum resistance genes against this disease have been described recently. However, to obtain durable resistance in potato cultivars more genes are needed to be identified to realize strategies such as gene pyramiding or use of genotype mixtures based on diverse genes. Results A major resistance gene, Rpi-rzc1, against P. infestans originating from Solanum ruiz-ceballosii was mapped to potato chromosome X using Diversity Array Technology (DArT and sequence-specific PCR markers. The gene provided high level of resistance in both detached leaflet and tuber slice tests. It was linked, at a distance of 3.4 cM, to violet flower colour most likely controlled by the previously described F locus. The marker-trait association with the closest marker, violet flower colour, explained 87.1% and 85.7% of variance, respectively, for mean detached leaflet and tuber slice resistance. A genetic linkage map that consisted of 1,603 DArT markers and 48 reference sequence-specific PCR markers of known chromosomal localization with a total map length of 1204.8 cM was constructed. Conclusions The Rpi-rzc1 gene described here can be used for breeding potatoes resistant to P. infestans and the breeding process can be expedited using the molecular markers and the phenotypic marker, violet flower colour, identified in this study. Knowledge of the chromosomal localization of Rpi-rzc1 can be useful for design of gene pyramids. The genetic linkage map constructed in this study contained 1,149 newly mapped DArT markers and will be a valuable resource for future mapping projects using this technology in the Solanum genus.

  12. Transcriptome Sequencing of Chemically Induced Aquilaria sinensis to Identify Genes Related to Agarwood Formation

    Science.gov (United States)

    Ye, Wei; Wu, Hongqing; He, Xin; Wang, Lei; Zhang, Weimin; Li, Haohua; Fan, Yunfei; Tan, Guohui; Liu, Taomei; Gao, Xiaoxia

    2016-01-01

    Background Agarwood is a traditional Chinese medicine used as a clinical sedative, carminative, and antiemetic drug. Agarwood is formed in Aquilaria sinensis when A. sinensis trees are threatened by external physical, chemical injury or endophytic fungal irritation. However, the mechanism of agarwood formation via chemical induction remains unclear. In this study, we characterized the transcriptome of different parts of a chemically induced A. sinensis trunk sample with agarwood. The Illumina sequencing platform was used to identify the genes involved in agarwood formation. Methodology/Principal Findings A five-year-old Aquilaria sinensis treated by formic acid was selected. The white wood part (B1 sample), the transition part between agarwood and white wood (W2 sample), the agarwood part (J3 sample), and the rotten wood part (F5 sample) were collected for transcriptome sequencing. Accordingly, 54,685,634 clean reads, which were assembled into 83,467 unigenes, were obtained with a Q20 value of 97.5%. A total of 50,565 unigenes were annotated using the Nr, Nt, SWISS-PROT, KEGG, COG, and GO databases. In particular, 171,331,352 unigenes were annotated by various pathways, including the sesquiterpenoid (ko00909) and plant–pathogen interaction (ko03040) pathways. These pathways were related to sesquiterpenoid biosynthesis and defensive responses to chemical stimulation. Conclusions/Significance The transcriptome data of the different parts of the chemically induced A. sinensis trunk provide a rich source of materials for discovering and identifying the genes involved in sesquiterpenoid production and in defensive responses to chemical stimulation. This study is the first to use de novo sequencing and transcriptome assembly for different parts of chemically induced A. sinensis. Results demonstrate that the sesquiterpenoid biosynthesis pathway and WRKY transcription factor play important roles in agarwood formation via chemical induction. The comparative analysis of the transcriptome data of agarwood and A. sinensis lays the foundation for elucidating the mechanism of agarwood formation via chemical induction, and thus, enables future improvements in agarwood quality while protecting endangered wild A. sinensis. PMID:27182594

  13. Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study

    DEFF Research Database (Denmark)

    Druley, Todd E; Wang, Lihua; Lin, Shiow J; Lee, Joseph H; Zhang, Qunyuan; Daw, E Warwick; Abel, Haley J; Chasnoff, Sara E; Ramos, Enrique I; Levinson, Benjamin T; Thyagarajan, Bharat; Newman, Anne B; Christensen, Kaare; Mayeux, Richard; Province, Michael A

    2016-01-01

    BACKGROUND: The Long Life Family Study (LLFS) is an international study to identify the genetic components of various healthy aging phenotypes. We hypothesized that pedigree-specific rare variants at longevity-associated genes could have a similar functional impact on healthy phenotypes. METHODS......: We performed custom hybridization capture sequencing to identify the functional variants in 464 candidate genes for longevity or the major diseases of aging in 615 pedigrees (4,953 individuals) from the LLFS, using a multiplexed, custom hybridization capture. Variants were analyzed individually or as...... individuals from six pedigrees. OBFC1 (chromosome 10) is involved in telomere maintenance, and falls within a linkage peak recently reported from an analysis of telomere length in LLFS families. Two different algorithms for single gene associations identified three genes with an enrichment of variation that...

  14. Use of reporter genes to identify recessive trans-acting mutations specifically involved in the regulation of Aspergillus nidulans penicillin biosynthesis genes.

    OpenAIRE

    Brakhage, A. A.; Van den Brulle, J

    1995-01-01

    Starting from three amino acid precursors, penicillin biosynthesis is catalyzed by three enzymes which are encoded by the following three genes: acvA (pcbAB), ipnA (pcbC), and aat (penDE). To identify trans-acting mutations which are specifically involved in the regulation of these secondary metabolism genes, a molecular approach was employed by using an Aspergillus nidulans strain (AXTII9) carrying acvA-uidA and ipnA-lacZ gene fusions integrated in double copies at the chromosomal argB gene....

  15. A novel rare copy number variant of the ABCF1 gene identified among dengue fever patients from Peninsular Malaysia.

    Science.gov (United States)

    Hoh, B P; Sam, S S; Umi, S H; Mahiran, M; Nik Khairudin, N Y; Rafidah Hanim, S; Abubakar, S

    2014-01-01

    Copy number variation (CNV) is a form of genetic variation in addition to single nucleotide polymorphisms. The significance of CNV in the manifestation of a number of diseases is only recently receiving considerable attention. We genotyped 163 dengue patients from Peninsular Malaysia for genes possibly linked to dengue infection using quantitative real-time PCR. Here, we report a serendipitous discovery of a novel rare CNV of the ABCF1 gene among the dengue patients. Among these patients, two had a gain of 1 copy (CN = 3) and one had lost 1 copy (CN = 1), indicating that a rare CNV of the ABCF1 gene was detected among dengue patients from Peninsular Malaysia. Although the gene is suspected to regulate inflammatory responses and pathogen-induced cytokine storm, its relevance to dengue requires further investigation. PMID:24634119

  16. DNA methylation in transcriptional repression of two differentially expressed X-linked genes, GPC3 and SYBL1

    OpenAIRE

    Huber, Reid; Hansen, R. Scott; Strazzullo, Maria; Pengue, Gina; Mazzarella, Richard; D’Urso, Michele; Schlessinger, David; Pilia, Giuseppe; Gartler, Stanley M.; D’Esposito, Maurizio

    1999-01-01

    Methylation of CpG islands is an established transcriptional repressive mechanism and is a feature of silencing in X chromosome inactivation. Housekeeping genes that are subject to X inactivation exhibit differential methylation of their CpG islands such that the inactive alleles are hypermethylated. In this report, we examine two contrasting X-linked genes with CpG islands for regulation by DNA methylation: SYBL1, a housekeeping gene in the Xq pseudoautosomal region, and GPC3, a tissue-speci...

  17. Gene expression profiling of tumours derived from rasV12/E1A-transformed mouse embryonic fibroblasts to identify genes required for tumour development

    Directory of Open Access Journals (Sweden)

    Dagorn Jean

    2005-01-01

    Full Text Available Abstract Background In cancer, cellular transformation is followed by tumour development. Knowledge on the mechanisms of transformation, involving activation of proto-oncogenes and inactivation of tumour-suppressor genes has considerably improved whereas tumour development remains poorly understood. An interesting way of gaining information on tumour progression mechanisms would be to identify genes whose expression is altered during tumour formation. We used the Affymetrix-based DNA microarray technology to analyze gene expression profiles of tumours derived from rasV12/E1A-transformed mouse embryo fibroblasts in order to identify the genes that could be involved in tumour development. Results Among the 12,000 genes analyzed in this study, only 489 showed altered expression during tumour development, 213 being up-regulated and 276 down-regulated. The genes differentially expressed are involved in a variety of cellular functions, including control of transcription, regulation of mRNA maturation and processing, regulation of protein translation, activation of interferon-induced genes, intracellular signalling, apoptosis, cell growth, angiogenesis, cytoskeleton, cell-to-cell interaction, extracellular matrix formation, metabolism and production of secretory factors. Conclusions Some of the genes identified in this work, whose expression is altered upon rasV12/E1A transformation of MEFs, could be new cancer therapeutic targets.

  18. Identification of markers linked to genes for sprouting tolerance (independent of grain color) in hard white winter wheat (HWWW)

    Science.gov (United States)

    Identification of markers linked to genes for sprouting tolerance (independent of grain color) in hard white winter wheat (HWWW) ABSTRACT Pre-harvest sprouting (PHS) of wheat (Triticum aestivum L.) can negatively impact end-use quality and seed viability at planting. Due to preferences for white ...

  19. A conceptual model linking functional gene expression and reductive dechlorination rates of chlorinated ethenes in clay rich groundwater sediment

    DEFF Research Database (Denmark)

    Bælum, Jacob; Chambon, Julie Claire Claudia; Scheutz, Charlotte; Binning, Philip John; Laier, Troels; Bjerg, Poul Løgstrup; Jacobsen, Carsten

    2013-01-01

    We used current knowledge of cellular processes involved in reductive dechlorination to develop a conceptual model to describe the regulatory system of dechlorination at the cell level; the model links bacterial growth and substrate consumption to the abundance of messenger RNA of functional genes...

  20. Combinatorial high-throughput experimental and bioinformatic approach identifies molecular pathways linked with the sensitivity to anticancer target drugs

    OpenAIRE

    Venkova, Larisa; Aliper, Alexander; Suntsova, Maria; Kholodenko, Roman; Shepelin, Denis; Borisov, Nicolas; Malakhova, Galina; Vasilov, Raif; Roumiantsev, Sergey; Zhavoronkov, Alex; Buzdin, Anton

    2015-01-01

    Effective choice of anticancer drugs is important problem of modern medicine. We developed a method termed OncoFinder for the analysis of new type of biomarkers reflecting activation of intracellular signaling and metabolic molecular pathways. These biomarkers may be linked with the sensitivity to anticancer drugs. In this study, we compared the experimental data obtained in our laboratory and in the Genomics of Drug Sensitivity in Cancer (GDS) project for testing response to anticancer drugs...

  1. Antibody-linked polymerase assay on protein blots: a novel method for identifying polymerases following SDS-polyacrylamide gel electrophoresis

    OpenAIRE

    van der Meer, J.; Dorssers, L.C.J.; Zabel, P.

    1983-01-01

    We describe a method for correlating polymerase activity with a particular polypeptide band in an SDS-polyacrylamide gel which does not require renaturation of the SDS-denatured enzyme. The method involves the following steps: (i) transfer of proteins from an SDS-polyacrylamide gel onto nitrocellulose; (ii) incubation with excess antiserum raised against a partially purified polymerase preparation to link one Fab site of an antibody molecule to the denatured enzyme on the nitrocellulose; (iii...

  2. Conservation of the links between gene transcription and chromosomal organization in the highly reduced genome of Buchnera aphidicola

    Directory of Open Access Journals (Sweden)

    Febvay Grard

    2007-06-01

    Full Text Available Abstract Background Genomic studies on bacteria have clearly shown the existence of chromosomal organization as regards, for example, to gene localization, order and orientation. Moreover, transcriptomic analyses have demonstrated that, in free-living bacteria, gene transcription levels and chromosomal organization are mutually influenced. We have explored the possible conservation of relationships between mRNA abundances and chromosomal organization in the highly reduced genome of Buchnera aphidicola, the primary endosymbiont of the aphids, and a close relative to Escherichia coli. Results Using an oligonucleotide-based microarray, we normalized the transcriptomic data by genomic DNA signals in order to have access to inter-gene comparison data. Our analysis showed that mRNA abundances, gene organization (operon and gene essentiality are correlated in Buchnera (i.e., the most expressed genes are essential genes organized in operons whereas no link between mRNA abundances and gene strand bias was found. The effect of Buchnera genome evolution on gene expression levels has also been analysed in order to assess the constraints imposed by the obligate symbiosis with aphids, underlining the importance of some gene sets for the survival of the two partners. Finally, our results show the existence of spatial periodic transcriptional patterns in the genome of Buchnera. Conclusion Despite an important reduction in its genome size and an apparent decay of its capacity for regulating transcription, this work reveals a significant correlation between mRNA abundances and chromosomal organization of the aphid-symbiont Buchnera.

  3. Gene expression identifies heterogeneity of metastatic propensity in high-grade soft tissue sarcomas

    DEFF Research Database (Denmark)

    Skubitz, Keith M; Francis, Princy; Skubitz, Amy P N; Luo, Xianghua; Nilbert, Mef

    2012-01-01

    Metastatic propensity of soft tissue sarcoma (STS) is heterogeneous and may be determined by gene expression patterns that do not correlate well with morphology. The authors have reported gene expression patterns that distinguish 2 broad classes of clear cell renal carcinoma (ccRCC-gene set), and...

  4. Impaired Ig class switch in mice deficient for the X-linked lymphoproliferative disease gene Sap.

    Science.gov (United States)

    Al-Alem, Umaima; Li, Cuiling; Forey, Nathalie; Relouzat, Francis; Fondanche, Marie-Claude; Tavtigian, Sean V; Wang, Zhao-Qi; Latour, Sylvain; Yin, Luo

    2005-09-15

    X-linked lymphoproliferative disease (XLP) is characterized by abnormal immune responses to Epstein-Barr virus attributed to inactivating mutations of the SAP gene. Previous studies showed immunoglobulin E (IgE) deficiency and low serum IgG levels in Sap-deficient mice before and after viral infections, which are associated with impaired CD4+ T-helper function. In the present work, we find that signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is expressed in B cells and this expression is down-regulated after stimulation with lipopolysaccharide (LPS) and interleukin 4 (IL-4). We demonstrate that B cells from Sap-deficient mice exhibit reduced IgG and IgA production in vitro. This impairment correlates with decreased circular transcript levels of Ialpha, Igamma2a, Igamma2b, and Igamma3 after stimulation, which indicate a defective Ig switch recombination in Sap-deficient B cells. While XLP is believed to cause defects in T, natural killer T (NKT), and natural killer (NK) cells, our results indicate that B cells are also affected. PMID:15941917

  5. LitMiner and WikiGene: identifying problem-related key players of gene regulation using publication abstracts.

    Science.gov (United States)

    Maier, Holger; Döhr, Stefanie; Grote, Korbinian; O'Keeffe, Sean; Werner, Thomas; Hrabé de Angelis, Martin; Schneider, Ralf

    2005-07-01

    The LitMiner software is a literature data-mining tool that facilitates the identification of major gene regulation key players related to a user-defined field of interest in PubMed abstracts. The prediction of gene-regulatory relationships is based on co-occurrence analysis of key terms within the abstracts. LitMiner predicts relationships between key terms from the biomedical domain in four categories (genes, chemical compounds, diseases and tissues). Owing to the limitations (no direction, unverified automatic prediction) of the co-occurrence approach, the primary data in the LitMiner database represent postulated basic gene-gene relationships. The usefulness of the LitMiner system has been demonstrated recently in a study that reconstructed disease-related regulatory networks by promoter modelling that was initiated by a LitMiner generated primary gene list. To overcome the limitations and to verify and improve the data, we developed WikiGene, a Wiki-based curation tool that allows revision of the data by expert users over the Internet. LitMiner (http://andromeda.gsf.de/litminer) and WikiGene (http://andromeda.gsf.de/wiki) can be used unrestricted with any Internet browser. PMID:15980584

  6. From the genome to the phenome and back: linking genes with human brain function and structure using genetically informed neuroimaging

    DEFF Research Database (Denmark)

    Siebner, H R; Callicott, J H; Sommer, T; Mattay, V S

    2009-01-01

    In recent years, an array of brain mapping techniques has been successfully employed to link individual differences in circuit function or structure in the living human brain with individual variations in the human genome. Several proof-of-principle studies provided converging evidence that brain...... imaging can establish important links between genes and behaviour. The overarching goal is to use genetically informed brain imaging to pinpoint neurobiological mechanisms that contribute to behavioural intermediate phenotypes or disease states. This special issue on "Linking Genes to Brain Function in...... Health and Disease" provides an overview over how the "imaging genetics" approach is currently applied in the various fields of systems neuroscience to reveal the genetic underpinnings of complex behaviours and brain diseases. While the rapidly emerging field of imaging genetics holds great promise, the...

  7. Aberrant host immune response induced by highly virulent PRRSV identified by digital gene expression tag profiling

    Science.gov (United States)

    2010-01-01

    Background There was a large scale outbreak of the highly pathogenic porcine reproductive and respiratory syndrome (PRRS) in China and Vietnam during 2006 and 2007 that resulted in unusually high morbidity and mortality among pigs of all ages. The mechanisms underlying the molecular pathogenesis of the highly virulent PRRS virus (H-PRRSV) remains unknown. Therefore, the relationship between pulmonary gene expression profiles after H-PRRSV infection and infection pathology were analyzed in this study using high-throughput deep sequencing and histopathology. Results H-PRRSV infection resulted in severe lung pathology. The results indicate that aberrant host innate immune responses to H-PRRSV and induction of an anti-apoptotic state could be responsible for the aggressive replication and dissemination of H-PRRSV. Prolific rapid replication of H-PRRSV could have triggered aberrant sustained expression of pro-inflammatory cytokines and chemokines leading to a markedly robust inflammatory response compounded by significant cell death and increased oxidative damage. The end result was severe tissue damage and high pathogenicity. Conclusions The systems analysis utilized in this study provides a comprehensive basis for better understanding the pathogenesis of H-PRRSV. Furthermore, it allows the genetic components involved in H-PRRSV resistance/susceptibility in swine populations to be identified. PMID:20929578

  8. The CpA135 gene as a marker to identify Cryptosporidium species infecting humans.

    Science.gov (United States)

    Tosini, Fabio; Drumo, Rosanna; Elwin, Kristin; Chalmers, Rachel M; Pozio, Edoardo; Cacci, Simone M

    2010-12-01

    Of the 22 species currently recognized as valid in the Cryptosporidium genus, C. parvum and C. hominis account for most cases of human infections worldwide. However, C. meleagridis, C. canis, C. felis, C. suis, C. muris, as well as the cervine, rabbit and monkey Cryptosporidium genotypes, have also been recognized as the etiologic cause of both sporadic and epidemic cryptosporidiosis in humans. Molecular methods are necessary to distinguish species and genotypes of Cryptosporidium, due to the lack of reliable morphological variations. The aim of this work was to determine the genetic polymorphisms in a fragment of the A135 gene in isolates of C. parvum, C. hominis, C. meleagridis, C. canis, C. muris, C. andersoni and the Cryptosporidium cervine genotype. Primers were designed on conserved regions identified on a multiple alignment of the C. parvum, C. hominis and C. muris sequences, the three species for which information is available at the genome level. PCR amplification and direct sequencing of a 576 bp fragment revealed the presence of numerous single nucleotide polymorphisms (SNPs) among the species/genotype tested. The genetic variability was exploited to design a PCR-RFLP assay useful for a rapid identification of the most important human pathogens in the genus Cryptosporidium. PMID:20831899

  9. Aberrant host immune response induced by highly virulent PRRSV identified by digital gene expression tag profiling

    Directory of Open Access Journals (Sweden)

    Zhao Xiao

    2010-10-01

    Full Text Available Abstract Background There was a large scale outbreak of the highly pathogenic porcine reproductive and respiratory syndrome (PRRS in China and Vietnam during 2006 and 2007 that resulted in unusually high morbidity and mortality among pigs of all ages. The mechanisms underlying the molecular pathogenesis of the highly virulent PRRS virus (H-PRRSV remains unknown. Therefore, the relationship between pulmonary gene expression profiles after H-PRRSV infection and infection pathology were analyzed in this study using high-throughput deep sequencing and histopathology. Results H-PRRSV infection resulted in severe lung pathology. The results indicate that aberrant host innate immune responses to H-PRRSV and induction of an anti-apoptotic state could be responsible for the aggressive replication and dissemination of H-PRRSV. Prolific rapid replication of H-PRRSV could have triggered aberrant sustained expression of pro-inflammatory cytokines and chemokines leading to a markedly robust inflammatory response compounded by significant cell death and increased oxidative damage. The end result was severe tissue damage and high pathogenicity. Conclusions The systems analysis utilized in this study provides a comprehensive basis for better understanding the pathogenesis of H-PRRSV. Furthermore, it allows the genetic components involved in H-PRRSV resistance/susceptibility in swine populations to be identified.

  10. Comparing cancer vs normal gene expression profiles identifies new disease entities and common transcriptional programs in AML patients

    DEFF Research Database (Denmark)

    Rapin, Nicolas; Bagger, Frederik Otzen; Jendholm, Johan; Mora-Jensen, Helena; Krogh, Anders; Kohlmann, Alexander; Thiede, Christian; Borregaard, Niels; Bullinger, Lars; Winther, Ole; Theilgaard-Mnch, Kim; Porse, Bo T.

    2014-01-01

    Gene expression profiling has been used extensively to characterize cancer, identify novel subtypes, and improve patient stratification. However, it has largely failed to identify transcriptional programs that differ between cancer and corresponding normal cells and has not been efficient in...... identifying expression changes fundamental to disease etiology. Here we present a method that facilitates the comparison of any cancer sample to its nearest normal cellular counterpart, using acute myeloid leukemia (AML) as a model. We first generated a gene expression-based landscape of the normal...... hematopoietic hierarchy, using expression profiles from normal stem/progenitor cells, and next mapped the AML patient samples to this landscape. This allowed us to identify the closest normal counterpart of individual AML samples and determine gene expression changes between cancer and normal. We find the...

  11. Enriching regulatory networks by bootstrap learning using optimised GO-based gene similarity and gene links mined from PubMed abstracts

    Energy Technology Data Exchange (ETDEWEB)

    Taylor, Ronald C.; Sanfilippo, Antonio P.; McDermott, Jason E.; Baddeley, Robert L.; Riensche, Roderick M.; Jensen, Russell S.; Verhagen, Marc; Pustejovsky, James

    2011-02-18

    Transcriptional regulatory networks are being determined using reverse engineering methods that infer connections based on correlations in gene state. Corroboration of such networks through independent means such as evidence from the biomedical literature is desirable. Here, we explore a novel approach, a bootstrapping version of our previous Cross-Ontological Analytic method (XOA) that can be used for semi-automated annotation and verification of inferred regulatory connections, as well as for discovery of additional functional relationships between the genes. First, we use our annotation and network expansion method on a biological network learned entirely from the literature. We show how new relevant links between genes can be iteratively derived using a gene similarity measure based on the Gene Ontology that is optimized on the input network at each iteration. Second, we apply our method to annotation, verification, and expansion of a set of regulatory connections found by the Context Likelihood of Relatedness algorithm.

  12. A rapid method for identifying the thymidine kinase genes of avipoxviruses.

    Science.gov (United States)

    Schnitzlein, W M; Ghildyal, N; Tripathy, D N

    1988-08-01

    The thymidine kinase (TK) genes of poxviruses can be rapidly located without using TK- mutants or having to restriction map and clone the viral genomes. Identification of the TK gene is based on in situ gel hybridization with an end-labelled degenerate oligonucleotide probe, representing a consensus sequence near the 3' end of the gene. Restriction fragments of the viral DNAs are electrophoresed in agarose gels and annealed with the probe. Using this method, the TK genes of fowl pox (FPV) and quail pox (QPV) viruses were initially localized to HindIII fragments of approximately 3.8 and 6.7 kb, respectively. After inserting these fragments into pUC 19, recombinant plasmids containing the TK genes were screened by a modified in situ gel annealing procedure. Restriction mapping of the two cloned fragments and subsequent hybridization analysis more precisely placed at least the 3' portion of the FPV and QPV TK genes within a 1.4 kb ClaI-XbaI and 1.7 kb ClaI-PstI fragment, respectively. The site of the FPV TK gene was verified by comparison to the mapped position of the similar gene in an Australian FPV. The location of the QPV TK gene was confirmed by hybridization with the FPV TK gene, despite the apparent divergency of these two genes. PMID:2846602

  13. Identificação de marcadores RAPD ligados a um gene de resistência ao cancro da haste da soja Identification of RAPD markers linked to a soybean stem canker resistance gene

    Directory of Open Access Journals (Sweden)

    GERALDO A. CARVALHO

    2002-09-01

    Full Text Available O cancro da haste da soja (Glycine max é uma importante doença causada pelo fungo Diaporthe phaseolorum f. sp. meridionalis/Phomopsis phaseoli f. sp. meridionalis. Visando identificar marcadores RAPD associados a genes de resistência ao cancro da haste, causado pelo isolado CH8, presentes na linhagem UFV 91-61, foi realizado, inicialmente, um estudo sobre a herança da resistência, por meio do cruzamento desta linhagem com a variedade suscetível Paranaíba. Os resultados indicaram que um gene dominante controla a resistência a este isolado. Através de análises com marcadores moleculares na população F2 foram identificados dois marcadores RAPD produzidos pela amplificação do primer OPAB19. Os dois fragmentos de DNA de aproximadamente 1.150 e 1.320 pb produzidos por este primer estão ligadas em fases de repulsão e acoplamento, respectivamente, a uma distância de 4,7 cM do gene de resistência da linhagem UFV 91-61. Estes marcadores poderão ser usados para monitorar a introgressão deste gene em cultivares de soja adaptados e abre a possibilidade de uma sistemática procura de marcadores ligados a outros genes de resistência para o cancro da haste da soja, os quais poderiam ser posteriormente piramidados num único background genético.Soybean stem canker is a serious soybean (Glycine max disease caused by the fungi Diaporthe phaseolorum f. sp. meridionalis/Phomopsis phaseoli f. sp. meridionalis. We have crossed the soybean resistant line UFV 91-61 with the susceptible cultivar Paranaiba, and analyze the F2 population in order to understand the genetics underlying resistance to this pathogen (isolate CH8 and to identify molecular markers linked to it. The results indicate that a single dominant gene controls resistance to this isolate. RAPD analysis in the F2 population identified two DNA fragments of approximately 1,150 and 1,320 bp of primer OPAB19 linked in the repulsion and coupling phase at 4.7 cM of the resistance gene of line UFV 91-61. These markers will be very useful for monitoring the introgression of this gene into soybean adapted cultivars, and open up the possibility for a systematic search for markers linked to other resistance genes for stem canker that could be pyramided into the same genetic background.

  14. Global analysis of gene expression in NGF-deprived sympathetic neurons identifies molecular pathways associated with cell death

    Directory of Open Access Journals (Sweden)

    Kristiansen Mark

    2011-11-01

    Full Text Available Abstract Background Developing sympathetic neurons depend on nerve growth factor (NGF for survival and die by apoptosis after NGF withdrawal. This process requires de novo gene expression but only a small number of genes induced by NGF deprivation have been identified so far, either by a candidate gene approach or in mRNA differential display experiments. This is partly because it is difficult to obtain large numbers of sympathetic neurons for in vitro studies. Here, we describe for the first time, how advances in gene microarray technology have allowed us to investigate the expression of all known genes in sympathetic neurons cultured in the presence and absence of NGF. Results We have used Affymetrix Exon arrays to study the pattern of expression of all known genes in NGF-deprived sympathetic neurons. We identified 415 up- and 813 down-regulated genes, including most of the genes previously known to be regulated in this system. NGF withdrawal activates the mixed lineage kinase (MLK-c-Jun N-terminal kinase (JNK-c-Jun pathway which is required for NGF deprivation-induced death. By including a mixed lineage kinase (MLK inhibitor, CEP-11004, in our experimental design we identified which of the genes induced after NGF withdrawal are potential targets of the MLK-JNK-c-Jun pathway. A detailed Gene Ontology and functional enrichment analysis also identified genetic pathways that are highly enriched and overrepresented amongst the genes expressed after NGF withdrawal. Five genes not previously studied in sympathetic neurons - trib3, ddit3, txnip, ndrg1 and mxi1 - were validated by real time-PCR. The proteins encoded by these genes also increased in level after NGF withdrawal and this increase was prevented by CEP-11004, suggesting that these genes are potential targets of the MLK-JNK-c-Jun pathway. Conclusions The sympathetic neuron model is one of the best studied models of neuronal apoptosis. Overall, our microarray data gives a comprehensive overview of, and provides new information about, signalling pathways and transcription factors that are regulated by NGF withdrawal.

  15. Suppression subtractive hybridization identifies an autotransporter adhesin gene of E. coli IMT5155 specifically associated with avian pathogenic Escherichia coli (APEC

    Directory of Open Access Journals (Sweden)

    Dai Jianjun

    2010-09-01

    Full Text Available Abstract Background Extraintestinal pathogenic E. coli (ExPEC represent a phylogenetically diverse group of bacteria which are implicated in a large range of infections in humans and animals. Although subgroups of different ExPEC pathotypes, including uropathogenic, newborn meningitis causing, and avian pathogenic E. coli (APEC share a number of virulence features, there still might be factors specifically contributing to the pathogenesis of a certain subset of strains or a distinct pathotype. Thus, we made use of suppression subtractive hybridization and compared APEC strain IMT5155 (O2:K1:H5; sequence type complex 95 with human uropathogenic E. coli strain CFT073 (O6:K2:H5; sequence type complex 73 to identify factors which may complete the currently existing model of APEC pathogenicity and further elucidate the position of this avian pathoype within the whole ExPEC group. Results Twenty-eight different genomic loci were identified, which are present in IMT5155 but not in CFT073. One of these loci contained a gene encoding a putative autotransporter adhesin. The open reading frame of the gene spans a 3,498 bp region leading to a putative 124-kDa adhesive protein. A specific antibody was raised against this protein and expression of the adhesin was shown under laboratory conditions. Adherence and adherence inhibition assays demonstrated a role for the corresponding protein in adhesion to DF-1 chicken fibroblasts. Sequence analyses revealed that the flanking regions of the chromosomally located gene contained sequences of mobile genetic elements, indicating a probable spread among different strains by horizontal gene transfer. In accordance with this hypothesis, the adhesin was found to be present not only in different phylogenetic groups of extraintestinal pathogenic but also of commensal E. coli strains, yielding a significant association with strains of avian origin. Conclusions We identified a chromosomally located autotransporter gene in a highly virulent APEC strain which confers increased adherence of a non-fimbriated E. coli K-12 strain to a chicken fibroblast cell line. Even though flanked by mobile genetic elements and three different genetic regions upstream of the gene, most probably indicating horizontal gene transfer events, the adhesin gene was significantly linked with strains of avian origin. Due to the nucleotide sequence similarity of 98% to a recently published adhesin-related gene, located on plasmid pAPEC-O1-ColBM, the name aatA (APEC autotransporter adhesin A was adopted from that study. Our data substantiate that AatA might not only be of relevance in APEC pathogenicity but also in facilitating their reservoir life style in the chicken intestine, which might pave the way for future intestinal preventive strategies.

  16. A novel missense mutation in the FERM domain containing 7 (FRMD7) gene causing X-linked idiopathic congenital nystagmus in a Chinese family

    Science.gov (United States)

    Liu, Zhirong; Mao, Shanying; Pu, Jiali; Ding, Yao; Zhang, Baorong

    2013-01-01

    Purpose: Idiopathic congenital nystagmus (ICN) is a genetically heterogeneous disease. Thus far, the disease gene has been identified as the FERM domain containing 7 (FRMD7) gene. The purpose of this study was to elucidate the clinical and genetic characteristics of a four- generation Chinese family with ICN. Methods: The clinical data and the genomic DNA of a Chinese ICN family were collected following the provision of informed consent. All coding exons of the FRMD7 gene were amplified by PCR and then sequenced. Af?nity GST-p21 activated kinase 2 (PAK2) precipitation was used to investigate whether this novel FRMD7 mutant influenced Rac1 signaling activation in the human embryonic kidney 293 T cells (HEK 293T) cells transiently cotransfected with wild-type or mutant FRMD7 and Rac1. Results: A novel missense mutation (c.635T>C) was identified in all affected members. Obligate female carriers were heterozygous in these mutations and the affected males were homozygous, consistent with X-linked inheritance. This mutation is a substitution of proline for leucine. Function analysis showed that this novel mutant influences Rac1 signaling in human HEK 293T cells. Conclusions: This study widens the mutation spectrum of the FRMD7 gene. This mutant was shown to activate GTPase Rac1 signaling in vitro; however, the quantity of activated Rac1 was obviously decreased compared with the wild type (p<0.05). Taken together, our data strongly support the hypothesis that the identified FRMD7 mutant influences GTPase Rac1 signaling, which regulates neurite development. This mutation may be related to the pathogenesis of X-linked ICN. PMID:23946638

  17. Identifying and Classifying Trait Linked Polymorphisms in Non-Reference Species by Walking Coloured de Bruijn Graphs

    OpenAIRE

    Richard M. Leggett; Ramirez-Gonzalez, Ricardo H; Verweij, Walter; Kawashima, Cintia G.; Iqbal, Zamin; Jones, Jonathan D. G.; Caccamo, Mario; MacLean, Daniel

    2013-01-01

    Single Nucleotide Polymorphisms are invaluable markers for tracing the genetic basis of inheritable traits and the ability to create marker libraries quickly is vital for timely identification of target genes. Next-generation sequencing makes it possible to sample a genome rapidly, but polymorphism detection relies on having a reference genome to which reads can be aligned and variants detected. We present Bubbleparse, a method for detecting variants directly from next-generation reads withou...

  18. Direct effects of X and Y-linked genes on sex-specific differences in the brain and behaviour

    Directory of Open Access Journals (Sweden)

    Robin Lovell-Badge

    2009-06-01

    Full Text Available In mammalian sex determination, the Y-linked gene Sry acts within the early gonad as a switch to trigger high expression of Sox9 in cells of the supporting cell lineage. SOX9 then acts on many target genes required for Sertoli cell differentiation and function. These include signalling molecules such as AMH, which eliminates the anlagen of the female reproductive tract in male embryos, as well as other molecules that direct the differentiation of other cell types along the male pathway, including steroidogenic cell precursors, which differentiate into Leydig cells. The latter synthesise testosterone (T, which masculinises the rest of the embryo either directly or after to conversion to dihydrotestosterone (DHT or estrogen (E at sites of action, including the brain. Until fairly recently many believed that all differences in the brain and behaviour were due to the activity of T or high levels of E during late fetal or early postnatal development. However, there are many genes on the X and a few on the Y chromosome that could exert direct effects, either independently of steroid hormone action or in conjunction with it. Indeed recent work has suggested that this is indeed the case. Sry itself is expressed in the brain, as are other Y-linked genes. And despite the process of X chromosome inactivation, which equalises X-linked gene dosage between males and females, many X-linked genes can have an effect either because they escape inactivation or because they are subject to parental genomic imprinting (where alleles behave differently according to whether they are maternally or paternally inherited. I will review the current status of research in this area as well as describe our own contribution.

  19. A Gene-Targeting Approach Identifies a Function for the First Intron in Expression of the ?1(I) Collagen Gene

    OpenAIRE

    Hormuzdi, Sheriar G.; Penttinen, Risto; Jaenisch, Rudolf; Bornstein, Paul

    1998-01-01

    The role of the first intron of the Col1A1 gene in the regulation of type I collagen synthesis remains uncertain and controversial despite numerous studies that have made use of transgenic and transfection experiments. To examine the importance of the first intron in regulation of the gene, we have used the double-replacement method of gene targeting to introduce, by homologous recombination in embryonic stem (ES) cells, a mutated Col1A1 allele (Col-Int?). The Col-Int? allele contains a 1.3-k...

  20. Searching for RFLP markers to identify genes for aluminum tolerance in maize

    International Nuclear Information System (INIS)

    The objective of this study was to identify restriction fragment length polymorphism (RFLP) markers linked to Quantitative Trait Loci (QTL) that control aluminum (Al) tolerance in maize. The strategy used was bulked segregant analysis (BSA) and the genetic materials utilized were the F2, F3 and F4 populations derived from a cross between the Al-susceptible inbred line L53 and Al-tolerant inbred line L1327. The populations were evaluated in a nutrient solution containing a toxic concentration of Al (6 ppm) and relative seminal root length (RSRL) was used as a phenotypic measure of tolerance. Seedlings of the F2 population with the highest and lowest RSRL values were transplanted to the field and subsequently selfed to obtain F3 and F4 families. The efficiency of the phenotypic index for selection was found to be greater when mean values were used instead of individual RSRL values. F3 and F4 families were then evaluated in nutrient solution to identify those that were not segregating. One hundred and thirteen probes, with an average interval of 30 cM, covering the 10 maize chromosomes were tested for their ability to discriminate the parental lines. Fifty four of these probes were polymorphic with 46 showing codominance. These probes were hybridized with DNA from two F3 contrasting, bulks and three probes on chromosome 8 were found to be able distinguish the F3 contrasting bulks on the basis of band position and intensity. DNA of families from the F3 bulks hybridized with these probes showed the presence of heterozygous individuals. These three selected probes were also hybridized with DNA from F2 individuals. Two of them showed a significant regression coefficient with the character. However, each of these probes explained only about 10% of the phenotypic variance observed in 70 F2 individuals. One of the probes UMC 103 was hybridized with DNA from 168 F4 families and the regression analysis of RFLP data showed a significant regression coefficient with a determination coefficient of 4.7%. These results suggest that on chromosome 8 in maize there is a region related to aluminum tolerance. (author)

  1. Using geoinformatics and cultural anthropology to identify links between land change, driving forces and actors in the Okavango catchment

    Science.gov (United States)

    Röder, Achim; Stellmes, Marion; Pröpper, Michael; Schneibel, Anne

    2015-04-01

    The recent acceleration of land use transformations, coupled with an increasing global population has manifested in an alteration of almost all terrestrial ecosystems (Millenium Ecosystem Assessment 2005). In particular, the extension and intensification of agricultural and pastoral uses has supported unprecedented rates of population growth (Ellis and Ramankutty 2008). However, this development stands opposed to increased greenhouse gas emissions, declining biodiversity, declining air quality and increasing soil degradation, being reflected in the general reduction in ecosystem services and functions (Sala, Chapin III et al. 2000; Butchart, Walpole et al. 2010; Banwart 2011; Lal 2013). Such global change processes are to a large degree driven by land-use transformations or modifications (Foley, Defries et al. 2005). These are in turn a result of the complex interaction of factors playing out at different scales, varying from global market dynamics through national policies to regional planning and local traditions (Hein, van Koppen et al. 2006). The Okavango Basin represents a highly complex social-ecological system, where the variation in physio-geographic characteristics is reflected by manifold livelihood strategies in the three adjacent countries Angola, Namibia and Botswana. In mostly rural areas, small-scale subsistence agriculture, livestock-keeping and the utilization of natural resources such as thatch grass, timber, fruits etc. have traditionally formed the basis for human well-being. These strategies are juxtaposed by recent urban and transportation infrastructure developments, the expansion of commodity markets, the creation of commercial irrigated farming schemes and dams for energy production, or the growing role of tourism, in particular in the Delta region, as a major source of income generation. At present, the three countries bordering the river have individual legislations governing the use of natural resources, which usually originate at central institutions and are implemented in different ways at subordinate levels. Commonly, communities make their own decisions regarding the use of natural resources within the framework of statutory and traditional governance and national legislation. The Permanent Okavango River Basin Water Commission (OKACOM) has been created between Angola, Namibia and Botswana to deal with transboundary subjects and facilitate informed policies. Developing such informed policies is even more urgent given demographic and climatological predictions. The African population is expected to almost double by the end of this century (Haub 2012), while climate predictions indicate an overall increase in average temperatures, added to by an increase in dry spells during the wet season and overall decreases in precipitation (IPCC 2013). This will result in increasing demands for food, paralleled by less favorable production conditions. The appropriation of resources in the wider region is therefore characterized by various, potentially conflicting demands that are likely to accumulate in space and time (Röder, Stellmes et al. 2013). A particular constraint draws from upstream-downstream issues, with a predicted increase in upstream water utilization for drinking and irrigation, while the Delta region relies on regular flood pulses of clean water to sustain its biodiversity, to which the tourist sector as a major source of national income is linked. This is threatened by the increasing concentrations of pesticides and herbicides used in the frame of irrigation schemes lowering water quality, and the change of flood pulse cycles through damming projects (Lindemann 2009). Besides national policies and regional planning programs, an equally important element in understanding the utilization of natural resources is the individual perspective of actors that may range from the conservation of traditions and cultures to stronger market integration and consumerism (Pröpper, Falk et al. 2013) that result from rapidly changing social and environmental framework conditions (Weber, Krogman et al. 2012). In this study, we integrated knowledge on determining factors at different levels with remote sensing techniques to understand which ecological, policy-, planning-, and human-related drivers and causes underlie the actors' decisions that have eventually shaped the present-day land use systems. These may in turn serve as a baseline for future integrated policies and sustainable local land management. A special focus is set on the unique cross-border situation in Northern Namibia and Southern Angola, which share physio-geographic properties on both sides of the Cubango River, but vastly differ in respect to their recent history. While Namibia has experienced a period of stability since its independence in 1990, Angola is still recovering from the civil war that, with some interludes, lasted from 1975 until 2002. We used a set of multi-temporal Landsat-5 TM and -7ETM+ data sets covering the period from 1989 to 2010 to assess the contrasting development of resource utilization on both sides of the Okavango River and to identify temporal trends. Reflecting the high spectral variability in surface types, support vector machine (SVM) classification was used to map major land use types. SVM uses kernel functions to map non-linear decision boundaries in the original data space into linear ones in a feature space of higher dimensionality (Huang, Davis et al. 2002) and is particularly useful when differentiating complex spectral classes with small numbers of training data. To further discriminate Savanna ecosystems, we used Iterative Spectral Mixture Analysis (ISMA) (Rogge, Rivard et al. 2006) that estimates the abundance of prevailing materials present in each pixel as an independent linear combination of reference spectra. To assess scale-dependencies of observable phenomena, MODIS and Quickbird data were employed. These provide context at a coarser scale (broad vegetation/ land use categories classified using phenology descriptors derived from 16-day EVI composites) (Jönsson and Eklundh 2004) and explanatory details (better understanding of mixed spectral signatures at Landsat resolution) at finer resolutions, respectively. Census and household surveys as well as landscape value mapping were utilized to understand the local actors' perspectives, while literature reviews provide information on regional to national frameworks in terms of regulations and policies (Pröpper, Falk et al. 2013; Rieprich 2013). We found the conversion of woodland savannah to arable land to be by far the dominant land use change process during the observation period. Strong spatial change gradients occurred in relation to determining factors, such as accessibility, proximity to water, urban centers etc., while relations to settlements where less obvious (Röder et al., 2015). Assessing results by country illustrated the difference in land use intensity and resource consumption between Angola and Namibia, which relate directly to historical developments, with a long period of stability in Namibia standing opposed to the recent and ongoing recovery from civil war in Angola. These are added to by statutory and traditional policy frameworks, the national endowment with natural capital (e.g. oil, uranium, diamonds, and zinc) and the integration into global markets, which strongly affects national economies of both countries at large. Underlying land use decisions were found to be largely driven by individualized perspectives on growth ideologies, consumerism and wealth-aspirations connected to globalization processes. However, at present the result of these perspectives is still mainly a small-structured conversion to rainfed agriculture as a component of subsistence strategies of local livelihoods, and thus stands opposed to other regions of the world, where change processes are much more driven by large companies or follow national regulations and result in more intensive uses, although the same processes are likely to occur in parts of the Okavango region in the future. Literature: Banwart, S. (2011). "Save our soils." Nature 474: 151-152. Bürgi, M., A. M. Hersperger, et al. (2004). "Driving forces of landscape change - current and new directions." Landscape Ecology 19: 857-868. Butchart, S. H. M., M. Walpole, et al. (2010). "Global Biodiversity: Indicators of Recent Declines." Science 328(5982): 1164-1168. Ellis, E. C. and N. Ramankutty (2008). "Putting people in the map: anthropogenic biomes of the world." Frontiers in Ecology and the Environment 6(8): 439-447. Foley, J. A., R. Defries, et al. (2005). "Global consequences of land use." Science 309(5734): 570-574. Geist, H. J. and E. F. Lambin (2002). "Proximate causes and underlying driving forces of tropical deforestation." BioScience 52(2): 143-150. Haub, C. (2012) World Population Data Sheet. World Population Hein, L., K. van Koppen, et al. (2006). "Spatial scales, stakeholders and the valuation of ecosystem services." Ecological Economics 57: 209-228. Hersperger, A. M., M.-P. Gennaio, et al. (2010). "Linking land change with driving forces and actors: four conceptual models." Ecology and Society 15(4): 1-17. Huang, C., L. S. Davis, et al. (2002). "An assessment of support vector machines for land cover classification." International Journal of Remote Sensing 23(4): 725-749. IPCC (2013). Climate Change 2013: The Physical Science Basis. Contribution of Working Group I to the Fifth Assessment Report of the Intergovernmental Panel on Climate Change. T. F. Stocker, G. Qin, G.-K. Plattneret al. Cambridge, Cambridge University Press. Jönsson, P. and L. Eklundh (2004). "TIMESAT - a program for analysing time-series of satellite sensor data." Computers and Geosciences 30(833-845). Kowalski, B., N. Azebaze, et al. (2013). "Mashare - The People." Biodiversity & Ecology 5: 121-128. Lal, R. (2013). "Climate-strategic agriculture and the water-soil-waste nexus." Journal of Plant Nutrition and Soil Science 176: 479-493. Lindemann, S. (2009). Success and failure in international river basin management - the case of Southern Africa. Facing global environmental change: environmental, human, energy, food, health and water security concepts. H.-G. Brauch, U. Oswald Spring, J. Grinet al. Berlin, Springer: 699-710. Millenium Ecosystem Assessment (2005). Ecosystems and human well-being: Synthesis. Washington, D.C., Island Press. Pröpper, M., T. Falk, et al. (2013). "Partly subsistent household economies and modern consumerism in the Namibian Kavango: Assets, income, expenditure and socio-economic stratification." Biodiversity & Ecology 5: 379-391. Rieprich, R. (2013). Mapping Environmental Valuations. An Ethnographic Case Study of Ecosystem Services and Landscape Values in Kavango, Namibia. Social and Cultural Anthropology. Hamburg, University of Hamburg. Master of Arts: 111. Röder, A., M. Stellmes, et al. (2013). "Cumulative effects of policy and management actions on ecosystem services. Challenges and methodological approaches in the Future Okavango project." Biodiversity & Ecology 5: 167-183. Röder, A., Pröpper, M., Stellmes, M., Schneibel, A. & Hill, J. (2015): Assessing urban growth and rural land use transformations in a cross-border situation in Northern Namibia and Southern Angola. Land Use Policy 42: 340-254. Rogge, D. M., B. Rivard, et al. (2006). "Iterative spectral unmixing for optimizing per-pixel endmember sets." IEEE Transactions on Geoscience and Remote Sensing 44(12): 3725-3736. Sala, O. E., F. S. Chapin III, et al. (2000). "Global biodiversity scenarios for the year 2011." Science 287: 1770-1774. Weber, M., N. Krogman, et al. (2012). "Cumulative Effects Assessment: Linking Social, Ecological, and Governance Dimensions." Ecology and Society 17(2)

  2. A complementary bioinformatics approach to identify potential plant cell wall glycosyltransferase-encoding genes.

    Science.gov (United States)

    Egelund, Jack; Skjøt, Michael; Geshi, Naomi; Ulvskov, Peter; Petersen, Bent Larsen

    2004-09-01

    Plant cell wall (CW) synthesizing enzymes can be divided into the glycan (i.e. cellulose and callose) synthases, which are multimembrane spanning proteins located at the plasma membrane, and the glycosyltransferases (GTs), which are Golgi localized single membrane spanning proteins, believed to participate in the synthesis of hemicellulose, pectin, mannans, and various glycoproteins. At the Carbohydrate-Active enZYmes (CAZy) database where e.g. glucoside hydrolases and GTs are classified into gene families primarily based on amino acid sequence similarities, 415 Arabidopsis GTs have been classified. Although much is known with regard to composition and fine structures of the plant CW, only a handful of CW biosynthetic GT genes-all classified in the CAZy system-have been characterized. In an effort to identify CW GTs that have not yet been classified in the CAZy database, a simple bioinformatics approach was adopted. First, the entire Arabidopsis proteome was run through the Transmembrane Hidden Markov Model 2.0 server and proteins containing one or, more rarely, two transmembrane domains within the N-terminal 150 amino acids were collected. Second, these sequences were submitted to the SUPERFAMILY prediction server, and sequences that were predicted to belong to the superfamilies NDP-sugartransferase, UDP-glycosyltransferase/glucogen-phosphorylase, carbohydrate-binding domain, Gal-binding domain, or Rossman fold were collected, yielding a total of 191 sequences. Fifty-two accessions already classified in CAZy were discarded. The resulting 139 sequences were then analyzed using the Three-Dimensional-Position-Specific Scoring Matrix and mGenTHREADER servers, and 27 sequences with similarity to either the GT-A or the GT-B fold were obtained. Proof of concept of the present approach has to some extent been provided by our recent demonstration that two members of this pool of 27 non-CAZy-classified putative GTs are xylosyltransferases involved in synthesis of pectin rhamnogalacturonan II (J. Egelund, B.L. Petersen, A. Faik, M.S. Motawia, C.E. Olsen, T. Ishii, H. Clausen, P. Ulvskov, and N. Geshi, unpublished data). PMID:15333752

  3. Identifying Moderators of the Link Between Parent and Child Anxiety Sensitivity: The Roles of Gender, Positive Parenting, and Corporal Punishment.

    Science.gov (United States)

    Graham, Rebecca A; Weems, Carl F

    2015-07-01

    A substantial body of literature suggests that anxiety sensitivity is a risk factor for the development of anxiety problems and research has now begun to examine the links between parenting, parent anxiety sensitivity and their child's anxiety sensitivity. However, the extant literature has provided mixed findings as to whether parent anxiety sensitivity is associated with child anxiety sensitivity, with some evidence suggesting that other factors may influence the association. Theoretically, specific parenting behaviors may be important to the development of child anxiety sensitivity and also in understanding the association between parent and child anxiety sensitivity. In this study, 191 families (n = 255 children and adolescents aged 6-17 and their parents) completed measures of child anxiety sensitivity (CASI) and parenting (APQ-C), and parents completed measures of their own anxiety sensitivity (ASI) and their parenting (APQ-P). Corporal punishment was associated with child anxiety sensitivity and the child's report of their parent's positive parenting behaviors moderated the association between parent and child anxiety sensitivity. The child's gender was also found to moderate the association between parent and child anxiety sensitivity, such that there was a positive association between girls' and their parents anxiety sensitivity and a negative association in boys. The findings advance the understanding of child anxiety sensitivity by establishing a link with corporal punishment and by showing that the association between parent and child anxiety sensitivity may depend upon the parenting context and child's gender. PMID:25301177

  4. A novel method to identify high order gene-gene interactions in genome-wide association studies: Gene-based MDR

    OpenAIRE

    Oh Sohee; Lee Jaehoon; Kwon Min-Seok; Weir Bruce; Ha Kyooseob; Park Taesung

    2012-01-01

    Abstract Background Because common complex diseases are affected by multiple genes and environmental factors, it is essential to investigate gene-gene and/or gene-environment interactions to understand genetic architecture of complex diseases. After the great success of large scale genome-wide association (GWA) studies using the high density single nucleotide polymorphism (SNP) chips, the study of gene-gene interaction becomes a next challenge. Multifactor dimensionality reduction (MDR) analy...

  5. How well do HapMap haplotypes identify common haplotypes of genes? A comparison with haplotypes of 334 genes resequenced in the environmental genome project.

    Science.gov (United States)

    Taylor, Jack A; Xu, Zong-Li; Kaplan, Norman L; Morris, Richard W

    2006-01-01

    One of the goals of the International HapMap Project is the identification of common haplotypes in genes. However, HapMap uses an incomplete catalogue of single nucleotide polymorphisms (SNPs) and might miss some common haplotypes. We examined this issue using data from the Environmental Genome Project (EGP) which resequenced 335 genes in 90 people, and thus, has a nearly complete catalogue of gene SNPs. The EGP identified a total of 45,243 SNPs, of which 10,780 were common SNPs (minor allele frequency >or=0.1). Using EGP common SNP genotype data, we identified 1,459 haplotypes with frequency >or=0.05 and we use these as "benchmark" haplotypes. HapMap release 16 had genotype information for 1,573 of 10,780 (15%) EGP common SNPs. Using these SNPs, we identified common HapMap haplotypes (frequency >or=0.05) in each of the four HapMap ethnic groups. To compare common HapMap haplotypes to EGP benchmark haplotypes, we collapsed benchmark haplotypes to the set of 1,573 SNPs. Ninety-eight percent of the collapsed benchmark haplotypes could be found as common HapMap haplotypes in one or more of the four HapMap ethnic groups. However, collapsing benchmark haplotypes to the set of SNPs available in HapMap resulted in a loss of haplotype information: 545 of 1,459 (37%) benchmark haplotypes were uniquely identified, and only 25% of genes had all their benchmark haplotypes uniquely identified. We resampled the EGP data to examine the effect of increasing the number of HapMap SNPs to 5 million, and estimate that approximately 40% of common SNPs in genes will be sampled and that half of the genes will have sufficient SNPs to identify all common haplotypes. This inability to distinguish common haplotypes of genes may result in loss of power when examining haplotype-disease association. PMID:16434598

  6. Localization of a non-syndromic X-linked mental retardation gene (MRX80) to Xq22-q24.

    Science.gov (United States)

    Verot, Lucie; Alloisio, Nicole; Morl, Laurette; Bozon, Muriel; Touraine, Renaud; Plauchu, Henri; Edery, Patrick

    2003-09-15

    Isolated mental retardation is clinically and genetically heterogenous and may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. We report here a linkage analysis in a large family including 15 members, 6 of whom presenting X-linked non-syndromic mental retardation (MRX). Two-point linkage analysis using 23 polymorphic markers covering the entire X chromosome demonstrated significant linkage between the causative gene and DXS8055 with a maximum LOD score of 2.98 at theta = 0.00. Haplotype analysis indicated location for the disease gene in a 23.1 cM interval between DXS1106 and DXS8067. This MRX localization overlaps with 7 XLMR loci (MRX23, MRX27, MRX30, MRX35, MRX47, MRX53, and MRX63). This interval contains two genes associated with non-syndromic mental retardation (NSMR), namely the PAK3 gene, encoding a p21-activated kinase (MRX30 and MRX47) and the FACL4 gene encoding a fatty acyl-CoA ligase (MRX63). As skewed X-inactivation, an apparently constant feature in FACL4 carrier females was not observed in an obligate carrier belonging to the MRX family presented here, the PAK3 gene should be considered as the strongest candidate for this MRX locus. PMID:12949969

  7. Cambial-region-specific expression of the Agrobacterium iaa genes in transgenic aspen visualized by a linked uidA reporter gene.

    Science.gov (United States)

    Tuominen, H; Puech, L; Regan, S; Fink, S; Olsson, O; Sundberg, B

    2000-06-01

    The level of indole-3-acetic acid (IAA) was locally modified in cambial tissues of transgenic aspen (Populus tremula L. x Populus tremuloides Michx.). We also demonstrate the use of a linked reporter gene to visualize the expression of the iaa genes. The rate-limiting bacterial IAA-biosynthetic gene iaaM and the reporter gene for beta-glucuronidase (GUS), uidA, were each fused to the cambial-region-specific Agrobacterium rhizogenes rolC promoter and linked on the same T-DNA. In situ hybridization of the iaaM gene confirmed that histochemical analysis of GUS activity could be used to predict iaaM gene expression. Moreover, quantitative fluorometric analysis of GUS activity allowed estimation of the level of de novo production of IAA in transgenic lines carrying a single-copy insert of the iaaM, uidA T-DNA. Microscale analysis of the IAA concentration across the cambial region tissues showed an increase in IAA concentration of about 35% to 40% in the two transgenic lines, but no changes in the radial distribution pattern of IAA compared with wild-type plants. This increase did not result in any changes in the developmental pattern of cambial derivatives or the cambial growth rate, which emphasizes the importance of the radial distribution pattern of IAA in controlling the development of secondary xylem, and suggests that a moderate increase in IAA concentration does not necessarily stimulate growth. PMID:10859183

  8. Strategies to identify and further characterize novel and known genes involved in regulation of skeletogenesis

    OpenAIRE

    Schlaubitz, Silke

    2007-01-01

    372 osteochondrodysplasias and genetically determined dysostoses were reported in 2007 [Superti-Furga and Unger, 2007]. For 215 of these conditions, an association with one or more genes can be stated, while the molecular changes for the remaining syndromes remain illusive to date. Thus, the present dissertation aims at the identification of novel genes involved in processes regarding cartilage/ bone formation, growth, differentiation and homeostasis, which may serve as candidate genes fo...

  9. Medial prefrontal cortex: genes linked to bipolar disorder and schizophrenia have altered expression in the highly social maternal phenotype

    Directory of Open Access Journals (Sweden)

    Brian E Eisinger

    2014-04-01

    Full Text Available The transition to motherhood involves CNS changes that modify sociability and affective state. However, these changes also put females at risk for postpartum depression and psychosis, which impairs parenting abilities and adversely affects children. Thus, changes in expression and interactions in a core subset of genes may be critical for emergence of a healthy maternal phenotype, but inappropriate changes of the same genes could put women at risk for postpartum disorders. This study evaluated microarray gene expression changes in medial prefrontal cortex (mPFC, a region implicated in both maternal behavior and psychiatric disorders. Postpartum mice were compared to virgin controls housed with females and isolated for identical durations. Using the Modular Single-set Enrichment Test (MSET, we found that the genetic landscape of maternal mPFC bears statistical similarity to gene databases associated with schizophrenia (5 of 5 sets and bipolar disorder (BPD, 3 of 3 sets. In contrast to previous studies of maternal lateral septum and medial preoptic area, enrichment of autism and depression-linked genes was not significant (2 of 9 sets, 0 of 4 sets. Among genes linked to multiple disorders were fatty acid binding protein 7 (Fabp7, glutamate metabotropic receptor 3 (Grm3, platelet derived growth factor, beta polypeptide (Pdgfrb, and nuclear receptor subfamily 1, group D, member 1 (Nr1d1. RT-qPCR confirmed these gene changes as well as FMS-like tyrosine kinase 1 (Flt1 and proenkephalin (Penk. Systems-level methods revealed involvement of developmental gene networks in establishing the maternal phenotype and indirectly suggested a role for numerous microRNAs and transcription factors in mediating expression changes. Together, this study suggests that a subset of genes involved in shaping the healthy maternal brain may also be dysregulated in mental health disorders and put females at risk for postpartum psychosis with aspects of schizophrenia and BPD.

  10. Molecular Cloning and Functional Characterization of Two Brachypodium distachyon UBC13 Genes Whose Products Promote K63-Linked Polyubiquitination

    Science.gov (United States)

    Guo, Huiping; Wen, Rui; Liu, Zhi; Datla, Raju; Xiao, Wei

    2016-01-01

    Living organisms are constantly subject to DNA damage from environmental sources. Due to the sessile nature of plants, UV irradiation is a major genotoxic agent and imposes a significant threat on plant survival, genome stability and crop yield. In addition, other environmental chemicals can also influence the stability of the plant genome. Eukaryotic organisms have evolved a mechanism to cope with replication-blocking lesions and stabilize the genome. This mechanism is known as error-free DNA damage tolerance, and is mediated by K63-linked PCNA polyubiquitination. Genes related to K63-linked polyubiquitination have been isolated recently from model plants like Arabidopsis and rice, but we are unaware of such reports on the crop model Brachypodium distachyon. Here, we report the identification and functional characterization of two B. distachyon UBC13 genes. Both Ubc13s form heterodimers with Uevs from other species, which are capable of catalyzing K63 polyubiquitination in vitro. Both genes can functionally rescue the yeast ubc13 null mutant from killing by DNA-damaging agents. These results suggest that Ubc13-Uev-promoted K63-linked polyubiquitination is highly conserved in eukaryotes including B. distachyon. Consistent with recent findings that K63-linked polyubiquitination is involved in several developmental and stress-responsive pathways, the expression of BdUbc13s appears to be constitutive and is regulated by abnormal temperatures. PMID:26779244

  11. A novel point mutation within the EDA gene causes an exon dropping in mature RNA in Holstein Friesian cattle breed affected by X-linked anhidrotic ectodermal dysplasia

    Directory of Open Access Journals (Sweden)

    Pariset Lorraine

    2011-07-01

    Full Text Available Abstract Background X-linked anhidrotic ectodermal dysplasia is a disorder characterized by abnormal development of tissues and organs of ectodermal origin caused by mutations in the EDA gene. The bovine EDA gene encodes the ectodysplasin A, a membrane protein expressed in keratinocytes, hair follicles and sweat glands, which is involved in the interactions between cell and cell and/or cell and matrix. Four mutations causing ectodermal dysplasia in cattle have been described so far. Results We identified a new single nucleotide polymorphism (SNP at the 9th base of exon 8 in the EDA gene in two calves of Holstein Friesian cattle breed affected by ectodermal dysplasia. This SNP is located in the exonic splicing enhancer (ESEs recognized by SRp40 protein. As a consequence, the spliceosome machinery is no longer able to recognize the sequence as exonic and causes exon skipping. The mutation determines the deletion of the entire exon (131 bp in the RNA processing, causing a severe alteration of the protein structure and thus the disease. Conclusion We identified a mutation, never described before, that changes the regulation of alternative splicing in the EDA gene and causes ectodermal dysplasia in cattle. The analysis of the SNP allows the identification of carriers that can transmit the disease to the offspring. This mutation can thus be exploited for a rational and efficient selection of unequivocally healthy cows for breeding.

  12. Genes Involved in the Osteoarthritis Process Identified through Genome Wide Expression Analysis in Articular Cartilage; the RAAK Study

    OpenAIRE

    Ramos, Y.F.M.; Hollander, W. den; Bovee, J.V.; Bomer, N.; van der Breggen, R.; Lakenberg, N.; Keurentjes, J. C.; Goeman, J.J.; Slagboom, P. E.; Nelissen, R.G.; Bos, S. D.; Meulenbelt, I

    2014-01-01

    OBJECTIVE: Identify gene expression profiles associated with OA processes in articular cartilage and determine pathways changing during the disease process. METHODS: Genome wide gene expression was determined in paired samples of OA affected and preserved cartilage of the same joint using microarray analysis for 33 patients of the RAAK study. Results were replicated in independent samples by RT-qPCR and immunohistochemistry. Profiles were analyzed with the online analysis tools DAVID and STRI...

  13. Pathway-based analysis of GWAs data identifies association of sex determination genes with susceptibility to testicular germ cell tumors

    OpenAIRE

    Koster, Roelof,; MITRA, NANDITA; D'Andrea, Kurt; Vardhanabhuti, Saran; Chung, Charles C.; Wang, Zhaoming; Loren Erickson, R.; Vaughn, David J; Litchfield, Kevin; Rahman, Nazneen; Greene, Mark H.; McGlynn, Katherine A.; Turnbull, Clare; Chanock, Stephen J.; Nathanson, Katherine L

    2014-01-01

    Genome-wide association (GWA) studies of testicular germ cell tumor (TGCT) have identified 18 susceptibility loci, some containing genes encoding proteins important in male germ cell development. Deletions of one of these genes, DMRT1, lead to male-to-female sex reversal and are associated with development of gonadoblastoma. To further explore genetic association with TGCT, we undertook a pathway-based analysis of SNP marker associations in the Penn GWAs (349 TGCT cases and 919 controls). We ...

  14. Semantic interrogation of a multi knowledge domain ontological model of tendinopathy identifies four strong candidate risk genes

    OpenAIRE

    Colleen J. Saunders; Mahjoubeh Jalali Sefid Dashti; Junaid Gamieldien

    2016-01-01

    Tendinopathy is a multifactorial syndrome characterised by tendon pain and thickening, and impaired performance during activity. Candidate gene association studies have identified genetic factors that contribute to intrinsic risk of developing tendinopathy upon exposure to extrinsic factors. Bioinformatics approaches that data-mine existing knowledge for biological relationships may assist with the identification of candidate genes. The aim of this study was to data-mine functional annotation...

  15. Cationic polymethacrylates with covalently linked membrane destabilizing peptides as gene delivery vectors.

    Science.gov (United States)

    Funhoff, Arjen M; van Nostrum, Cornelus F; Lok, Martin C; Kruijtzer, John A W; Crommelin, Daan J A; Hennink, Wim E

    2005-01-01

    A membrane-disrupting peptide derived from the influenza virus was covalently linked to different polymethacrylates (pDMAEMA, pDAMA and the degradable pHPMA-DMAE, monomers depicted in Fig. 1) using N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP) as coupling agent to increase the transfection efficiency of polyplexes based on these polymers. It was shown by circular dichroism (CD) measurements that the polymer-conjugated peptide was, as the free peptide, able to undergo a conformational change of a random coil to an alpha helix upon lowering the pH to 5.0. This indicates that the property of the peptide to destabilize the endosomal membrane was preserved after its conjugation to the cationic polymers. In line herewith, a liposome leakage assay revealed that the polymer-bound peptide has comparable activity as the free peptide. The DNA condensing properties of the synthesized polymer-peptide conjugates were studied with dynamic light scattering and zeta-potential measurements, and it was shown that small (100 to 250 nm), positively charged (+15 to +20 mV) particles were formed. In vitro transfection and toxicity was tested in COS-7 cells, and these experiments showed that the polyplexes with grafted peptide had a substantially higher transfection activity than the control polyplexes, while the toxicity remained unchanged. Cellular uptake of the polyplexes was visualized with confocal laser scanning microscopy, and no differences in cellular uptake could be determined between the peptide containing systems and the control formulation. This shows that the increased transfection activity is indeed due to a better endosomal escape of the peptide grafted polyplexes. This study demonstrates that it is possible to covalently conjugate an endosome disruptive peptide to cationic gene delivery polymers with preservation of its membrane destabilization activity, making these conjugates suitable for in vivo DNA delivery. PMID:15588908

  16. ESTs and putative line-specific (broiler and layer SNPs identified in genes expressed in Gallus gallus pituitary and hypothalamus

    Directory of Open Access Journals (Sweden)

    Clarissa Sanches da Silva Cassoli

    2007-01-01

    Full Text Available Brazilian poultry industry has reached a high level of development in both meat and egg production as a result of constant technological modernization. Further improvements can be achieved through genomics, but before this can be accomplished, a better understanding of gene expression profiles and nucleotide polymorphisms is necessary. Since animal physiology is directly or indirectly controlled by the pituitary and hypothalamus, the aim of the present work was to identify and analyze genes expressed in these tissues in chicken lines with different growth potential. Two pituitary and hypothalamus cDNA libraries from 21 day broiler (TT and layer (CC chickens lines were constructed and allowed identification of 3,074 unique sequences and 77 single nucleotide polymorphisms (SNPs. The collection of expressed sequence tags (ESTs and SNPs identified in this study represents an important resource for future studies aimed at identifying genes responsible for growth in chicken.

  17. A small interfering RNA screen of genes involved in DNA repair identifies tumor-specific radiosensitization by POLQ knockdown

    DEFF Research Database (Denmark)

    Higgins, Geoff S; Prevo, Remko; Lee, Yin-Fai; Helleday, Thomas; Muschel, Ruth J; Taylor, Steve; Yoshimura, Michio; Hickson, Ian David; Bernhard, Eric J; McKenna, W Gillies

    2010-01-01

    radiosensitivity are largely unknown. We have conducted a small interfering RNA (siRNA) screen of 200 genes involved in DNA damage repair aimed at identifying genes whose knockdown increased tumor radiosensitivity. Para