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Sample records for rare gene variation

  1. Rare Copy Number Variations in Adults with Tetralogy of Fallot Implicate Novel Risk Gene Pathways

    Costain, Gregory; Merico, Daniele; Migita, Ohsuke; Liu, Ben; Yuen, Tracy; Rickaby, Jessica; Thiruvahindrapuram, Bhooma; Marshall, Christian R.; Scherer, Stephen W.; Bassett, Anne S.

    2012-01-01

    Structural genetic changes, especially copy number variants (CNVs), represent a major source of genetic variation contributing to human disease. Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease, but to date little is known about the role of CNVs in the etiology of TOF. Using high-resolution genome-wide microarrays and stringent calling methods, we investigated rare CNVs in a prospectively recruited cohort of 433 unrelated adults with TOF and/or pulmonary atresia at a single centre. We excluded those with recognized syndromes, including 22q11.2 deletion syndrome. We identified candidate genes for TOF based on converging evidence between rare CNVs that overlapped the same gene in unrelated individuals and from pathway analyses comparing rare CNVs in TOF cases to those in epidemiologic controls. Even after excluding the 53 (10.7%) subjects with 22q11.2 deletions, we found that adults with TOF had a greater burden of large rare genic CNVs compared to controls (8.82% vs. 4.33%, p = 0.0117). Six loci showed evidence for recurrence in TOF or related congenital heart disease, including typical 1q21.1 duplications in four (1.18%) of 340 Caucasian probands. The rare CNVs implicated novel candidate genes of interest for TOF, including PLXNA2, a gene involved in semaphorin signaling. Independent pathway analyses highlighted developmental processes as potential contributors to the pathogenesis of TOF. These results indicate that individually rare CNVs are collectively significant contributors to the genetic burden of TOF. Further, the data provide new evidence for dosage sensitive genes in PLXNA2-semaphorin signaling and related developmental processes in human cardiovascular development, consistent with previous animal models. PMID:22912587

  2. A rare FANCA gene variation as a breast cancer susceptibility allele in an Iranian population.

    Abbasi, Sakineh; Rasouli, Mina

    2017-06-01

    Fanconi Anemia (FA) is an autosomal recessive syndrome characterized by congenital abnormalities, progressive bone marrow failure and Fanconi anemia complementation group A (FANCA) is also a potential breast and ovarian cancer susceptibility gene. A novel allele with tandem duplication of 13 base pair sequence in promoter region was identified. To investigate whether the 13 base pair sequence of tandem duplication in promoter region of the FANCA gene is of high penetrance in patients with breast cancer and to determine if the presence of the duplicated allele was associated with an altered risk of breast cancer, the present study screened DNA in blood samples from 304 breast cancer patients and 295 normal individuals as controls. The duplication allele had a frequency of 35.4 and 21.2% in patients with breast cancer and normal controls, respectively. There was a significant increase in the frequency of the duplication allele in patients with familial breast cancer compared with controls (45.1%, P=0.001). Furthermore, the estimated risk of breast cancer in individuals with a homozygote [odds ratio (OR), 4.093; 95% confidence intervals (CI), 1.957‑8.561] or heterozygote duplicated genotype (OR, 3.315; 95% CI, 1.996‑5.506) was higher compared with the corresponding normal homozygote genotype. In conclusion, the present study indicated that the higher the frequency of the duplicated allele, the higher the risk of breast cancer. To the best of our knowledge, the present study is the first to report FANCA gene duplication in patients with breast cancer.

  3. The power of gene-based rare variant methods to detect disease-associated variation and test hypotheses about complex disease.

    Loukas Moutsianas

    2015-04-01

    Full Text Available Genome and exome sequencing in large cohorts enables characterization of the role of rare variation in complex diseases. Success in this endeavor, however, requires investigators to test a diverse array of genetic hypotheses which differ in the number, frequency and effect sizes of underlying causal variants. In this study, we evaluated the power of gene-based association methods to interrogate such hypotheses, and examined the implications for study design. We developed a flexible simulation approach, using 1000 Genomes data, to (a generate sequence variation at human genes in up to 10K case-control samples, and (b quantify the statistical power of a panel of widely used gene-based association tests under a variety of allelic architectures, locus effect sizes, and significance thresholds. For loci explaining ~1% of phenotypic variance underlying a common dichotomous trait, we find that all methods have low absolute power to achieve exome-wide significance (~5-20% power at α = 2.5 × 10(-6 in 3K individuals; even in 10K samples, power is modest (~60%. The combined application of multiple methods increases sensitivity, but does so at the expense of a higher false positive rate. MiST, SKAT-O, and KBAC have the highest individual mean power across simulated datasets, but we observe wide architecture-dependent variability in the individual loci detected by each test, suggesting that inferences about disease architecture from analysis of sequencing studies can differ depending on which methods are used. Our results imply that tens of thousands of individuals, extensive functional annotation, or highly targeted hypothesis testing will be required to confidently detect or exclude rare variant signals at complex disease loci.

  4. A variational Bayes discrete mixture test for rare variant association.

    Logsdon, Benjamin A; Dai, James Y; Auer, Paul L; Johnsen, Jill M; Ganesh, Santhi K; Smith, Nicholas L; Wilson, James G; Tracy, Russell P; Lange, Leslie A; Jiao, Shuo; Rich, Stephen S; Lettre, Guillaume; Carlson, Christopher S; Jackson, Rebecca D; O'Donnell, Christopher J; Wurfel, Mark M; Nickerson, Deborah A; Tang, Hua; Reiner, Alexander P; Kooperberg, Charles

    2014-01-01

    Recently, many statistical methods have been proposed to test for associations between rare genetic variants and complex traits. Most of these methods test for association by aggregating genetic variations within a predefined region, such as a gene. Although there is evidence that "aggregate" tests are more powerful than the single marker test, these tests generally ignore neutral variants and therefore are unable to identify specific variants driving the association with phenotype. We propose a novel aggregate rare-variant test that explicitly models a fraction of variants as neutral, tests associations at the gene-level, and infers the rare-variants driving the association. Simulations show that in the practical scenario where there are many variants within a given region of the genome with only a fraction causal our approach has greater power compared to other popular tests such as the Sequence Kernel Association Test (SKAT), the Weighted Sum Statistic (WSS), and the collapsing method of Morris and Zeggini (MZ). Our algorithm leverages a fast variational Bayes approximate inference methodology to scale to exome-wide analyses, a significant computational advantage over exact inference model selection methodologies. To demonstrate the efficacy of our methodology we test for associations between von Willebrand Factor (VWF) levels and VWF missense rare-variants imputed from the National Heart, Lung, and Blood Institute's Exome Sequencing project into 2,487 African Americans within the VWF gene. Our method suggests that a relatively small fraction (~10%) of the imputed rare missense variants within VWF are strongly associated with lower VWF levels in African Americans.

  5. Relationships among and variation within rare breeds of swine.

    Roberts, K S; Lamberson, W R

    2015-08-01

    Extinction of rare breeds of livestock threatens to reduce the total genetic variation available for selection in the face of the changing environment and new diseases. Swine breeds facing extinction typically share characteristics such as small size, slow growth rate, and high fat percentage, which limit them from contributing to commercial production. Compounding the risk of loss of variation is the lack of pedigree information for many rare breeds due to inadequate herd books, which increases the chance that producers are breeding closely related individuals. By making genetic data available, producers can make more educated breeding decisions to preserve genetic diversity in future generations, and conservation organizations can prioritize investments in breed preservation. The objective of this study was to characterize genetic variation within and among breeds of swine and prioritize heritage breeds for preservation. Genotypes from the Illumina PorcineSNP60 BeadChip (GeneSeek, Lincoln, NE) were obtained for Guinea, Ossabaw Island, Red Wattle, American Saddleback, Mulefoot, British Saddleback, Duroc, Landrace, Large White, Pietrain, and Tamworth pigs. A whole-genome analysis toolset was used to construct a genomic relationship matrix and to calculate inbreeding coefficients for the animals within each breed. Relatedness and average inbreeding coefficient differed among breeds, and pigs from rare breeds were generally more closely related and more inbred ( Guinea pigs. Tamworth, Duroc, and Mulefoot tended to not cluster with the other 7 breeds.

  6. A rare variation of the digastric muscle

    KALNIEV, MANOL; KRASTEV, DIMO; KRASTEV, NIKOLAY; VIDINOV, KALIN; VELTCHEV, LUDMIL; APOSTOLOV, ALEXANDER; MILEVA, MILKA

    2013-01-01

    The digastric muscle is composed by two muscle bellies: an anterior and a posterior, joined by an intermediate tendon. This muscle is situated in the anterior region of the neck. The region between the hyoid bone and the mandible is divided by an anterior belly into two triangles: the submandibular situated laterally and the submental triangle which is located medially. We found that the anatomical variations described in the literature relate mainly to the anterior belly and consist of differences in shape and attachment of the muscle. During routine dissection in February 2013 in the section hall of the Department of Anatomy and Histology in Medical University – Sofia we came across a very interesting variation of the digastric muscle. The digastric muscles that presented anatomical variations were photographed using a Sony Cyber-shot DSC-T1 camera, with a Carl Zeiss Vario-Tessar lens. We found out bilateral variation of the digastric muscle in one cadaver. The anterior bellies were very thin and insert to the hyoid bone. Two anterior bellies connect each other and thus they formed a loop. The anatomical variations observed of our study related only to the anterior belly, as previously described by other authors. It is very important to consider the occurrence of the above mentioned variations in the digastric muscle when surgical procedures are performed on the anterior region of the neck. PMID:26527971

  7. Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis

    Gaastra, Benjamin; Shatunov, Aleksey; Pulit, Sara; Jones, Ashley R; Sproviero, William; Gillett, Alexandra; Chen, Zhongbo; Kirby, Janine; Fogh, Isabella; Powell, John F; Leigh, P Nigel; Morrison, Karen E; Shaw, Pamela J; Shaw, Christopher E; van den Berg, Leonard H; Veldink, Jan H; Lewis, Cathryn M; Al-Chalabi, Ammar

    2016-01-01

    Our objective was to identify whether rare genetic variation in amyotrophic lateral sclerosis (ALS) candidate survival genes modifies ALS survival. Candidate genes were selected based on evidence for modifying ALS survival. Each tail of the extreme 1.5% of survival was selected from the UK MND DNA

  8. Rare copy number deletions predict individual variation in intelligence.

    Ronald A Yeo

    2011-01-01

    Full Text Available Phenotypic variation in human intellectual functioning shows substantial heritability, as demonstrated by a long history of behavior genetic studies. Many recent molecular genetic studies have attempted to uncover specific genetic variations responsible for this heritability, but identified effects capture little variance and have proven difficult to replicate. The present study, motivated an interest in "mutation load" emerging from evolutionary perspectives, examined the importance of the number of rare (or infrequent copy number variations (CNVs, and the total number of base pairs included in such deletions, for psychometric intelligence. Genetic data was collected using the Illumina 1MDuoBeadChip Array from a sample of 202 adult individuals with alcohol dependence, and a subset of these (N = 77 had been administered the Wechsler Abbreviated Scale of Intelligence (WASI. After removing CNV outliers, the impact of rare genetic deletions on psychometric intelligence was investigated in 74 individuals. The total length of the rare deletions significantly and negatively predicted intelligence (r = -.30, p = .01. As prior studies have indicated greater heritability in individuals with relatively higher parental socioeconomic status (SES, we also examined the impact of ethnicity (Anglo/White vs. Other, as a proxy measure of SES; these groups did not differ on any genetic variable. This categorical variable significantly moderated the effect of length of deletions on intelligence, with larger effects being noted in the Anglo/White group. Overall, these results suggest that rare deletions (between 5% and 1% population frequency or less adversely affect intellectual functioning, and that pleotropic effects might partly account for the association of intelligence with health and mental health status. Significant limitations of this research, including issues of generalizability and CNV measurement, are discussed.

  9. Rare Copy Number Deletions Predict Individual Variation in Intelligence

    Yeo, Ronald A.; Gangestad, Steven W.; Liu, Jingyu; Calhoun, Vince D.; Hutchison, Kent E.

    2011-01-01

    Phenotypic variation in human intellectual functioning shows substantial heritability, as demonstrated by a long history of behavior genetic studies. Many recent molecular genetic studies have attempted to uncover specific genetic variations responsible for this heritability, but identified effects capture little variance and have proven difficult to replicate. The present study, motivated an interest in “mutation load” emerging from evolutionary perspectives, examined the importance of the number of rare (or infrequent) copy number variations (CNVs), and the total number of base pairs included in such deletions, for psychometric intelligence. Genetic data was collected using the Illumina 1MDuoBeadChip Array from a sample of 202 adult individuals with alcohol dependence, and a subset of these (N = 77) had been administered the Wechsler Abbreviated Scale of Intelligence (WASI). After removing CNV outliers, the impact of rare genetic deletions on psychometric intelligence was investigated in 74 individuals. The total length of the rare deletions significantly and negatively predicted intelligence (r = −.30, p = .01). As prior studies have indicated greater heritability in individuals with relatively higher parental socioeconomic status (SES), we also examined the impact of ethnicity (Anglo/White vs. Other), as a proxy measure of SES; these groups did not differ on any genetic variable. This categorical variable significantly moderated the effect of length of deletions on intelligence, with larger effects being noted in the Anglo/White group. Overall, these results suggest that rare deletions (between 5% and 1% population frequency or less) adversely affect intellectual functioning, and that pleotropic effects might partly account for the association of intelligence with health and mental health status. Significant limitations of this research, including issues of generalizability and CNV measurement, are discussed. PMID:21298096

  10. An abundance of rare functional variants in 202 drug target genes sequenced in 14.002 people

    Nelson, Matthew R.; Wegmann, Daniel; Ehm, Margaret G.

    2012-01-01

    Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (1 every 17 bases)...

  11. A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK.

    Morgan, Sarah; Shatunov, Aleksey; Sproviero, William; Jones, Ashley R; Shoai, Maryam; Hughes, Deborah; Al Khleifat, Ahmad; Malaspina, Andrea; Morrison, Karen E; Shaw, Pamela J; Shaw, Christopher E; Sidle, Katie; Orrell, Richard W; Fratta, Pietro; Hardy, John; Pittman, Alan; Al-Chalabi, Ammar

    2017-06-01

    Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

  12. Rare anatomical variation of the musculocutaneous nerve - case report

    Sergio Ricardo Rios Nascimento

    2016-06-01

    Full Text Available ABSTRACT The clinical and surgical importance of anatomical knowledge of the musculocutaneous nerve and its variations is due to the fact that one of the complications in many upper-limb surgical procedures involves injury to this nerve. During routine dissection of the right upper limb of a male cadaver, we observed an anatomical variation of this nerve. The musculocutaneous nerve originated in the lateral cord and continued laterally, passing under the coracobrachialis muscle and then continuing until its first branch to the biceps brachialis muscle. Just after this, it supplied another two branches, i.e. the lateral cutaneous nerve of the forearm and a branch to the brachialis muscle, and then it joined the median nerve. The median nerve followed the arm medially to the region of the cubital fossa and then gave rise to the anterior intermediate nerve of the forearm. The union between the musculocutaneous nerve and the median nerve occurred approximately at the midpoint of the arm and the median nerve. Given that either our example is not covered by the classifications found in the literature or that it fits into more than one variation proposed, without us finding something truly similar, we consider this variation to be rare.

  13. Rare suprasellar chordoid meningioma with INI1 gene mutation ...

    Background: Chordoid Meningioma is a rare brain tumour characterized genetically by loss of genetic material from chromosome 22q at cytogenetic level resulting in mutation of NF2 gene. Objectives and case report: In the present report, we described a rare case of suprasellar chordoid meningioma, which presented in a ...

  14. Patterns of genic intolerance of rare copy number variation in 59,898 human exomes

    Ruderfer, Douglas M.; Hamamsy, Tymor; Lek, Monkol; Karczewski, Konrad J.; Kavanagh, David; Samocha, Kaitlin E.; Daly, Mark J.; MacArthur, Daniel G.; Fromer, Menachem; Purcell, Shaun M.

    2016-01-01

    Copy number variation (CNV) impacting protein-coding genes contributes significantly to human diversity and disease. Here we characterized the rates and properties of rare genic CNV (intolerance to CNVs that demonstrated moderate correlation with measures of genic constraint based on single-nucleotide variation (SNV) and was independently correlated with measures of evolutionary conservation. For individuals with schizophrenia, genes impacted by CNVs were more intolerant than in controls. ExAC CNV data constitutes a critical component of an integrated database spanning the spectrum of human genetic variation, aiding the interpretation of personal genomes as well as population-based disease studies. These data are freely available for download and visualization online. PMID:27533299

  15. Parkinson's disease and mitochondrial gene variations

    Andalib, Sasan; Vafaee, Manouchehr Seyedi; Gjedde, Albert

    2014-01-01

    Parkinson's disease (PD) is a common disorder of the central nervous system in the elderly. The pathogenesis of PD is a complex process, with genetics as an important contributing factor. This factor may stem from mitochondrial gene variations and mutations as well as from nuclear gene variations...

  16. Integrating common and rare genetic variation in diverse human populations.

    Altshuler, David M; Gibbs, Richard A; Peltonen, Leena; Altshuler, David M; Gibbs, Richard A; Peltonen, Leena; Dermitzakis, Emmanouil; Schaffner, Stephen F; Yu, Fuli; Peltonen, Leena; Dermitzakis, Emmanouil; Bonnen, Penelope E; Altshuler, David M; Gibbs, Richard A; de Bakker, Paul I W; Deloukas, Panos; Gabriel, Stacey B; Gwilliam, Rhian; Hunt, Sarah; Inouye, Michael; Jia, Xiaoming; Palotie, Aarno; Parkin, Melissa; Whittaker, Pamela; Yu, Fuli; Chang, Kyle; Hawes, Alicia; Lewis, Lora R; Ren, Yanru; Wheeler, David; Gibbs, Richard A; Muzny, Donna Marie; Barnes, Chris; Darvishi, Katayoon; Hurles, Matthew; Korn, Joshua M; Kristiansson, Kati; Lee, Charles; McCarrol, Steven A; Nemesh, James; Dermitzakis, Emmanouil; Keinan, Alon; Montgomery, Stephen B; Pollack, Samuela; Price, Alkes L; Soranzo, Nicole; Bonnen, Penelope E; Gibbs, Richard A; Gonzaga-Jauregui, Claudia; Keinan, Alon; Price, Alkes L; Yu, Fuli; Anttila, Verneri; Brodeur, Wendy; Daly, Mark J; Leslie, Stephen; McVean, Gil; Moutsianas, Loukas; Nguyen, Huy; Schaffner, Stephen F; Zhang, Qingrun; Ghori, Mohammed J R; McGinnis, Ralph; McLaren, William; Pollack, Samuela; Price, Alkes L; Schaffner, Stephen F; Takeuchi, Fumihiko; Grossman, Sharon R; Shlyakhter, Ilya; Hostetter, Elizabeth B; Sabeti, Pardis C; Adebamowo, Clement A; Foster, Morris W; Gordon, Deborah R; Licinio, Julio; Manca, Maria Cristina; Marshall, Patricia A; Matsuda, Ichiro; Ngare, Duncan; Wang, Vivian Ota; Reddy, Deepa; Rotimi, Charles N; Royal, Charmaine D; Sharp, Richard R; Zeng, Changqing; Brooks, Lisa D; McEwen, Jean E

    2010-09-02

    Despite great progress in identifying genetic variants that influence human disease, most inherited risk remains unexplained. A more complete understanding requires genome-wide studies that fully examine less common alleles in populations with a wide range of ancestry. To inform the design and interpretation of such studies, we genotyped 1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations, and sequenced ten 100-kilobase regions in 692 of these individuals. This integrated data set of common and rare alleles, called 'HapMap 3', includes both SNPs and copy number polymorphisms (CNPs). We characterized population-specific differences among low-frequency variants, measured the improvement in imputation accuracy afforded by the larger reference panel, especially in imputing SNPs with a minor allele frequency of variation and its role in human disease, and serves as a step towards a high-resolution map of the landscape of human genetic variation.

  17. De novo and rare inherited copy-number variations in the hemiplegic form of cerebral palsy.

    Zarrei, Mehdi; Fehlings, Darcy L; Mawjee, Karizma; Switzer, Lauren; Thiruvahindrapuram, Bhooma; Walker, Susan; Merico, Daniele; Casallo, Guillermo; Uddin, Mohammed; MacDonald, Jeffrey R; Gazzellone, Matthew J; Higginbotham, Edward J; Campbell, Craig; deVeber, Gabrielle; Frid, Pam; Gorter, Jan Willem; Hunt, Carolyn; Kawamura, Anne; Kim, Marie; McCormick, Anna; Mesterman, Ronit; Samdup, Dawa; Marshall, Christian R; Stavropoulos, Dimitri J; Wintle, Richard F; Scherer, Stephen W

    2018-02-01

    PurposeHemiplegia is a subtype of cerebral palsy (CP) in which one side of the body is affected. Our earlier study of unselected children with CP demonstrated de novo and clinically relevant rare inherited genomic copy-number variations (CNVs) in 9.6% of participants. Here, we examined the prevalence and types of CNVs specifically in hemiplegic CP.MethodsWe genotyped 97 unrelated probands with hemiplegic CP and their parents. We compared their CNVs to those of 10,851 population controls, in order to identify rare CNVs (<0.1% frequency) that might be relevant to CP. We also sequenced exomes of "CNV-positive" trios.ResultsWe detected de novo CNVs and/or sex chromosome abnormalities in 7/97 (7.2%) of probands, impacting important developmental genes such as GRIK2, LAMA1, DMD, PTPRM, and DIP2C. In 18/97 individuals (18.6%), rare inherited CNVs were found, affecting loci associated with known genomic disorders (17p12, 22q11.21) or involving genes linked to neurodevelopmental disorders.ConclusionWe found an increased rate of de novo CNVs in the hemiplegic CP subtype (7.2%) compared to controls (1%). This result is similar to that for an unselected CP group. Combined with rare inherited CNVs, the genomic data impacts the understanding of the potential etiology of hemiplegic CP in 23/97 (23.7%) of participants.

  18. Analysis of rare, exonic variation amongst subjects with autism spectrum disorders and population controls.

    Li Liu

    2013-04-01

    Full Text Available We report on results from whole-exome sequencing (WES of 1,039 subjects diagnosed with autism spectrum disorders (ASD and 870 controls selected from the NIMH repository to be of similar ancestry to cases. The WES data came from two centers using different methods to produce sequence and to call variants from it. Therefore, an initial goal was to ensure the distribution of rare variation was similar for data from different centers. This proved straightforward by filtering called variants by fraction of missing data, read depth, and balance of alternative to reference reads. Results were evaluated using seven samples sequenced at both centers and by results from the association study. Next we addressed how the data and/or results from the centers should be combined. Gene-based analyses of association was an obvious choice, but should statistics for association be combined across centers (meta-analysis or should data be combined and then analyzed (mega-analysis? Because of the nature of many gene-based tests, we showed by theory and simulations that mega-analysis has better power than meta-analysis. Finally, before analyzing the data for association, we explored the impact of population structure on rare variant analysis in these data. Like other recent studies, we found evidence that population structure can confound case-control studies by the clustering of rare variants in ancestry space; yet, unlike some recent studies, for these data we found that principal component-based analyses were sufficient to control for ancestry and produce test statistics with appropriate distributions. After using a variety of gene-based tests and both meta- and mega-analysis, we found no new risk genes for ASD in this sample. Our results suggest that standard gene-based tests will require much larger samples of cases and controls before being effective for gene discovery, even for a disorder like ASD.

  19. Analysis of Rare, Exonic Variation amongst Subjects with Autism Spectrum Disorders and Population Controls

    Liu, Li; Sabo, Aniko; Neale, Benjamin M.; Nagaswamy, Uma; Stevens, Christine; Lim, Elaine; Bodea, Corneliu A.; Muzny, Donna; Reid, Jeffrey G.; Banks, Eric; Coon, Hillary; DePristo, Mark; Dinh, Huyen; Fennel, Tim; Flannick, Jason; Gabriel, Stacey; Garimella, Kiran; Gross, Shannon; Hawes, Alicia; Lewis, Lora; Makarov, Vladimir; Maguire, Jared; Newsham, Irene; Poplin, Ryan; Ripke, Stephan; Shakir, Khalid; Samocha, Kaitlin E.; Wu, Yuanqing; Boerwinkle, Eric; Buxbaum, Joseph D.; Cook, Edwin H.; Devlin, Bernie; Schellenberg, Gerard D.; Sutcliffe, James S.; Daly, Mark J.; Gibbs, Richard A.; Roeder, Kathryn

    2013-01-01

    We report on results from whole-exome sequencing (WES) of 1,039 subjects diagnosed with autism spectrum disorders (ASD) and 870 controls selected from the NIMH repository to be of similar ancestry to cases. The WES data came from two centers using different methods to produce sequence and to call variants from it. Therefore, an initial goal was to ensure the distribution of rare variation was similar for data from different centers. This proved straightforward by filtering called variants by fraction of missing data, read depth, and balance of alternative to reference reads. Results were evaluated using seven samples sequenced at both centers and by results from the association study. Next we addressed how the data and/or results from the centers should be combined. Gene-based analyses of association was an obvious choice, but should statistics for association be combined across centers (meta-analysis) or should data be combined and then analyzed (mega-analysis)? Because of the nature of many gene-based tests, we showed by theory and simulations that mega-analysis has better power than meta-analysis. Finally, before analyzing the data for association, we explored the impact of population structure on rare variant analysis in these data. Like other recent studies, we found evidence that population structure can confound case-control studies by the clustering of rare variants in ancestry space; yet, unlike some recent studies, for these data we found that principal component-based analyses were sufficient to control for ancestry and produce test statistics with appropriate distributions. After using a variety of gene-based tests and both meta- and mega-analysis, we found no new risk genes for ASD in this sample. Our results suggest that standard gene-based tests will require much larger samples of cases and controls before being effective for gene discovery, even for a disorder like ASD. PMID:23593035

  20. Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease.

    Lubbe, S J; Escott-Price, V; Brice, A; Gasser, T; Pittman, A M; Bras, J; Hardy, J; Heutink, P; Wood, N M; Singleton, A B; Grosset, D G; Carroll, C B; Law, M H; Demenais, F; Iles, M M; Bishop, D T; Newton-Bishop, J; Williams, N M; Morris, H R

    2016-12-01

    A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  1. Genotyping common and rare variation using overlapping pool sequencing

    Pasaniuc Bogdan

    2011-07-01

    Full Text Available Abstract Background Recent advances in sequencing technologies set the stage for large, population based studies, in which the ANA or RNA of thousands of individuals will be sequenced. Currently, however, such studies are still infeasible using a straightforward sequencing approach; as a result, recently a few multiplexing schemes have been suggested, in which a small number of ANA pools are sequenced, and the results are then deconvoluted using compressed sensing or similar approaches. These methods, however, are limited to the detection of rare variants. Results In this paper we provide a new algorithm for the deconvolution of DNA pools multiplexing schemes. The presented algorithm utilizes a likelihood model and linear programming. The approach allows for the addition of external data, particularly imputation data, resulting in a flexible environment that is suitable for different applications. Conclusions Particularly, we demonstrate that both low and high allele frequency SNPs can be accurately genotyped when the DNA pooling scheme is performed in conjunction with microarray genotyping and imputation. Additionally, we demonstrate the use of our framework for the detection of cancer fusion genes from RNA sequences.

  2. Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome.

    Bassett, Anne S; Lowther, Chelsea; Merico, Daniele; Costain, Gregory; Chow, Eva W C; van Amelsvoort, Therese; McDonald-McGinn, Donna; Gur, Raquel E; Swillen, Ann; Van den Bree, Marianne; Murphy, Kieran; Gothelf, Doron; Bearden, Carrie E; Eliez, Stephan; Kates, Wendy; Philip, Nicole; Sashi, Vandana; Campbell, Linda; Vorstman, Jacob; Cubells, Joseph; Repetto, Gabriela M; Simon, Tony; Boot, Erik; Heung, Tracy; Evers, Rens; Vingerhoets, Claudia; van Duin, Esther; Zackai, Elaine; Vergaelen, Elfi; Devriendt, Koen; Vermeesch, Joris R; Owen, Michael; Murphy, Clodagh; Michaelovosky, Elena; Kushan, Leila; Schneider, Maude; Fremont, Wanda; Busa, Tiffany; Hooper, Stephen; McCabe, Kathryn; Duijff, Sasja; Isaev, Karin; Pellecchia, Giovanna; Wei, John; Gazzellone, Matthew J; Scherer, Stephen W; Emanuel, Beverly S; Guo, Tingwei; Morrow, Bernice E; Marshall, Christian R

    2017-11-01

    Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression. Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: a schizophrenia group and those with no psychotic disorder at age ≥25 years. The authors assessed whether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia. Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci. The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.

  3. Rare and common regulatory variation in population-scale sequenced human genomes.

    Stephen B Montgomery

    2011-07-01

    Full Text Available Population-scale genome sequencing allows the characterization of functional effects of a broad spectrum of genetic variants underlying human phenotypic variation. Here, we investigate the influence of rare and common genetic variants on gene expression patterns, using variants identified from sequencing data from the 1000 genomes project in an African and European population sample and gene expression data from lymphoblastoid cell lines. We detect comparable numbers of expression quantitative trait loci (eQTLs when compared to genotypes obtained from HapMap 3, but as many as 80% of the top expression quantitative trait variants (eQTVs discovered from 1000 genomes data are novel. The properties of the newly discovered variants suggest that mapping common causal regulatory variants is challenging even with full resequencing data; however, we observe significant enrichment of regulatory effects in splice-site and nonsense variants. Using RNA sequencing data, we show that 46.2% of nonsynonymous variants are differentially expressed in at least one individual in our sample, creating widespread potential for interactions between functional protein-coding and regulatory variants. We also use allele-specific expression to identify putative rare causal regulatory variants. Furthermore, we demonstrate that outlier expression values can be due to rare variant effects, and we approximate the number of such effects harboured in an individual by effect size. Our results demonstrate that integration of genomic and RNA sequencing analyses allows for the joint assessment of genome sequence and genome function.

  4. The Matchmaker Exchange: a platform for rare disease gene discovery.

    Philippakis, Anthony A; Azzariti, Danielle R; Beltran, Sergi; Brookes, Anthony J; Brownstein, Catherine A; Brudno, Michael; Brunner, Han G; Buske, Orion J; Carey, Knox; Doll, Cassie; Dumitriu, Sergiu; Dyke, Stephanie O M; den Dunnen, Johan T; Firth, Helen V; Gibbs, Richard A; Girdea, Marta; Gonzalez, Michael; Haendel, Melissa A; Hamosh, Ada; Holm, Ingrid A; Huang, Lijia; Hurles, Matthew E; Hutton, Ben; Krier, Joel B; Misyura, Andriy; Mungall, Christopher J; Paschall, Justin; Paten, Benedict; Robinson, Peter N; Schiettecatte, François; Sobreira, Nara L; Swaminathan, Ganesh J; Taschner, Peter E; Terry, Sharon F; Washington, Nicole L; Züchner, Stephan; Boycott, Kym M; Rehm, Heidi L

    2015-10-01

    There are few better examples of the need for data sharing than in the rare disease community, where patients, physicians, and researchers must search for "the needle in a haystack" to uncover rare, novel causes of disease within the genome. Impeding the pace of discovery has been the existence of many small siloed datasets within individual research or clinical laboratory databases and/or disease-specific organizations, hoping for serendipitous occasions when two distant investigators happen to learn they have a rare phenotype in common and can "match" these cases to build evidence for causality. However, serendipity has never proven to be a reliable or scalable approach in science. As such, the Matchmaker Exchange (MME) was launched to provide a robust and systematic approach to rare disease gene discovery through the creation of a federated network connecting databases of genotypes and rare phenotypes using a common application programming interface (API). The core building blocks of the MME have been defined and assembled. Three MME services have now been connected through the API and are available for community use. Additional databases that support internal matching are anticipated to join the MME network as it continues to grow. © 2015 WILEY PERIODICALS, INC.

  5. Functional impact of global rare copy number variation in autism spectrum disorders.

    Pinto, Dalila; Pagnamenta, Alistair T; Klei, Lambertus; Anney, Richard; Merico, Daniele; Regan, Regina; Conroy, Judith; Magalhaes, Tiago R; Correia, Catarina; Abrahams, Brett S; Almeida, Joana; Bacchelli, Elena; Bader, Gary D; Bailey, Anthony J; Baird, Gillian; Battaglia, Agatino; Berney, Tom; Bolshakova, Nadia; Bölte, Sven; Bolton, Patrick F; Bourgeron, Thomas; Brennan, Sean; Brian, Jessica; Bryson, Susan E; Carson, Andrew R; Casallo, Guillermo; Casey, Jillian; Chung, Brian H Y; Cochrane, Lynne; Corsello, Christina; Crawford, Emily L; Crossett, Andrew; Cytrynbaum, Cheryl; Dawson, Geraldine; de Jonge, Maretha; Delorme, Richard; Drmic, Irene; Duketis, Eftichia; Duque, Frederico; Estes, Annette; Farrar, Penny; Fernandez, Bridget A; Folstein, Susan E; Fombonne, Eric; Freitag, Christine M; Gilbert, John; Gillberg, Christopher; Glessner, Joseph T; Goldberg, Jeremy; Green, Andrew; Green, Jonathan; Guter, Stephen J; Hakonarson, Hakon; Heron, Elizabeth A; Hill, Matthew; Holt, Richard; Howe, Jennifer L; Hughes, Gillian; Hus, Vanessa; Igliozzi, Roberta; Kim, Cecilia; Klauck, Sabine M; Kolevzon, Alexander; Korvatska, Olena; Kustanovich, Vlad; Lajonchere, Clara M; Lamb, Janine A; Laskawiec, Magdalena; Leboyer, Marion; Le Couteur, Ann; Leventhal, Bennett L; Lionel, Anath C; Liu, Xiao-Qing; Lord, Catherine; Lotspeich, Linda; Lund, Sabata C; Maestrini, Elena; Mahoney, William; Mantoulan, Carine; Marshall, Christian R; McConachie, Helen; McDougle, Christopher J; McGrath, Jane; McMahon, William M; Merikangas, Alison; Migita, Ohsuke; Minshew, Nancy J; Mirza, Ghazala K; Munson, Jeff; Nelson, Stanley F; Noakes, Carolyn; Noor, Abdul; Nygren, Gudrun; Oliveira, Guiomar; Papanikolaou, Katerina; Parr, Jeremy R; Parrini, Barbara; Paton, Tara; Pickles, Andrew; Pilorge, Marion; Piven, Joseph; Ponting, Chris P; Posey, David J; Poustka, Annemarie; Poustka, Fritz; Prasad, Aparna; Ragoussis, Jiannis; Renshaw, Katy; Rickaby, Jessica; Roberts, Wendy; Roeder, Kathryn; Roge, Bernadette; Rutter, Michael L; Bierut, Laura J; Rice, John P; Salt, Jeff; Sansom, Katherine; Sato, Daisuke; Segurado, Ricardo; Sequeira, Ana F; Senman, Lili; Shah, Naisha; Sheffield, Val C; Soorya, Latha; Sousa, Inês; Stein, Olaf; Sykes, Nuala; Stoppioni, Vera; Strawbridge, Christina; Tancredi, Raffaella; Tansey, Katherine; Thiruvahindrapduram, Bhooma; Thompson, Ann P; Thomson, Susanne; Tryfon, Ana; Tsiantis, John; Van Engeland, Herman; Vincent, John B; Volkmar, Fred; Wallace, Simon; Wang, Kai; Wang, Zhouzhi; Wassink, Thomas H; Webber, Caleb; Weksberg, Rosanna; Wing, Kirsty; Wittemeyer, Kerstin; Wood, Shawn; Wu, Jing; Yaspan, Brian L; Zurawiecki, Danielle; Zwaigenbaum, Lonnie; Buxbaum, Joseph D; Cantor, Rita M; Cook, Edwin H; Coon, Hilary; Cuccaro, Michael L; Devlin, Bernie; Ennis, Sean; Gallagher, Louise; Geschwind, Daniel H; Gill, Michael; Haines, Jonathan L; Hallmayer, Joachim; Miller, Judith; Monaco, Anthony P; Nurnberger, John I; Paterson, Andrew D; Pericak-Vance, Margaret A; Schellenberg, Gerard D; Szatmari, Peter; Vicente, Astrid M; Vieland, Veronica J; Wijsman, Ellen M; Scherer, Stephen W; Sutcliffe, James S; Betancur, Catalina

    2010-07-15

    The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

  6. Rare variation in the origin of the right vertebral artery

    Enrique

    34. SA JOURNAL OF RADIOLOGY • May 2004. Introduction. Anomalous origin of the right ver- tebral artery from the distal part of the aortic arch is very rare and is discov- ered as an incidental finding during an angiographic study or in laborato- ry specimens. It has been suggested that these anomalies are of diagnostic.

  7. An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis.

    Petrovski, Slavé; Todd, Jamie L; Durheim, Michael T; Wang, Quanli; Chien, Jason W; Kelly, Fran L; Frankel, Courtney; Mebane, Caroline M; Ren, Zhong; Bridgers, Joshua; Urban, Thomas J; Malone, Colin D; Finlen Copeland, Ashley; Brinkley, Christie; Allen, Andrew S; O'Riordan, Thomas; McHutchison, John G; Palmer, Scott M; Goldstein, David B

    2017-07-01

    Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology. The aim of this study was to use whole-exome sequencing to improve understanding of the genetic architecture of pulmonary fibrosis. We performed a case-control exome-wide collapsing analysis including 262 unrelated individuals with pulmonary fibrosis clinically classified as IPF according to American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines (81.3%), usual interstitial pneumonia secondary to autoimmune conditions (11.5%), or fibrosing nonspecific interstitial pneumonia (7.2%). The majority (87%) of case subjects reported no family history of pulmonary fibrosis. We searched 18,668 protein-coding genes for an excess of rare deleterious genetic variation using whole-exome sequence data from 262 case subjects with pulmonary fibrosis and 4,141 control subjects drawn from among a set of individuals of European ancestry. Comparing genetic variation across 18,668 protein-coding genes, we found a study-wide significant (P RTEL1, and PARN. A model qualifying ultrarare, deleterious, nonsynonymous variants implicated TERT and RTEL1, and a model specifically qualifying loss-of-function variants implicated RTEL1 and PARN. A subanalysis of 186 case subjects with sporadic IPF confirmed TERT, RTEL1, and PARN as study-wide significant contributors to sporadic IPF. Collectively, 11.3% of case subjects with sporadic IPF carried a qualifying variant in one of these three genes compared with the 0.3% carrier rate observed among control subjects (odds ratio, 47.7; 95% confidence interval, 21.5-111.6; P = 5.5 × 10 -22 ). We identified TERT, RTEL1, and PARN-three telomere-related genes previously implicated in familial pulmonary fibrosis-as significant contributors to sporadic IPF. These results support the idea that telomere dysfunction is involved in IPF pathogenesis.

  8. Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum

    Ganna, Andrea; Satterstrom, F Kyle; Zekavat, Seyedeh M

    2018-01-01

    There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in ge...

  9. A Rare Variation of the Human Median Nerve Direction

    Barfi

    2016-04-01

    Full Text Available Introduction The brachial plexus, a complex network of nerves, innervates to the upper limbs. Variation in the course of the nerves in the upper limb is common. Case Presentation This paper describes two cases of upper limb variations in a cadaver dissected at Lorestan University of Medical Sciences. In the first variation, the median nerve in the arm has a different route, so that the median moves deep into the brachialis muscle. In the latter case, after piercing the coracobrachialis muscle a musculocutaneous nerve exists between the brachialis and biceps and goes to the lateral region of the forearm. This is known as the lateral cutaneous nerve of the forearm nerve, and innervates the skin of the lateral part of the forearm and the dorsal part of the hand. Conclusions Because of the possibility of damage to the brachial plexus branches is high in upper limb injuries and surgeries, full knowledge of normal anatomy and variations of these branches is essential for orthopedic specialists, neurosurgeons, radiologists, and anatomists.

  10. Unilateral Duplication Of Parotid Duct. A Rare Anatomical Variation

    Humberto Ferreira Arquez

    2017-11-01

    Full Text Available Background: The paired parotid glands are the largest of the major salivary glands and produces mainly serous secretions. The secretion of this gland reaches the oral cavity through single parotid duct (Stensen’s duct. The parotid duct begins at the anterior border of the gland, crosses the masseter muscle, and then pierces the buccinator muscle to reach the mucosa lining the mouth at the level of the cheek. The purpose of this study is determine the morphologic features of the parotid duct and describe an anatomical variation until now unreported. Methods and Findings: A total of 17 cadavers were used for this study in the Morphology Laboratory at the University of Pamplona. In a cadaver were findings: The main parotid duct originated two conducts: Left superior parotid duct and Left inferior parotid duct, is observed the criss-cross of the ducts, and then perforated the buccinator muscle and entered the oral cavity at a double parotid papilla containing a double opening, separated from each other in 0,98 mm. In the remaining  33 parotid regions (97.06% the parotid duct is conformed to the classical descriptions given in anatomical textbooks. Conclusions: The parotid duct anatomy is important for duct endoscopy, lithotripsy, sialography and trans-ductal facial nerve stimulation in the early stage of facial palsy in some cases. The anatomical variations also has clinical importance for parotid gland surgery and facial cosmetic surgery. To keep in mind the parotid duct variation will reduce iatrogenic injury risks and improve diagnosis of parotid duct injury.

  11. A scan statistic to extract causal gene clusters from case-control genome-wide rare CNV data

    Scherer Stephen W

    2011-05-01

    Full Text Available Abstract Background Several statistical tests have been developed for analyzing genome-wide association data by incorporating gene pathway information in terms of gene sets. Using these methods, hundreds of gene sets are typically tested, and the tested gene sets often overlap. This overlapping greatly increases the probability of generating false positives, and the results obtained are difficult to interpret, particularly when many gene sets show statistical significance. Results We propose a flexible statistical framework to circumvent these problems. Inspired by spatial scan statistics for detecting clustering of disease occurrence in the field of epidemiology, we developed a scan statistic to extract disease-associated gene clusters from a whole gene pathway. Extracting one or a few significant gene clusters from a global pathway limits the overall false positive probability, which results in increased statistical power, and facilitates the interpretation of test results. In the present study, we applied our method to genome-wide association data for rare copy-number variations, which have been strongly implicated in common diseases. Application of our method to a simulated dataset demonstrated the high accuracy of this method in detecting disease-associated gene clusters in a whole gene pathway. Conclusions The scan statistic approach proposed here shows a high level of accuracy in detecting gene clusters in a whole gene pathway. This study has provided a sound statistical framework for analyzing genome-wide rare CNV data by incorporating topological information on the gene pathway.

  12. Frequency in Japan of carriers of the rare recessive gene causing actalasemia

    Hamilton, H B; Neel, J V; Kobara, T Y; Ozaki, Kyoko

    1961-05-17

    A rapid and simple method to detect the hypocatalasemic heterozygotes for the gene responsible for acatalasemia is described. A total of 13,647 blood specimens from individuals residing in Hiroshima and Nagasaki have been examined in this manner, and the frequency of hypocatalasemia found to be 0.09%. Surveys in other parts of Japan have revealed frequencies of the order of 1.4%. This unevenness in the distribution of a rare recessive gene, taken in conjunction with the known variation from locality to locality in the frequency of inbreeding, has important implications for the interpretation of data on inbreeding effects. Some of these implications are discussed. 17 references, 1 figure, 6 tables.

  13. Intraspecific chromosome number variation: a neglected threat to the conservation of rare plants.

    Severns, Paul M; Liston, Aaron

    2008-12-01

    The effectiveness of rare plant conservation will increase when life history, demographic, and genetic data are considered simultaneously. Inbreeding depression is a widely recognized genetic concern in rare plant conservation, and the mixing of genetically diverse populations in restoration efforts is a common remedy. Nevertheless, if populations with unrecognized intraspecific chromosome variation are crossed, progeny fitness losses will range from partial to complete sterility, and reintroductions and population augmentation of rare plants may fail. To assess the current state of cytological knowledge of threatened and endangered plants in the continental United States, we searched available resources for chromosome counts. We also reviewed recovery plans to discern whether recovery criteria potentially place listed species at risk by requiring reintroductions or population augmentation in the absence of cytological information. Over half the plants lacked a chromosome count, and when a taxon did have a count it generally originated from a sampling intensity too limited to detect intraspecific chromosome variation. Despite limited past cytological sampling, we found 11 plants with documented intraspecific cytological variation, while 8 others were ambiguous for intraspecific chromosome variation. Nevertheless, only one recovery plan addressed the chromosome differences. Inadequate within-species cytological characterization, incomplete sampling among listed taxa, and the prevalence of interspecific and intraspecific chromosome variation in listed genera, suggests that other rare plants are likely to have intraspecific chromosome variation. Nearly 90% of all recovery plans called for reintroductions or population augmentation as part of recovery criteria despite the dearth of cytological knowledge. We recommend screening rare plants for intraspecific chromosome variation before reintroductions or population augmentation projects are undertaken to safeguard

  14. Two novel mutations in the PPIB gene cause a rare pedigree of osteogenesis imperfecta type IX.

    Jiang, Yu; Pan, Jingxin; Guo, Dongwei; Zhang, Wei; Xie, Jie; Fang, Zishui; Guo, Chunmiao; Fang, Qun; Jiang, Weiying; Guo, Yibin

    2017-06-01

    Osteogenesis imperfecta (OI) is a rare genetic skeletal disorder characterized by increased bone fragility and vulnerability to fractures. PPIB is identified as a candidate gene for OI-IX, here we detect two pathogenic mutations in PPIB and analyze the genotype-phenotype correlation in a Chinese family with OI. Next-generation sequencing (NGS) was used to screen the whole exome of the parents of proband. Screening of variation frequency, evolutionary conservation comparisons, pathogenicity evaluation, and protein structure prediction were conducted to assess the pathogenicity of the novel mutations. Sanger sequencing was used to confirm the candidate variants. RTQ-PCR was used to analyze the PPIB gene expression. All mutant genes screened out by NGS were excluded except PPIB. Two novel heterozygous PPIB mutations (father, c.25A>G; mother, c.509G>A) were identified in relation to osteogenesis imperfecta type IX. Both mutations were predicted to be pathogenic by bioinformatics analysis and RTQ-PCR analysis revealed downregulated PPIB expression in the two carriers. We report a rare pedigree with an autosomal recessive osteogenesis imperfecta type IX (OI-IX) caused by two novel PPIB mutations identified for the first time in China. The current study expands our knowledge of PPIB mutations and their associated phenotypes, and provides new information on the genetic defects associated with this disease for clinical diagnosis. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Topological variation in single-gene phylogenetic trees

    Castresana, Jose

    2007-01-01

    A recent large-scale phylogenomic study has shown the great degree of topological variation that can be found among eukaryotic phylogenetic trees constructed from single genes, highlighting the problems that can be associated with gene sampling in phylogenetic studies.

  16. GxGrare: gene-gene interaction analysis method for rare variants from high-throughput sequencing data.

    Kwon, Minseok; Leem, Sangseob; Yoon, Joon; Park, Taesung

    2018-03-19

    With the rapid advancement of array-based genotyping techniques, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with common complex diseases. However, it has been shown that only a small proportion of the genetic etiology of complex diseases could be explained by the genetic factors identified from GWAS. This missing heritability could possibly be explained by gene-gene interaction (epistasis) and rare variants. There has been an exponential growth of gene-gene interaction analysis for common variants in terms of methodological developments and practical applications. Also, the recent advancement of high-throughput sequencing technologies makes it possible to conduct rare variant analysis. However, little progress has been made in gene-gene interaction analysis for rare variants. Here, we propose GxGrare which is a new gene-gene interaction method for the rare variants in the framework of the multifactor dimensionality reduction (MDR) analysis. The proposed method consists of three steps; 1) collapsing the rare variants, 2) MDR analysis for the collapsed rare variants, and 3) detect top candidate interaction pairs. GxGrare can be used for the detection of not only gene-gene interactions, but also interactions within a single gene. The proposed method is illustrated with 1080 whole exome sequencing data of the Korean population in order to identify causal gene-gene interaction for rare variants for type 2 diabetes. The proposed GxGrare performs well for gene-gene interaction detection with collapsing of rare variants. GxGrare is available at http://bibs.snu.ac.kr/software/gxgrare which contains simulation data and documentation. Supported operating systems include Linux and OS X.

  17. Rare codons effect on expression of recombinant gene cassette in Escherichia coli BL21(DE3

    Aghil Esmaeili-Bandboni

    2017-11-01

    Full Text Available Objective: To demonstrate the sensitivity of expression of fusion genes to existence of a large number of rare codons in recombinant gene sequenced. Methods: Primers for amplification of cholera toxin B, Shiga toxin B and gfp genes were designed by Primer3 software and synthesized. All of these 3 genes were cloned. Then the genes were fused together by restriction sites and enzymatic method. Two linkers were used as a flexible bridge in connection of these genes. Results: Cloning and fusion of cholera toxin B, Shiga toxin B and gfp genes were done correctly. After that, expression of the recombinant gene construction was surveyed. Conclusions: According to what was seen, because of the accumulation of 12 rare codons of Shiga toxin B and 19 rare codons of cholera toxin B in this gene cassette, the expression of the recombinant gene cassette, in Escherichia coli BL21, failed.

  18. Distinguishing the rates of gene activation from phenotypic variations.

    Chen, Ye; Lv, Cheng; Li, Fangting; Li, Tiejun

    2015-06-18

    Stochastic genetic switching driven by intrinsic noise is an important process in gene expression. When the rates of gene activation/inactivation are relatively slow, fast, or medium compared with the synthesis/degradation rates of mRNAs and proteins, the variability of protein and mRNA levels may exhibit very different dynamical patterns. It is desirable to provide a systematic approach to identify their key dynamical features in different regimes, aiming at distinguishing which regime a considered gene regulatory network is in from their phenotypic variations. We studied a gene expression model with positive feedbacks when genetic switching rates vary over a wide range. With the goal of providing a method to distinguish the regime of the switching rates, we first focus on understanding the essential dynamics of gene expression system in different cases. In the regime of slow switching rates, we found that the effective dynamics can be reduced to independent evolutions on two separate layers corresponding to gene activation and inactivation states, and the transitions between two layers are rare events, after which the system goes mainly along deterministic ODE trajectories on a particular layer to reach new steady states. The energy landscape in this regime can be well approximated by using Gaussian mixture model. In the regime of intermediate switching rates, we analyzed the mean switching time to investigate the stability of the system in different parameter ranges. We also discussed the case of fast switching rates from the viewpoint of transition state theory. Based on the obtained results, we made a proposal to distinguish these three regimes in a simulation experiment. We identified the intermediate regime from the fact that the strength of cellular memory is lower than the other two cases, and the fast and slow regimes can be distinguished by their different perturbation-response behavior with respect to the switching rates perturbations. We proposed a

  19. Genetic mechanisms and age-related macular degeneration: common variants, rare variants, copy number variations, epigenetics, and mitochondrial genetics

    Liu Melissa M

    2012-08-01

    Full Text Available Abstract Age-related macular degeneration (AMD is a complex and multifaceted disease involving contributions from both genetic and environmental influences. Previous work exploring the genetic contributions of AMD has implicated numerous genomic regions and a variety of candidate genes as modulators of AMD susceptibility. Nevertheless, much of this work has revolved around single-nucleotide polymorphisms (SNPs, and it is apparent that a significant portion of the heritability of AMD cannot be explained through these mechanisms. In this review, we consider the role of common variants, rare variants, copy number variations, epigenetics, microRNAs, and mitochondrial genetics in AMD. Copy number variations in regulators of complement activation genes (CFHR1 and CFHR3 and glutathione S transferase genes (GSTM1 and GSTT1 have been associated with AMD, and several additional loci have been identified as regions of potential interest but require further evaluation. MicroRNA dysregulation has been linked to the retinal pigment epithelium degeneration in geographic atrophy, ocular neovascularization, and oxidative stress, all of which are hallmarks in the pathogenesis of AMD. Certain mitochondrial DNA haplogroups and SNPs in mitochondrially encoded NADH dehydrogenase genes have also been associated with AMD. The role of these additional mechanisms remains only partly understood, but the importance of their further investigation is clear to elucidate more completely the genetic basis of AMD.

  20. The Matchmaker Exchange: a platform for rare disease gene discovery

    Philippakis, A.A.; Azzariti, D.R.; Beltran, S.; Brookes, A.J.; Brownstein, C.A.; Brudno, M.; Brunner, H.G.; Buske, O.J.; Carey, K.; Doll, C.; Dumitriu, S.; Dyke, S.O.M.; Dunnen, J.T. den; Firth, H.V.; Gibbs, R.A.; Girdea, M.; Gonzalez, M.; Haendel, M.A.; Hamosh, A.; Holm, I.A.; Huang, L.; Hurles, M.E.; Hutton, B.; Krier, J.B.; Misyura, A.; Mungall, C.J.; Paschall, J.; Paten, B.; Robinson, P.N.; Schiettecatte, F.; Sobreira, N.L.; Swaminathan, G.J.; Taschner, P.E.M.; Terry, S.F.; Washington, N.L.; Zuchner, S.; Boycott, K.M.; Rehm, H.L.

    2015-01-01

    There are few better examples of the need for data sharing than in the rare disease community, where patients, physicians, and researchers must search for "the needle in a haystack" to uncover rare, novel causes of disease within the genome. Impeding the pace of discovery has been the existence of

  1. Accessory mental foramen: A rare anatomical variation detected by cone-beam computed tomography

    Torres, Marianna Guanaes Gomes; De Faro Valverde, Ludmila; Vidal, Manuela Torres Andion; Crusoe-Rebello, Ieda Margarida [Dept. of Oral Radiology, School of Dentistry, Federal University of Bahia, Salvador (Brazil)

    2015-03-15

    The mental foramen is a bilateral opening in the vestibular portion of the mandible through which nerve endings, such as the mental nerve, emerge. In general, the mental foramen is located between the lower premolars. This region is a common area for the placement of dental implants. It is very important to identify anatomical variations in presurgical imaging exams since damage to neurovascular bundles may have a direct influence on treatment success. In the hemimandible, the mental foramen normally appears as a single structure, but there are some rare reports on the presence and number of anatomical variations; these variations may include accessory foramina. The present report describes the presence of accessory mental foramina in the right mandible, as detected by cone-beam computed tomography before dental implant placement.

  2. Genomic variation in Salmonella enterica core genes for epidemiological typing

    Leekitcharoenphon, Pimlapas; Lukjancenko, Oksana; Rundsten, Carsten Friis

    2012-01-01

    Background: Technological advances in high throughput genome sequencing are making whole genome sequencing (WGS) available as a routine tool for bacterial typing. Standardized procedures for identification of relevant genes and of variation are needed to enable comparison between studies and over...... genomes and evaluate their value as typing targets, comparing whole genome typing and traditional methods such as 16S and MLST. A consensus tree based on variation of core genes gives much better resolution than 16S and MLST; the pan-genome family tree is similar to the consensus tree, but with higher...... that there is a positive selection towards mutations leading to amino acid changes. Conclusions: Genomic variation within the core genome is useful for investigating molecular evolution and providing candidate genes for bacterial genome typing. Identification of genes with different degrees of variation is important...

  3. Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study

    Druley, Todd E; Wang, Lihua; Lin, Shiow J

    2016-01-01

    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......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...

  4. Variation across mitochondrial gene trees provides evidence for systematic error: How much gene tree variation is biological?

    Richards, Emilie J; Brown, Jeremy M; Barley, Anthony J; Chong, Rebecca A; Thomson, Robert C

    2018-02-19

    The use of large genomic datasets in phylogenetics has highlighted extensive topological variation across genes. Much of this discordance is assumed to result from biological processes. However, variation among gene trees can also be a consequence of systematic error driven by poor model fit, and the relative importance of biological versus methodological factors in explaining gene tree variation is a major unresolved question. Using mitochondrial genomes to control for biological causes of gene tree variation, we estimate the extent of gene tree discordance driven by systematic error and employ posterior prediction to highlight the role of model fit in producing this discordance. We find that the amount of discordance among mitochondrial gene trees is similar to the amount of discordance found in other studies that assume only biological causes of variation. This similarity suggests that the role of systematic error in generating gene tree variation is underappreciated and critical evaluation of fit between assumed models and the data used for inference is important for the resolution of unresolved phylogenetic questions.

  5. A role for gene duplication and natural variation of gene expression in the evolution of metabolism.

    Daniel J Kliebenstein

    Full Text Available BACKGROUND: Most eukaryotic genomes have undergone whole genome duplications during their evolutionary history. Recent studies have shown that the function of these duplicated genes can diverge from the ancestral gene via neo- or sub-functionalization within single genotypes. An additional possibility is that gene duplicates may also undergo partitioning of function among different genotypes of a species leading to genetic differentiation. Finally, the ability of gene duplicates to diverge may be limited by their biological function. METHODOLOGY/PRINCIPAL FINDINGS: To test these hypotheses, I estimated the impact of gene duplication and metabolic function upon intraspecific gene expression variation of segmental and tandem duplicated genes within Arabidopsis thaliana. In all instances, the younger tandem duplicated genes showed higher intraspecific gene expression variation than the average Arabidopsis gene. Surprisingly, the older segmental duplicates also showed evidence of elevated intraspecific gene expression variation albeit typically lower than for the tandem duplicates. The specific biological function of the gene as defined by metabolic pathway also modulated the level of intraspecific gene expression variation. The major energy metabolism and biosynthetic pathways showed decreased variation, suggesting that they are constrained in their ability to accumulate gene expression variation. In contrast, a major herbivory defense pathway showed significantly elevated intraspecific variation suggesting that it may be under pressure to maintain and/or generate diversity in response to fluctuating insect herbivory pressures. CONCLUSION: These data show that intraspecific variation in gene expression is facilitated by an interaction of gene duplication and biological activity. Further, this plays a role in controlling diversity of plant metabolism.

  6. Population genetic variation in gene expression is associated withphenotypic variation in Saccharomyces cerevisiae

    Fay, Justin C.; McCullough, Heather L.; Sniegowski, Paul D.; Eisen, Michael B.

    2004-02-25

    The relationship between genetic variation in gene expression and phenotypic variation observable in nature is not well understood. Identifying how many phenotypes are associated with differences in gene expression and how many gene-expression differences are associated with a phenotype is important to understanding the molecular basis and evolution of complex traits. Results: We compared levels of gene expression among nine natural isolates of Saccharomyces cerevisiae grown either in the presence or absence of copper sulfate. Of the nine strains, two show a reduced growth rate and two others are rust colored in the presence of copper sulfate. We identified 633 genes that show significant differences in expression among strains. Of these genes,20 were correlated with resistance to copper sulfate and 24 were correlated with rust coloration. The function of these genes in combination with their expression pattern suggests the presence of both correlative and causative expression differences. But the majority of differentially expressed genes were not correlated with either phenotype and showed the same expression pattern both in the presence and absence of copper sulfate. To determine whether these expression differences may contribute to phenotypic variation under other environmental conditions, we examined one phenotype, freeze tolerance, predicted by the differential expression of the aquaporin gene AQY2. We found freeze tolerance is associated with the expression of AQY2. Conclusions: Gene expression differences provide substantial insight into the molecular basis of naturally occurring traits and can be used to predict environment dependent phenotypic variation.

  7. Host genetic variation influences gene expression response to rhinovirus infection.

    Minal Çalışkan

    2015-04-01

    Full Text Available Rhinovirus (RV is the most prevalent human respiratory virus and is responsible for at least half of all common colds. RV infections may result in a broad spectrum of effects that range from asymptomatic infections to severe lower respiratory illnesses. The basis for inter-individual variation in the response to RV infection is not well understood. In this study, we explored whether host genetic variation is associated with variation in gene expression response to RV infections between individuals. To do so, we obtained genome-wide genotype and gene expression data in uninfected and RV-infected peripheral blood mononuclear cells (PBMCs from 98 individuals. We mapped local and distant genetic variation that is associated with inter-individual differences in gene expression levels (eQTLs in both uninfected and RV-infected cells. We focused specifically on response eQTLs (reQTLs, namely, genetic associations with inter-individual variation in gene expression response to RV infection. We identified local reQTLs for 38 genes, including genes with known functions in viral response (UBA7, OAS1, IRF5 and genes that have been associated with immune and RV-related diseases (e.g., ITGA2, MSR1, GSTM3. The putative regulatory regions of genes with reQTLs were enriched for binding sites of virus-activated STAT2, highlighting the role of condition-specific transcription factors in genotype-by-environment interactions. Overall, we suggest that the 38 loci associated with inter-individual variation in gene expression response to RV-infection represent promising candidates for affecting immune and RV-related respiratory diseases.

  8. Host genetic variation influences gene expression response to rhinovirus infection.

    Çalışkan, Minal; Baker, Samuel W; Gilad, Yoav; Ober, Carole

    2015-04-01

    Rhinovirus (RV) is the most prevalent human respiratory virus and is responsible for at least half of all common colds. RV infections may result in a broad spectrum of effects that range from asymptomatic infections to severe lower respiratory illnesses. The basis for inter-individual variation in the response to RV infection is not well understood. In this study, we explored whether host genetic variation is associated with variation in gene expression response to RV infections between individuals. To do so, we obtained genome-wide genotype and gene expression data in uninfected and RV-infected peripheral blood mononuclear cells (PBMCs) from 98 individuals. We mapped local and distant genetic variation that is associated with inter-individual differences in gene expression levels (eQTLs) in both uninfected and RV-infected cells. We focused specifically on response eQTLs (reQTLs), namely, genetic associations with inter-individual variation in gene expression response to RV infection. We identified local reQTLs for 38 genes, including genes with known functions in viral response (UBA7, OAS1, IRF5) and genes that have been associated with immune and RV-related diseases (e.g., ITGA2, MSR1, GSTM3). The putative regulatory regions of genes with reQTLs were enriched for binding sites of virus-activated STAT2, highlighting the role of condition-specific transcription factors in genotype-by-environment interactions. Overall, we suggest that the 38 loci associated with inter-individual variation in gene expression response to RV-infection represent promising candidates for affecting immune and RV-related respiratory diseases.

  9. Rare coding variants associated with blood pressure variation in 15 914 individuals of African ancestry.

    Nandakumar, Priyanka; Lee, Dongwon; Richard, Melissa A; Tekola-Ayele, Fasil; Tayo, Bamidele O; Ware, Erin; Sung, Yun J; Salako, Babatunde; Ogunniyi, Adesola; Gu, C Charles; Grove, Megan L; Fornage, Myriam; Kardia, Sharon; Rotimi, Charles; Cooper, Richard S; Morrison, Alanna C; Ehret, Georg; Chakravarti, Aravinda

    2017-07-01

    Hypertension is a major risk factor for all cardiovascular diseases, especially among African Americans. This study focuses on identifying specific blood pressure (BP) genes using 15 914 individuals of African ancestry from eight cohorts (Africa America Diabetes Mellitus, Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in young Adults, Genetics Network, Genetic Epidemiology Network of Arteriopathy, Howard University Family Study, Hypertension Genetic Epidemiology Network, and Loyola University Chicago Cohort) to further genetic findings in this population which has generally been underrepresented in BP studies. We genotyped and performed various single variant and gene-based exome-wide analyses on 15 914 individuals on the Illumina HumanExome Beadchip v1.0 or v1.1 to test association with SBP and DBP long-term average residuals that were adjusted for age, age-squared, sex, and BMI. We identified rare variants affecting SBP and DBP in 10 genes: AFF1, GAPDHS, SLC28A3, COL6A1, CRYBA2, KRBA1, SEL1L3, YOD1, CCDC13, and QSOX1. Prior experimental evidence for six of these 10 candidate genes supports their involvement in cardiovascular mechanisms, corroborating their potential roles in BP regulation. Although our results require replication or validation due to their low numbers of carriers, and an ethnicity-specific genotyping array may be more informative, this study, which has identified several candidate genes in this population most susceptible to hypertension, presents one of the largest African-ancestry BP studies to date and the largest including analysis of rare variants.

  10. Clock gene variation in Tachycineta swallows.

    Dor, Roi; Cooper, Caren B; Lovette, Irby J; Massoni, Viviana; Bulit, Flor; Liljesthrom, Marcela; Winkler, David W

    2012-01-01

    Many animals use photoperiod cues to synchronize reproduction with environmental conditions and thereby improve their reproductive success. The circadian clock, which creates endogenous behavioral and physiological rhythms typically entrained to photoperiod, is well characterized at the molecular level. Recent work provided evidence for an association between Clock poly-Q length polymorphism and latitude and, within a population, an association with the date of laying and the length of the incubation period. Despite relatively high overall breeding synchrony, the timing of clutch initiation has a large impact on the fitness of swallows in the genus Tachycineta. We compared length polymorphism in the Clock poly-Q region among five populations from five different Tachycineta species that breed across a hemisphere-wide latitudinal gradient (Fig. 1). Clock poly-Q variation was not associated with latitude; however, there was an association between Clock poly-Q allele diversity and the degree of clutch size decline within breeding seasons. We did not find evidence for an association between Clock poly-Q variation and date of clutch initiation in for any of the five Tachycineta species, nor did we found a relationship between incubation duration and Clock genotype. Thus, there is no general association between latitude, breeding phenology, and Clock polymorphism in this clade of closely related birds.Figure 1Photos of Tachycineta swallows that were used in this study: A) T. bicolor from Ithaca, New York, B) T. leucorrhoa from Chascomús, Argentina, C) T. albilinea from Hill Bank, Belize, D) T. meyeni from Puerto Varas, Chile, and E) T. thalassina from Mono Lake, California, Photographers: B: Valentina Ferretti; A, C-E: David Winkler.

  11. Flagellar-phase variation: isolation of the rh1 gene

    Silverman, M.; Zieg, J.; Simon, M.

    1979-01-01

    In Salmonella, expression of flagellar antigen alternates between two serotypes (phases) encoded by two genes, H1 and H2. The mechanism which controls the alternative expression of the H1 and H2 genes was examined by cloning these genes and the genetic elements which control their activity on hybrid vehicles in Escherichia coli. H2 gene activity was shown to be controlled by a recombinational switch located adjacent to the H2 gene. Activity of the H1 gene is thought to be repressed, when the H2 gene is expressed, by the product of another gene, rhl (repressor of H1), which is controlled coordinately with the H2 gene. In this report, we describe the construction of hybrid lambda vehicles which contain, in addition to the H2 gene, a genetic activity corresponding to rhl. Variation of flagellar antigens analogous to that observed in Salmonella was observed when E. coli strains were transduced with the hybrid lambda. By using the lambda H2rhl hybrid to program protein syntheis in uv-irradiated cells, the synthesis of a polypeptide was correlated with rhl gene product activity. We conclude that the H2 region consists of two cotranscribed genes, H2 and rhl. The expression of both gene products is regulated by the same recombinational event

  12. Gene copy number variation throughout the Plasmodium falciparum genome

    Stewart Lindsay B

    2009-08-01

    Full Text Available Abstract Background Gene copy number variation (CNV is responsible for several important phenotypes of the malaria parasite Plasmodium falciparum, including drug resistance, loss of infected erythrocyte cytoadherence and alteration of receptor usage for erythrocyte invasion. Despite the known effects of CNV, little is known about its extent throughout the genome. Results We performed a whole-genome survey of CNV genes in P. falciparum using comparative genome hybridisation of a diverse set of 16 laboratory culture-adapted isolates to a custom designed high density Affymetrix GeneChip array. Overall, 186 genes showed hybridisation signals consistent with deletion or amplification in one or more isolate. There is a strong association of CNV with gene length, genomic location, and low orthology to genes in other Plasmodium species. Sub-telomeric regions of all chromosomes are strongly associated with CNV genes independent from members of previously described multigene families. However, ~40% of CNV genes were located in more central regions of the chromosomes. Among the previously undescribed CNV genes, several that are of potential phenotypic relevance are identified. Conclusion CNV represents a major form of genetic variation within the P. falciparum genome; the distribution of gene features indicates the involvement of highly non-random mutational and selective processes. Additional studies should be directed at examining CNV in natural parasite populations to extend conclusions to clinical settings.

  13. gsSKAT: Rapid gene set analysis and multiple testing correction for rare-variant association studies using weighted linear kernels.

    Larson, Nicholas B; McDonnell, Shannon; Cannon Albright, Lisa; Teerlink, Craig; Stanford, Janet; Ostrander, Elaine A; Isaacs, William B; Xu, Jianfeng; Cooney, Kathleen A; Lange, Ethan; Schleutker, Johanna; Carpten, John D; Powell, Isaac; Bailey-Wilson, Joan E; Cussenot, Olivier; Cancel-Tassin, Geraldine; Giles, Graham G; MacInnis, Robert J; Maier, Christiane; Whittemore, Alice S; Hsieh, Chih-Lin; Wiklund, Fredrik; Catalona, William J; Foulkes, William; Mandal, Diptasri; Eeles, Rosalind; Kote-Jarai, Zsofia; Ackerman, Michael J; Olson, Timothy M; Klein, Christopher J; Thibodeau, Stephen N; Schaid, Daniel J

    2017-05-01

    Next-generation sequencing technologies have afforded unprecedented characterization of low-frequency and rare genetic variation. Due to low power for single-variant testing, aggregative methods are commonly used to combine observed rare variation within a single gene. Causal variation may also aggregate across multiple genes within relevant biomolecular pathways. Kernel-machine regression and adaptive testing methods for aggregative rare-variant association testing have been demonstrated to be powerful approaches for pathway-level analysis, although these methods tend to be computationally intensive at high-variant dimensionality and require access to complete data. An additional analytical issue in scans of large pathway definition sets is multiple testing correction. Gene set definitions may exhibit substantial genic overlap, and the impact of the resultant correlation in test statistics on Type I error rate control for large agnostic gene set scans has not been fully explored. Herein, we first outline a statistical strategy for aggregative rare-variant analysis using component gene-level linear kernel score test summary statistics as well as derive simple estimators of the effective number of tests for family-wise error rate control. We then conduct extensive simulation studies to characterize the behavior of our approach relative to direct application of kernel and adaptive methods under a variety of conditions. We also apply our method to two case-control studies, respectively, evaluating rare variation in hereditary prostate cancer and schizophrenia. Finally, we provide open-source R code for public use to facilitate easy application of our methods to existing rare-variant analysis results. © 2017 WILEY PERIODICALS, INC.

  14. Pathogenicity gene variations within the order Entomophthorales

    Grell, Morten Nedergaard; Jensen, Annette Bruun; Lange, Lene

    Fungi within the order Entomophthorales (subphylum Entomophthoromycotina) are obligate biotrophic pathogens of arthropods with a remarkable narrow host range. Infection takes place through the cuticle when conidia hit a susceptible host, facilitated by enzymatic and mechanical mechanisms. In the ...... pathogenicity genes within genera Entomophthora and Pandora, using fungal genomic DNA originating from field-collected, infected insect host species of dipteran (flies, mosquitoes) or hemipteran (aphid) origin.......Fungi within the order Entomophthorales (subphylum Entomophthoromycotina) are obligate biotrophic pathogens of arthropods with a remarkable narrow host range. Infection takes place through the cuticle when conidia hit a susceptible host, facilitated by enzymatic and mechanical mechanisms......, conidia are produced and discharged when humidity gets high—usually during night. In an earlier secretome study of field-collected grain aphids (Sitobion avenae) infected with entomophthoralean fungi, a number of pathogenesis-related, secreted enzymes were discovered (Fungal Genetics and Biology 2011, vol...

  15. Population genetic analysis reveals barriers and corridors for gene flow within and among riparian populations of a rare plant.

    Hevroy, Tanya H; Moody, Michael L; Krauss, Siegfried L

    2018-02-01

    Landscape features and life-history traits affect gene flow, migration and drift to impact on spatial genetic structure of species. Understanding this is important for managing genetic diversity of threatened species. This study assessed the spatial genetic structure of the rare riparian Grevillea sp. Cooljarloo (Proteaceae), which is restricted to a 20 km 2 region impacted by mining in the northern sandplains of the Southwest Australian Floristic Region, an international biodiversity hotspot. Within creek lines and floodplains, the distribution is largely continuous. Models of dispersal within riparian systems were assessed by spatial genetic analyses including population level partitioning of genetic variation and individual Bayesian clustering. High levels of genetic variation and weak isolation by distance within creek line and floodplain populations suggest large effective population sizes and strong connectivity, with little evidence for unidirectional gene flow as might be expected from hydrochory. Regional clustering of creek line populations and strong divergence among creek line populations suggest substantially lower levels of gene flow among creek lines than within creek lines. There was however a surprising amount of genetic admixture in floodplain populations, which could be explained by irregular flooding and/or movements by highly mobile nectar-feeding bird pollinators. Our results highlight that for conservation of rare riparian species, avoiding an impact to hydrodynamic processes, such as water tables and flooding dynamics, may be just as critical as avoiding direct impacts on the number of plants.

  16. Gene transposition causing natural variation for growth in Arabidopsis thaliana.

    Vlad, Daniela; Rappaport, Fabrice; Simon, Matthieu; Loudet, Olivier

    2010-05-13

    A major challenge in biology is to identify molecular polymorphisms responsible for variation in complex traits of evolutionary and agricultural interest. Using the advantages of Arabidopsis thaliana as a model species, we sought to identify new genes and genetic mechanisms underlying natural variation for shoot growth using quantitative genetic strategies. More quantitative trait loci (QTL) still need be resolved to draw a general picture as to how and where in the pathways adaptation is shaping natural variation and the type of molecular variation involved. Phenotypic variation for shoot growth in the Bur-0 x Col-0 recombinant inbred line set was decomposed into several QTLs. Nearly-isogenic lines generated from the residual heterozygosity segregating among lines revealed an even more complex picture, with major variation controlled by opposite linked loci and masked by the segregation bias due to the defective phenotype of SG3 (Shoot Growth-3), as well as epistasis with SG3i (SG3-interactor). Using principally a fine-mapping strategy, we have identified the underlying gene causing phenotypic variation at SG3: At4g30720 codes for a new chloroplast-located protein essential to ensure a correct electron flow through the photosynthetic chain and, hence, photosynthesis efficiency and normal growth. The SG3/SG3i interaction is the result of a structural polymorphism originating from the duplication of the gene followed by divergent paralogue's loss between parental accessions. Species-wide, our results illustrate the very dynamic rate of duplication/transposition, even over short periods of time, resulting in several divergent--but still functional-combinations of alleles fixed in different backgrounds. In predominantly selfing species like Arabidopsis, this variation remains hidden in wild populations but is potentially revealed when divergent individuals outcross. This work highlights the need for improved tools and algorithms to resolve structural variation

  17. Burden of rare variants in ALS genes influences survival in familial and sporadic ALS.

    Pang, Shirley Yin-Yu; Hsu, Jacob Shujui; Teo, Kay-Cheong; Li, Yan; Kung, Michelle H W; Cheah, Kathryn S E; Chan, Danny; Cheung, Kenneth M C; Li, Miaoxin; Sham, Pak-Chung; Ho, Shu-Leong

    2017-10-01

    Genetic variants are implicated in the development of amyotrophic lateral sclerosis (ALS), but it is unclear whether the burden of rare variants in ALS genes has an effect on survival. We performed whole genome sequencing on 8 familial ALS (FALS) patients with superoxide dismutase 1 (SOD1) mutation and whole exome sequencing on 46 sporadic ALS (SALS) patients living in Hong Kong and found that 67% had at least 1 rare variant in the exons of 40 ALS genes; 22% had 2 or more. Patients with 2 or more rare variants had lower probability of survival than patients with 0 or 1 variant (p = 0.001). After adjusting for other factors, each additional rare variant increased the risk of respiratory failure or death by 60% (p = 0.0098). The presence of the rare variant was associated with the risk of ALS (Odds ratio 1.91, 95% confidence interval 1.03-3.61, p = 0.03), and ALS patients had higher rare variant burden than controls (MB, p = 0.004). Our findings support an oligogenic basis with the burden of rare variants affecting the development and survival of ALS. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  18. Clinical significance of rare copy number variations in epilepsy: a case-control survey using microarray-based comparative genomic hybridization.

    Striano, Pasquale; Coppola, Antonietta; Paravidino, Roberta; Malacarne, Michela; Gimelli, Stefania; Robbiano, Angela; Traverso, Monica; Pezzella, Marianna; Belcastro, Vincenzo; Bianchi, Amedeo; Elia, Maurizio; Falace, Antonio; Gazzerro, Elisabetta; Ferlazzo, Edoardo; Freri, Elena; Galasso, Roberta; Gobbi, Giuseppe; Molinatto, Cristina; Cavani, Simona; Zuffardi, Orsetta; Striano, Salvatore; Ferrero, Giovanni Battista; Silengo, Margherita; Cavaliere, Maria Luigia; Benelli, Matteo; Magi, Alberto; Piccione, Maria; Dagna Bricarelli, Franca; Coviello, Domenico A; Fichera, Marco; Minetti, Carlo; Zara, Federico

    2012-03-01

    To perform an extensive search for genomic rearrangements by microarray-based comparative genomic hybridization in patients with epilepsy. Prospective cohort study. Epilepsy centers in Italy. Two hundred seventy-nine patients with unexplained epilepsy, 265 individuals with nonsyndromic mental retardation but no epilepsy, and 246 healthy control subjects were screened by microarray-based comparative genomic hybridization. Identification of copy number variations (CNVs) and gene enrichment. Rare CNVs occurred in 26 patients (9.3%) and 16 healthy control subjects (6.5%) (P = .26). The CNVs identified in patients were larger (P = .03) and showed higher gene content (P = .02) than those in control subjects. The CNVs larger than 1 megabase (P = .002) and including more than 10 genes (P = .005) occurred more frequently in patients than in control subjects. Nine patients (34.6%) among those harboring rare CNVs showed rearrangements associated with emerging microdeletion or microduplication syndromes. Mental retardation and neuropsychiatric features were associated with rare CNVs (P = .004), whereas epilepsy type was not. The CNV rate in patients with epilepsy and mental retardation or neuropsychiatric features is not different from that observed in patients with mental retardation only. Moreover, significant enrichment of genes involved in ion transport was observed within CNVs identified in patients with epilepsy. Patients with epilepsy show a significantly increased burden of large, rare, gene-rich CNVs, particularly when associated with mental retardation and neuropsychiatric features. The limited overlap between CNVs observed in the epilepsy group and those observed in the group with mental retardation only as well as the involvement of specific (ion channel) genes indicate a specific association between the identified CNVs and epilepsy. Screening for CNVs should be performed for diagnostic purposes preferentially in patients with epilepsy and mental retardation or

  19. Huntingtin gene repeat size variations affect risk of lifetime depression

    Gardiner, Sarah L.; van Belzen, Martine J.; Boogaard, Merel W.

    2017-01-01

    Huntington disease (HD) is a severe neuropsychiatric disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the HTT gene. Although HD is frequently complicated by depression, it is still unknown to what extent common HTT CAG repeat size variations in the normal range could affect...

  20. Human PTCHD3 nulls: rare copy number and sequence variants suggest a non-essential gene

    Lionel Anath C

    2011-03-01

    Full Text Available Abstract Background Copy number variations (CNVs can contribute to variable degrees of fitness and/or disease predisposition. Recent studies show that at least 1% of any given genome is copy number variable when compared to the human reference sequence assembly. Homozygous deletions (or CNV nulls that are found in the normal population are of particular interest because they may serve to define non-essential genes in human biology. Results In a genomic screen investigating CNV in Autism Spectrum Disorders (ASDs we detected a heterozygous deletion on chromosome 10p12.1, spanning the Patched-domain containing 3 (PTCHD3 gene, at a frequency of ~1.4% (6/427. This finding seemed interesting, given recent discoveries on the role of another Patched-domain containing gene (PTCHD1 in ASD. Screening of another 177 ASD probands yielded two additional heterozygous deletions bringing the frequency to 1.3% (8/604. The deletion was found at a frequency of ~0.73% (27/3,695 in combined control population from North America and Northern Europe predominately of European ancestry. Screening of the human genome diversity panel (HGDP-CEPH covering worldwide populations yielded deletions in 7/1,043 unrelated individuals and those detected were confined to individuals of European/Mediterranean/Middle Eastern ancestry. Breakpoint mapping yielded an identical 102,624 bp deletion in all cases and controls tested, suggesting a common ancestral event. Interestingly, this CNV occurs at a break of synteny between humans and mouse. Considering all data, however, no significant association of these rare PTCHD3 deletions with ASD was observed. Notwithstanding, our RNA expression studies detected PTCHD3 in several tissues, and a novel shorter isoform for PTCHD3 was characterized. Expression in transfected COS-7 cells showed PTCHD3 isoforms colocalize with calnexin in the endoplasmic reticulum. The presence of a patched (Ptc domain suggested a role for PTCHD3 in various biological

  1. Functional annotation of rare gene aberration drivers of pancreatic cancer | Office of Cancer Genomics

    As we enter the era of precision medicine, characterization of cancer genomes will directly influence therapeutic decisions in the clinic. Here we describe a platform enabling functionalization of rare gene mutations through their high-throughput construction, molecular barcoding and delivery to cancer models for in vivo tumour driver screens. We apply these technologies to identify oncogenic drivers of pancreatic ductal adenocarcinoma (PDAC).

  2. Expression profiles of variation integration genes in bladder urothelial carcinoma.

    Wang, J M; Wang, Y Q; Gao, Z L; Wu, J T; Shi, B K; Yu, C C

    2014-04-30

    Bladder cancer is a common cancer worldwide and its incidence continues to increase. There are approximately 261,000 cases of bladder cancer resulting in 115,000 deaths annually. This study aimed to integrate bladder cancer genome copy number variation information and bladder cancer gene transcription level expression data to construct a causal-target module network of the range of bladder cancer-related genomes. Here, we explored the control mechanism underlying bladder cancer phenotype expression regulation by the major bladder cancer genes. We selected 22 modules as the initial module network to expand the search to screen more networks. After bootstrapping 100 times, we obtained 16 key regulators. These 16 key candidate regulatory genes were further expanded to identify the expression changes of 11,676 genes in 275 modules, which may all have the same regulation. In conclusion, a series of modules associated with the terms 'cancer' or 'bladder' were considered to constitute a potential network.

  3. Pulmonary phenotypes associated with genetic variation in telomere-related genes.

    Hoffman, Thijs W; van Moorsel, Coline H M; Borie, Raphael; Crestani, Bruno

    2018-05-01

    Genomic mutations in telomere-related genes have been recognized as a cause of familial forms of idiopathic pulmonary fibrosis (IPF). However, it has become increasingly clear that telomere syndromes and telomere shortening are associated with various types of pulmonary disease. Additionally, it was found that also single nucleotide polymorphisms (SNPs) in telomere-related genes are risk factors for the development of pulmonary disease. This review focuses on recent updates on pulmonary phenotypes associated with genetic variation in telomere-related genes. Genomic mutations in seven telomere-related genes cause pulmonary disease. Pulmonary phenotypes associated with these mutations range from many forms of pulmonary fibrosis to emphysema and pulmonary vascular disease. Telomere-related mutations account for up to 10% of sporadic IPF, 25% of familial IPF, 10% of connective-tissue disease-associated interstitial lung disease, and 1% of COPD. Mixed disease forms have also been found. Furthermore, SNPs in TERT, TERC, OBFC1, and RTEL1, as well as short telomere length, have been associated with several pulmonary diseases. Treatment of pulmonary disease caused by telomere-related gene variation is currently based on disease diagnosis and not on the underlying cause. Pulmonary phenotypes found in carriers of telomere-related gene mutations and SNPs are primarily pulmonary fibrosis, sometimes emphysema and rarely pulmonary vascular disease. Genotype-phenotype relations are weak, suggesting that environmental factors and genetic background of patients determine disease phenotypes to a large degree. A disease model is presented wherever genomic variation in telomere-related genes cause specific pulmonary disease phenotypes whenever triggered by environmental exposure, comorbidity, or unknown factors.

  4. Comparison of gene-based rare variant association mapping methods for quantitative traits in a bovine population with complex familial relationships.

    Zhang, Qianqian; Guldbrandtsen, Bernt; Calus, Mario P L; Lund, Mogens Sandø; Sahana, Goutam

    2016-08-17

    There is growing interest in the role of rare variants in the variation of complex traits due to increasing evidence that rare variants are associated with quantitative traits. However, association methods that are commonly used for mapping common variants are not effective to map rare variants. Besides, livestock populations have large half-sib families and the occurrence of rare variants may be confounded with family structure, which makes it difficult to disentangle their effects from family mean effects. We compared the power of methods that are commonly applied in human genetics to map rare variants in cattle using whole-genome sequence data and simulated phenotypes. We also studied the power of mapping rare variants using linear mixed models (LMM), which are the method of choice to account for both family relationships and population structure in cattle. We observed that the power of the LMM approach was low for mapping a rare variant (defined as those that have frequencies lower than 0.01) with a moderate effect (5 to 8 % of phenotypic variance explained by multiple rare variants that vary from 5 to 21 in number) contributing to a QTL with a sample size of 1000. In contrast, across the scenarios studied, statistical methods that are specialized for mapping rare variants increased power regardless of whether multiple rare variants or a single rare variant underlie a QTL. Different methods for combining rare variants in the test single nucleotide polymorphism set resulted in similar power irrespective of the proportion of total genetic variance explained by the QTL. However, when the QTL variance is very small (only 0.1 % of the total genetic variance), these specialized methods for mapping rare variants and LMM generally had no power to map the variants within a gene with sample sizes of 1000 or 5000. We observed that the methods that combine multiple rare variants within a gene into a meta-variant generally had greater power to map rare variants compared

  5. Structure, Variation, and Co-occurrence of Soil Microbial Communities in Abandoned Sites of a Rare Earth Elements Mine.

    Chao, Yuanqing; Liu, Wenshen; Chen, Yanmei; Chen, Wenhui; Zhao, Lihua; Ding, Qiaobei; Wang, Shizhong; Tang, Ye-Tao; Zhang, Tong; Qiu, Rong-Liang

    2016-11-01

    Mining activity for rare earth elements (REEs) has caused serious environmental pollution, particularly for soil ecosystems. However, the effects of REEs on soil microbiota are still poorly understood. In this study, soils were collected from abandoned sites of a REEs mine, and the structure, diversity, and co-occurrence patterns of soil microbiota were evaluated by Illumina high-throughput sequencing targeting 16S rRNA genes. Although microbiota developed significantly along with the natural restoration, the microbial structure on the site abandoned for 10 years still significantly differed from that on the unmined site. Potential plant growth promoting bacteria (PGPB) were identified by comparing 16S sequences against a self-constructed PGPB database via BLAST, and it was found that siderophore-producing and phosphorus-solubilizing bacteria were more abundant in the studied soils than in reference soils. Canonical correspondence analysis indicated that species richness of plant community was the prime factor affecting microbial structure, followed by limiting nutrients (total carbon and total nitrogen) and REEs content. Further co-occurring network analysis revealed nonrandom assembly patterns of microbiota in the studied soils. These results increase our understanding of microbial variation and assembly pattern during natural restoration in REE contaminated soils.

  6. Partitioning of genetic variation between regulatory and coding gene segments: the predominance of software variation in genes encoding introvert proteins.

    Mitchison, A

    1997-01-01

    In considering genetic variation in eukaryotes, a fundamental distinction can be made between variation in regulatory (software) and coding (hardware) gene segments. For quantitative traits the bulk of variation, particularly that near the population mean, appears to reside in regulatory segments. The main exceptions to this rule concern proteins which handle extrinsic substances, here termed extrovert proteins. The immune system includes an unusually large proportion of this exceptional category, but even so its chief source of variation may well be polymorphism in regulatory gene segments. The main evidence for this view emerges from genome scanning for quantitative trait loci (QTL), which in the case of the immune system points to a major contribution of pro-inflammatory cytokine genes. Further support comes from sequencing of major histocompatibility complex (Mhc) class II promoters, where a high level of polymorphism has been detected. These Mhc promoters appear to act, in part at least, by gating the back-signal from T cells into antigen-presenting cells. Both these forms of polymorphism are likely to be sustained by the need for flexibility in the immune response. Future work on promoter polymorphism is likely to benefit from the input from genome informatics.

  7. Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene.

    Fishman, G A; Stone, E M; Grover, S; Derlacki, D J; Haines, H L; Hockey, R R

    1999-04-01

    To report the spectrum of ophthalmic findings in patients with Stargardt dystrophy or fundus flavimaculatus who have a specific sequence variation in the ABCR gene. Twenty-nine patients with Stargardt dystrophy or fundus flavimaculatus from different pedigrees were identified with possible disease-causing sequence variations in the ABCR gene from a group of 66 patients who were screened for sequence variations in this gene. Patients underwent a routine ocular examination, including slitlamp biomicroscopy and a dilated fundus examination. Fluorescein angiography was performed on 22 patients, and electroretinographic measurements were obtained on 24 of 29 patients. Kinetic visual fields were measured with a Goldmann perimeter in 26 patients. Single-strand conformation polymorphism analysis and DNA sequencing were used to identify variations in coding sequences of the ABCR gene. Three clinical phenotypes were observed among these 29 patients. In phenotype I, 9 of 12 patients had a sequence change in exon 42 of the ABCR gene in which the amino acid glutamic acid was substituted for glycine (Gly1961Glu). In only 4 of these 9 patients was a second possible disease-causing mutation found on the other ABCR allele. In addition to an atrophic-appearing macular lesion, phenotype I was characterized by localized perifoveal yellowish white flecks, the absence of a dark choroid, and normal electroretinographic amplitudes. Phenotype II consisted of 10 patients who showed a dark choroid and more diffuse yellowish white flecks in the fundus. None exhibited the Gly1961Glu change. Phenotype III consisted of 7 patients who showed extensive atrophic-appearing changes of the retinal pigment epithelium. Electroretinographic cone and rod amplitudes were reduced. One patient showed the Gly1961Glu change. A wide variation in clinical phenotype can occur in patients with sequence changes in the ABCR gene. In individual patients, a certain phenotype seems to be associated with the presence of

  8. Genomic and gene variation in Mycoplasma hominis strains

    Christiansen, Gunna; Andersen, H; Birkelund, Svend

    1987-01-01

    DNAs from 14 strains of Mycoplasma hominis isolated from various habitats, including strain PG21, were analyzed for genomic heterogeneity. DNA-DNA filter hybridization values were from 51 to 91%. Restriction endonuclease digestion patterns, analyzed by agarose gel electrophoresis, revealed...... no identity or cluster formation between strains. Variation within M. hominis rRNA genes was analyzed by Southern hybridization of EcoRI-cleaved DNA hybridized with a cloned fragment of the rRNA gene from the mycoplasma strain PG50. Five of the M. hominis strains showed identical hybridization patterns....... These hybridization patterns were compared with those of 12 other mycoplasma species, which showed a much more complex band pattern. Cloned nonribosomal RNA gene fragments of M. hominis PG21 DNA were analyzed, and the fragments were used to demonstrate heterogeneity among the strains. A monoclonal antibody against...

  9. Signatures of rare-earth elements in banded corals of Kalpeni atoll-Lakshadweep archipelago in response to monsoonal variations

    Naqvi, S.A.S.; Nath, B.N.; Balaram, V.

    Concentrations of rare-earth elements (REE) have been determined in seasonal bands of Porites species collected from the Lakshadweep lagoon. Total REE (REE) are very low (less than 3 ppm) in these corals. Seasonal variations in REE appear to have...

  10. Differential effects of ADORA2A gene variations in pre-attentive visual sensory memory subprocesses.

    Beste, Christian; Stock, Ann-Kathrin; Ness, Vanessa; Epplen, Jörg T; Arning, Larissa

    2012-08-01

    The ADORA2A gene encodes the adenosine A(2A) receptor that is highly expressed in the striatum where it plays a role in modulating glutamatergic and dopaminergic transmission. Glutamatergic signaling has been suggested to play a pivotal role in cognitive functions related to the pre-attentive processing of external stimuli. Yet, the precise molecular mechanism of these processes is poorly understood. Therefore, we aimed to investigate whether ADORA2A gene variation has modulating effects on visual pre-attentive sensory memory processing. Studying two polymorphisms, rs5751876 and rs2298383, in 199 healthy control subjects who performed a partial-report paradigm, we find that ADORA2A variation is associated with differences in the efficiency of pre-attentive sensory memory sub-processes. We show that especially the initial visual availability of stimulus information is rendered more efficiently in the homozygous rare genotype groups. Processes related to the transfer of information into working memory and the duration of visual sensory (iconic) memory are compromised in the homozygous rare genotype groups. Our results show a differential genotype-dependent modulation of pre-attentive sensory memory sub-processes. Hence, we assume that this modulation may be due to differential effects of increased adenosine A(2A) receptor signaling on glutamatergic transmission and striatal medium spiny neuron (MSN) interaction. Copyright © 2011 Elsevier B.V. and ECNP. All rights reserved.

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

    Barbara E Stranger

    2005-12-01

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

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

    2005-12-01

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

  13. Single-nucleotide variations in the genes encoding the mitochondrial Hsp60/Hsp10 chaperone system and their disease-causing potential

    Bross, Peter; Li, Zhijie; Hansen, Jakob

    2007-01-01

    for variations in the HSPD1 and HSPE1 genes encoding the mitochondrial Hsp60/Hsp10 chaperone complex: two patients with multiple mitochondrial enzyme deficiency, 61 sudden infant death syndrome cases (MIM: #272120), and 60 patients presenting with ethylmalonic aciduria carrying non-synonymous susceptibility...... variations in the ACADS gene (MIM: *606885 and #201470). Besides previously reported variations we detected six novel variations: two in the bidirectional promoter region, and one synonymous and three non-synonymous variations in the HSPD1 coding region. One of the non-synonymous variations was polymorphic...... in patient and control samples, and the rare variations were each only found in single patients and absent in 100 control chromosomes. Functional investigation of the effects of the variations in the promoter region and the non-synonymous variations in the coding region indicated that none of them had...

  14. Normosmic idiopathic hypogonadotrophic hypogonadism due to a rare KISS1R gene mutation

    N Chelaghma

    2018-04-01

    Full Text Available Hypogonadotrophic hypogonadism is due to impaired or reduced gonadotrophin secretion from the pituitary gland. In the absence of any anatomical or functional lesions of the pituitary or hypothalamic gland, the hypogonadotrophic hypogonadism is referred to as idiopathic hypogonadotrophic hypogonadism (IHH. We present a case of a young lady born to consanguineous parents who was found to have IHH due to a rare gene mutation.

  15. Proteogenomics of rare taxonomic phyla: A prospective treasure trove of protein coding genes.

    Kumar, Dhirendra; Mondal, Anupam Kumar; Kutum, Rintu; Dash, Debasis

    2016-01-01

    Sustainable innovations in sequencing technologies have resulted in a torrent of microbial genome sequencing projects. However, the prokaryotic genomes sequenced so far are unequally distributed along their phylogenetic tree; few phyla contain the majority, the rest only a few representatives. Accurate genome annotation lags far behind genome sequencing. While automated computational prediction, aided by comparative genomics, remains a popular choice for genome annotation, substantial fraction of these annotations are erroneous. Proteogenomics utilizes protein level experimental observations to annotate protein coding genes on a genome wide scale. Benefits of proteogenomics include discovery and correction of gene annotations regardless of their phylogenetic conservation. This not only allows detection of common, conserved proteins but also the discovery of protein products of rare genes that may be horizontally transferred or taxonomy specific. Chances of encountering such genes are more in rare phyla that comprise a small number of complete genome sequences. We collated all bacterial and archaeal proteogenomic studies carried out to date and reviewed them in the context of genome sequencing projects. Here, we present a comprehensive list of microbial proteogenomic studies, their taxonomic distribution, and also urge for targeted proteogenomics of underexplored taxa to build an extensive reference of protein coding genes. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Frequency of rare mutations and common genetic variations in severe hypertriglyceridemia in the general population of Spain.

    Lamiquiz-Moneo, Itziar; Blanco-Torrecilla, Cristian; Bea, Ana M; Mateo-Gallego, Rocío; Pérez-Calahorra, Sofía; Baila-Rueda, Lucía; Cenarro, Ana; Civeira, Fernando; de Castro-Orós, Isabel

    2016-04-23

    Hypertriglyceridemia (HTG) is a common complex metabolic trait that results of the accumulation of relatively common genetic variants in combination with other modifier genes and environmental factors resulting in increased plasma triglyceride (TG) levels. The majority of severe primary hypertriglyceridemias is diagnosed in adulthood and their molecular bases have not been fully defined yet. The prevalence of HTG is highly variable among populations, possibly caused by differences in environmental factors and genetic background. However, the prevalence of very high TG and the frequency of rare mutations causing HTG in a whole non-selected population have not been previously studied. The total of 23,310 subjects over 18 years from a primary care-district in a middle-class area of Zaragoza (Spain) with TG >500 mg/dL were selected to establish HTG prevalence. Those affected of primary HTG were considered for further genetic analysis. The promoters, coding regions and exon-intron boundaries of LPL, LMF1, APOC2, APOA5, APOE and GPIHBP1 genes were sequenced. The frequency of rare variants identified was studied in 90 controls. One hundred ninety-four subjects (1.04%) had HTG and 90 subjects (46.4%) met the inclusion criteria for primary HTG. In this subgroup, nine patients (12.3%) were carriers of 7 rare variants in LPL, LMF1, APOA5, GPIHBP1 or APOE genes. Three of these mutations are described for the first time in this work. The presence of a rare pathogenic mutation did not confer a differential phenotype or a higher family history of HTG. The prevalence of rare mutations in candidate genes in subjects with primary HTG is low. The low frequency of rare mutations, the absence of a more severe phenotype or the dominant transmission of the HTG would not suggest the use of genetic analysis in the clinical practice in this population.

  17. PAX6 gene variations associated with aniridia in south India

    Shashikant Shetty

    2004-04-01

    Full Text Available Abstract Background Mutations in the transcription factor gene PAX6 have been shown to be the cause of the aniridia phenotype. The purpose of this study was to analyze patients with aniridia to uncover PAX6 gene mutations in south Indian population. Methods Total genomic DNA was isolated from peripheral blood of twenty-eight members of six clinically diagnosed aniridia families and 60 normal healthy controls. The coding exons of the human PAX6 gene were amplified by PCR and allele specific variations were detected by single strand conformation polymorphism (SSCP followed by automated sequencing. Results The sequencing results revealed novel PAX6 mutations in three patients with sporadic aniridia: c.715ins5, [c.1201delA; c.1239A>G] and c.901delA. Two previously reported nonsense mutations were also found: c.482C>A, c.830G>A. A neutral polymorphism was detected (IVS9-12C>T at the boundary of intron 9 and exon 10. The two nonsense mutations found in the coding region of human PAX6 gene are reported for the first time in the south Indian population. Conclusion The genetic analysis confirms that haploinsuffiency of the PAX6 gene causes the classic aniridia phenotype. Most of the point mutations detected in our study results in stop codons. Here we add three novel PAX6 gene mutations in south Indian population to the existing spectrum of mutations, which is not a well-studied ethnic group. Our study supports the hypothesis that a mutation in the PAX6 gene correlates with expression of aniridia.

  18. Diversity and impact of rare variants in genes encoding the platelet G protein-coupled receptors.

    Jones, Matthew L; Norman, Jane E; Morgan, Neil V; Mundell, Stuart J; Lordkipanidzé, Marie; Lowe, Gillian C; Daly, Martina E; Simpson, Michael A; Drake, Sian; Watson, Steve P; Mumford, Andrew D

    2015-04-01

    Platelet responses to activating agonists are influenced by common population variants within or near G protein-coupled receptor (GPCR) genes that affect receptor activity. However, the impact of rare GPCR gene variants is unknown. We describe the rare single nucleotide variants (SNVs) in the coding and splice regions of 18 GPCR genes in 7,595 exomes from the 1,000-genomes and Exome Sequencing Project databases and in 31 cases with inherited platelet function disorders (IPFDs). In the population databases, the GPCR gene target regions contained 740 SNVs (318 synonymous, 410 missense, 7 stop gain and 6 splice region) of which 70 % had global minor allele frequency (MAF) < 0.05 %. Functional annotation using six computational algorithms, experimental evidence and structural data identified 156/740 (21 %) SNVs as potentially damaging to GPCR function, most commonly in regions encoding the transmembrane and C-terminal intracellular receptor domains. In 31 index cases with IPFDs (Gi-pathway defect n=15; secretion defect n=11; thromboxane pathway defect n=3 and complex defect n=2) there were 256 SNVs in the target regions of 15 stimulatory platelet GPCRs (34 unique; 12 with MAF< 1 % and 22 with MAF≥ 1 %). These included rare variants predicting R122H, P258T and V207A substitutions in the P2Y12 receptor that were annotated as potentially damaging, but only partially explained the platelet function defects in each case. Our data highlight that potentially damaging variants in platelet GPCR genes have low individual frequencies, but are collectively abundant in the population. Potentially damaging variants are also present in pedigrees with IPFDs and may contribute to complex laboratory phenotypes.

  19. Theories of Population Variation in Genes and Genomes

    Christiansen, Freddy

    This textbook provides an authoritative introduction to both classical and coalescent approaches to population genetics. Written for graduate students and advanced undergraduates by one of the world’s leading authorities in the field, the book focuses on the theoretical background of population...... genetics, while emphasizing the close interplay between theory and empiricism. Traditional topics such as genetic and phenotypic variation, mutation, migration, and linkage are covered and advanced by contemporary coalescent theory, which describes the genealogy of genes in a population, ultimately...... connecting them to a single common ancestor. Effects of selection, particularly genomic effects, are discussed with reference to molecular genetic variation. The book is designed for students of population genetics, bioinformatics, evolutionary biology, molecular evolution, and theoretical biology—as well...

  20. Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of monogenic diabetes.

    Torsvik, Janniche; Johansson, Stefan; Johansen, Anders; Ek, Jakob; Minton, Jayne; Raeder, Helge; Ellard, Sian; Hattersley, Andrew; Pedersen, Oluf; Hansen, Torben; Molven, Anders; Njølstad, Pål R

    2010-01-01

    We have previously shown that heterozygous single-base deletions in the carboxyl-ester lipase (CEL) gene cause exocrine and endocrine pancreatic dysfunction in two multigenerational families. These deletions were found in the first and fourth repeats of a variable number of tandem repeats (VNTR), which has proven challenging to sequence due to high GC-content and considerable length variation. We have therefore developed a screening method consisting of a multiplex PCR followed by fragment analysis. The method detected putative disease-causing insertions and deletions in the proximal repeats of the VNTR, and determined the VNTR-length of each allele. When blindly testing 56 members of the two families with known single-base deletions in the CEL VNTR, the method correctly assessed the mutation carriers. Screening of 241 probands from suspected maturity-onset diabetes of the young (MODY) families negative for mutations in known MODY genes (95 individuals from Denmark and 146 individuals from UK) revealed no deletions in the proximal repeats of the CEL VNTR. However, we found one Danish patient with a short, novel CEL allele containing only three VNTR repeats (normal range 7-23 in healthy controls). This allele co-segregated with diabetes or impaired glucose tolerance in the patient's family as six of seven mutation carriers were affected. We also identified individuals who had three copies of a complete CEL VNTR. In conclusion, the CEL gene is highly polymorphic, but mutations in CEL are likely to be a rare cause of monogenic diabetes.

  1. [Variation of CAG repeats in coding region of ATXN2 gene in different ethnic groups].

    Chen, Xiao-Chen; Sun, Hao; Mi, Dong-Qing; Huang, Xiao-Qin; Lin, Ke-Qin; Yi, Wen; Yu, Liang; Shi, Lei; Shi, Li; Yang, Zhao-Qing; Chu, Jia-You

    2011-04-01

    Toinvestigate CAG repeats variation of ATXN2 gene coding region in six ethnic groups that live in comparatively different environments, to evaluate whether these variations are under positive selection, and to find factors driving selection effects, 291 unrelated healthy individuals were collected from six ethnic groups and their STR geneotyping was performed. The frequencies of alleles and genotypes were counted and thereby Slatkin's linearized Fst values were calculated. The UPGMA tree against this gene was constructed. The MDS analysis among these groups was carried out as well. The results from the linearized Fst values indicated that there were significant evolutionary differences of the STR in ATXN2 gene between Hui and Yi groups, but not among the other 4 groups. Further analysis was performed by combining our data with published data obtained from other groups. These results indicated that there were significant differences between Japanese and other groups including Hui, Hani, Yunnan Mongolian, and Inner Mongolian. Both Hui and Mongolian from Inner Mongolia were significantly different from Han. In conclusion, the six ethnic groups had their own distribution characterizations of allelic frequencies of ATXN2 STR, and the potential cause of frequency changes in rare alleles could be the consequence of positive selection.

  2. Common Variation in the DOPA Decarboxylase (DDC) Gene and Human Striatal DDC Activity In Vivo.

    Eisenberg, Daniel P; Kohn, Philip D; Hegarty, Catherine E; Ianni, Angela M; Kolachana, Bhaskar; Gregory, Michael D; Masdeu, Joseph C; Berman, Karen F

    2016-08-01

    The synthesis of multiple amine neurotransmitters, such as dopamine, norepinephrine, serotonin, and trace amines, relies in part on DOPA decarboxylase (DDC, AADC), an enzyme that is required for normative neural operations. Because rare, loss-of-function mutations in the DDC gene result in severe enzymatic deficiency and devastating autonomic, motor, and cognitive impairment, DDC common genetic polymorphisms have been proposed as a source of more moderate, but clinically important, alterations in DDC function that may contribute to risk, course, or treatment response in complex, heritable neuropsychiatric illnesses. However, a direct link between common genetic variation in DDC and DDC activity in the living human brain has never been established. We therefore tested for this association by conducting extensive genotyping across the DDC gene in a large cohort of 120 healthy individuals, for whom DDC activity was then quantified with [(18)F]-FDOPA positron emission tomography (PET). The specific uptake constant, Ki, a measure of DDC activity, was estimated for striatal regions of interest and found to be predicted by one of five tested haplotypes, particularly in the ventral striatum. These data provide evidence for cis-acting, functional common polymorphisms in the DDC gene and support future work to determine whether such variation might meaningfully contribute to DDC-mediated neural processes relevant to neuropsychiatric illness and treatment.

  3. Variations in CCL3L gene cluster sequence and non-specific gene copy numbers

    Edberg Jeffrey C

    2010-03-01

    Full Text Available Abstract Background Copy number variations (CNVs of the gene CC chemokine ligand 3-like1 (CCL3L1 have been implicated in HIV-1 susceptibility, but the association has been inconsistent. CCL3L1 shares homology with a cluster of genes localized to chromosome 17q12, namely CCL3, CCL3L2, and, CCL3L3. These genes are involved in host defense and inflammatory processes. Several CNV assays have been developed for the CCL3L1 gene. Findings Through pairwise and multiple alignments of these genes, we have shown that the homology between these genes ranges from 50% to 99% in complete gene sequences and from 70-100% in the exonic regions, with CCL3L1 and CCL3L3 being identical. By use of MEGA 4 and BioEdit, we aligned sense primers, anti-sense primers, and probes used in several previously described assays against pre-multiple alignments of all four chemokine genes. Each set of probes and primers aligned and matched with overlapping sequences in at least two of the four genes, indicating that previously utilized RT-PCR based CNV assays are not specific for only CCL3L1. The four available assays measured median copies of 2 and 3-4 in European and African American, respectively. The concordance between the assays ranged from 0.44-0.83 suggesting individual discordant calls and inconsistencies with the assays from the expected gene coverage from the known sequence. Conclusions This indicates that some of the inconsistencies in the association studies could be due to assays that provide heterogenous results. Sequence information to determine CNV of the three genes separately would allow to test whether their association with the pathogenesis of a human disease or phenotype is affected by an individual gene or by a combination of these genes.

  4. Phylogenomic analysis demonstrates a pattern of rare and ancient horizontal gene transfer between plants and fungi.

    Richards, Thomas A; Soanes, Darren M; Foster, Peter G; Leonard, Guy; Thornton, Christopher R; Talbot, Nicholas J

    2009-07-01

    Horizontal gene transfer (HGT) describes the transmission of genetic material across species boundaries and is an important evolutionary phenomenon in the ancestry of many microbes. The role of HGT in plant evolutionary history is, however, largely unexplored. Here, we compare the genomes of six plant species with those of 159 prokaryotic and eukaryotic species and identify 1689 genes that show the highest similarity to corresponding genes from fungi. We constructed a phylogeny for all 1689 genes identified and all homolog groups available from the rice (Oryza sativa) genome (3177 gene families) and used these to define 14 candidate plant-fungi HGT events. Comprehensive phylogenetic analyses of these 14 data sets, using methods that account for site rate heterogeneity, demonstrated support for nine HGT events, demonstrating an infrequent pattern of HGT between plants and fungi. Five HGTs were fungi-to-plant transfers and four were plant-to-fungi HGTs. None of the fungal-to-plant HGTs involved angiosperm recipients. These results alter the current view of organismal barriers to HGT, suggesting that phagotrophy, the consumption of a whole cell by another, is not necessarily a prerequisite for HGT between eukaryotes. Putative functional annotation of the HGT candidate genes suggests that two fungi-to-plant transfers have added phenotypes important for life in a soil environment. Our study suggests that genetic exchange between plants and fungi is exceedingly rare, particularly among the angiosperms, but has occurred during their evolutionary history and added important metabolic traits to plant lineages.

  5. Sequence variations in the FAD2 gene in seeded pumpkins.

    Ge, Y; Chang, Y; Xu, W L; Cui, C S; Qu, S P

    2015-12-21

    Seeded pumpkins are important economic crops; the seeds contain various unsaturated fatty acids, such as oleic acid and linoleic acid, which are crucial for human and animal nutrition. The fatty acid desaturase-2 (FAD2) gene encodes delta-12 desaturase, which converts oleic acid to linoleic acid. However, little is known about sequence variations in FAD2 in seeded pumpkins. Twenty-seven FAD2 clones from 27 accessions of Cucurbita moschata, Cucurbita maxima, Cucurbita pepo, and Cucurbita ficifolia were obtained (totally 1152 bp; a single gene without introns). More than 90% nucleotide identities were detected among the 27 FAD2 clones. Nucleotide substitution, rather than nucleotide insertion and deletion, led to sequence polymorphism in the 27 FAD2 clones. Furthermore, the 27 FAD2 selected clones all encoded the FAD2 enzyme (delta-12 desaturase) with amino acid sequence identities from 91.7 to 100% for 384 amino acids. The same main-function domain between 47 and 329 amino acids was identified. The four species clustered separately based on differences in the sequences that were identified using the unweighted pair group method with arithmetic mean. Geographic origin and species were found to be closely related to sequence variation in FAD2.

  6. Oxytocin receptor gene variation predicts subjective responses to MDMA.

    Bershad, Anya K; Weafer, Jessica J; Kirkpatrick, Matthew G; Wardle, Margaret C; Miller, Melissa A; de Wit, Harriet

    2016-12-01

    3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") enhances desire to socialize and feelings of empathy, which are thought to be related to increased oxytocin levels. Thus, variation in the oxytocin receptor gene (OXTR) may influence responses to the drug. Here, we examined the influence of a single OXTR nucleotide polymorphism (SNP) on responses to MDMA in humans. Based on findings that carriers of the A allele at rs53576 exhibit reduced sensitivity to oxytocin-induced social behavior, we hypothesized that these individuals would show reduced subjective responses to MDMA, including sociability. In this three-session, double blind, within-subjects study, healthy volunteers with past MDMA experience (N = 68) received a MDMA (0, 0.75 mg/kg, and 1.5 mg/kg) and provided self-report ratings of sociability, anxiety, and drug effects. These responses were examined in relation to rs53576. MDMA (1.5 mg/kg) did not increase sociability in individuals with the A/A genotype as it did in G allele carriers. The genotypic groups did not differ in responses at the lower MDMA dose, or in cardiovascular or other subjective responses. These findings are consistent with the idea that MDMA-induced sociability is mediated by oxytocin, and that variation in the oxytocin receptor gene may influence responses to the drug.

  7. Unusual Congenital Aortic Anomaly with Rare Common Celiamesenteric Trunk Variation: MR Angiography and Digital Substraction Angiography Findings

    Tosun, Ozgur; Sanlidilek, Umman; Cetin, Huseyin; Ozdemir, Ozcan; Kurt, Aydin; Sakarya, Mehmet Emin; Tas, Ismet

    2007-01-01

    Magnetic resonance angiography and digital substraction angiography (DSA) findings in a case with a rare congenital thoracoabdominal aortic hypoplasia and common celiamesenteric trunk variation with occlusion of infrarenal abdominal aorta are described here. To our knowledge, this aortic anomaly has not been previously described in the English literature. DSA is the optimum imaging modality for determination of aortic hypoplasia, associated vascular malformations, collateral vessels, and direction of flow within vessels

  8. Two novel rare variants of APOA5 gene found in subjects with severe hypertriglyceridemia.

    Pisciotta, Livia; Fresa, Raffaele; Bellocchio, Antonella; Guido, Virgilia; Priore Oliva, Claudio; Calandra, Sebastiano; Bertolini, Stefano

    2011-11-20

    Common variants of APOA5 gene affect plasma triglyceride (TG) in the population and a number of rare variants APOA5 have been reported in individuals with hypertriglyceridemia (HTG). APOA5 was analysed in 98 HTG individuals (plasma TG >9 mmol/L) in whom no mutations in LPL and APOC2 had been found. Two patients were found to be heterozygous for two novel APOA5 variants. The first variant (p.L253P) was identified in an obese male who consumed a diet rich in fat and simple sugars. He was also a carrier in trans of the common TG-raising p.S19W SNP (5*3 haplotype). The second variant (c.295-297 del GAG, p.E99 del) was found in a lean male with no life style or metabolic factors known to affect plasma TG. He was a carrier in trans of the TG-raising 5*2 haplotype and was homozygous for the rare c.1337T allele of a SNP of GCKR gene. No mutations in other genes affecting plasma TG (LMF1 and GPIHBP1) were found in these patients. These APOA5 variants, resulted to be deleterious in silico, were not found in 350 control subjects. These novel APOA5 variants predispose to HTG in combination with other genetic or nutritional factors. Copyright © 2011 Elsevier B.V. All rights reserved.

  9. Haplotypes and Sequence Variation in the Ovine Adiponectin Gene (ADIPOQ

    Qing-Ming An

    2015-11-01

    Full Text Available The adiponectin gene (ADIPOQ plays an important role in energy homeostasis. In this study five separate regions (regions 1 to 5 of ovine ADIPOQ were analysed using PCR-SSCP. Four different PCR-SSCP patterns (A1-D1, A2-D2 were detected in region-1 and region-2, respectively, with seven and six SNPs being revealed. In region-3, three different patterns (A3-C3 and three SNPs were observed. Two patterns (A4-B4, A5-B5 and two and one SNPs were observed in region-4 and region-5, respectively. In total, nineteen SNPs were detected, with five of them in the coding region and two (c.46T/C and c.515G/A putatively resulting in amino acid changes (p.Tyr16His and p.Lys172Arg. In region-1, -2 and -3 of 316 sheep from eight New Zealand breeds, variants A1, A2 and A3 were the most common, although variant frequencies differed in the eight breeds. Across region-1 and region-3, nine haplotypes were identified and haplotypes A1-A3, A1-C3, B1-A3 and B1-C3 were most common. These results indicate that the ADIPOQ gene is polymorphic and suggest that further analysis is required to see if the variation in the gene is associated with animal production traits.

  10. The impact of gene expression variation on the robustness and evolvability of a developmental gene regulatory network.

    David A Garfield

    2013-10-01

    Full Text Available Regulatory interactions buffer development against genetic and environmental perturbations, but adaptation requires phenotypes to change. We investigated the relationship between robustness and evolvability within the gene regulatory network underlying development of the larval skeleton in the sea urchin Strongylocentrotus purpuratus. We find extensive variation in gene expression in this network throughout development in a natural population, some of which has a heritable genetic basis. Switch-like regulatory interactions predominate during early development, buffer expression variation, and may promote the accumulation of cryptic genetic variation affecting early stages. Regulatory interactions during later development are typically more sensitive (linear, allowing variation in expression to affect downstream target genes. Variation in skeletal morphology is associated primarily with expression variation of a few, primarily structural, genes at terminal positions within the network. These results indicate that the position and properties of gene interactions within a network can have important evolutionary consequences independent of their immediate regulatory role.

  11. Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

    Lin, Honghuang; van Setten, Jessica; Smith, Albert V

    2018-01-01

    BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequ...

  12. Variation of Rare Earth Elements (REEs) in the Sulu and Celebes ...

    This study provides a dataset of rare earth elements (REEs) in the seawater of Sulu and Celebes Seas of Malaysian waters during the PMSE 09' expedition, which was conducted to define the pattern of REEs in both seas. Samples were collected, filtered and pre-concentrated on-board ship then analyzed by using ICP-MS.

  13. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.

    Glessner, Joseph T; Wang, Kai; Cai, Guiqing; Korvatska, Olena; Kim, Cecilia E; Wood, Shawn; Zhang, Haitao; Estes, Annette; Brune, Camille W; Bradfield, Jonathan P; Imielinski, Marcin; Frackelton, Edward C; Reichert, Jennifer; Crawford, Emily L; Munson, Jeffrey; Sleiman, Patrick M A; Chiavacci, Rosetta; Annaiah, Kiran; Thomas, Kelly; Hou, Cuiping; Glaberson, Wendy; Flory, James; Otieno, Frederick; Garris, Maria; Soorya, Latha; Klei, Lambertus; Piven, Joseph; Meyer, Kacie J; Anagnostou, Evdokia; Sakurai, Takeshi; Game, Rachel M; Rudd, Danielle S; Zurawiecki, Danielle; McDougle, Christopher J; Davis, Lea K; Miller, Judith; Posey, David J; Michaels, Shana; Kolevzon, Alexander; Silverman, Jeremy M; Bernier, Raphael; Levy, Susan E; Schultz, Robert T; Dawson, Geraldine; Owley, Thomas; McMahon, William M; Wassink, Thomas H; Sweeney, John A; Nurnberger, John I; Coon, Hilary; Sutcliffe, James S; Minshew, Nancy J; Grant, Struan F A; Bucan, Maja; Cook, Edwin H; Buxbaum, Joseph D; Devlin, Bernie; Schellenberg, Gerard D; Hakonarson, Hakon

    2009-05-28

    Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with approximately 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x 10(-3)). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 10(-6)). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.

  14. Short rare hTERT-VNTR2-2nd alleles are associated with prostate cancer susceptibility and influence gene expression

    Yoon, Se-Lyun; Cheon, Sang-Hyeon; Leem, Sun-Hee; Jung, Se-Il; Do, Eun-Ju; Lee, Se-Ra; Lee, Sang-Yeop; Chu, In-Sun; Kim, Wun-Jae; Jung, Jaeil; Kim, Choung Soo

    2010-01-01

    The hTERT (human telomerase reverse transcriptase) gene contains five variable number tandem repeats (VNTR) and previous studies have described polymorphisms for hTERT-VNTR2-2 nd . We investigated how allelic variation in hTERT-VNTR2-2 nd may affect susceptibility to prostate cancer. A case-control study was performed using DNA from 421 cancer-free male controls and 329 patients with prostate cancer. In addition, to determine whether the VNTR polymorphisms have a functional consequence, we examined the transcriptional levels of a reporter gene linked to these VNTRs and driven by the hTERT promoter in cell lines. Three new rare alleles were detected from this study, two of which were identified only in cancer subjects. A statistically significant association between rare hTERT-VNTR2-2 nd alleles and risk of prostate cancer was observed [OR, 5.17; 95% confidence interval (CI), 1.09-24.43; P = 0.021]. Furthermore, the results indicated that these VNTRs inserted in the enhancer region could influence the expression of hTERT in prostate cancer cell lines. This is the first study to report that rare hTERT VNTRs are associated with prostate cancer predisposition and that the VNTRs can induce enhanced levels of hTERT promoter activity in prostate cancer cell lines. Thus, the hTERT-VNTR2-2 nd locus may function as a modifier of prostate cancer risk by affecting gene expression

  15. Allelic diversity in an NLR gene BPH9 enables rice to combat planthopper variation.

    Zhao, Yan; Huang, Jin; Wang, Zhizheng; Jing, Shengli; Wang, Yang; Ouyang, Yidan; Cai, Baodong; Xin, Xiu-Fang; Liu, Xin; Zhang, Chunxiao; Pan, Yufang; Ma, Rui; Li, Qiaofeng; Jiang, Weihua; Zeng, Ya; Shangguan, Xinxin; Wang, Huiying; Du, Bo; Zhu, Lili; Xu, Xun; Feng, Yu-Qi; He, Sheng Yang; Chen, Rongzhi; Zhang, Qifa; He, Guangcun

    2016-10-24

    Brown planthopper (BPH), Nilaparvata lugens Stål, is one of the most devastating insect pests of rice (Oryza sativa L.). Currently, 30 BPH-resistance genes have been genetically defined, most of which are clustered on specific chromosome regions. Here, we describe molecular cloning and characterization of a BPH-resistance gene, BPH9, mapped on the long arm of rice chromosome 12 (12L). BPH9 encodes a rare type of nucleotide-binding and leucine-rich repeat (NLR)-containing protein that localizes to the endomembrane system and causes a cell death phenotype. BPH9 activates salicylic acid- and jasmonic acid-signaling pathways in rice plants and confers both antixenosis and antibiosis to BPH. We further demonstrated that the eight BPH-resistance genes that are clustered on chromosome 12L, including the widely used BPH1, are allelic with each other. To honor the priority in the literature, we thus designated this locus as BPH1/9 These eight genes can be classified into four allelotypes, BPH1/9-1, -2, -7, and -9 These allelotypes confer varying levels of resistance to different biotypes of BPH. The coding region of BPH1/9 shows a high level of diversity in rice germplasm. Homologous fragments of the nucleotide-binding (NB) and leucine-rich repeat (LRR) domains exist, which might have served as a repository for generating allele diversity. Our findings reveal a rice plant strategy for modifying the genetic information to gain the upper hand in the struggle against insect herbivores. Further exploration of natural allelic variation and artificial shuffling within this gene may allow breeding to be tailored to control emerging biotypes of BPH.

  16. Variation of the rare earth element concentrations in the soil, soil extract and in individual plants from the same site

    Wyttenbach, A.; Tobler, L.; Furrer, V.; Schleppi, P.

    1998-01-01

    Samples of various types (spruce needles, blackberry leaves, soils, and soil extracts) have each been taken at 6 places from the same site. In addition, 4 whirls each from 2 spruce trees were sampled. Rare earth elements (REEs) were determined in these samples by neutron activation analysis with a chemical group separation. Variations between places were found to be small with soils and soil extracts, but large with plants. Variations between whirls were small. Plants neither reflected the soil nor the soil extract. Both plant species were dissimilar, but the logarithm of their ratio was a linear function of the atomic number of the REE. A negative Ce anomaly (with respect to soil) was found in both plant species. (author)

  17. Conceptual Variation or Incoherence? Textbook Discourse on Genes in Six Countries

    Gericke, Niklas M.; Hagberg, Mariana; dos Santos, Vanessa Carvalho; Joaquim, Leyla Mariane; El-Hani, Charbel N.

    2014-01-01

    The aim of this paper is to investigate in a systematic and comparative way previous results of independent studies on the treatment of genes and gene function in high school textbooks from six different countries. We analyze how the conceptual variation within the scientific domain of Genetics regarding gene function models and gene concepts is…

  18. Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa

    Huckins, L M; Hatzikotoulas, K; Southam, L; Thornton, L M; Steinberg, J; Aguilera-McKay, F; Treasure, J; Schmidt, U; Gunasinghe, C; Romero, A; Curtis, C; Rhodes, D; Moens, J; Kalsi, G; Dempster, D; Leung, R; Keohane, A; Burghardt, R; Ehrlich, S; Hebebrand, J; Hinney, A; Ludolph, A; Walton, E; Deloukas, P; Hofman, A; Palotie, A; Palta, P; van Rooij, F J A; Stirrups, K; Adan, R; Boni, C; Cone, R; Dedoussis, G; van Furth, E; Gonidakis, F; Gorwood, P; Hudson, J; Kaprio, J; Kas, M; Keski-Rahonen, A; Kiezebrink, K; Knudsen, G-P; Slof-Op 't Landt, M C T; Maj, M; Monteleone, A M; Monteleone, P; Raevuori, A H; Reichborn-Kjennerud, T; Tozzi, F; Tsitsika, A; van Elburg, A; Adan, R A H; Alfredsson, L; Ando, T; Andreassen, O A; Aschauer, H; Baker, J H; Barrett, J C; Bencko, V; Bergen, A W; Berrettini, W H; Birgegard, A; Boni, C; Boraska Perica, V; Brandt, H; Breen, G; Bulik, C M; Carlberg, L; Cassina, M; Cichon, S; Clementi, M; Cohen-Woods, S; Coleman, J; Cone, R D; Courtet, P; Crawford, S; Crow, S; Crowley, J; Danner, U N; Davis, O S P; de Zwaan, M; Dedoussis, G; Degortes, D; DeSocio, J E; Dick, D M; Dikeos, D; Dina, C; Ding, B; Dmitrzak-Weglarz, M; Docampo, E; Duncan, L; Egberts, K; Ehrlich, S; Escaramís, G; Esko, T; Espeseth, T; Estivill, X; Favaro, A; Fernández-Aranda, F; Fichter, M M; Finan, C; Fischer, K; Floyd, J A B; Foretova, L; Forzan, M; Franklin, C S; Gallinger, S; Gambaro, G; Gaspar, H A; Giegling, I; Gonidakis, F; Gorwood, P; Gratacos, M; Guillaume, S; Guo, Y; Hakonarson, H; Halmi, K A; Hatzikotoulas, K; Hauser, J; Hebebrand, J; Helder, S; Herms, S; Herpertz-Dahlmann, B; Herzog, W; Hilliard, C E; Hinney, A; Hübel, C; Huckins, L M; Hudson, J I; Huemer, J; Inoko, H; Janout, V; Jiménez-Murcia, S; Johnson, C; Julià, A; Juréus, A; Kalsi, G; Kaminska, D; Kaplan, A S; Kaprio, J; Karhunen, L; Karwautz, A; Kas, M J H; Kaye, W; Kennedy, J L; Keski-Rahkonen, A; Kiezebrink, K; Klareskog, L; Klump, K L; Knudsen, G P S; Koeleman, B P C; Koubek, D; La Via, M C; Landén, M; Le Hellard, S; Levitan, R D; Li, D; Lichtenstein, P; Lilenfeld, L; Lissowska, J; Lundervold, A; Magistretti, P; Maj, M; Mannik, K; Marsal, S; Martin, N; Mattingsdal, M; McDevitt, S; McGuffin, P; Merl, E; Metspalu, A; Meulenbelt, I; Micali, N; Mitchell, J; Mitchell, K; Monteleone, P; Monteleone, A M; Mortensen, P; Munn-Chernoff, M A; Navratilova, M; Nilsson, I; Norring, C; Ntalla, I; Ophoff, R A; O'Toole, J K; Palotie, A; Pante, J; Papezova, H; Pinto, D; Rabionet, R; Raevuori, A; Rajewski, A; Ramoz, N; Rayner, N W; Reichborn-Kjennerud, T; Ripatti, S; Roberts, M; Rotondo, A; Rujescu, D; Rybakowski, F; Santonastaso, P; Scherag, A; Scherer, S W; Schmidt, U; Schork, N J; Schosser, A; Slachtova, L; Sladek, R; Slagboom, P E; Slof-Op 't Landt, M C T; Slopien, A; Soranzo, N; Southam, L; Steen, V M; Strengman, E; Strober, M; Sullivan, P F; Szatkiewicz, J P; Szeszenia-Dabrowska, N; Tachmazidou, I; Tenconi, E; Thornton, L M; Tortorella, A; Tozzi, F; Treasure, J; Tsitsika, A; Tziouvas, K; van Elburg, A A; van Furth, E F; Wagner, G; Walton, E; Watson, H; Wichmann, H-E; Widen, E; Woodside, D B; Yanovski, J; Yao, S; Yilmaz, Z; Zeggini, E; Zerwas, S; Zipfel, S; Collier, D A; Sullivan, P F; Breen, G; Bulik, C M; Zeggini, E

    2018-01-01

    Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10−6), and rs7700147, an intergenic variant (P=2.93 × 10−5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes. PMID:29155802

  19. Atrazine affects kidney and adrenal hormones (AHs) related genes expressions of rare minnow (Gobiocypris rarus).

    Yang, Lihua; Zha, Jinmiao; Li, Wei; Li, Zhaoli; Wang, Zijian

    2010-05-05

    Atrazine, one of the most widely used herbicides, has been proved to interfere with sexual hormones. However few studies have considered the effects of atrazine on adrenal hormones (AH). In this study, rare minnow (Gobiocypris rarus) was exposed to 0, 3, 10, 33, 100 and 333microg/l atrazine for 28 days. The histopathology of kidney and gill was examined and the expressions of AHs-related genes including Na(+),K(+)-ATPase, glucocorticoid receptor (gr), heat shock protein 70 (hsp70), and heat shock protein 90 (hsp90) in kidney and gill were quantitatively determined. Histopathological observation revealed obvious lesions in gill including hyperplasia, necrosis in epithelium region, aneurysm and lamellar fusion at concentrations as low as 10microg/l. The observed lesions in kidney included extensive expansion in the lumen, degenerative and necrotic changes of the tubular epithelia, shrinkage of the glomerulus as well as increase of the Bowman's space at concentrations as low as 10microg/l. The expressions of Na(+),K(+)-ATPase, gr, hsp70 and hsp90 in the kidney of females were significantly decreased at all concentrations. For males, the expressions of hsp90 in the kidney of all treated groups were significantly down-regulated, while gr at all concentrations and hsp70 at 10, 33, 100microg/l were significantly up-regulated. However in the gill, the expressions of these genes were not significantly different from the control. These results indicated that exposure to atrazine caused impairments of kidney and gill of fish at environmental related concentrations. Histopathological lesions could partly attribute to the changes of the expressions of AHs-related genes in kidney. We concluded also that atrazine is a potential AHs-disruptor and AHs-related genes in kidney of fish could be used as sensitive molecular biomarkers.

  20. Atrazine affects kidney and adrenal hormones (AHs) related genes expressions of rare minnow (Gobiocypris rarus)

    Yang Lihua; Zha Jinmiao; Li Wei; Li Zhaoli [State Key Laboratory of Environmental Aquatic Chemistry, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Shuangqing Road 18, P.O. Box 2871, Beijing 100085 (China); Wang Zijian, E-mail: wangzj@rcees.ac.cn [State Key Laboratory of Environmental Aquatic Chemistry, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Shuangqing Road 18, P.O. Box 2871, Beijing 100085 (China)

    2010-05-05

    Atrazine, one of the most widely used herbicides, has been proved to interfere with sexual hormones. However few studies have considered the effects of atrazine on adrenal hormones (AH). In this study, rare minnow (Gobiocypris rarus) was exposed to 0, 3, 10, 33, 100 and 333 {mu}g/l atrazine for 28 days. The histopathology of kidney and gill was examined and the expressions of AHs-related genes including Na{sup +},K{sup +}-ATPase, glucocorticoid receptor (gr), heat shock protein 70 (hsp70), and heat shock protein 90 (hsp90) in kidney and gill were quantitatively determined. Histopathological observation revealed obvious lesions in gill including hyperplasia, necrosis in epithelium region, aneurysm and lamellar fusion at concentrations as low as 10 {mu}g/l. The observed lesions in kidney included extensive expansion in the lumen, degenerative and necrotic changes of the tubular epithelia, shrinkage of the glomerulus as well as increase of the Bowman's space at concentrations as low as 10 {mu}g/l. The expressions of Na{sup +},K{sup +}-ATPase, gr, hsp70 and hsp90 in the kidney of females were significantly decreased at all concentrations. For males, the expressions of hsp90 in the kidney of all treated groups were significantly down-regulated, while gr at all concentrations and hsp70 at 10, 33, 100 {mu}g/l were significantly up-regulated. However in the gill, the expressions of these genes were not significantly different from the control. These results indicated that exposure to atrazine caused impairments of kidney and gill of fish at environmental related concentrations. Histopathological lesions could partly attribute to the changes of the expressions of AHs-related genes in kidney. We concluded also that atrazine is a potential AHs-disruptor and AHs-related genes in kidney of fish could be used as sensitive molecular biomarkers.

  1. Atrazine affects kidney and adrenal hormones (AHs) related genes expressions of rare minnow (Gobiocypris rarus)

    Yang Lihua; Zha Jinmiao; Li Wei; Li Zhaoli; Wang Zijian

    2010-01-01

    Atrazine, one of the most widely used herbicides, has been proved to interfere with sexual hormones. However few studies have considered the effects of atrazine on adrenal hormones (AH). In this study, rare minnow (Gobiocypris rarus) was exposed to 0, 3, 10, 33, 100 and 333 μg/l atrazine for 28 days. The histopathology of kidney and gill was examined and the expressions of AHs-related genes including Na + ,K + -ATPase, glucocorticoid receptor (gr), heat shock protein 70 (hsp70), and heat shock protein 90 (hsp90) in kidney and gill were quantitatively determined. Histopathological observation revealed obvious lesions in gill including hyperplasia, necrosis in epithelium region, aneurysm and lamellar fusion at concentrations as low as 10 μg/l. The observed lesions in kidney included extensive expansion in the lumen, degenerative and necrotic changes of the tubular epithelia, shrinkage of the glomerulus as well as increase of the Bowman's space at concentrations as low as 10 μg/l. The expressions of Na + ,K + -ATPase, gr, hsp70 and hsp90 in the kidney of females were significantly decreased at all concentrations. For males, the expressions of hsp90 in the kidney of all treated groups were significantly down-regulated, while gr at all concentrations and hsp70 at 10, 33, 100 μg/l were significantly up-regulated. However in the gill, the expressions of these genes were not significantly different from the control. These results indicated that exposure to atrazine caused impairments of kidney and gill of fish at environmental related concentrations. Histopathological lesions could partly attribute to the changes of the expressions of AHs-related genes in kidney. We concluded also that atrazine is a potential AHs-disruptor and AHs-related genes in kidney of fish could be used as sensitive molecular biomarkers.

  2. Study of rare-gas dimer ions by the variational cellular method

    Wentzcovitch, R.M.M.

    1982-01-01

    The Variational Cellular Method to study ionized molecules in their ground and excited states with the scope of testing the validity of such method in these cases have been used. The ions studied are Ne +2 , Ar +2 , where the latter is the system with the largest number of electrons tested by VCM so far. The electronic transitions in these systems are important mechanisms of efficiency decay for the noble gas halide lasers ('excimer lasers'). (Author) [pt

  3. Variation in gene expression within clones of the earthworm Dendrobaena octaedra.

    Marina Mustonen

    Full Text Available Gene expression is highly plastic, which can help organisms to both acclimate and adapt to changing environments. Possible variation in gene expression among individuals with the same genotype (among clones is not widely considered, even though it could impact the results of studies that focus on gene expression phenotypes, for example studies using clonal lines. We examined the extent of within and between clone variation in gene expression in the earthworm Dendrobaena octaedra, which reproduces through apomictic parthenogenesis. Five microsatellite markers were developed and used to confirm that offspring are genetic clones of their parent. After that, expression of 12 genes was measured from five individuals each from six clonal lines after exposure to copper contaminated soil. Variation in gene expression was higher over all genotypes than within genotypes, as initially assumed. A subset of the genes was also examined in the offspring of exposed individuals in two of the clonal lines. In this case, variation in gene expression within genotypes was as high as that observed over all genotypes. One gene in particular (chymotrypsin inhibitor also showed significant differences in the expression levels among genetically identical individuals. Gene expression can vary considerably, and the extent of variation may depend on the genotypes and genes studied. Ensuring a large sample, with many different genotypes, is critical in studies comparing gene expression phenotypes. Researchers should be especially cautious inferring gene expression phenotypes when using only a single clonal or inbred line, since the results might be specific to only certain genotypes.

  4. A targeted sequencing panel identifies rare damaging variants in multiple genes in the cranial neural tube defect, anencephaly.

    Ishida, M; Cullup, T; Boustred, C; James, C; Docker, J; English, C; Lench, N; Copp, A J; Moore, G E; Greene, N D E; Stanier, P

    2018-04-01

    Neural tube defects (NTDs) affecting the brain (anencephaly) are lethal before or at birth, whereas lower spinal defects (spina bifida) may lead to lifelong neurological handicap. Collectively, NTDs rank among the most common birth defects worldwide. This study focuses on anencephaly, which despite having a similar frequency to spina bifida and being the most common type of NTD observed in mouse models, has had more limited inclusion in genetic studies. A genetic influence is strongly implicated in determining risk of NTDs and a molecular diagnosis is of fundamental importance to families both in terms of understanding the origin of the condition and for managing future pregnancies. Here we used a custom panel of 191 NTD candidate genes to screen 90 patients with cranial NTDs (n = 85 anencephaly and n = 5 craniorachischisis) with a targeted exome sequencing platform. After filtering and comparing to our in-house control exome database (N = 509), we identified 397 rare variants (minor allele frequency, MAF < 1%), 21 of which were previously unreported and predicted damaging. This included 1 frameshift (PDGFRA), 2 stop-gained (MAT1A; NOS2) and 18 missense variations. Together with evidence for oligogenic inheritance, this study provides new information on the possible genetic causation of anencephaly. © 2017 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Spectrum of sequence variations in the FANCA gene: an International Fanconi Anemia Registry (IFAR) study.

    Levran, Orna; Diotti, Raffaella; Pujara, Kanan; Batish, Sat D; Hanenberg, Helmut; Auerbach, Arleen D

    2005-02-01

    Fanconi anemia (FA) is an autosomal recessive disorder that is defined by cellular hypersensitivity to DNA cross-linking agents, and is characterized clinically by developmental abnormalities, progressive bone-marrow failure, and predisposition to leukemia and solid tumors. There is extensive genetic heterogeneity, with at least 11 different FA complementation groups. FA-A is the most common group, accounting for approximately 65% of all affected individuals. The mutation spectrum of the FANCA gene, located on chromosome 16q24.3, is highly heterogeneous. Here we summarize all sequence variations (mutations and polymorphisms) in FANCA described in the literature and listed in the Fanconi Anemia Mutation Database as of March 2004, and report 61 novel FANCA mutations identified in FA patients registered in the International Fanconi Anemia Registry (IFAR). Thirty-eight novel SNPs, previously unreported in the literature or in dbSNP, were also identified. We studied the segregation of common FANCA SNPs in FA families to generate haplotypes. We found that FANCA SNP data are highly useful for carrier testing, prenatal diagnosis, and preimplantation genetic diagnosis, particularly when the disease-causing mutations are unknown. Twenty-two large genomic deletions were identified by detection of apparent homozygosity for rare SNPs. In addition, a conserved SNP haplotype block spanning at least 60 kb of the FANCA gene was identified in individuals from various ethnic groups. (c) 2005 Wiley-Liss, Inc.

  6. Trifid nasopalatine canal: case report of a rare anatomical variation and its surgical implications

    Guanaes Gomes Torres, Marianna; Crusoé-Rebello, Margarida Iêda; Faro Valverde, Ludmila de; Torres Andion Vidal, Manuela

    2016-01-01

    The nasopalatine canal is a long slender structure present in the midline of the anterior maxilla that connects the palate to the floor of the nasal cavity. The nasopalatine canal contains the nasopalatine nerve, the terminal branch of the nasopalatine artery, fibrous connective tissue, adipose tissue, and minor salivary glands. The purpose of this article was to report a case of a trifid nasopalatine canal detected by cone beam computed tomography prior to dental implant placement. A 47-year-old female patient was submitted to cone beam computed tomography. Axial and sagittal sections revealed a trifurcation of the nasopalatine canal. Each canal was separated from the other by bony septa and extended independently from the floor of the nasal cavity to the incisive foramen in the remnant of the alveolar process in the anterior region of the maxilla. Cone beam computed tomography has permitted better visualization of the details and anatomical variations of the nasopalatine canal. Detailed knowledge of variations in the shape, number and size of the nasopalatine canal is fundamental for surgical procedures, such as local anesthesia in the anterior maxillary region and placement of dental implants, in order to prevent damage to important arteries and nerves. (author)

  7. Huntingtin gene repeat size variations affect risk of lifetime depression.

    Gardiner, Sarah L; van Belzen, Martine J; Boogaard, Merel W; van Roon-Mom, Willeke M C; Rozing, Maarten P; van Hemert, Albert M; Smit, Johannes H; Beekman, Aartjan T F; van Grootheest, Gerard; Schoevers, Robert A; Oude Voshaar, Richard C; Roos, Raymund A C; Comijs, Hannie C; Penninx, Brenda W J H; van der Mast, Roos C; Aziz, N Ahmad

    2017-12-11

    Huntington disease (HD) is a severe neuropsychiatric disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the HTT gene. Although HD is frequently complicated by depression, it is still unknown to what extent common HTT CAG repeat size variations in the normal range could affect depression risk in the general population. Using binary logistic regression, we assessed the association between HTT CAG repeat size and depression risk in two well-characterized Dutch cohorts─the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Older Persons─including 2165 depressed and 1058 non-depressed persons. In both cohorts, separately as well as combined, there was a significant non-linear association between the risk of lifetime depression and HTT CAG repeat size in which both relatively short and relatively large alleles were associated with an increased risk of depression (β = -0.292 and β = 0.006 for the linear and the quadratic term, respectively; both P < 0.01 after adjustment for the effects of sex, age, and education level). The odds of lifetime depression were lowest in persons with a HTT CAG repeat size of 21 (odds ratio: 0.71, 95% confidence interval: 0.52 to 0.98) compared to the average odds in the total cohort. In conclusion, lifetime depression risk was higher with both relatively short and relatively large HTT CAG repeat sizes in the normal range. Our study provides important proof-of-principle that repeat polymorphisms can act as hitherto unappreciated but complex genetic modifiers of depression.

  8. Luminescence of Lanthanoides (Rare-earth elements) – Probes of structural variations in minerals

    Lenz, C.

    2015-01-01

    This cumulative PhD thesis summarises several individual studies on the luminescence of REE (rare-earth elements; i.e., trivalent lanthanoides), which are typically incorporated in accessory minerals such as zircon, titanite, monazite–(Ce) and xenotime–(Y). A main objective of these studies is to examine the powerfulness of REE luminescence-spectroscopy as structural probe. In particular, this concerns the potential use of REE3+ emissions in characterising structural disorder of their accessory host minerals as caused by radiation damage and/or compositional heterogeneity. Especially the former (i.e., mineral disorder due to radiation damage) is of interest to Earth and materials scientists, for instance for the understanding of changed physicochemical properties of initially crystalline materials that are affected by structural damage as caused by the radioactive decay of actinides. Moreover, a substantial contribution of the studies presented lies in the field of basic properties of the REE luminescence of natural accessory minerals. First, the investigations have addressed the identification of diverse REE species in diverse natural host minerals (which is done using synthetic REE-doped analogues). Second, factors that may bias the quantitative estimation of spectroscopic parameters have been studied, including effects of experimental parameters (crystal orientation and temperature) and the samples’ compositional heterogeneity. The results will be particularly useful to the growing community of Earth scientists who apply REE luminescence-spectroscopy in studying geological materials. (author) [de

  9. Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trial

    Skylar W. Marvel

    2017-05-01

    Full Text Available Background Individuals with type 2 diabetes are at an increased risk of cardiovascular disease. Alterations in circulating lipid levels, total cholesterol (TC, low-density lipoprotein (LDL, high-density lipoprotein (HDL, and triglycerides (TG are heritable risk factors for cardiovascular disease. Here we conduct a genome-wide association study (GWAS of common and rare variants to investigate associations with baseline lipid levels in 7,844 individuals with type 2 diabetes from the ACCORD clinical trial. Methods DNA extracted from stored blood samples from ACCORD participants were genotyped using the Affymetrix Axiom Biobank 1 Genotyping Array. After quality control and genotype imputation, association of common genetic variants (CV, defined as minor allele frequency (MAF ≥ 3%, with baseline levels of TC, LDL, HDL, and TG was tested using a linear model. Rare variant (RV associations (MAF < 3% were conducted using a suite of methods that collapse multiple RV within individual genes. Results Many statistically significant CV (p < 1 × 10−8 replicate findings in large meta-analyses in non-diabetic subjects. RV analyses also confirmed findings in other studies, whereas significant RV associations with CNOT2, HPN-AS1, and SIRPD appear to be novel (q < 0.1. Discussion Here we present findings for the largest GWAS of lipid levels in people with type 2 diabetes to date. We identified 17 statistically significant (p < 1 × 10−8 associations of CV with lipid levels in 11 genes or chromosomal regions, all of which were previously identified in meta-analyses of mostly non-diabetic cohorts. We also identified 13 associations in 11 genes based on RV, several of which represent novel findings.

  10. Genetic variation in the ABCA1 gene, HDL cholesterol, and risk of ischemic heart disease in the general population

    Frikke-Schmidt, Ruth

    2010-01-01

    Epidemiological studies consistently demonstrate a strong inverse association between low levels of high-density lipoprotein (HDL) cholesterol and increased risk of ischemic heart disease (IHD). This review focuses on whether both rare and common genetic variation in ABCA1 contributes to plasma...... levels of HDL cholesterol and to risk of IHD in the general population, and further seeks to understand whether low levels of HDL cholesterol per se are causally related to IHD. Studies of the ABCA1 gene demonstrate a general strategy for detecting functional genetic variants, and show that both common...... and rare ABCA1 variants contribute to levels of HDL cholesterol and risk of IHD in the general population. The association between ABCA1 variants and risk of IHD appears, however, to be independent of plasma levels of HDL cholesterol. With the recent identification of the largest number of individuals...

  11. Estimating variation within the genes and inferring the phylogeny of 186 sequenced diverse Escherichia coli genomes

    Kaas, Rolf Sommer; Rundsten, Carsten Friis; Ussery, David

    2012-01-01

    Background Escherichia coli exists in commensal and pathogenic forms. By measuring the variation of individual genes across more than a hundred sequenced genomes, gene variation can be studied in detail, including the number of mutations found for any given gene. This knowledge will be useful...... for creating better phylogenies, for determination of molecular clocks and for improved typing techniques. Results We find 3,051 gene clusters/families present in at least 95% of the genomes and 1,702 gene clusters present in 100% of the genomes. The former 'soft core' of about 3,000 gene families is perhaps...... more biologically relevant, especially considering that many of these genome sequences are draft quality. The E. coli pan-genome for this set of isolates contains 16,373 gene clusters. A core-gene tree, based on alignment and a pan-genome tree based on gene presence/absence, maps the relatedness...

  12. Absence of the musculocutaneous nerve: a rare anatomical variation with possible clinical-surgical implications

    José Humberto Tavares Guerreiro Fregnani

    Full Text Available CONTEXT: The musculocutaneous nerve is one of the terminal branches of the lateral fasciculus of the brachial plexus, and is responsible for innervation of the flexor musculature of the elbow and for skin sensitivity on the lateral surface of the forearm. Its absence has been described previously, but its real prevalence is unknown. CASE REPORT: A case of absence of the musculocutaneous nerve that was observed during the dissection of the right arm of a male cadaver is described. The area of innervation was supplied by the median nerve. From this, three branches emerged: one to the coracobrachialis muscle, another to the biceps brachii muscle and the third to the brachialis muscle. This last branch continued as a lateral antebrachial cutaneous nerve. This is an anatomical variation that has clinical-surgical implications, considering that injury to the median nerve in this case would have caused unexpected paralysis of the flexor musculature of the elbow and hypoesthesia of the lateral surface of the forearm.

  13. Genetic variation at Exon2 of TLR4 gene and its association with ...

    This study was conducted to analyze the polymorphisms of chicken Toll-like receptors 4(TLR4) gene and aimed to provide a theoretical foundation for a further research on correlation between chicken TLR4 gene and disease resistance. Genetic variations at exon 2 of TLR4 gene in 14 chicken breeds and the red jungle ...

  14. A four-gene operon in Bacillus cereus produces two rare spore-decorating sugars.

    Li, Zi; Mukherjee, Thiya; Bowler, Kyle; Namdari, Sholeh; Snow, Zachary; Prestridge, Sarah; Carlton, Alexandra; Bar-Peled, Maor

    2017-05-05

    Bacterial glycan structures on cell surfaces are critical for cell-cell recognition and adhesion and in host-pathogen interactions. Accordingly, unraveling the sugar composition of bacterial cell surfaces can shed light on bacterial growth and pathogenesis. Here, we found that two rare sugars with a 3- C -methyl-6-deoxyhexose structure were linked to spore glycans in Bacillus cereus ATCC 14579 and ATCC 10876. Moreover, we identified a four-gene operon in B. cereus ATCC 14579 that encodes proteins with the following sequential enzyme activities as determined by mass spectrometry and one- and two-dimensional NMR methods: CTP:glucose-1-phosphate cytidylyltransferase, CDP-Glc 4,6-dehydratase, NADH-dependent SAM: C -methyltransferase, and NADPH-dependent CDP-3- C -methyl-6-deoxyhexose 4-reductase. The last enzyme predominantly yielded CDP-3- C -methyl-6-deoxygulose (CDP-cereose) and likely generated a 4-epimer CDP-3- C -methyl-6-deoxyallose (CDP-cillose). Some members of the B. cereus sensu lato group produce CDP-3- C -methyl-6-deoxy sugars for the formation of cereose-containing glycans on spores, whereas others such as Bacillus anthracis do not. Gene knockouts of the Bacillus C -methyltransferase and the 4-reductase confirmed their involvement in the formation of cereose-containing glycan on B. cereus spores. We also found that cereose represented 0.2-1% spore dry weight. Moreover, mutants lacking cereose germinated faster than the wild type, yet the mutants exhibited no changes in sporulation or spore resistance to heat. The findings reported here may provide new insights into the roles of the uncommon 3- C -methyl-6-deoxy sugars in cell-surface recognition and host-pathogen interactions of the genus Bacillus . © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. Rare earth element and uranium-thorium variations in tufa deposits from the Mono Basin, CA

    Wilcox, E. S.; Tomascak, P. B.; Hemming, N.; Hemming, S. R.; Rasbury, T.; Stine, S.; Zimmerman, S. R.

    2009-12-01

    Samples of fossil tufa deposits from several localities in the Mono Basin, eastern California, were analyzed for trace element concentrations in order to better understand changes in lake composition in the past. These deposits were formed during the last glacial cycle, mostly during deglaciation (Benson et al., 1990, PPP). Three elevations are represented by the analyses. Samples from near Highway 167 were sampled between 2063 and 2069 m asl. Samples from near Thompson Road were sampled between 2015 and 2021 m. One layered mound was sampled at 1955 m. Concentrations of the lanthanide rare earth elements (REE), in particular the heavy/light (HREE/LREE) distributions, have been shown to be sensitive to alkalinity in modern saline lakes (e.g., Johannesson et al., 1994, GRL, 21, 773-776), and the same has been suggested for U/Th (Anderson et al., 1982, Science, 216, 514-516). Holocene to near-modern tufa towers exist in shallow water and around the current shoreline (1945 m). Tufa towers above 2000 m include a characteristic morphology termed thinolite, interpreted to represent pseudomorphs after the very cold water mineral ikaite. Most lower elevation towers do not have the thinolite morphology, but some layered tufa mounds at low elevations include several layers of thinolite, such as the one sampled for this project. Analyses were made on millimeter-scale bulk samples from tufa towers. Measurements were made on sample solutions with a Varian 820MS quadrupole ICP-MS. Mono Basin tufa samples have total REE concentrations ranging from 0.029 to 0.77 times average shales. Samples have flat to moderately HREE-enriched shale-normalized patterns with limited overall variability ([La/Lu]SN of 1.8 to 9.6) but with some variability in the slope of the HREE portion of the patterns. Tufa towers sampled from three elevations have (Gd/Lu)SN of 0.40 to 1.5. The REE patterns of most samples have small positive Ce anomalies, but a minority of samples, all from the layered tufa mound

  16. Common and rare variants in the exons and regulatory regions of osteoporosis-related genes improve osteoporotic fracture risk prediction.

    Lee, Seung Hun; Kang, Moo Il; Ahn, Seong Hee; Lim, Kyeong-Hye; Lee, Gun Eui; Shin, Eun-Soon; Lee, Jong-Eun; Kim, Beom-Jun; Cho, Eun-Hee; Kim, Sang-Wook; Kim, Tae-Ho; Kim, Hyun-Ju; Yoon, Kun-Ho; Lee, Won Chul; Kim, Ghi Su; Koh, Jung-Min; Kim, Shin-Yoon

    2014-11-01

    Osteoporotic fracture risk is highly heritable, but genome-wide association studies have explained only a small proportion of the heritability to date. Genetic data may improve prediction of fracture risk in osteopenic subjects and assist early intervention and management. To detect common and rare variants in coding and regulatory regions related to osteoporosis-related traits, and to investigate whether genetic profiling improves the prediction of fracture risk. This cross-sectional study was conducted in three clinical units in Korea. Postmenopausal women with extreme phenotypes (n = 982) were used for the discovery set, and 3895 participants were used for the replication set. We performed targeted resequencing of 198 genes. Genetic risk scores from common variants (GRS-C) and from common and rare variants (GRS-T) were calculated. Nineteen common variants in 17 genes (of the discovered 34 functional variants in 26 genes) and 31 rare variants in five genes (of the discovered 87 functional variants in 15 genes) were associated with one or more osteoporosis-related traits. Accuracy of fracture risk classification was improved in the osteopenic patients by adding GRS-C to fracture risk assessment models (6.8%; P risk in an osteopenic individual.

  17. Genomic Features That Predict Allelic Imbalance in Humans Suggest Patterns of Constraint on Gene Expression Variation

    Fédrigo, Olivier; Haygood, Ralph; Mukherjee, Sayan; Wray, Gregory A.

    2009-01-01

    Variation in gene expression is an important contributor to phenotypic diversity within and between species. Although this variation often has a genetic component, identification of the genetic variants driving this relationship remains challenging. In particular, measurements of gene expression usually do not reveal whether the genetic basis for any observed variation lies in cis or in trans to the gene, a distinction that has direct relevance to the physical location of the underlying genetic variant, and which may also impact its evolutionary trajectory. Allelic imbalance measurements identify cis-acting genetic effects by assaying the relative contribution of the two alleles of a cis-regulatory region to gene expression within individuals. Identification of patterns that predict commonly imbalanced genes could therefore serve as a useful tool and also shed light on the evolution of cis-regulatory variation itself. Here, we show that sequence motifs, polymorphism levels, and divergence levels around a gene can be used to predict commonly imbalanced genes in a human data set. Reduction of this feature set to four factors revealed that only one factor significantly differentiated between commonly imbalanced and nonimbalanced genes. We demonstrate that these results are consistent between the original data set and a second published data set in humans obtained using different technical and statistical methods. Finally, we show that variation in the single allelic imbalance-associated factor is partially explained by the density of genes in the region of a target gene (allelic imbalance is less probable for genes in gene-dense regions), and, to a lesser extent, the evenness of expression of the gene across tissues and the magnitude of negative selection on putative regulatory regions of the gene. These results suggest that the genomic distribution of functional cis-regulatory variants in the human genome is nonrandom, perhaps due to local differences in evolutionary

  18. Rapid Gene Turnover as a Significant Source of Genetic Variation in a Recently Seeded Population of a Healthcare-Associated Pathogen

    Lucía Graña-Miraglia

    2017-09-01

    Full Text Available Genome sequencing has been useful to gain an understanding of bacterial evolution. It has been used for studying the phylogeography and/or the impact of mutation and recombination on bacterial populations. However, it has rarely been used to study gene turnover at microevolutionary scales. Here, we sequenced Mexican strains of the human pathogen Acinetobacter baumannii sampled from the same locale over a 3 year period to obtain insights into the microevolutionary dynamics of gene content variability. We found that the Mexican A. baumannii population was recently founded and has been emerging due to a rapid clonal expansion. Furthermore, we noticed that on average the Mexican strains differed from each other by over 300 genes and, notably, this gene content variation has accrued more frequently and faster than the accumulation of mutations. Moreover, due to its rapid pace, gene content variation reflects the phylogeny only at very short periods of time. Additionally, we found that the external branches of the phylogeny had almost 100 more genes than the internal branches. All in all, these results show that rapid gene turnover has been of paramount importance in producing genetic variation within this population and demonstrate the utility of genome sequencing to study alternative forms of genetic variation.

  19. Genetic variation in a member of the laminin gene family affects variation in body composition in Drosophila and humans

    Hunter Gary R

    2008-08-01

    Full Text Available Abstract Background The objective of the present study was to map candidate loci influencing naturally occurring variation in triacylglycerol (TAG storage using quantitative complementation procedures in Drosophila melanogaster. Based on our results from Drosophila, we performed a human population-based association study to investigate the effect of natural variation in LAMA5 gene on body composition in humans. Results We identified four candidate genes that contributed to differences in TAG storage between two strains of D. melanogaster, including Laminin A (LanA, which is a member of the α subfamily of laminin chains. We confirmed the effects of this gene using a viable LanA mutant and showed that female flies homozygous for the mutation had significantly lower TAG storage, body weight, and total protein content than control flies. Drosophila LanA is closely related to human LAMA5 gene, which maps to the well-replicated obesity-linkage region on chromosome 20q13.2-q13.3. We tested for association between three common single nucleotide polymorphisms (SNPs in the human LAMA5 gene and variation in body composition and lipid profile traits in a cohort of unrelated women of European American (EA and African American (AA descent. In both ethnic groups, we found that SNP rs659822 was associated with weight (EA: P = 0.008; AA: P = 0.05 and lean mass (EA: P= 0.003; AA: P = 0.03. We also found this SNP to be associated with height (P = 0.01, total fat mass (P = 0.01, and HDL-cholesterol (P = 0.003 but only in EA women. Finally, significant associations of SNP rs944895 with serum TAG levels (P = 0.02 and HDL-cholesterol (P = 0.03 were observed in AA women. Conclusion Our results suggest an evolutionarily conserved role of a member of the laminin gene family in contributing to variation in weight and body composition.

  20. Bone Morphogenetic Protein 3 (BMP3) Gene Variation in some ...

    DR BRILLIANT

    showed Gst value as 0.013 while gene flow estimates using sequence data information revealed, Delta St ... information that will help in better understanding the relatedness in the functions of the .... differentiated enough across these species.

  1. Variations in angiotensin-converting enzyme gene insertion/deletion ...

    Unknown

    single D allele in the genotype enhanced the activity up to 37⋅56 ± 3⋅13%. The results suggested ethnic .... as hypertension, cardiovascular disease, diabetes and neph- ritis. ... Clarkson P 1998 Human gene for physical performance;.

  2. Distinguishing the rates of gene activation from phenotypic variations

    Chen, Ye; Lv, Cheng; Li, Fangting; Li, Tiejun

    2015-01-01

    Background Stochastic genetic switching driven by intrinsic noise is an important process in gene expression. When the rates of gene activation/inactivation are relatively slow, fast, or medium compared with the synthesis/degradation rates of mRNAs and proteins, the variability of protein and mRNA levels may exhibit very different dynamical patterns. It is desirable to provide a systematic approach to identify their key dynamical features in different regimes, aiming at distinguishing which r...

  3. Transcriptome analysis reveals novel patterning and pigmentation genes underlying Heliconius butterfly wing pattern variation

    Hines Heather M

    2012-06-01

    Full Text Available Abstract Background Heliconius butterfly wing pattern diversity offers a unique opportunity to investigate how natural genetic variation can drive the evolution of complex adaptive phenotypes. Positional cloning and candidate gene studies have identified a handful of regulatory and pigmentation genes implicated in Heliconius wing pattern variation, but little is known about the greater developmental networks within which these genes interact to pattern a wing. Here we took a large-scale transcriptomic approach to identify the network of genes involved in Heliconius wing pattern development and variation. This included applying over 140 transcriptome microarrays to assay gene expression in dissected wing pattern elements across a range of developmental stages and wing pattern morphs of Heliconius erato. Results We identified a number of putative early prepattern genes with color-pattern related expression domains. We also identified 51 genes differentially expressed in association with natural color pattern variation. Of these, the previously identified color pattern “switch gene” optix was recovered as the first transcript to show color-specific differential expression. Most differentially expressed genes were transcribed late in pupal development and have roles in cuticle formation or pigment synthesis. These include previously undescribed transporter genes associated with ommochrome pigmentation. Furthermore, we observed upregulation of melanin-repressing genes such as ebony and Dat1 in non-melanic patterns. Conclusions This study identifies many new genes implicated in butterfly wing pattern development and provides a glimpse into the number and types of genes affected by variation in genes that drive color pattern evolution.

  4. Combining Shigella Tn-seq data with gold-standard E. coli gene deletion data suggests rare transitions between essential and non-essential gene functionality.

    Freed, Nikki E; Bumann, Dirk; Silander, Olin K

    2016-09-06

    Gene essentiality - whether or not a gene is necessary for cell growth - is a fundamental component of gene function. It is not well established how quickly gene essentiality can change, as few studies have compared empirical measures of essentiality between closely related organisms. Here we present the results of a Tn-seq experiment designed to detect essential protein coding genes in the bacterial pathogen Shigella flexneri 2a 2457T on a genome-wide scale. Superficial analysis of this data suggested that 481 protein-coding genes in this Shigella strain are critical for robust cellular growth on rich media. Comparison of this set of genes with a gold-standard data set of essential genes in the closely related Escherichia coli K12 BW25113 revealed that an excessive number of genes appeared essential in Shigella but non-essential in E. coli. Importantly, and in converse to this comparison, we found no genes that were essential in E. coli and non-essential in Shigella, implying that many genes were artefactually inferred as essential in Shigella. Controlling for such artefacts resulted in a much smaller set of discrepant genes. Among these, we identified three sets of functionally related genes, two of which have previously been implicated as critical for Shigella growth, but which are dispensable for E. coli growth. The data presented here highlight the small number of protein coding genes for which we have strong evidence that their essentiality status differs between the closely related bacterial taxa E. coli and Shigella. A set of genes involved in acetate utilization provides a canonical example. These results leave open the possibility of developing strain-specific antibiotic treatments targeting such differentially essential genes, but suggest that such opportunities may be rare in closely related bacteria.

  5. Rare CNVs in Suicide Attempt include Schizophrenia-Associated Loci and Neurodevelopmental Genes: A Pilot Genome-Wide and Family-Based Study.

    Marcus Sokolowski

    Full Text Available Suicidal behavior (SB has a complex etiology involving genes and environment. One of the genetic components in SB could be copy number variations (CNVs, as CNVs are implicated in neurodevelopmental disorders. However, a recently published genome-wide and case-control study did not observe any significant role of CNVs in SB. Here we complemented these initial observations by instead using a family-based trio-sample that is robust to control biases, having severe suicide attempt (SA in offspring as main outcome (n = 660 trios. We first tested for CNV associations on the genome-wide Illumina 1M SNP-array by using FBAT-CNV methodology, which allows for evaluating CNVs without reliance on CNV calling algorithms, analogous to a common SNP-based GWAS. We observed association of certain T-cell receptor markers, but this likely reflected inter-individual variation in somatic rearrangements rather than association with SA outcome. Next, we used the PennCNV software to call 385 putative rare (100 kb CNVs, observed in n = 225 SA offspring. Nine SA offspring had rare CNV calls in a set of previously schizophrenia-associated loci, indicating the importance of such CNVs in certain SA subjects. Several additional, very large (>1MB sized CNV calls in 15 other SA offspring also spanned pathogenic regions or other neural genes of interest. Overall, 45 SA had CNVs enriched for 65 medically relevant genes previously shown to be affected by CNVs, which were characterized by a neurodevelopmental biology. A neurodevelopmental implication was partly congruent with our previous SNP-based GWAS, but follow-up analysis here indicated that carriers of rare CNVs had a decreased burden of common SNP risk-alleles compared to non-carriers. In conclusion, while CNVs did not show genome-wide association by the FBAT-CNV methodology, our preliminary observations indicate rare pathogenic CNVs affecting neurodevelopmental functions in a subset of SA, who were distinct from SA having

  6. Positive association of vitamin D receptor gene variations with multiple sclerosis in South East Iranian population.

    Narooie-Nejad, Mehrnaz; Moossavi, Maryam; Torkamanzehi, Adam; Moghtaderi, Ali

    2015-01-01

    Among the factors postulated to play a role in MS susceptibility, the role of vitamin D is outstanding. Since the function of vitamin D receptor (VDR) represents the effect of vitamin D on the body and genetic variations in VDR gene may affect its function, we aim to highlight the association of two VDR gene polymorphisms with MS susceptibility. In current study, we recruited 113 MS patients and 122 healthy controls. TaqI (rs731236) and ApaI (rs7975232) genetic variations in these two groups were evaluated using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. All genotype and allele frequencies in both variations showed association with the disease status. However, to find the definite connection between genetic variations in VDR gene and MS disease in a population of South East of Iran, more researches on gene structure and its function with regard to patients' conditions are required.

  7. Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages

    Phelan, Jody E.; Coll, Francesc; Bergval, Indra; Anthony, Richard M.; Warren, Rob; Sampson, Samantha L.; Gey van Pittius, Nicolaas C.; Glynn, Judith R.; Crampin, Amelia C.; Alves, Adriana; Bessa, Theolis Barbosa; Campino, Susana; Dheda, Keertan; Grandjean, Louis; Hasan, Rumina; Hasan, Zahra; Miranda, Anabela; Moore, David; Panaiotov, Stefan; Perdigao, Joao; Portugal, Isabel; Sheen, Patricia; de Oliveira Sousa, Erivelton; Streicher, Elizabeth M.; van Helden, Paul D.; Viveiros, Miguel; Hibberd, Martin L.; Pain, Arnab; McNerney, Ruth; Clark, Taane G.

    2016-01-01

    . tuberculosis complex genomes and long read sequence data were used to validate the approach. SNP analysis revealed that variation in the majority of the 168 pe/ppe genes studied was consistent with lineage. Several recombination hotspots were identified

  8. Polymorphisms in the WNK1 gene are associated with blood pressure variation and urinary potassium excretion.

    Stephen Newhouse

    Full Text Available WNK1--a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP control--is an excellent candidate gene for essential hypertension (EH. We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT study case-control resource (1700 hypertensive cases and 1700 normotensive controls. We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p = 0.0005, diastolic blood pressure, DBP (7/28 tSNPs min-p = 0.002 and 24 hour urinary potassium excretion (10/28 tSNPs min-p = 0.0004. Associations with SBP and urine potassium remained significant after correction for multiple testing (p = 0.02 and p = 0.01 respectively. The major allele (A of rs765250, located in intron 1, demonstrated the strongest evidence for association with SBP, effect size 3.14 mmHg (95%CI:1.23-4.9, DBP 1.9 mmHg (95%CI:0.7-3.2 and hypertension, odds ratio (OR: 1.3 [95%CI: 1.0-1.7].We genotyped this variant in six independent populations (n = 14,451 and replicated the association between rs765250 and SBP in a meta-analysis (p = 7 x 10(-3, combined with BRIGHT data-set p = 2 x 10(-4, n = 17,851. The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p10 mmHg reduction and risk for hypertension (OR<0.60. Our data indicates that multiple rare and common WNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH.

  9. Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder

    Elia, Josephine; Glessner, Joseph T; Wang, Kai; Takahashi, Nagahide; Shtir, Corina J; Hadley, Dexter; Sleiman, Patrick M A; Zhang, Haitao; Kim, Cecilia E; Robison, Reid; Lyon, Gholson J; Flory, James H; Bradfield, Jonathan P; Imielinski, Marcin; Hou, Cuiping; Frackelton, Edward C; Chiavacci, Rosetta M; Sakurai, Takeshi; Rabin, Cara; Middleton, Frank A; Thomas, Kelly A; Garris, Maria; Mentch, Frank; Freitag, Christine M; Steinhausen, Hans-Christoph; Todorov, Alexandre A; Reif, Andreas; Rothenberger, Aribert; Franke, Barbara; Mick, Eric O; Roeyers, Herbert; Buitelaar, Jan; Lesch, Klaus-Peter; Banaschewski, Tobias; Ebstein, Richard P; Mulas, Fernando; Oades, Robert D; Sergeant, Joseph; Sonuga-Barke, Edmund; Renner, Tobias J; Romanos, Marcel; Romanos, Jasmin; Warnke, Andreas; Walitza, Susanne; Meyer, Jobst; Pálmason, Haukur; Seitz, Christiane; Loo, Sandra K; Smalley, Susan L; Biederman, Joseph; Kent, Lindsey; Asherson, Philip; Anney, Richard J L; Gaynor, J William; Shaw, Philip; Devoto, Marcella; White, Peter S; Grant, Struan F A; Buxbaum, Joseph D; Rapoport, Judith L; Williams, Nigel M; Nelson, Stanley F; Faraone, Stephen V; Hakonarson, Hakon

    2014-01-01

    Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10−9). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10−6). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ~10% of the cases (P = 4.38 × 10−10) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts. PMID:22138692

  10. Looking on the bright side of serotonin transporter gene variation.

    Homberg, J.R.; Lesch, K.P.

    2011-01-01

    Converging evidence indicates an association of the short (s), low-expressing variant of the repeat length polymorphism, serotonin transporter-linked polymorphic region (5-HTTLPR), in the human serotonin transporter gene (5-HTT, SERT, SLC6A4) with anxiety-related traits and increased risk for

  11. Structural variations in the H-2 genes of AKR lymphomas.

    K. Hui; L. Minamide; N. Prandoni; H. Festenstein; F.G. Grosveld (Frank)

    1986-01-01

    textabstractK36.16 is an AKR H-2k thymoma which expresses an aberrant H-2Dd-like allospecificity, does not have a detectable amount of the H-2Kk syngeneic antigen and grows very easily in syngeneic mice. By DNA-mediated gene transfer experiments, we were able to obtain transformed clones which do

  12. Short communication Identification of gene variation within porcine ...

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    characteristics and possible biological function of porcine PRDM16 gene have been less reported. ... included the heart, liver, spleen, lung, kidney, brain, longissimus dorsi muscle, interior fat, stomach, small ... al., 2008), and the copy number of PRDM16 molecules of patients with osteosarcoma was .... BMC Cancer 4, 45.

  13. Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans.

    Douglas R Smith

    Full Text Available Rare genetic variants in the core endocannabinoid system genes CNR1, CNR2, DAGLA, MGLL and FAAH were identified in molecular testing data from 6,032 patients with a broad spectrum of neurological disorders. The variants were evaluated for association with phenotypes similar to those observed in the orthologous gene knockouts in mice. Heterozygous rare coding variants in CNR1, which encodes the type 1 cannabinoid receptor (CB1, were found to be significantly associated with pain sensitivity (especially migraine, sleep and memory disorders-alone or in combination with anxiety-compared to a set of controls without such CNR1 variants. Similarly, heterozygous rare variants in DAGLA, which encodes diacylglycerol lipase alpha, were found to be significantly associated with seizures and neurodevelopmental disorders, including autism and abnormalities of brain morphology, compared to controls. Rare variants in MGLL, FAAH and CNR2 were not associated with any neurological phenotypes in the patients tested. Diacylglycerol lipase alpha synthesizes the endocannabinoid 2-AG in the brain, which interacts with CB1 receptors. The phenotypes associated with rare CNR1 variants are reminiscent of those implicated in the theory of clinical endocannabinoid deficiency syndrome. The severe phenotypes associated with rare DAGLA variants underscore the critical role of rapid 2-AG synthesis and the endocannabinoid system in regulating neurological function and development. Mapping of the variants to the 3D structure of the type 1 cannabinoid receptor, or primary structure of diacylglycerol lipase alpha, reveals clustering of variants in certain structural regions and is consistent with impacts to function.

  14. Flexor accessorius longus: A rare variation of the deep extrinsic digital flexors of the leg and its phylogenetic significance

    Jaijesh P

    2006-01-01

    Full Text Available Anomalies of the calf muscles are rare. One such anomalous muscle, known as the Muscle Flexor accessorius longus (also named accessorius ad accessorium, accessorius secondus, accessory flexor digitorum longus or pronator pedis is of morphological significance. When present, this originates in the deep fascia of the tibia or fibula and inserts in the foot either into the flexor digitorum accessorius or into the tendons of the flexor digitorum longus. In this report we present a discussion of the morphological significance and phylogenetic history of one such muscle observed. In this case report we describe an anomalous calf muscle which extends from the popliteal region, runs along the posterior compartment of the leg, reaches the sole and is inserted to the flexor digitorum longus muscle. This kind of muscle variations are considered to be the higher origin of the flexor digitorum accessorius muscle of the sole. Here we discuss the phylogenetic history of this muscle as this muscle variant is present in some primitive mammals, absent in apes and in this particular case appeared as one of the muscles of the flexor compartment of the leg.

  15. Transcriptomic variation among six Arabidopsis thaliana accessions identified several novel genes controlling aluminium tolerance.

    Kusunoki, Kazutaka; Nakano, Yuki; Tanaka, Keisuke; Sakata, Yoichi; Koyama, Hiroyuki; Kobayashi, Yuriko

    2017-02-01

    Differences in the expression levels of aluminium (Al) tolerance genes are a known determinant of Al tolerance among plant varieties. We combined transcriptomic analysis of six Arabidopsis thaliana accessions with contrasting Al tolerance and a reverse genetic approach to identify Al-tolerance genes responsible for differences in Al tolerance between accession groups. Gene expression variation increased in the signal transduction process under Al stress and in growth-related processes in the absence of stress. Co-expression analysis and promoter single nucleotide polymorphism searching suggested that both trans-acting polymorphisms of Al signal transduction pathway and cis-acting polymorphisms in the promoter sequences caused the variations in gene expression associated with Al tolerance. Compared with the wild type, Al sensitivity increased in T-DNA knockout (KO) lines for five genes, including TARGET OF AVRB OPERATION1 (TAO1) and an unannotated gene (At5g22530). These were identified from 53 Al-inducible genes showing significantly higher expression in tolerant accessions than in sensitive accessions. These results indicate that the difference in transcriptional signalling is partly associated with the natural variation in Al tolerance in Arabidopsis. Our study also demonstrates the feasibility of comparative transcriptome analysis by using natural genetic variation for the identification of genes responsible for Al stress tolerance. © 2016 John Wiley & Sons Ltd.

  16. Natural variation of rice blast resistance gene Pi-d2

    Studying natural variation of rice resistance (R) genes in cultivated and wild rice relatives can predict resistance stability to rice blast fungus. In the present study, the protein coding regions of rice R gene Pi-d2 in 35 rice accessions of subgroups, aus (AUS), indica (IND), temperate japonica (...

  17. Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

    Jim, Heather S L; Lin, Hui-Yi; Tyrer, Jonathan P

    2016-01-01

    Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovari...

  18. Discovery of rare protein-coding genes in model methylotroph Methylobacterium extorquens AM1.

    Kumar, Dhirendra; Mondal, Anupam Kumar; Yadav, Amit Kumar; Dash, Debasis

    2014-12-01

    Proteogenomics involves the use of MS to refine annotation of protein-coding genes and discover genes in a genome. We carried out comprehensive proteogenomic analysis of Methylobacterium extorquens AM1 (ME-AM1) from publicly available proteomics data with a motive to improve annotation for methylotrophs; organisms capable of surviving in reduced carbon compounds such as methanol. Besides identifying 2482(50%) proteins, 29 new genes were discovered and 66 annotated gene models were revised in ME-AM1 genome. One such novel gene is identified with 75 peptides, lacks homolog in other methylobacteria but has glycosyl transferase and lipopolysaccharide biosynthesis protein domains, indicating its potential role in outer membrane synthesis. Many novel genes are present only in ME-AM1 among methylobacteria. Distant homologs of these genes in unrelated taxonomic classes and low GC-content of few genes suggest lateral gene transfer as a potential mode of their origin. Annotations of methylotrophy related genes were also improved by the discovery of a short gene in methylotrophy gene island and redefining a gene important for pyrroquinoline quinone synthesis, essential for methylotrophy. The combined use of proteogenomics and rigorous bioinformatics analysis greatly enhanced the annotation of protein-coding genes in model methylotroph ME-AM1 genome. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Genetic spectrum of low density lipoprotein receptor gene variations in South Indian population.

    ArulJothi, K N; Suruthi Abirami, B; Devi, Arikketh

    2018-03-01

    Low density lipoprotein receptor (LDLR) is a membrane bound receptor maintaining cholesterol homeostasis along with Apolipoprotein B (APOB), Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) and other genes of lipid metabolism. Any pathogenic variation in these genes alters the function of the receptor and leads to Familial Hypercholesterolemia (FH) and other cardiovascular diseases. This study was aimed at screening the LDLR, APOB and PCSK9 genes in Hypercholesterolemic patients to define the genetic spectrum of FH in Indian population. Familial Hypercholesterolemia patients (n=78) of South Indian Tamil population with LDL cholesterol and Total cholesterol levels above 4.9mmol/l and 7.5mmol/l with family history of Myocardial infarction were involved. DNA was isolated by organic extraction method from blood samples and LDLR, APOB and PCSK9 gene exons were amplified using primers that cover exon-intron boundaries. The amplicons were screened using High Resolution Melt (HRM) Analysis and the screened samples were sequenced after purification. This study reports 20 variations in South Indian population for the first time. In this set of variations 9 are novel variations which are reported for the first time, 11 were reported in other studies also. The in silico analysis for all the variations detected in this study were done to predict the probabilistic effect in pathogenicity of FH. This study adds 9 novel variations and 11 recurrent variations to the spectrum of LDLR gene mutations in Indian population. All these variations are reported for the first time in Indian population. This spectrum of variations was different from the variations of previous Indian reports. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. nef gene sequence variation among HIV-1-infected African children

    Chakraborty, R.; Reiniš, Milan; Rostron, T.; Philpott, S.; Dong, T.; D'Agostino, A.; Musoke, R.; de Silva, E.; Stumpf, M.; Weiser, B.; Burger, H.; Rowland-Jones, S.L.

    2006-01-01

    Roč. 7, č. 2 (2006), s. 75-84 ISSN 1464-2662 Grant - others:Fogarty International Center, NIH(US) 3D43TW00915; NIH(US) RO1 AI 42555 Institutional research plan: CEZ:AV0Z50520514 Keywords : HIV-1 nef gene * non-clade B * Kenya Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.674, year: 2006

  1. Extensive gene content variation in the Brachypodium distachyon pan-genome correlates with population structure.

    Gordon, Sean P; Contreras-Moreira, Bruno; Woods, Daniel P; Des Marais, David L; Burgess, Diane; Shu, Shengqiang; Stritt, Christoph; Roulin, Anne C; Schackwitz, Wendy; Tyler, Ludmila; Martin, Joel; Lipzen, Anna; Dochy, Niklas; Phillips, Jeremy; Barry, Kerrie; Geuten, Koen; Budak, Hikmet; Juenger, Thomas E; Amasino, Richard; Caicedo, Ana L; Goodstein, David; Davidson, Patrick; Mur, Luis A J; Figueroa, Melania; Freeling, Michael; Catalan, Pilar; Vogel, John P

    2017-12-19

    While prokaryotic pan-genomes have been shown to contain many more genes than any individual organism, the prevalence and functional significance of differentially present genes in eukaryotes remains poorly understood. Whole-genome de novo assembly and annotation of 54 lines of the grass Brachypodium distachyon yield a pan-genome containing nearly twice the number of genes found in any individual genome. Genes present in all lines are enriched for essential biological functions, while genes present in only some lines are enriched for conditionally beneficial functions (e.g., defense and development), display faster evolutionary rates, lie closer to transposable elements and are less likely to be syntenic with orthologous genes in other grasses. Our data suggest that differentially present genes contribute substantially to phenotypic variation within a eukaryote species, these genes have a major influence in population genetics, and transposable elements play a key role in pan-genome evolution.

  2. Role of novel and rare nucleotide substitutions of the β-globin gene

    Margherita Vinciguerra

    2012-11-01

    Full Text Available The Laboratory for Molecular Prenatal Diagnosis of Hemoglobinopathies at the Villa Sofia-Cervello Hospital in Palermo, Italy, carries out an intensive screening program aimed at identifying the healthy carriers of thalassemia and, consequently, the couples at risk of bearing an affected fetus. The diagnostic process is basically divided into two phases: i hematologic and hemoglobin data; ii molecular analysis of globin genes and, when possible, a genetic study of the family. Since 2003, we have been performing DNA sequence analysis on those cases in which classical molecular methods failed to give a complete diagnostic response, particularly in phenotypes with borderline values of HbA2 with mild or absent microcytosis. During ten years of screening activities (from 2003 to 2012, twenty- seven unknown or rare nucleotide changes of the β-globin gene have been identified; hematologic and hemoglobin data have been carefully evaluated and, wherever possible, we have conducted a family study to evaluate whether a phenotypic expression could be associated to these nucleotide changes. Because of the limited numbers of cases for each mutation, the significance of these nucleotide substitutions has still not been fully clarified, and this raises a number of questions that need to be answered when carrying out appropriate genetic counseling for couples presumed to be at risk. 意大利巴勒莫Villa Sofia-Cervello医院血红蛋白病分子产前诊断实验室进行密集的筛选程序,旨在识别健康的地中海贫血携带者和有怀上地中海贫血胎儿风险的夫妇。 诊断过程基本上分为两个阶段:1)血液及血红蛋白数据;2)珠蛋白基因分子分析以及家族遗传研究(如有可能)。 自2003年以来,我们已对这类病例进行DNA序列分析:传统的分子方法无法给出完整的诊断响应,尤其是有轻微小红细胞症或缺乏小红细胞症的HbA2临界值表型。

  3. Natural genetic variation in Arabidopsis thaliana defense metabolism genes modulates field fitness.

    Kerwin, Rachel; Feusier, Julie; Corwin, Jason; Rubin, Matthew; Lin, Catherine; Muok, Alise; Larson, Brandon; Li, Baohua; Joseph, Bindu; Francisco, Marta; Copeland, Daniel; Weinig, Cynthia; Kliebenstein, Daniel J

    2015-04-13

    Natural populations persist in complex environments, where biotic stressors, such as pathogen and insect communities, fluctuate temporally and spatially. These shifting biotic pressures generate heterogeneous selective forces that can maintain standing natural variation within a species. To directly test if genes containing causal variation for the Arabidopsis thaliana defensive compounds, glucosinolates (GSL) control field fitness and are therefore subject to natural selection, we conducted a multi-year field trial using lines that vary in only specific causal genes. Interestingly, we found that variation in these naturally polymorphic GSL genes affected fitness in each of our environments but the pattern fluctuated such that highly fit genotypes in one trial displayed lower fitness in another and that no GSL genotype or genotypes consistently out-performed the others. This was true both across locations and within the same location across years. These results indicate that environmental heterogeneity may contribute to the maintenance of GSL variation observed within Arabidopsis thaliana.

  4. Identification of rare high-risk copy number variants affecting the dopamine transporter gene in mental disorders

    Hoeffding, Louise Kristine Enggaard; Duong, Linh T T; Ingason, Andres

    2016-01-01

    BACKGROUND: The dopamine transporter, also known as solute carrier 6A3 (SLC6A3), plays an important role in synaptic transmission by regulating the reuptake of dopamine in the synapses. In line with this, variations in the gene encoding this transporter have been linked to both schizophrenia and ...

  5. Genetic variation of the major histocompatibility complex (MHC class II B gene in the threatened Hume's pheasant, Syrmaticus humiae.

    Weicai Chen

    Full Text Available Major histocompatibility complex (MHC genes are the most polymorphic genes in vertebrates and encode molecules that play a crucial role in pathogen resistance. As a result of their diversity, they have received much attention in the fields of evolutionary and conservation biology. Here, we described the genetic variation of MHC class II B (MHCIIB exon 2 in a wild population of Hume's pheasant (Syrmaticus humiae, which has suffered a dramatic decline in population over the last three decades across its ranges in the face of heavy exploitation and habitat loss. Twenty-four distinct alleles were found in 73 S. humiae specimens. We found seven shared alleles among four geographical groups as well as six rare MHCIIB alleles. Most individuals displayed between one to five alleles, suggesting that there are at least three MHCIIB loci of the Hume's pheasant. The dN ⁄ dS ratio at putative antigen-binding sites (ABS was significantly greater than one, indicating balancing selection is acting on MHCIIB exon 2. Additionally, recombination and gene conversion contributed to generating MHCIIB diversity in the Hume's pheasant. One to three recombination events and seventy-five significant gene conversion events were observed within the Hume's pheasant MHCIIB loci. The phylogenetic tree and network analysis revealed that the Hume's pheasant alleles do not cluster together, but are scattered through the tree or network indicating a trans-species evolutionary mode. These findings revealed the evolution of the Hume's pheasant MHC after suffering extreme habitat fragmentation.

  6. Rare Variants in Genes Encoding MuRF1 and MuRF2 Are Modifiers of Hypertrophic Cardiomyopathy

    Ming Su

    2014-05-01

    Full Text Available Modifier genes contribute to the diverse clinical manifestations of hypertrophic cardiomyopathy (HCM, but are still largely unknown. Muscle ring finger (MuRF proteins are a class of muscle-specific ubiquitin E3-ligases that appear to modulate cardiac mass and function by regulating the ubiquitin-proteasome system. In this study we screened all the three members of the MuRF family, MuRF1, MuRF2 and MuRF3, in 594 unrelated HCM patients and 307 healthy controls by targeted resequencing. Identified rare variants were confirmed by capillary Sanger sequencing. The prevalence of rare variants in both MuRF1 and MuRF2 in HCM patients was higher than that in control subjects (MuRF1 13/594 (2.2% vs. 1/307 (0.3%, p = 0.04; MuRF2 22/594 (3.7% vs. 2/307 (0.7%; p = 0.007. Patients with rare variants in MuRF1 or MuRF2 were younger (p = 0.04 and had greater maximum left ventricular wall thickness (p = 0.006 than those without such variants. Mutations in genes encoding sarcomere proteins were present in 19 (55.9% of the 34 HCM patients with rare variants in MuRF1 and MuRF2. These data strongly supported that rare variants in MuRF1 and MuRF2 are associated with higher penetrance and more severe clinical manifestations of HCM. The findings suggest that dysregulation of the ubiquitin-proteasome system contributes to the pathogenesis of HCM.

  7. Genetic variation in eleven phase I drug metabolism genes in an ethnically diverse population.

    Solus, Joseph F; Arietta, Brenda J; Harris, James R; Sexton, David P; Steward, John Q; McMunn, Chara; Ihrie, Patrick; Mehall, Janelle M; Edwards, Todd L; Dawson, Elliott P

    2004-10-01

    The extent of genetic variation found in drug metabolism genes and its contribution to interindividual variation in response to medication remains incompletely understood. To better determine the identity and frequency of variation in 11 phase I drug metabolism genes, the exons and flanking intronic regions of the cytochrome P450 (CYP) isoenzyme genes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5 were amplified from genomic DNA and sequenced. A total of 60 kb of bi-directional sequence was generated from each of 93 human DNAs, which included Caucasian, African-American and Asian samples. There were 388 different polymorphisms identified. These included 269 non-coding, 45 synonymous and 74 non-synonymous polymorphisms. Of these, 54% were novel and included 176 non-coding, 14 synonymous and 21 non-synonymous polymorphisms. Of the novel variants observed, 85 were represented by single occurrences of the minor allele in the sample set. Much of the variation observed was from low-frequency alleles. Comparatively, these genes are variation-rich. Calculations measuring genetic diversity revealed that while the values for the individual genes are widely variable, the overall nucleotide diversity of 7.7 x 10(-4) and polymorphism parameter of 11.5 x 10(-4) are higher than those previously reported for other gene sets. Several independent measurements indicate that these genes are under selective pressure, particularly for polymorphisms corresponding to non-synonymous amino acid changes. There is relatively little difference in measurements of diversity among the ethnic groups, but there are large differences among the genes and gene subfamilies themselves. Of the three CYP subfamilies involved in phase I drug metabolism (1, 2, and 3), subfamily 2 displays the highest levels of genetic diversity.

  8. New genes often acquire male-specific functions but rarely become essential in Drosophila.

    Kondo, Shu; Vedanayagam, Jeffrey; Mohammed, Jaaved; Eizadshenass, Sogol; Kan, Lijuan; Pang, Nan; Aradhya, Rajaguru; Siepel, Adam; Steinhauer, Josefa; Lai, Eric C

    2017-09-15

    Relatively little is known about the in vivo functions of newly emerging genes, especially in metazoans. Although prior RNAi studies reported prevalent lethality among young gene knockdowns, our phylogenomic analyses reveal that young Drosophila genes are frequently restricted to the nonessential male reproductive system. We performed large-scale CRISPR/Cas9 mutagenesis of "conserved, essential" and "young, RNAi-lethal" genes and broadly confirmed the lethality of the former but the viability of the latter. Nevertheless, certain young gene mutants exhibit defective spermatogenesis and/or male sterility. Moreover, we detected widespread signatures of positive selection on young male-biased genes. Thus, young genes have a preferential impact on male reproductive system function. © 2017 Kondo et al.; Published by Cold Spring Harbor Laboratory Press.

  9. Variation-preserving normalization unveils blind spots in gene expression profiling

    Roca, Carlos P.; Gomes, Susana I. L.; Amorim, Mónica J. B.; Scott-Fordsmand, Janeck J.

    2017-01-01

    RNA-Seq and gene expression microarrays provide comprehensive profiles of gene activity, but lack of reproducibility has hindered their application. A key challenge in the data analysis is the normalization of gene expression levels, which is currently performed following the implicit assumption that most genes are not differentially expressed. Here, we present a mathematical approach to normalization that makes no assumption of this sort. We have found that variation in gene expression is much larger than currently believed, and that it can be measured with available assays. Our results also explain, at least partially, the reproducibility problems encountered in transcriptomics studies. We expect that this improvement in detection will help efforts to realize the full potential of gene expression profiling, especially in analyses of cellular processes involving complex modulations of gene expression. PMID:28276435

  10. A Phyletically Rare Gene Promotes the Niche-specific Fitness of an E. coli Pathogen during Bacteremia

    Wiles, Travis J.; Lewis, Adam J.; Mobley, Harry L. T.; Casjens, Sherwood R.; Mulvey, Matthew A.

    2013-01-01

    In bacteria, laterally acquired genes are often concentrated within chromosomal regions known as genomic islands. Using a recently developed zebrafish infection model, we set out to identify unique factors encoded within genomic islands that contribute to the fitness and virulence of a reference urosepsis isolate—extraintestinal pathogenic Escherichia coli strain CFT073. By screening a series of deletion mutants, we discovered a previously uncharacterized gene, neaT, that is conditionally required by the pathogen during systemic infections. In vitro assays indicate that neaT can limit bacterial interactions with host phagocytes and alter the aggregative properties of CFT073. The neaT gene is localized within an integrated P2-like bacteriophage in CFT073, but was rarely found within other proteobacterial genomes. Sequence-based analyses revealed that neaT homologues are present, but discordantly conserved, within a phyletically diverse set of bacterial species. In CFT073, neaT appears to be unameliorated, having an exceptionally A+T-rich composition along with a notably altered codon bias. These data suggest that neaT was recently brought into the proteobacterial pan-genome from an extra-phyletic source. Interestingly, even in G+C-poor genomes, as found within the Firmicutes lineage, neaT-like genes are often unameliorated. Sequence-level features of neaT homologues challenge the common supposition that the A+T-rich nature of many recently acquired genes reflects the nucleotide composition of their genomes of origin. In total, these findings highlight the complexity of the evolutionary forces that can affect the acquisition, utilization, and assimilation of rare genes that promote the niche-dependent fitness and virulence of a bacterial pathogen. PMID:23459509

  11. Natural Genetic Variation and Candidate Genes for Morphological Traits in Drosophila melanogaster

    Carreira, Valeria Paula; Mensch, Julián; Hasson, Esteban; Fanara, Juan José

    2016-01-01

    Body size is a complex character associated to several fitness related traits that vary within and between species as a consequence of environmental and genetic factors. Latitudinal and altitudinal clines for different morphological traits have been described in several species of Drosophila and previous work identified genomic regions associated with such variation in D. melanogaster. However, the genetic factors that orchestrate morphological variation have been barely studied. Here, our main objective was to investigate genetic variation for different morphological traits associated to the second chromosome in natural populations of D. melanogaster along latitudinal and altitudinal gradients in Argentina. Our results revealed weak clinal signals and a strong population effect on morphological variation. Moreover, most pairwise comparisons between populations were significant. Our study also showed important within-population genetic variation, which must be associated to the second chromosome, as the lines are otherwise genetically identical. Next, we examined the contribution of different candidate genes to natural variation for these traits. We performed quantitative complementation tests using a battery of lines bearing mutated alleles at candidate genes located in the second chromosome and six second chromosome substitution lines derived from natural populations which exhibited divergent phenotypes. Results of complementation tests revealed that natural variation at all candidate genes studied, invected, Fasciclin 3, toucan, Reticulon-like1, jing and CG14478, affects the studied characters, suggesting that they are Quantitative Trait Genes for morphological traits. Finally, the phenotypic patterns observed suggest that different alleles of each gene might contribute to natural variation for morphological traits. However, non-additive effects cannot be ruled out, as wild-derived strains differ at myriads of second chromosome loci that may interact

  12. Illustrating, Quantifying, and Correcting for Bias in Post-hoc Analysis of Gene-Based Rare Variant Tests of Association

    Grinde, Kelsey E.; Arbet, Jaron; Green, Alden; O'Connell, Michael; Valcarcel, Alessandra; Westra, Jason; Tintle, Nathan

    2017-01-01

    To date, gene-based rare variant testing approaches have focused on aggregating information across sets of variants to maximize statistical power in identifying genes showing significant association with diseases. Beyond identifying genes that are associated with diseases, the identification of causal variant(s) in those genes and estimation of their effect is crucial for planning replication studies and characterizing the genetic architecture of the locus. However, we illustrate that straightforward single-marker association statistics can suffer from substantial bias introduced by conditioning on gene-based test significance, due to the phenomenon often referred to as “winner's curse.” We illustrate the ramifications of this bias on variant effect size estimation and variant prioritization/ranking approaches, outline parameters of genetic architecture that affect this bias, and propose a bootstrap resampling method to correct for this bias. We find that our correction method significantly reduces the bias due to winner's curse (average two-fold decrease in bias, p bias and improve inference in post-hoc analysis of gene-based tests under a wide variety of genetic architectures. PMID:28959274

  13. Comparison of gene-based rare variant association mapping methods for quantitative traits in a bovine population with complex familial relationships

    Zhang, Qianqian; Guldbrandtsen, Bernt; Calus, Mario P.L.; Lund, Mogens Sandø; Sahana, Goutam

    2016-01-01

    Background: There is growing interest in the role of rare variants in the variation of complex traits due to increasing evidence that rare variants are associated with quantitative traits. However, association methods that are commonly used for mapping common variants are not effective to map

  14. Pooled Sequencing of 531 Genes in Inflammatory Bowel Disease Identifies an Associated Rare Variant in BTNL2 and Implicates Other Immune Related Genes

    Prescott, Natalie J.; Lehne, Benjamin; Stone, Kristina; Lee, James C.; Taylor, Kirstin; Knight, Jo; Papouli, Efterpi; Mirza, Muddassar M.; Simpson, Michael A.; Spain, Sarah L.; Lu, Grace; Fraternali, Franca; Bumpstead, Suzannah J.; Gray, Emma; Amar, Ariella; Bye, Hannah; Green, Peter; Chung-Faye, Guy; Hayee, Bu’Hussain; Pollok, Richard; Satsangi, Jack; Parkes, Miles; Barrett, Jeffrey C.; Mansfield, John C.; Sanderson, Jeremy; Lewis, Cathryn M.; Weale, Michael E.; Schlitt, Thomas; Mathew, Christopher G.

    2015-01-01

    The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn’s disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10−10, OR = 2.3[95% CI = 1.75–3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis. PMID:25671699

  15. Transcriptome analyses of sex differential gene expression in brains of rare minnow (Gobiocypris rarus and effects of tributyltin exposure

    Ji-liang Zhang

    2018-06-01

    Full Text Available RNA-sequencing was used to identify sex-biased gene expression in brains of rare minnow (Gobiocypris rarus by comparing transcriptomic profiles between females and males. Furthermore, transcriptomic responses to 10 ng/L tributyltin (TBT in both male and female brains were also investigated to understand whether TBT affects the identified sex-biased genes. Differentially expressed genes (DEGs were identified using the IDEG6 web tool. In this article, we presented male- and female-biased DEGs, and up-regulated and down-regulated DEGs after TBT exposure. The raw reads data supporting the present analyses has been deposited in NCBI Sequence Read Archive (SRA, http://www.ncbi.nlm.nih.gov/Traces/sra with accession number PRJNA376634. The data presented in this article are related to the research article entitled “Transcriptomic analyses of sexual dimorphism of rare minnow (G. rarus brains and effects of tributyltin exposure” (doi: 10.1016/j.ecoenv.2018.02.049.

  16. Meiotic gene-conversion rate and tract length variation in the human genome.

    Padhukasahasram, Badri; Rannala, Bruce

    2013-02-27

    Meiotic recombination occurs in the form of two different mechanisms called crossing-over and gene-conversion and both processes have an important role in shaping genetic variation in populations. Although variation in crossing-over rates has been studied extensively using sperm-typing experiments, pedigree studies and population genetic approaches, our knowledge of variation in gene-conversion parameters (ie, rates and mean tract lengths) remains far from complete. To explore variability in population gene-conversion rates and its relationship to crossing-over rate variation patterns, we have developed and validated using coalescent simulations a comprehensive Bayesian full-likelihood method that can jointly infer crossing-over and gene-conversion rates as well as tract lengths from population genomic data under general variable rate models with recombination hotspots. Here, we apply this new method to SNP data from multiple human populations and attempt to characterize for the first time the fine-scale variation in gene-conversion parameters along the human genome. We find that the estimated ratio of gene-conversion to crossing-over rates varies considerably across genomic regions as well as between populations. However, there is a great degree of uncertainty associated with such estimates. We also find substantial evidence for variation in the mean conversion tract length. The estimated tract lengths did not show any negative relationship with the local heterozygosity levels in our analysis.European Journal of Human Genetics advance online publication, 27 February 2013; doi:10.1038/ejhg.2013.30.

  17. Illustrating, Quantifying, and Correcting for Bias in Post-hoc Analysis of Gene-Based Rare Variant Tests of Association

    Kelsey E. Grinde

    2017-09-01

    Full Text Available To date, gene-based rare variant testing approaches have focused on aggregating information across sets of variants to maximize statistical power in identifying genes showing significant association with diseases. Beyond identifying genes that are associated with diseases, the identification of causal variant(s in those genes and estimation of their effect is crucial for planning replication studies and characterizing the genetic architecture of the locus. However, we illustrate that straightforward single-marker association statistics can suffer from substantial bias introduced by conditioning on gene-based test significance, due to the phenomenon often referred to as “winner's curse.” We illustrate the ramifications of this bias on variant effect size estimation and variant prioritization/ranking approaches, outline parameters of genetic architecture that affect this bias, and propose a bootstrap resampling method to correct for this bias. We find that our correction method significantly reduces the bias due to winner's curse (average two-fold decrease in bias, p < 2.2 × 10−6 and, consequently, substantially improves mean squared error and variant prioritization/ranking. The method is particularly helpful in adjustment for winner's curse effects when the initial gene-based test has low power and for relatively more common, non-causal variants. Adjustment for winner's curse is recommended for all post-hoc estimation and ranking of variants after a gene-based test. Further work is necessary to continue seeking ways to reduce bias and improve inference in post-hoc analysis of gene-based tests under a wide variety of genetic architectures.

  18. Sex Differences in Drosophila Somatic Gene Expression: Variation and Regulation by doublesex

    Michelle N. Arbeitman

    2016-07-01

    Full Text Available Sex differences in gene expression have been widely studied in Drosophila melanogaster. Sex differences vary across strains, but many molecular studies focus on only a single strain, or on genes that show sexually dimorphic expression in many strains. How extensive variability is and whether this variability occurs among genes regulated by sex determination hierarchy terminal transcription factors is unknown. To address these questions, we examine differences in sexually dimorphic gene expression between two strains in Drosophila adult head tissues. We also examine gene expression in doublesex (dsx mutant strains to determine which sex-differentially expressed genes are regulated by DSX, and the mode by which DSX regulates expression. We find substantial variation in sex-differential expression. The sets of genes with sexually dimorphic expression in each strain show little overlap. The prevalence of different DSX regulatory modes also varies between the two strains. Neither the patterns of DSX DNA occupancy, nor mode of DSX regulation explain why some genes show consistent sex-differential expression across strains. We find that the genes identified as regulated by DSX in this study are enriched with known sites of DSX DNA occupancy. Finally, we find that sex-differentially expressed genes and genes regulated by DSX are highly enriched on the fourth chromosome. These results provide insights into a more complete pool of potential DSX targets, as well as revealing the molecular flexibility of DSX regulation.

  19. Relationships between protein-encoding gene abundance and corresponding process are commonly assumed yet rarely observed

    Rocca, Jennifer D.; Hall, Edward K.; Lennon, Jay T.; Evans, Sarah E.; Waldrop, Mark P.; Cotner, James B.; Nemergut, Diana R.; Graham, Emily B.; Wallenstein, Matthew D.

    2015-01-01

    For any enzyme-catalyzed reaction to occur, the corresponding protein-encoding genes and transcripts are necessary prerequisites. Thus, a positive relationship between the abundance of gene or transcripts and corresponding process rates is often assumed. To test this assumption, we conducted a meta-analysis of the relationships between gene and/or transcript abundances and corresponding process rates. We identified 415 studies that quantified the abundance of genes or transcripts for enzymes involved in carbon or nitrogen cycling. However, in only 59 of these manuscripts did the authors report both gene or transcript abundance and rates of the appropriate process. We found that within studies there was a significant but weak positive relationship between gene abundance and the corresponding process. Correlations were not strengthened by accounting for habitat type, differences among genes or reaction products versus reactants, suggesting that other ecological and methodological factors may affect the strength of this relationship. Our findings highlight the need for fundamental research on the factors that control transcription, translation and enzyme function in natural systems to better link genomic and transcriptomic data to ecosystem processes.

  20. Regulatory Architecture of Gene Expression Variation in the Threespine Stickleback Gasterosteus aculeatus.

    Pritchard, Victoria L; Viitaniemi, Heidi M; McCairns, R J Scott; Merilä, Juha; Nikinmaa, Mikko; Primmer, Craig R; Leder, Erica H

    2017-01-05

    Much adaptive evolutionary change is underlain by mutational variation in regions of the genome that regulate gene expression rather than in the coding regions of the genes themselves. An understanding of the role of gene expression variation in facilitating local adaptation will be aided by an understanding of underlying regulatory networks. Here, we characterize the genetic architecture of gene expression variation in the threespine stickleback (Gasterosteus aculeatus), an important model in the study of adaptive evolution. We collected transcriptomic and genomic data from 60 half-sib families using an expression microarray and genotyping-by-sequencing, and located expression quantitative trait loci (eQTL) underlying the variation in gene expression in liver tissue using an interval mapping approach. We identified eQTL for several thousand expression traits. Expression was influenced by polymorphism in both cis- and trans-regulatory regions. Trans-eQTL clustered into hotspots. We did not identify master transcriptional regulators in hotspot locations: rather, the presence of hotspots may be driven by complex interactions between multiple transcription factors. One observed hotspot colocated with a QTL recently found to underlie salinity tolerance in the threespine stickleback. However, most other observed hotspots did not colocate with regions of the genome known to be involved in adaptive divergence between marine and freshwater habitats. Copyright © 2017 Pritchard et al.

  1. Regulatory Architecture of Gene Expression Variation in the Threespine Stickleback Gasterosteus aculeatus

    Victoria L. Pritchard

    2017-01-01

    Full Text Available Much adaptive evolutionary change is underlain by mutational variation in regions of the genome that regulate gene expression rather than in the coding regions of the genes themselves. An understanding of the role of gene expression variation in facilitating local adaptation will be aided by an understanding of underlying regulatory networks. Here, we characterize the genetic architecture of gene expression variation in the threespine stickleback (Gasterosteus aculeatus, an important model in the study of adaptive evolution. We collected transcriptomic and genomic data from 60 half-sib families using an expression microarray and genotyping-by-sequencing, and located expression quantitative trait loci (eQTL underlying the variation in gene expression in liver tissue using an interval mapping approach. We identified eQTL for several thousand expression traits. Expression was influenced by polymorphism in both cis- and trans-regulatory regions. Trans-eQTL clustered into hotspots. We did not identify master transcriptional regulators in hotspot locations: rather, the presence of hotspots may be driven by complex interactions between multiple transcription factors. One observed hotspot colocated with a QTL recently found to underlie salinity tolerance in the threespine stickleback. However, most other observed hotspots did not colocate with regions of the genome known to be involved in adaptive divergence between marine and freshwater habitats.

  2. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

    Chornokur, Ganna; Lin, Hui-Yi; Tyrer, Jonathan P.; Lawrenson, Kate; Dennis, Joe; Amankwah, Ernest K.; Qu, Xiaotao; Tsai, Ya-Yu; Jim, Heather S. L.; Chen, Zhihua; Chen, Ann Y.; Permuth-Wey, Jennifer; Aben, Katja KH.; Anton-Culver, Hoda; Antonenkova, Natalia

    2015-01-01

    Background\\ud \\ud Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contribu...

  3. The association of environmental, individual factors, and dopamine pathway gene variation with smoking cessation.

    Li, Suyun; Wang, Qiang; Pan, Lulu; Yang, Xiaorong; Li, Huijie; Jiang, Fan; Zhang, Nan; Han, Mingkui; Jia, Chongqi

    2017-09-01

    This study aimed to examine whether dopamine (DA) pathway gene variation were associated with smoking cessation, and compare the relative importance of infulence factors on smoking cessation. Participants were recruited from 17 villages of Shandong Province, China. Twenty-five single nucleotide polymorphisms in 8 DA pathway genes were genotyped. Weighted gene score of each gene was used to analyze the whole gene effect. Logistic regression was used to calculate odds ratios (OR) of the total gene score for smoking cessation. Dominance analysis was employed to compare the relative importance of individual, heaviness of smoking, psychological and genetic factors on smoking cessation. 415 successful spontaneous smoking quitters served as the cases, and 404 unsuccessful quitters served as the controls. A significant negative association of total DA pathway gene score and smoking cessation was observed (p smoking cessation was heaviness of smoking score (42%), following by individual (40%), genetic (10%) and psychological score (8%). In conclusion, although the DA pathway gene variation was significantly associated with successful smoking cessation, heaviness of smoking and individual factors had bigger effect than genetic factors on smoking cessation.

  4. Facing the facts: The Runx2 gene is associated with variation in facial morphology in primates.

    Ritzman, Terrence B; Banovich, Nicholas; Buss, Kaitlin P; Guida, Jennifer; Rubel, Meagan A; Pinney, Jennifer; Khang, Bao; Ravosa, Matthew J; Stone, Anne C

    2017-10-01

    The phylogenetic and adaptive factors that cause variation in primate facial form-including differences among the major primate clades and variation related to feeding and/or social behavior-are relatively well understood. However, comparatively little is known about the genetic mechanisms that underlie diversity in facial form in primates. Because it is essential for osteoblastic differentiation and skeletal development, the runt-related transcription factor 2 (Runx2) is one gene that may play a role in these genetic mechanisms. Specifically, polymorphisms in the QA ratio (determined by the ratio of the number of polyglutamines to polyalanines in one functional domain of Runx2) have been shown to be correlated with variation in facial length and orientation in other mammal groups. However, to date, the relationship between variation in this gene and variation in facial form in primates has not been explicitly tested. To test the hypothesis that the QA ratio is correlated with facial form in primates, the current study quantified the QA ratio, facial length, and facial angle in a sample of 33 primate species and tested for correlation using phylogenetic generalized least squares. The results indicate that the QA ratio of the Runx2 gene is positively correlated with variation in relative facial length in anthropoid primates. However, no correlation was found in strepsirrhines, and there was no correlation between facial angle and the QA ratio in any groups. These results suggest that, in primates, the QA ratio of the Runx2 gene may play a role in modulating facial size, but not facial orientation. This study therefore provides important clues about the genetic and developmental mechanisms that may underlie variation in facial form in primates. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Variations of the candidate SEZ6L2 gene on Chromosome 16p11.2 in patients with autism spectrum disorders and in human populations.

    Marina Konyukh

    Full Text Available BACKGROUND: Autism spectrum disorders (ASD are a group of severe childhood neurodevelopmental disorders with still unknown etiology. One of the most frequently reported associations is the presence of recurrent de novo or inherited microdeletions and microduplications on chromosome 16p11.2. The analysis of rare variations of 8 candidate genes among the 27 genes located in this region suggested SEZ6L2 as a compelling candidate. METHODOLOGY/PRINCIPAL FINDINGS: We further explored the role of SEZ6L2 variations by screening its coding part in a group of 452 individuals, including 170 patients with ASD and 282 individuals from different ethnic backgrounds of the Human Genome Diversity Panel (HGDP, complementing the previously reported screening. We detected 7 previously unidentified non-synonymous variations of SEZ6L2 in ASD patients. We also identified 6 non-synonymous variations present only in HGDP. When we merged our results with the previously published, no enrichment of non-synonymous variation in SEZ6L2 was observed in the ASD group compared with controls. CONCLUSIONS/SIGNIFICANCE: Our results provide an extensive ascertainment of the genetic variability of SEZ6L2 in human populations and do not support a major role for SEZ6L2 sequence variations in the susceptibility to ASD.

  6. Genetic variation in genes of the fatty acid synthesis pathway and breast cancer risk

    Campa, Daniele; McKay, James; Sinilnikova, Olga

    2009-01-01

    and FASN) is related to breast cancer risk and body-mass index (BMI) by studying 1,294 breast cancer cases and 2,452 controls from the European Prospective Investigation on Cancer (EPIC). We resequenced the FAS gene and combined information of SNPs found by resequencing and SNPs from public databases....... Using a tagging approach and selecting 20 SNPs, we covered all the common genetic variation of these genes. In this study we were not able to find any statistically significant association between the SNPs in the FAS, ChREBP and SREPB-1 genes and an increased risk of breast cancer overall...

  7. Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2.

    Visschedijk, Marijn C; Alberts, Rudi; Mucha, Soren; Deelen, Patrick; de Jong, Dirk J; Pierik, Marieke; Spekhorst, Lieke M; Imhann, Floris; van der Meulen-de Jong, Andrea E; van der Woude, C Janneke; van Bodegraven, Adriaan A; Oldenburg, Bas; Löwenberg, Mark; Dijkstra, Gerard; Ellinghaus, David; Schreiber, Stefan; Wijmenga, Cisca; Rivas, Manuel A; Franke, Andre; van Diemen, Cleo C; Weersma, Rinse K

    2016-01-01

    Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC.

  8. Sequence variation in TgROP7 gene among Toxoplasma gondii ...

    Yomi

    2012-03-27

    Mar 27, 2012 ... Toxoplasma gondii can infect a wide range of hosts including mammals and birds, causing toxoplasmosis which is one of the most common parasitic zoonoses worldwide. The present study examined sequence variation in rhoptry 7 (ROP7) gene among different T. gondii isolates from different hosts and ...

  9. Variations in Spike Glycoprotein Gene of MERS-CoV, South Korea, 2015.

    Kim, Dae-Won; Kim, You-Jin; Park, Sung Han; Yun, Mi-Ran; Yang, Jeong-Sun; Kang, Hae Ji; Han, Young Woo; Lee, Han Saem; Kim, Heui Man; Kim, Hak; Kim, A-Reum; Heo, Deok Rim; Kim, Su Jin; Jeon, Jun Ho; Park, Deokbum; Kim, Joo Ae; Cheong, Hyang-Min; Nam, Jeong-Gu; Kim, Kisoon; Kim, Sung Soon

    2016-01-01

    An outbreak of nosocomial infections with Middle East respiratory syndrome coronavirus occurred in South Korea in May 2015. Spike glycoprotein genes of virus strains from South Korea were closely related to those of strains from Riyadh, Saudi Arabia. However, virus strains from South Korea showed strain-specific variations.

  10. The Ser311Cys variation in the paraoxonase 2 gene increases the ...

    Supplementary data: The Ser311Cys variation in the paraoxonase 2 gene increases the risk of type 2 diabetes in northern Chinese. Yanchun Qu, Ze Yang, Feng Jin, Liang Sun, Chuanfang Zhang, Linong Ji, Hong Sun, Binyou Wang and Li Wang. J. Genet. 87, 165–169. Table 1. Clinical characteristics of case and control.

  11. Variation in the PTEN-induced putative kinase 1 gene associated ...

    with the increase risk of type 2 diabetes in northern Chinese. YANCHUN QU1†∗ ... and genetic variation analysis have indicated the involvement of PINK1 gene in the ... Qualitative variables were analysed by a chi-squared test. The level of ...

  12. CAG repeat length variation in the polymerase gamma (POLG) gene: effect on semen quality

    Westerveld, G. H.; Kaaij-Visser, L.; Tanck, M.; van der Veen, F.; Repping, S.

    2008-01-01

    Several case-control studies have investigated the effect of CAG repeat length variation in the POLG gene on male fertility and semen quality. Some described an association between the homozygous not10 CAG-repeat genotype and male subfertility and/or reduced semen quality, whereas others did not.

  13. Gene Flow among Populations of Two Rare Co-Occurring Fern Species Differing in Ploidy Level

    Bucharová, Anna; Münzbergová, Zuzana

    2012-01-01

    Roč. 7, č. 9 (2012), e45855 E-ISSN 1932-6203 R&D Projects: GA MŠk 2B06178; GA ČR GA526/09/0549 Institutional support: RVO:67985939 Keywords : genetic variation * tetraploid species * diploid species Subject RIV: EF - Botanics Impact factor: 3.730, year: 2012

  14. Genetic variation of the Borrelia burgdorferi gene vlsE involves cassette-specific, segmental gene conversion.

    Zhang, J R; Norris, S J

    1998-08-01

    The Lyme disease spirochete Borrelia burgdorferi possesses 15 silent vls cassettes and a vls expression site (vlsE) encoding a surface-exposed lipoprotein. Segments of the silent vls cassettes have been shown to recombine with the vlsE cassette region in the mammalian host, resulting in combinatorial antigenic variation. Despite promiscuous recombination within the vlsE cassette region, the 5' and 3' coding sequences of vlsE that flank the cassette region are not subject to sequence variation during these recombination events. The segments of the silent vls cassettes recombine in the vlsE cassette region through a unidirectional process such that the sequence and organization of the silent vls loci are not affected. As a result of recombination, the previously expressed segments are replaced by incoming segments and apparently degraded. These results provide evidence for a gene conversion mechanism in VlsE antigenic variation.

  15. Rate variation in parasitic plants: correlated and uncorrelated patterns among plastid genes of different function

    dePamphilis Claude W

    2005-02-01

    Full Text Available Abstract Background The analysis of synonymous and nonsynonymous rates of DNA change can help in the choice among competing explanations for rate variation, such as differences in constraint, mutation rate, or the strength of genetic drift. Nonphotosynthetic plants of the Orobanchaceae have increased rates of DNA change. In this study 38 taxa of Orobanchaceae and relatives were used and 3 plastid genes were sequenced for each taxon. Results Phylogenetic reconstructions of relative rates of sequence evolution for three plastid genes (rbcL, matK and rps2 show significant rate heterogeneity among lineages and among genes. Many of the non-photosynthetic plants have increases in both synonymous and nonsynonymous rates, indicating that both (1 selection is relaxed, and (2 there has been a change in the rate at which mutations are entering the population in these species. However, rate increases are not always immediate upon loss of photosynthesis. Overall there is a poor correlation of synonymous and nonsynonymous rates. There is, however, a strong correlation of synonymous rates across the 3 genes studied and the lineage-speccific pattern for each gene is strikingly similar. This indicates that the causes of synonymous rate variation are affecting the whole plastid genome in a similar way. There is a weaker correlation across genes for nonsynonymous rates. Here the picture is more complex, as could be expected if there are many causes of variation, differing from taxon to taxon and gene to gene. Conclusions The distinctive pattern of rate increases in Orobanchaceae has at least two causes. It is clear that there is a relaxation of constraint in many (though not all non-photosynthetic lineages. However, there is also some force affecting synonymous sites as well. At this point, it is not possible to tell whether it is generation time, speciation rate, mutation rate, DNA repair efficiency or some combination of these factors.

  16. Systematic Prioritization and Integrative Analysis of Copy Number Variations in Schizophrenia Reveal Key Schizophrenia Susceptibility Genes

    Luo, Xiongjian; Huang, Liang; Han, Leng; Luo, Zhenwu; Hu, Fang; Tieu, Roger; Gan, Lin

    2014-01-01

    Schizophrenia is a common mental disorder with high heritability and strong genetic heterogeneity. Common disease-common variants hypothesis predicts that schizophrenia is attributable in part to common genetic variants. However, recent studies have clearly demonstrated that copy number variations (CNVs) also play pivotal roles in schizophrenia susceptibility and explain a proportion of missing heritability. Though numerous CNVs have been identified, many of the regions affected by CNVs show poor overlapping among different studies, and it is not known whether the genes disrupted by CNVs contribute to the risk of schizophrenia. By using cumulative scoring, we systematically prioritized the genes affected by CNVs in schizophrenia. We identified 8 top genes that are frequently disrupted by CNVs, including NRXN1, CHRNA7, BCL9, CYFIP1, GJA8, NDE1, SNAP29, and GJA5. Integration of genes affected by CNVs with known schizophrenia susceptibility genes (from previous genetic linkage and association studies) reveals that many genes disrupted by CNVs are also associated with schizophrenia. Further protein-protein interaction (PPI) analysis indicates that protein products of genes affected by CNVs frequently interact with known schizophrenia-associated proteins. Finally, systematic integration of CNVs prioritization data with genetic association and PPI data identifies key schizophrenia candidate genes. Our results provide a global overview of genes impacted by CNVs in schizophrenia and reveal a densely interconnected molecular network of de novo CNVs in schizophrenia. Though the prioritized top genes represent promising schizophrenia risk genes, further work with different prioritization methods and independent samples is needed to confirm these findings. Nevertheless, the identified key candidate genes may have important roles in the pathogenesis of schizophrenia, and further functional characterization of these genes may provide pivotal targets for future therapeutics and

  17. Genetic and epigenetic variation in 5S ribosomal RNA genes reveals genome dynamics in Arabidopsis thaliana.

    Simon, Lauriane; Rabanal, Fernando A; Dubos, Tristan; Oliver, Cecilia; Lauber, Damien; Poulet, Axel; Vogt, Alexander; Mandlbauer, Ariane; Le Goff, Samuel; Sommer, Andreas; Duborjal, Hervé; Tatout, Christophe; Probst, Aline V

    2018-04-06

    Organized in tandem repeat arrays in most eukaryotes and transcribed by RNA polymerase III, expression of 5S rRNA genes is under epigenetic control. To unveil mechanisms of transcriptional regulation, we obtained here in depth sequence information on 5S rRNA genes from the Arabidopsis thaliana genome and identified differential enrichment in epigenetic marks between the three 5S rDNA loci situated on chromosomes 3, 4 and 5. We reveal the chromosome 5 locus as the major source of an atypical, long 5S rRNA transcript characteristic of an open chromatin structure. 5S rRNA genes from this locus translocated in the Landsberg erecta ecotype as shown by linkage mapping and chromosome-specific FISH analysis. These variations in 5S rDNA locus organization cause changes in the spatial arrangement of chromosomes in the nucleus. Furthermore, 5S rRNA gene arrangements are highly dynamic with alterations in chromosomal positions through translocations in certain mutants of the RNA-directed DNA methylation pathway and important copy number variations among ecotypes. Finally, variations in 5S rRNA gene sequence, chromatin organization and transcripts indicate differential usage of 5S rDNA loci in distinct ecotypes. We suggest that both the usage of existing and new 5S rDNA loci resulting from translocations may impact neighboring chromatin organization.

  18. A rare sugar, d-allose, confers resistance to rice bacterial blight with upregulation of defense-related genes in Oryza sativa.

    Kano, Akihito; Gomi, Kenji; Yamasaki-Kokudo, Yumiko; Satoh, Masaru; Fukumoto, Takeshi; Ohtani, Kouhei; Tajima, Shigeyuki; Izumori, Ken; Tanaka, Keiji; Ishida, Yutaka; Tada, Yasuomi; Nishizawa, Yoko; Akimitsu, Kazuya

    2010-01-01

    We investigated responses of rice plant to three rare sugars, d-altrose, d-sorbose, and d-allose, due to establishment of mass production methods for these rare sugars. Root growth and shoot growth were significantly inhibited by d-allose but not by the other rare sugars. A large-scale gene expression analysis using a rice microarray revealed that d-allose treatment causes a high upregulation of many defense-related, pathogenesis-related (PR) protein genes in rice. The PR protein genes were not upregulated by other rare sugars. Furthermore, d-allose treatment of rice plants conferred limited resistance of the rice against the pathogen Xanthomonas oryzae pv. oryzae but the other tested sugars did not. These results indicate that d-allose has a growth inhibitory effect but might prove to be a candidate elicitor for reducing disease development in rice.

  19. Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies

    Lal, Dennis; Ruppert, Ann-Kathrin; Trucks, Holger

    2015-01-01

    contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent...

  20. Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

    Hendricks, Audrey E.; Bochukova, Elena G.; Marenne, Gaëlle; Keogh, Julia M.; Atanassova, Neli; Bounds, Rebecca; Wheeler, Eleanor; Mistry, Vanisha; Henning, Elana; Körner, Antje; Muddyman, Dawn; McCarthy, Shane; Hinney, Anke; Hebebrand, Johannes; Scott, Robert A.; Langenberg, Claudia; Wareham, Nick J.; Surendran, Praveen; Howson, Joanna M M; Butterworth, Adam S.; Danesh, John; Nordestgaard, Børge G.; Nielsen, Sune F.; Afzal, Shoaib; Papadia, Sofia; Ashford, Sofie; Garg, Sumedha; Millhauser, Glenn L.; Palomino, Rafael I.; Kwasniewska, Alexandra; Tachmazidou, Ioanna; O'Rahilly, Stephen; Zeggini, Eleftheria; Barroso, Inês; Farooqi, I. Sadaf; Benzeval, Michaela; Burton, Jonathan; Buck, Nicholas; Jäckle, Annette; Kumari, Meena; Laurie, Heather; Lynn, Peter; Pudney, Stephen; Rabe, Birgitta; Wolke, Dieter; Overvad, Kim; Tjønneland, Anne; Clavel-Chapelon, Francoise; Kaaks, Rudolf; Boeing, Heiner; Trichopoulou, Antonia; Ferrari, Pietro; Palli, Domenico; Krogha, Vittorio; Panico, Salvatore; Tuminoa, Rosario; Matullo, Giuseppe; Boer, Jolanda Ma; Van Der Schouw, Yvonne; Weiderpass, Elisabete; Quiros, J. Ramon; Sánchez, María José; Navarro, Carmen; Moreno-Iribas, Conchi; Arriola, Larraitz; Melander, Olle; Wennberg, Patrik; Key, Timothy J.; Riboli, Elio; Al-Turki, Saeed; Anderson, Carl A; Anney, Richard; Antony, Dinu; Soler Artigas, María; Ayub, Muhammad; Bala, Senduran; Barrett, Jeffrey C; Beales, Phil; Bentham, Jamie; Bhattacharyaa, Shoumo; Birney, Ewan; Blackwooda, Douglas; Bobrow, Martin; Bolton, Patrick F.; Boustred, Chris; Breen, Gerome; Calissanoa, Mattia; Carss, Keren; Charlton, Ruth; Chatterjee, Krishna; Chen, Lu; Ciampia, Antonio; Cirak, Sebahattin; Clapham, Peter; Clement, Gail; Coates, Guy; Coccaa, Massimiliano; Collier, David A; Cosgrove, Catherine; Coxa, Tony; Craddock, Nick; Crooks, Lucy; Curran, Sarah; Curtis, David; Daly, Allan; Danecek, Petr; Day, Ian N M; Day-Williams, Aaron G; Dominiczak, Anna; Down, Thomas; Du, Yuanping; Dunham, Ian; Durbin, Richard; Edkins, Sarah; Ekong, Rosemary; Ellis, Peter; Evansa, David M.; FitzPatrick, David R.; Flicek, Paul; Floyd, James S.; Foley, A. Reghan; Franklin, Christopher S.; Futema, Marta; Gallagher, Louise; Gaunt, Tom R.; Geihs, Matthias; Geschwind, Daniel H.; Greenwood, Celia M.T.; Griffin, Heather; Grozeva, Detelina; Guo, Xiaosen; Guo, Xueqin; Gurling, Hugh; Hart, Deborah J.; Holmans, Peter A; Howie, Bryan; Huang, Jie; Huang, Liren; Hubbard, Tim; Humphries, Steve E.; Hurles, Matthew E.; Hysi, Pirro G.; Iotchkova, Valentina; Jackson, David K.; Jamshidi, Yalda; Joyce, Chris; Karczewski, Konrad J.; Kaye, Jane; Keane, Thomas; Kemp, John P.; Kennedy, Karen; Kent, Alastair; Khawaja, Farrah; Van Kogelenberg, Margriet; Kolb-Kokocinski, Anja; Lachance, Genevieve; Langford, Cordelia; Lawson, Daniel; Lee, Irene; Lek, Monkol; Li, Rui; Li, Yingrui; Liang, Jieqin; Lin, Hong; Liu, Ryan; Lönnqvist, Jouko; Lopes, Luis R.; Lopes, Margarida; MacArthur, Daniel G.; Mangino, Massimo; Marchini, Jonathan; Maslen, John; Mathieson, Iain; McGuffin, Peter; McIntosh, Andrew M.; McKechanie, Andrew G.; McQuillin, Andrew; Memari, Yasin; Metrustry, Sarah; Migone, Nicola; Min, Josine L.; Mitchison, Hannah M; Moayyeri, Alireza; Morris, Andrew D.; Morris, James; Muntoni, Francesco; Northstone, Kate; O'Donovan, Michael C.; Onoufriadis, Alexandros; Oualkacha, Karim; Owen, Michael J; Palotie, Aarno; Panoutsopoulou, Kalliope; Parker, Victoria; Parr, Jeremy R.; Paternoster, Lavinia; Paunio, Tiina; Payne, Felicity; Payne, Stewart J.; Perry, John R. B.; Pietilainen, Olli; Plagnol, Vincent; Pollitt, Rebecca C.; Porteous, David J.; Povey, Sue; Quail, Michael A.; Quaye, Lydia; Raymond, F. Lucy; Rehnström, Karola; Richards, J Brent; Ridout, Cheryl K.; Ring, Susan M.; Ritchie, Graham R.S.; Roberts, Nicola; Robinson, Rachel L.; Savage, David B.; Scambler, Peter; Schiffels, Stephan; Schmidts, Miriam; Schoenmakers, Nadia; Scott, Richard H.; Semple, Robert K.; Serra, Eva; Sharp, Sally I.; Shaw, Adam; Shihab, Hashem A.; Shin, So Youn; Skuse, David; Small, Kerrin S; Smee, Carol; Smith, Blair H.; Davey Smith, George; Soranzo, Nicole; Southam, Lorraine; Spasic-Boskovic, Olivera; Spector, Timothy D; St Clair, David; St Pourcain, Beate; Stalker, Jim; Stevens, Elizabeth; Sun, Jianping; Surdulescu, Gabriela L; Suvisaari, Jaana; Syrris, Petros; Taylor, Rohan; Tian, Jing; Timpson, Nicholas J.; Tobin, Martin D; Valdes, Ana M.; Vandersteen, Anthony M.; Vijayarangakannan, Parthiban; Visscher, Peter M.; Wain, Louise V.; Walter, Klaudia; Walters, James T.R.; Wang, Guangbiao; Wang, Jun; Wang, Nai-Yu; Ward, Kirsten; Whyte, Tamieka; Williams, Hywel J.; Williamson, Kathleen A.; Wilson, Crispian; Wilson, Scott G.; Wong, Kim; Xu, Changjiang; Yang, Jian; Zhang, Feng; Zhang, Pingbo; Zheng, Hou Feng

    2017-01-01

    Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS,

  1. Rare variant analysis of human and rodent obesity genes in individuals with severe childhood obesity

    Hendricks, Audrey E.; Bochukova, Elena G.; Marenne, Gaëlle

    2017-01-01

    Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GN...

  2. Geographic Variation in Advertisement Calls in a Tree Frog Species: Gene Flow and Selection Hypotheses

    Jang, Yikweon; Hahm, Eun Hye; Lee, Hyun-Jung; Park, Soyeon; Won, Yong-Jin; Choe, Jae C.

    2011-01-01

    Background In a species with a large distribution relative to its dispersal capacity, geographic variation in traits may be explained by gene flow, selection, or the combined effects of both. Studies of genetic diversity using neutral molecular markers show that patterns of isolation by distance (IBD) or barrier effect may be evident for geographic variation at the molecular level in amphibian species. However, selective factors such as habitat, predator, or interspecific interactions may be critical for geographic variation in sexual traits. We studied geographic variation in advertisement calls in the tree frog Hyla japonica to understand patterns of variation in these traits across Korea and provide clues about the underlying forces for variation. Methodology We recorded calls of H. japonica in three breeding seasons from 17 localities including localities in remote Jeju Island. Call characters analyzed were note repetition rate (NRR), note duration (ND), and dominant frequency (DF), along with snout-to-vent length. Results The findings of a barrier effect on DF and a longitudinal variation in NRR seemed to suggest that an open sea between the mainland and Jeju Island and mountain ranges dominated by the north-south Taebaek Mountains were related to geographic variation in call characters. Furthermore, there was a pattern of IBD in mitochondrial DNA sequences. However, no comparable pattern of IBD was found between geographic distance and call characters. We also failed to detect any effects of habitat or interspecific interaction on call characters. Conclusions Geographic variations in call characters as well as mitochondrial DNA sequences were largely stratified by geographic factors such as distance and barriers in Korean populations of H. japoinca. Although we did not detect effects of habitat or interspecific interaction, some other selective factors such as sexual selection might still be operating on call characters in conjunction with restricted gene

  3. Identifying Rare Variation in Cases of Schizophrenia in the Isolated Population of the Faroe Islands using Whole-genome Sequencing

    Als, Thomas Damm; Lescai, Francesco; Dahl, Hans

    to map risk variants involved in complex traits. We aim at utilizing samples of cases and controls of the isolated population of the Faroe Islands to conduct whole-genome-sequence analysis in order to identify rare genetic variants associated with schizophrenia. We will search for rare genetic variants...... of developing SZ. However, these studies are designed to examining only “the common variant” proportion of the genomic landscape of SZ. Due to increased genetic drift during founding and potential bottlenecks, followed by population expansion, isolated populations may be particularly useful in identifying rare...... disease variants, that may appear at higher frequencies and/or within a more clearly distinct haplotype structure compared to outbred populations. Small isolated populations also typically show reduced phenotypic, genetic and environmental heterogeneity, thus making them advantageous in studies aiming...

  4. Analysis of rare variants in the CFH gene in patients with the cuticular drusen subtype of age-related macular degeneration

    Duvvari, M.R.; Saksens, N.T.M.; Ven, J.P.H. van de; Jong-Hesse, Y. de; Schick, T.; Nillesen, W.M.; Fauser, S.; Hoefsloot, L.H.; Hoyng, C.B.; Jong, E.K.; Hollander, A.I. den

    2015-01-01

    PURPOSE: Age-related macular degeneration (AMD) and cuticular drusen (CD), a clinical subtype of AMD, have been linked to genetic variants in the complement factor H (CFH) gene. In this study, we aimed to investigate the frequency of rare variants in the CFH gene in 180 cases with CD. In addition,

  5. Genome-wide assessment of the association of rare and common copy number variations to testicular germ cell cancer

    Edsgard, Stefan Daniel; Dalgaard, Marlene Danner; Weinhold, Nils

    2013-01-01

    Testicular germ cell cancer (TGCC) is one of the most heritable forms of cancer. Previous genome-wide association studies have focused on single nucleotide polymorphisms, largely ignoring the influence of copy number variants (CNVs). Here we present a genome-wide study of CNV on a cohort of 212...... of rare CNVs related to cell migration (false-discovery rate = 0.021, 1.8% of cases and 1.1% of controls). Dysregulation during migration of primordial germ cells has previously been suspected to be a part of TGCC development and this set of multiple rare variants may thereby have a minor contribution...

  6. Sequence Variation in Toxoplasma gondii rop17 Gene among Strains from Different Hosts and Geographical Locations

    Nian-Zhang Zhang

    2014-01-01

    Full Text Available Genetic diversity of T. gondii is a concern of many studies, due to the biological and epidemiological diversity of this parasite. The present study examined sequence variation in rhoptry protein 17 (ROP17 gene among T. gondii isolates from different hosts and geographical regions. The rop17 gene was amplified and sequenced from 10 T. gondii strains, and phylogenetic relationship among these T. gondii strains was reconstructed using maximum parsimony (MP, neighbor-joining (NJ, and maximum likelihood (ML analyses. The partial rop17 gene sequences were 1375 bp in length and A+T contents varied from 49.45% to 50.11% among all examined T. gondii strains. Sequence analysis identified 33 variable nucleotide positions (2.1%, 16 of which were identified as transitions. Phylogeny reconstruction based on rop17 gene data revealed two major clusters which could readily distinguish Type I and Type II strains. Analyses of sequence variations in nucleotides and amino acids among these strains revealed high ratio of nonsynonymous to synonymous polymorphisms (>1, indicating that rop17 shows signs of positive selection. This study demonstrated the existence of slightly high sequence variability in the rop17 gene sequences among T. gondii strains from different hosts and geographical regions, suggesting that rop17 gene may represent a new genetic marker for population genetic studies of T. gondii isolates.

  7. Gene flow and geographic variation in natural populations of Alnus acuminata ssp. arguta (Fagales: Betulaceae in Costa Rica and Panama

    Olman Murillo

    1999-12-01

    Full Text Available Seventeen natural populations in Costa Rica and Panama were used to asses gene flow and geographic patterns of genetic variation in this tree species. Gene flow analysis was based on the methods of rare alleles and FST (Index of genetic similarity M, using the only four polymorphic gene loci among 22 investigated (PGI-B, PGM-A, MNR-A and IDH-A. The geographic variation analysis was based on Pearson`s correlations between four geographic and 14 genetic variables. Some evidence of isolation by distance and a weak gene flow among geographic regions was found. Patterns of clinal variation in relation to altitude (r = -0.62 for genetic diversity and latitude (r= -0.77 for PGI-B3 were also observed, supporting the hypothesis of isolation by distance. No private alleles were found at the single population level.Diecisiete poblaciones naturales de esta especie forestal en Costa Rica y Panamá, fueron investigadas en relación con sus patrones de flujo genético y de variación geográfica. El análisis de flujo genético fue basado en los métodos de los alelos raros y de FST (Indice de similaridad genética M. Los análisis fueron a su vez basados en los únicos cuatro loci genéticos de un total de 22 investigados que mostraron polimorfismo (PGI-B, PGM-A, MNR-A and IDH-A. Los análisis de variación geográfica fueron basados en el desarrollo de correlaciones de Pearson entre 4 variables geográficas y 14 variables genéticas. Alguna evidencia de aislamiento por distancia así como un débil flujo genético entre regiones geográficas fue encontrado. Fueron también observados patrones de variación clinal en relación con la altitud (r = -0.62 para la diversidad genética y latitud (r= -0.77 en PGI-B3, que apoyan la hipotesis de aislamiento por distancia para esta especie. No se encontraron alelos privados en ninguna de las poblaciones investigadas.

  8. Replication of type 2 diabetes candidate genes variations in three geographically unrelated Indian population groups.

    Ali, Shafat; Chopra, Rupali; Manvati, Siddharth; Singh, Yoginder Pal; Kaul, Nabodita; Behura, Anita; Mahajan, Ankit; Sehajpal, Prabodh; Gupta, Subash; Dhar, Manoj K; Chainy, Gagan B N; Bhanwer, Amarjit S; Sharma, Swarkar; Bamezai, Rameshwar N K

    2013-01-01

    Type 2 diabetes (T2D) is a syndrome of multiple metabolic disorders and is genetically heterogeneous. India comprises one of the largest global populations with highest number of reported type 2 diabetes cases. However, limited information about T2D associated loci is available for Indian populations. It is, therefore, pertinent to evaluate the previously associated candidates as well as identify novel genetic variations in Indian populations to understand the extent of genetic heterogeneity. We chose to do a cost effective high-throughput mass-array genotyping and studied the candidate gene variations associated with T2D in literature. In this case-control candidate genes association study, 91 SNPs from 55 candidate genes have been analyzed in three geographically independent population groups from India. We report the genetic variants in five candidate genes: TCF7L2, HHEX, ENPP1, IDE and FTO, are significantly associated (after Bonferroni correction, ppopulation. Interestingly, SNP rs7903146 of the TCF7L2 gene passed the genome wide significance threshold (combined P value = 2.05E-08) in the studied populations. We also observed the association of rs7903146 with blood glucose (fasting and postprandial) levels, supporting the role of TCF7L2 gene in blood glucose homeostasis. Further, we noted that the moderate risk provided by the independently associated loci in combined population with Odds Ratio (OR)<1.38 increased to OR = 2.44, (95%CI = 1.67-3.59) when the risk providing genotypes of TCF7L2, HHEX, ENPP1 and FTO genes were combined, suggesting the importance of gene-gene interactions evaluation in complex disorders like T2D.

  9. Replication of type 2 diabetes candidate genes variations in three geographically unrelated Indian population groups.

    Shafat Ali

    Full Text Available Type 2 diabetes (T2D is a syndrome of multiple metabolic disorders and is genetically heterogeneous. India comprises one of the largest global populations with highest number of reported type 2 diabetes cases. However, limited information about T2D associated loci is available for Indian populations. It is, therefore, pertinent to evaluate the previously associated candidates as well as identify novel genetic variations in Indian populations to understand the extent of genetic heterogeneity. We chose to do a cost effective high-throughput mass-array genotyping and studied the candidate gene variations associated with T2D in literature. In this case-control candidate genes association study, 91 SNPs from 55 candidate genes have been analyzed in three geographically independent population groups from India. We report the genetic variants in five candidate genes: TCF7L2, HHEX, ENPP1, IDE and FTO, are significantly associated (after Bonferroni correction, p<5.5E-04 with T2D susceptibility in combined population. Interestingly, SNP rs7903146 of the TCF7L2 gene passed the genome wide significance threshold (combined P value = 2.05E-08 in the studied populations. We also observed the association of rs7903146 with blood glucose (fasting and postprandial levels, supporting the role of TCF7L2 gene in blood glucose homeostasis. Further, we noted that the moderate risk provided by the independently associated loci in combined population with Odds Ratio (OR<1.38 increased to OR = 2.44, (95%CI = 1.67-3.59 when the risk providing genotypes of TCF7L2, HHEX, ENPP1 and FTO genes were combined, suggesting the importance of gene-gene interactions evaluation in complex disorders like T2D.

  10. Natural variation in gene expression in the early development of dauer larvae of Caenorhabditis elegans

    Barker Gary LA

    2009-07-01

    Full Text Available Abstract Background The free-living nematode Caenorhabditis elegans makes a developmental decision based on environmental conditions: larvae either arrest as dauer larva, or continue development into reproductive adults. There is natural variation among C. elegans lines in the sensitivity of this decision to environmental conditions; that is, there is variation in the phenotypic plasticity of dauer larva development. We hypothesised that these differences may be transcriptionally controlled in early stage larvae. We investigated this by microarray analysis of different C. elegans lines under different environmental conditions, specifically the presence and absence of dauer larva-inducing pheromone. Results There were substantial transcriptional differences between four C. elegans lines under the same environmental conditions. The expression of approximately 2,000 genes differed between genetically different lines, with each line showing a largely line-specific transcriptional profile. The expression of genes that are markers of larval moulting suggested that the lines may be developing at different rates. The expression of a total of 89 genes was putatively affected by dauer larva or non-dauer larva-inducing conditions. Among the upstream regions of these genes there was an over-representation of DAF-16-binding motifs. Conclusion Under the same environmental conditions genetically different lines of C. elegans had substantial transcriptional differences. This variation may be due to differences in the developmental rates of the lines. Different environmental conditions had a rather smaller effect on transcription. The preponderance of DAF-16-binding motifs upstream of these genes was consistent with these genes playing a key role in the decision between development into dauer or into non-dauer larvae. There was little overlap between the genes whose expression was affected by environmental conditions and previously identified loci involved in

  11. Lack of influence of GTP cyclohydrolase gene (GCH1 variations on pain sensitivity in humans

    Dionne Raymond A

    2007-03-01

    Full Text Available Abstract Objectives To assess the effect of variations in GTP cyclohydrolase gene (GCH1 on pain sensitivity in humans. Methods Thermal and cold pain sensitivity were evaluated in a cohort of 735 healthy volunteers. Among this cohort, the clinical pain responses of 221 subjects after the surgical removal of impacted third molars were evaluated. Genotyping was done for 38 single nucleotide polymorphisms (SNPs whose heterozygosity > 0.2 in GCH1. Influence of the genetic variations including SNPs and haplotypes on pain sensitivity were analyzed. Results Minor allele frequencies and linkage disequilibrium show significant differences in European Americans, African Americans, Hispanic Americans and Asian Americans. Association analyses in European Americans do not replicate the previously reported important influence of GCH1 variations on pain sensitivity. Conclusion Considering population stratification, previously reported associations between GCH1 genetic variations and pain sensitivity appear weak or negligible in this well characterized model of pain.

  12. A functional bikaverin biosynthesis gene cluster in rare strains of Botrytis cinerea is positively controlled by VELVET.

    Julia Schumacher

    Full Text Available The gene cluster responsible for the biosynthesis of the red polyketidic pigment bikaverin has only been characterized in Fusarium ssp. so far. Recently, a highly homologous but incomplete and nonfunctional bikaverin cluster has been found in the genome of the unrelated phytopathogenic fungus Botrytis cinerea. In this study, we provided evidence that rare B. cinerea strains such as 1750 have a complete and functional cluster comprising the six genes orthologous to Fusarium fujikuroi ffbik1-ffbik6 and do produce bikaverin. Phylogenetic analysis confirmed that the whole cluster was acquired from Fusarium through a horizontal gene transfer (HGT. In the bikaverin-nonproducing strain B05.10, the genes encoding bikaverin biosynthesis enzymes are nonfunctional due to deleterious mutations (bcbik2-3 or missing (bcbik1 but interestingly, the genes encoding the regulatory proteins BcBIK4 and BcBIK5 do not harbor deleterious mutations which suggests that they may still be functional. Heterologous complementation of the F. fujikuroi Δffbik4 mutant confirmed that bcbik4 of strain B05.10 is indeed fully functional. Deletion of bcvel1 in the pink strain 1750 resulted in loss of bikaverin and overproduction of melanin indicating that the VELVET protein BcVEL1 regulates the biosynthesis of the two pigments in an opposite manner. Although strain 1750 itself expresses a truncated BcVEL1 protein (100 instead of 575 aa that is nonfunctional with regard to sclerotia formation, virulence and oxalic acid formation, it is sufficient to regulate pigment biosynthesis (bikaverin and melanin and fenhexamid HydR2 type of resistance. Finally, a genetic cross between strain 1750 and a bikaverin-nonproducing strain sensitive to fenhexamid revealed that the functional bikaverin cluster is genetically linked to the HydR2 locus.

  13. Natural genetic variation in Arabidopsis thaliana defense metabolism genes modulates field fitness

    Kerwin, Rachel; Feusier, Julie; Corwin, Jason; Rubin, Matthew; Lin, Catherine; Muok, Alise; Larson, Brandon; Li, Baohua; Joseph, Bindu; Francisco, Marta; Copeland, Daniel; Weinig, Cynthia; Kliebenstein, Daniel J

    2015-01-01

    Natural populations persist in complex environments, where biotic stressors, such as pathogen and insect communities, fluctuate temporally and spatially. These shifting biotic pressures generate heterogeneous selective forces that can maintain standing natural variation within a species. To directly test if genes containing causal variation for the Arabidopsis thaliana defensive compounds, glucosinolates (GSL) control field fitness and are therefore subject to natural selection, we conducted a multi-year field trial using lines that vary in only specific causal genes. Interestingly, we found that variation in these naturally polymorphic GSL genes affected fitness in each of our environments but the pattern fluctuated such that highly fit genotypes in one trial displayed lower fitness in another and that no GSL genotype or genotypes consistently out-performed the others. This was true both across locations and within the same location across years. These results indicate that environmental heterogeneity may contribute to the maintenance of GSL variation observed within Arabidopsis thaliana. DOI: http://dx.doi.org/10.7554/eLife.05604.001 PMID:25867014

  14. The Orphan Gene dauerless Regulates Dauer Development and Intraspecific Competition in Nematodes by Copy Number Variation.

    Melanie G Mayer

    2015-06-01

    Full Text Available Many nematodes form dauer larvae when exposed to unfavorable conditions, representing an example of phenotypic plasticity and a major survival and dispersal strategy. In Caenorhabditis elegans, the regulation of dauer induction is a model for pheromone, insulin, and steroid-hormone signaling. Recent studies in Pristionchus pacificus revealed substantial natural variation in various aspects of dauer development, i.e. pheromone production and sensing and dauer longevity and fitness. One intriguing example is a strain from Ohio, having extremely long-lived dauers associated with very high fitness and often forming the most dauers in response to other strains' pheromones, including the reference strain from California. While such examples have been suggested to represent intraspecific competition among strains, the molecular mechanisms underlying these dauer-associated patterns are currently unknown. We generated recombinant-inbred-lines between the Californian and Ohioan strains and used quantitative-trait-loci analysis to investigate the molecular mechanism determining natural variation in dauer development. Surprisingly, we discovered that the orphan gene dauerless controls dauer formation by copy number variation. The Ohioan strain has one dauerless copy causing high dauer formation, whereas the Californian strain has two copies, resulting in strongly reduced dauer formation. Transgenic animals expressing multiple copies do not form dauers. dauerless is exclusively expressed in CAN neurons, and both CAN ablation and dauerless mutations increase dauer formation. Strikingly, dauerless underwent several duplications and acts in parallel or downstream of steroid-hormone signaling but upstream of the nuclear-hormone-receptor daf-12. We identified the novel or fast-evolving gene dauerless as inhibitor of dauer development. Our findings reveal the importance of gene duplications and copy number variations for orphan gene function and suggest daf-12 as

  15. Temporal gene expression variation associated with eyespot size plasticity in Bicyclus anynana.

    Jeffrey C Oliver

    Full Text Available Seasonal polyphenism demonstrates an organism's ability to respond to predictable environmental variation with alternative phenotypes, each presumably better suited to its respective environment. However, the molecular mechanisms linking environmental variation to alternative phenotypes via shifts in development remain relatively unknown. Here we investigate temporal gene expression variation in the seasonally polyphenic butterfly Bicyclus anynana. This species shows drastic changes in eyespot size depending on the temperature experienced during larval development. The wet season form (larvae reared over 24°C has large ventral wing eyespots while the dry season form (larvae reared under 19°C has much smaller eyespots. We compared the expression of three proteins, Notch, Engrailed, and Distal-less, in the future eyespot centers of the two forms to determine if eyespot size variation is associated with heterochronic shifts in the onset of their expression. For two of these proteins, Notch and Engrailed, expression in eyespot centers occurred earlier in dry season than in wet season larvae, while Distal-less showed no temporal difference between the two forms. These results suggest that differences between dry and wet season adult wings could be due to a delay in the onset of expression of these eyespot-associated genes. Early in eyespot development, Notch and Engrailed may be functioning as repressors rather than activators of the eyespot gene network. Alternatively, temporal variation in the onset of early expressed genes between forms may have no functional consequences to eyespot size regulation and may indicate the presence of an 'hourglass' model of development in butterfly eyespots.

  16. Global and disease-associated genetic variation in the human Fanconi anemia gene family.

    Rogers, Kai J; Fu, Wenqing; Akey, Joshua M; Monnat, Raymond J

    2014-12-20

    Fanconi anemia (FA) is a human recessive genetic disease resulting from inactivating mutations in any of 16 FANC (Fanconi) genes. Individuals with FA are at high risk of developmental abnormalities, early bone marrow failure and leukemia. These are followed in the second and subsequent decades by a very high risk of carcinomas of the head and neck and anogenital region, and a small continuing risk of leukemia. In order to characterize base pair-level disease-associated (DA) and population genetic variation in FANC genes and the segregation of this variation in the human population, we identified 2948 unique FANC gene variants including 493 FA DA variants across 57,240 potential base pair variation sites in the 16 FANC genes. We then analyzed the segregation of this variation in the 7578 subjects included in the Exome Sequencing Project (ESP) and the 1000 Genomes Project (1KGP). There was a remarkably high frequency of FA DA variants in ESP/1KGP subjects: at least 1 FA DA variant was identified in 78.5% (5950 of 7578) individuals included in these two studies. Six widely used functional prediction algorithms correctly identified only a third of the known, DA FANC missense variants. We also identified FA DA variants that may be good candidates for different types of mutation-specific therapies. Our results demonstrate the power of direct DNA sequencing to detect, estimate the frequency of and follow the segregation of deleterious genetic variation in human populations. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

    Chornokur, Ganna; Lin, Hui-Yi; Tyrer, Jonathan P

    2015-01-01

    . As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. METHODS: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC......BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes...... and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted...

  18. Polymorphic Variation in Double Strand Break Repair Gene in Indian Population: A Comparative Approach with Worldwide Ethnic Group Variations.

    Mandal, Raju Kumar; Mittal, Rama Devi

    2018-04-01

    DNA repair capacity is essential in maintaining cellular functions and homeostasis. Identification of genetic polymorphisms responsible for reduced DNA repair capacity may allow better cancer prevention. Double strand break repair pathway plays critical roles in maintaining genome stability. Present study was conducted to determine distribution of XRCC3 Exon 7 (C18067T, rs861539) and XRCC7 Intron 8 (G6721T, rs7003908) gene polymorphisms in North Indian population and compare with different populations globally. The genotype assays were performed in 224 normal healthy individuals of similar ethnicity using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Allelic frequencies of wild type were 79% (C) in XRCC3 Exon 7 C > T and 57% (G) in XRCC7 Intron 8 (G > T) 57% (G) observed. On the other hand, the variant allele frequency were 21% (T) in XRCC3 Exon 7 C > T and 43% (T) in XRCC7 Intron 8 G > T respectively. Major differences from other ethnic populations were observed. Our results suggest that frequency in these DNA repair genes exhibit distinctive pattern in India that could be attributed to ethnicity variation. This could assist in high-risk screening of humans exposed to environmental carcinogens and cancer predisposition in different ethnic groups.

  19. Variation in the oxytocin receptor gene (OXTR) is associated with differences in moral judgment.

    Bernhard, Regan M; Chaponis, Jonathan; Siburian, Richie; Gallagher, Patience; Ransohoff, Katherine; Wikler, Daniel; Perlis, Roy H; Greene, Joshua D

    2016-12-01

    Moral judgments are produced through the coordinated interaction of multiple neural systems, each of which relies on a characteristic set of neurotransmitters. Genes that produce or regulate these neurotransmitters may have distinctive influences on moral judgment. Two studies examined potential genetic influences on moral judgment using dilemmas that reliably elicit competing automatic and controlled responses, generated by dissociable neural systems. Study 1 (N = 228) examined 49 common variants (SNPs) within 10 candidate genes and identified a nominal association between a polymorphism (rs237889) of the oxytocin receptor gene (OXTR) and variation in deontological vs utilitarian moral judgment (that is, judgments favoring individual rights vs the greater good). An association was likewise observed for rs1042615 of the arginine vasopressin receptor gene (AVPR1A). Study 2 (N = 322) aimed to replicate these findings using the aforementioned dilemmas as well as a new set of structurally similar medical dilemmas. Study 2 failed to replicate the association with AVPR1A, but replicated the OXTR finding using both the original and new dilemmas. Together, these findings suggest that moral judgment is influenced by variation in the oxytocin receptor gene and, more generally, that single genetic polymorphisms can have a detectable effect on complex decision processes. © The Author (2016). Published by Oxford University Press.

  20. Understanding gene sequence variation in the context of transcription regulation in yeast.

    Irit Gat-Viks

    2010-01-01

    Full Text Available DNA sequence polymorphism in a regulatory protein can have a widespread transcriptional effect. Here we present a computational approach for analyzing modules of genes with a common regulation that are affected by specific DNA polymorphisms. We identify such regulatory-linkage modules by integrating genotypic and expression data for individuals in a segregating population with complementary expression data of strains mutated in a variety of regulatory proteins. Our procedure searches simultaneously for groups of co-expressed genes, for their common underlying linkage interval, and for their shared regulatory proteins. We applied the method to a cross between laboratory and wild strains of S. cerevisiae, demonstrating its ability to correctly suggest modules and to outperform extant approaches. Our results suggest that middle sporulation genes are under the control of polymorphism in the sporulation-specific tertiary complex Sum1p/Rfm1p/Hst1p. In another example, our analysis reveals novel inter-relations between Swi3 and two mitochondrial inner membrane proteins underlying variation in a module of aerobic cellular respiration genes. Overall, our findings demonstrate that this approach provides a useful framework for the systematic mapping of quantitative trait loci and their role in gene expression variation.

  1. A relative variation-based method to unraveling gene regulatory networks.

    Yali Wang

    Full Text Available Gene regulatory network (GRN reconstruction is essential in understanding the functioning and pathology of a biological system. Extensive models and algorithms have been developed to unravel a GRN. The DREAM project aims to clarify both advantages and disadvantages of these methods from an application viewpoint. An interesting yet surprising observation is that compared with complicated methods like those based on nonlinear differential equations, etc., methods based on a simple statistics, such as the so-called Z-score, usually perform better. A fundamental problem with the Z-score, however, is that direct and indirect regulations can not be easily distinguished. To overcome this drawback, a relative expression level variation (RELV based GRN inference algorithm is suggested in this paper, which consists of three major steps. Firstly, on the basis of wild type and single gene knockout/knockdown experimental data, the magnitude of RELV of a gene is estimated. Secondly, probability for the existence of a direct regulation from a perturbed gene to a measured gene is estimated, which is further utilized to estimate whether a gene can be regulated by other genes. Finally, the normalized RELVs are modified to make genes with an estimated zero in-degree have smaller RELVs in magnitude than the other genes, which is used afterwards in queuing possibilities of the existence of direct regulations among genes and therefore leads to an estimate on the GRN topology. This method can in principle avoid the so-called cascade errors under certain situations. Computational results with the Size 100 sub-challenges of DREAM3 and DREAM4 show that, compared with the Z-score based method, prediction performances can be substantially improved, especially the AUPR specification. Moreover, it can even outperform the best team of both DREAM3 and DREAM4. Furthermore, the high precision of the obtained most reliable predictions shows that the suggested algorithm may be

  2. Novel Variations of FANCA Gene Provokes Fanconi Anemia: Molecular Diagnosis in a Special Chinese Family.

    Li, Niu; Song, Aiyun; Ding, Lixia; Zhu, Hua; Li, Guoqiang; Miao, Yan; Wang, Jian; Li, Benshang; Chen, Jing

    2018-07-01

    Fanconi anemia (FA) is a rare autosomal recessive or X-linked disorder with highly variable clinical manifestations and an incidence of ∼1 to 5 in 1 million births. To date, 15 bona fide FA genes have been reported to be responsible for the known FA complementation groups and the FANCA gene accounts for almost 60%. In the present study, we report a special Chinese family, which has 2 children with classic FA characteristics. Via 2-step analysis of the whole-exome sequencing data and verification using multiplex ligation-dependent probe amplification test, one child was found to have a novel compound heterozygous mutation of a splicing variant (c.1471-1G>A) and a large intragenic deletion (exons 23-30 del) of the FANCA gene. The other child had the same splicing variant and another novel large deletion (exons 1-18 del) in the FANCA gene. Clone sequencing showed the c.1471-1G>A variant generate an altered transcript with 1 cryptic splice site in intron 15, resulting in a premature termination codon (p.Val490HisfsX6). This study not only shows the complexity of FA molecular diagnosis via comprehensively studying the FA pathogenic genes and the mutational spectrum, but also has significant reference value for the future molecular diagnosis of FA.

  3. TIR-NBS-LRR genes are rare in monocots: evidence from diverse monocot orders

    Tarr D Ellen K

    2009-09-01

    Full Text Available Abstract Background Plant resistance (R gene products recognize pathogen effector molecules. Many R genes code for proteins containing nucleotide binding site (NBS and C-terminal leucine-rich repeat (LRR domains. NBS-LRR proteins can be divided into two groups, TIR-NBS-LRR and non-TIR-NBS-LRR, based on the structure of the N-terminal domain. Although both classes are clearly present in gymnosperms and eudicots, only non-TIR sequences have been found consistently in monocots. Since most studies in monocots have been limited to agriculturally important grasses, it is difficult to draw conclusions. The purpose of our study was to look for evidence of these sequences in additional monocot orders. Findings Using degenerate PCR, we amplified NBS sequences from four monocot species (C. blanda, D. marginata, S. trifasciata, and Spathiphyllum sp., a gymnosperm (C. revoluta and a eudicot (C. canephora. We successfully amplified TIR-NBS-LRR sequences from dicot and gymnosperm DNA, but not from monocot DNA. Using databases, we obtained NBS sequences from additional monocots, magnoliids and basal angiosperms. TIR-type sequences were not present in monocot or magnoliid sequences, but were present in the basal angiosperms. Phylogenetic analysis supported a single TIR clade and multiple non-TIR clades. Conclusion We were unable to find monocot TIR-NBS-LRR sequences by PCR amplification or database searches. In contrast to previous studies, our results represent five monocot orders (Poales, Zingiberales, Arecales, Asparagales, and Alismatales. Our results establish the presence of TIR-NBS-LRR sequences in basal angiosperms and suggest that although these sequences were present in early land plants, they have been reduced significantly in monocots and magnoliids.

  4. Variation in Assemblages of Small Fishes and Microcrustaceans After Inundation of Rarely Flooded Wetlands of the Lower Okavango Delta, Botswana

    Siziba, Nqobizitha; Chimbari, Moses J.; Masundire, Hillary; Mosepele, Ketlhatlogile; Ramberg, Lars

    2013-12-01

    Water extraction from floodplain river systems may alter patterns of inundation of adjacent wetlands and lead to loss of aquatic biodiversity. Water reaching the Okavango Delta (Delta), Botswana, may decrease due to excessive water extraction and climate change. However, due to poor understanding of the link between inundation of wetlands and biological responses, it is difficult to assess the impacts of these future water developments on aquatic biota. Large floods from 2009 to 2011 inundated both rarely and frequently flooded wetlands in the Delta, creating an opportunity to examine the ecological significance of flooding of wetlands with widely differing hydrological characteristics. We studied the assemblages of small fishes and microcrustaceans, together with their trophic relationships, in temporary wetlands of the lower Delta. Densities of microcrustaceans in temporary wetlands were generally lower than previously recorded in these habitats. Microcrustacean density varied with wetland types and hydrological phase of inundation. High densities of microcrustaceans were recorded in the 2009 to 2010 flooding season after inundation of rarely flooded sites. Large numbers of small fishes were observed during this study. Community structure of small fishes differed significantly across the studied wetlands, with poeciliids predominant in frequently flooded wetlands and juvenile cichlids most abundant in rarely flooded wetlands (analysis of similarity, P < 0.05). Small fishes of <20 mm fed largely on microcrustaceans and may have led to low microcrustacean densities within the wetlands. This result matched our prediction that rarely flooded wetlands would be more productive; hence, they supported greater populations of microcrustaceans and cichlids, which are aggressive feeders. However, the predominance of microcrustaceans in the guts of small fishes (<20 mm) suggests that predation by fishes may also be an important regulatory mechanism of microcrustacean

  5. Race/Ethnic Based Genetic Variations in Human Genes: Defining the Genetic Evidence for Disparity of Prostate Cancer Risk and Mortality Between Different Populations

    Franklin, John

    1999-01-01

    .... The study will evaluate variations in androgen receptor gene, the vitamin D receptor gene, and the APOJ/clusterin gene by amplifying specific DNA segments from certain genes utilizing a commonly used...

  6. Melanopsin Gene Variations Interact With Season to Predict Sleep Onset and Chronotype

    Roecklein, Kathryn A.; Wong, Patricia M.; Franzen, Peter L.; Hasler, Brant P.; Wood-Vasey, W. Michael; Nimgaonkar, Vishwajit L.; Miller, Megan A.; Kepreos, Kyle M.; Ferrell, Robert E.; Manuck, Stephen B.

    2012-01-01

    The human melanopsin gene has been reported to mediate risk for seasonal affective disorder (SAD), which is hypothesized to be caused by decreased photic input during winter when light levels fall below threshold, resulting in differences in circadian phase and/or sleep. However, it is unclear if melanopsin increases risk of SAD by causing differences in sleep or circadian phase, or if those differences are symptoms of the mood disorder. To determine if melanopsin sequence variations are asso...

  7. Candidate gene approach for parasite resistance in sheep--variation in immune pathway genes and association with fecal egg count.

    Kathiravan Periasamy

    Full Text Available Sheep chromosome 3 (Oar3 has the largest number of QTLs reported to be significantly associated with resistance to gastro-intestinal nematodes. This study aimed to identify single nucleotide polymorphisms (SNPs within candidate genes located in sheep chromosome 3 as well as genes involved in major immune pathways. A total of 41 SNPs were identified across 38 candidate genes in a panel of unrelated sheep and genotyped in 713 animals belonging to 22 breeds across Asia, Europe and South America. The variations and evolution of immune pathway genes were assessed in sheep populations across these macro-environmental regions that significantly differ in the diversity and load of pathogens. The mean minor allele frequency (MAF did not vary between Asian and European sheep reflecting the absence of ascertainment bias. Phylogenetic analysis revealed two major clusters with most of South Asian, South East Asian and South West Asian breeds clustering together while European and South American sheep breeds clustered together distinctly. Analysis of molecular variance revealed strong phylogeographic structure at loci located in immune pathway genes, unlike microsatellite and genome wide SNP markers. To understand the influence of natural selection processes, SNP loci located in chromosome 3 were utilized to reconstruct haplotypes, the diversity of which showed significant deviations from selective neutrality. Reduced Median network of reconstructed haplotypes showed balancing selection in force at these loci. Preliminary association of SNP genotypes with phenotypes recorded 42 days post challenge revealed significant differences (P<0.05 in fecal egg count, body weight change and packed cell volume at two, four and six SNP loci respectively. In conclusion, the present study reports strong phylogeographic structure and balancing selection operating at SNP loci located within immune pathway genes. Further, SNP loci identified in the study were found to have

  8. Association of variation in Fc gamma receptor 3B gene copy number with rheumatoid arthritis in Caucasian samples

    McKinney, Cushla; Fanciulli, Manuela; Merriman, Marilyn E.; Phipps-Green, Amanda; Alizadeh, Behrooz Z.; Koeleman, Bobby P. C.; Dalbeth, Nicola; Gow, Peter J.; Harrison, Andrew A.; Highton, John; Jones, Peter B.; Stamp, Lisa K.; Steer, Sophia; Barrera, Pilar; Coenen, Marieke J. H.; Franke, Barbara; van Riel, Piet L. C. M.; Vyse, Tim J.; Aitman, Tim J.; Radstake, Timothy R. D. J.; Merriman, Tony R.

    2010-01-01

    Objective There is increasing evidence that variation in gene copy number (CN) influences clinical phenotype. The low-affinity Fc gamma receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment to sites of inflammation and activation of

  9. Association of variation in Fcgamma receptor 3B gene copy number with rheumatoid arthritis in Caucasian samples.

    McKinney, C.; Fanciulli, M.; Merriman, M.E.; Phipps-Green, A.; Alizadeh, B.Z.; Koeleman, B.P.; Dalbeth, N.; Gow, P.J.; Harrison, A.A.; Highton, J.; Jones, P.B.; Stamp, L.K.; Steer, S.; Barrera, P.; Coenen, M.J.H.; Franke, B.; Riel, P.L.C.M. van; Vyse, T.J.; Aitman, T.J.; Radstake, T.R.D.J.; Merriman, T.R.

    2010-01-01

    OBJECTIVE: There is increasing evidence that variation in gene copy number (CN) influences clinical phenotype. The low-affinity Fcgamma receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment to sites of inflammation and activation of

  10. Effects of abhydrolase domain containing 5 gene (ABHD5) expression and variations on chicken fat metabolism.

    Ouyang, Hongjia; Liu, Qing; Xu, Jiguo; Zeng, Fang; Pang, Xiaolin; Jebessa, Endashaw; Liang, Shaodong; Nie, Qinghua; Zhang, Xiquan

    2016-01-01

    Abhydrolase domain containing 5 gene (ABHD5), also known as comparative gene identification 58 (CGI-58), is a member of the α/β-hydrolase family as a protein cofactor of ATGL stimulating its triacylglycerol hydrolase activity. In this study, we aim to characterize the expression and variations of ABHD5 and to study their functions in chicken fat metabolism. We compared the ABHD5 expression level in various tissues and under different nutrition conditions, identified the variations of ABHD5, and associated them with production traits in an F2 resource population of chickens. Overexpression analysis with two different genotypes and siRNA interfering analysis of ABHD5 were performed in chicken preadipocytes. Chicken ABDH5 was expressed widely and most predominantly in adipose tissue. Five SNPs of the ABHD5 gene were identified and genotyped in the F2 resource population. The c.490C > T SNP was associated with subcutaneous fat thickness (P  C SNP was also associated with chicken body weight (P chicken preadipocytes, overexpression of wild type ABDH5 did not affect the mRNA level of ATGL (adipose triglyceride lipase) but markedly decreased (P chickens with a high fat diet. These results suggest that expression and variations of ABHD5 may affect fat metabolism through regulating the activity of ATGL in chickens. © 2015 Poultry Science Association Inc.

  11. Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC).

    Jim, Heather S L; Lin, Hui-Yi; Tyrer, Jonathan P; Lawrenson, Kate; Dennis, Joe; Chornokur, Ganna; Chen, Zhihua; Chen, Ann Y; Permuth-Wey, Jennifer; Aben, Katja Kh; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V; Bean, Yukie T; Beckmann, Matthias W; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bunker, Clareann H; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Sieh, Weiva; Doherty, Jennifer A; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F; Eccles, Diana M; Edwards, Robert P; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goodman, Marc T; Gronwald, Jacek; Harter, Philipp; Hasmad, Hanis N; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Claus K; Hogdall, Estrid; Hosono, Satoyo; Iversen, Edwin S; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kellar, Melissa; Kiemeney, Lambertus A; Krakstad, Camilla; Kjaer, Susanne K; Kupryjanczyk, Jolanta; Vierkant, Robert A; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; McNeish, Ian; Menon, Usha; Milne, Roger L; Modugno, Francesmary; Thomsen, Lotte; Moysich, Kirsten B; Ness, Roberta B; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Palmieri Weber, Rachel; Paul, James; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M; Pike, Malcolm C; Poole, Elizabeth M; Schernhammer, Eva; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Song, Honglin; Southey, Melissa C; Spiewankiewicz, Beata; Sucheston-Campbell, Lara; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Tangen, Ingvild L; Tworoger, Shelley S; van Altena, Anne M; Vergote, Ignace; Walsh, Christine S; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Wu, Anna H; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Amankwah, Ernest; Berchuck, Andrew; Schildkraut, Joellen M; Kelemen, Linda E; Ramus, Susan J; Monteiro, Alvaro N A; Goode, Ellen L; Narod, Steven A; Gayther, Simon A; Pharoah, Paul D P; Sellers, Thomas A; Phelan, Catherine M

    Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10 -4 ]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1 , may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.

  12. Associations between dopamine D4 receptor gene variation with both infidelity and sexual promiscuity.

    Garcia, Justin R; MacKillop, James; Aller, Edward L; Merriwether, Ann M; Wilson, David Sloan; Lum, J Koji

    2010-11-30

    Human sexual behavior is highly variable both within and between populations. While sex-related characteristics and sexual behavior are central to evolutionary theory (sexual selection), little is known about the genetic bases of individual variation in sexual behavior. The variable number tandem repeats (VNTR) polymorphism in exon III of the human dopamine D4 receptor gene (DRD4) has been correlated with an array of behavioral phenotypes and may be predicatively responsible for variation in motivating some sexual behaviors, particularly promiscuity and infidelity. We administered an anonymous survey on personal history of sexual behavior and intimate relationships to 181 young adults. We also collected buccal wash samples and genotyped the DRD4 VNTR. Here we show that individuals with at least one 7-repeat allele (7R+) report a greater categorical rate of promiscuous sexual behavior (i.e., having ever had a "one-night stand") and report a more than 50% increase in instances of sexual infidelity. DRD4 VNTR genotype varies considerably within and among populations and has been subject to relatively recent, local selective pressures. Individual differences in sexual behavior are likely partially mediated by individual genetic variation in genes coding for motivation and reward in the brain. Conceptualizing these findings in terms of r/K selection theory suggests a mechanism for selective pressure for and against the 7R+ genotype that may explain the considerable global allelic variation for this polymorphism.

  13. Associations between Dopamine D4 Receptor Gene Variation with Both Infidelity and Sexual Promiscuity

    Garcia, Justin R.; MacKillop, James; Aller, Edward L.; Merriwether, Ann M.; Wilson, David Sloan; Lum, J. Koji

    2010-01-01

    Background Human sexual behavior is highly variable both within and between populations. While sex-related characteristics and sexual behavior are central to evolutionary theory (sexual selection), little is known about the genetic bases of individual variation in sexual behavior. The variable number tandem repeats (VNTR) polymorphism in exon III of the human dopamine D4 receptor gene (DRD4) has been correlated with an array of behavioral phenotypes and may be predicatively responsible for variation in motivating some sexual behaviors, particularly promiscuity and infidelity. Methodology/Principal Findings We administered an anonymous survey on personal history of sexual behavior and intimate relationships to 181 young adults. We also collected buccal wash samples and genotyped the DRD4 VNTR. Here we show that individuals with at least one 7-repeat allele (7R+) report a greater categorical rate of promiscuous sexual behavior (i.e., having ever had a “one-night stand”) and report a more than 50% increase in instances of sexual infidelity. Conclusions/Significance DRD4 VNTR genotype varies considerably within and among populations and has been subject to relatively recent, local selective pressures. Individual differences in sexual behavior are likely partially mediated by individual genetic variation in genes coding for motivation and reward in the brain. Conceptualizing these findings in terms of r/K selection theory suggests a mechanism for selective pressure for and against the 7R+ genotype that may explain the considerable global allelic variation for this polymorphism. PMID:21152404

  14. Associations between dopamine D4 receptor gene variation with both infidelity and sexual promiscuity.

    Justin R Garcia

    2010-11-01

    Full Text Available Human sexual behavior is highly variable both within and between populations. While sex-related characteristics and sexual behavior are central to evolutionary theory (sexual selection, little is known about the genetic bases of individual variation in sexual behavior. The variable number tandem repeats (VNTR polymorphism in exon III of the human dopamine D4 receptor gene (DRD4 has been correlated with an array of behavioral phenotypes and may be predicatively responsible for variation in motivating some sexual behaviors, particularly promiscuity and infidelity.We administered an anonymous survey on personal history of sexual behavior and intimate relationships to 181 young adults. We also collected buccal wash samples and genotyped the DRD4 VNTR. Here we show that individuals with at least one 7-repeat allele (7R+ report a greater categorical rate of promiscuous sexual behavior (i.e., having ever had a "one-night stand" and report a more than 50% increase in instances of sexual infidelity.DRD4 VNTR genotype varies considerably within and among populations and has been subject to relatively recent, local selective pressures. Individual differences in sexual behavior are likely partially mediated by individual genetic variation in genes coding for motivation and reward in the brain. Conceptualizing these findings in terms of r/K selection theory suggests a mechanism for selective pressure for and against the 7R+ genotype that may explain the considerable global allelic variation for this polymorphism.

  15. Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

    Weiner, Daniel J; Wigdor, Emilie M; Ripke, Stephan

    2017-01-01

    Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a nove...

  16. Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

    Weiner, Daniel J.; Wigdor, Emilie M.; Ripke, Stephan; Walters, Raymond K.; Kosmicki, Jack A.; Grove, Jakob; Samocha, Kaitlin E.; Goldstein, Jacqueline I.; Okbay, Aysu; Bybjerg-Grauholm, Jonas; Werge, Thomas; Hougaard, David M.; Taylor, Jacob; Skuse, David; Devlin, Bernie; Anney, Richard; Sanders, Stephan J.; Bishop, Somer; Mortensen, Preben Bo; Børglum, Anders D.; Smith, George Davey; Daly, Mark J.; Robinson, Elise B.; Bækvad-Hansen, Marie; Dumont, Ashley; Hansen, Christine; Hansen, Thomas F.; Howrigan, Daniel; Mattheisen, Manuel; Moran, Jennifer; Mors, Ole; Nordentoft, Merete; Nørgaard-Pedersen, Bent; Poterba, Timothy; Poulsen, Jesper; Stevens, Christine; Anttila, Verneri; Holmans, Peter; Huang, Hailiang; Klei, Lambertus; Lee, Phil H.; Medland, Sarah E.; Neale, Benjamin; Weiss, Lauren A.; Zwaigenbaum, Lonnie; Yu, Timothy W.; Wittemeyer, Kerstin; Willsey, A. Jeremy; Wijsman, Ellen M.; Wassink, Thomas H.; Waltes, Regina; Walsh, Christopher A.; Wallace, Simon; Vorstman, Jacob A.S.; Vieland, Veronica J.; Vicente, Astrid M.; Van Engeland, Herman; Tsang, Kathryn; Thompson, Ann P.; Szatmari, Peter; Svantesson, Oscar; Steinberg, Stacy; Stefansson, Kari; Stefansson, Hreinn; State, Matthew W.; Soorya, Latha; Silagadze, Teimuraz; Scherer, Stephen W.; Schellenberg, Gerard D.; Sandin, Sven; Saemundsen, Evald; Rouleau, Guy A.; Rogé, Bernadette; Roeder, Kathryn; Roberts, Wendy; Reichert, Jennifer; Reichenberg, Abraham; Rehnström, Karola; Regan, Regina; Poustka, Fritz; Poultney, Christopher S.; Piven, Joseph; Pinto, Dalila; Pericak-Vance, Margaret A.; Pejovic-Milovancevic, Milica; Pedersen, Marianne G.; Pedersen, Carsten B.; Paterson, Andrew D.; Parr, Jeremy R.; Pagnamenta, Alistair T.; Oliveira, Guiomar; Nurnberger, John I.; Murtha, Michael T.; Mouga, Susana; Morrow, Eric M.; DeLuca, Daniel Moreno; Monaco, Anthony P.; Minshew, Nancy; Merikangas, Alison; McMahon, William M.; McGrew, Susan G.; Martsenkovsky, Igor; Martin, Donna M.; Mane, Shrikant M.; Magnusson, Pall; Magalhaes, Tiago; Maestrini, Elena; Lowe, Jennifer K.; Lord, Catherine; Levitt, Pat; Martin, Christa Lese; Ledbetter, David H.; Leboyer, Marion; LeCouteur, Ann S.; Ladd-Acosta, Christine; Kolevzon, Alexander; Klauck, Sabine M.; Jacob, Suma; Iliadou, Bozenna; Hultman, Christina M.; Hertz-Picciotto, Irva; Hendren, Robert; Hansen, Christine S.; Haines, Jonathan L.; Guter, Stephen J.; Grice, Dorothy E.; Green, Jonathan M.; Green, Andrew; Goldberg, Arthur P.; Gillberg, Christopher; Gilbert, John; Gallagher, Louise; Freitag, Christine M.; Fombonne, Eric; Folstein, Susan E.; Fernandez, Bridget; Fallin, M. Daniele; Ercan-Sencicek, A. Gulhan; Ennis, Sean; Duque, Frederico; Duketis, Eftichia; Delorme, Richard; DeRubeis, Silvia; DeJonge, Maretha V.; Dawson, Geraldine; Cuccaro, Michael L.; Correia, Catarina T.; Conroy, Judith; Conceição, Inês C.; Chiocchetti, Andreas G.; Celestino-Soper, Patrícia B.S.; Casey, Jillian; Cantor, Rita M.; Cafe, Cátia; Brennan, Sean; Bourgeron, Thomas; Bolton, Patrick F.; Bölte, Sven; Bolshakova, Nadia; Betancur, Catalina; Bernier, Raphael; Beaudet, Arthur L.; Battaglia, Agatino; Bal, Vanessa H.; Baird, Gillian; Bailey, Anthony J.; Bader, Joel S.; Bacchelli, Elena; Anagnostou, Evdokia; Amaral, David; Almeida, Joana; Buxbaum, Joseph D.; Chakravarti, Aravinda; Cook, Edwin H.; Coon, Hilary; Geschwind, Daniel H.; Gill, Michael; Hakonarson, Hakon; Hallmayer, Joachim; Palotie, Aarno; Santangelo, Susan; Sutcliffe, James S.; Arking, Dan E.

    2017-01-01

    Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel

  17. Inherited Variation in Cytokine, Acute Phase Response, and Calcium Metabolism Genes Affects Susceptibility to Infective Endocarditis

    Anastasia V. Ponasenko

    2017-01-01

    Full Text Available Infective endocarditis (IE is a septic inflammation of the endocardium. Recognition of microbial patterns, cytokine and acute phase responses, hemostasis features, and alterations in plasma lipid and calcium profile all have been reported to affect pathogenesis and clinical course of IE. Having recruited 123 patients with IE and 300 age-, sex-, and ethnicity-matched healthy blood donors, we profiled their genomic DNA for 35 functionally significant polymorphisms within the 22 selected genes involved in the abovementioned pathways, with the further genetic association analysis. We found that the G/A genotype of the rs1143634 polymorphism within the IL1B gene, the G/T genotype of the rs3212227 polymorphism within the IL12B gene, the A/G genotype of the rs1130864 polymorphism within the CRP gene, and the G allele of the rs1801197 polymorphism within the CALCR gene were associated with a decreased risk of IE whereas the T/T genotype of the rs1205 polymorphism within the CRP gene was associated with a higher risk of IE. Furthermore, heterozygous genotypes of the rs1143634 and rs3212227 polymorphisms were associated with the higher plasma levels of IL-1β and IL-12, respectively. Our results indicate that inherited variation in the cytokine, acute phase response, and calcium metabolism pathways may be linked to IE.

  18. Inherited Variation in Cytokine, Acute Phase Response, and Calcium Metabolism Genes Affects Susceptibility to Infective Endocarditis

    Rutkovskaya, Natalia V.; Kondyukova, Natalia V.; Odarenko, Yuri N.; Kazachek, Yana V.; Tsepokina, Anna V.; Barbarash, Leonid S.

    2017-01-01

    Infective endocarditis (IE) is a septic inflammation of the endocardium. Recognition of microbial patterns, cytokine and acute phase responses, hemostasis features, and alterations in plasma lipid and calcium profile all have been reported to affect pathogenesis and clinical course of IE. Having recruited 123 patients with IE and 300 age-, sex-, and ethnicity-matched healthy blood donors, we profiled their genomic DNA for 35 functionally significant polymorphisms within the 22 selected genes involved in the abovementioned pathways, with the further genetic association analysis. We found that the G/A genotype of the rs1143634 polymorphism within the IL1B gene, the G/T genotype of the rs3212227 polymorphism within the IL12B gene, the A/G genotype of the rs1130864 polymorphism within the CRP gene, and the G allele of the rs1801197 polymorphism within the CALCR gene were associated with a decreased risk of IE whereas the T/T genotype of the rs1205 polymorphism within the CRP gene was associated with a higher risk of IE. Furthermore, heterozygous genotypes of the rs1143634 and rs3212227 polymorphisms were associated with the higher plasma levels of IL-1β and IL-12, respectively. Our results indicate that inherited variation in the cytokine, acute phase response, and calcium metabolism pathways may be linked to IE. PMID:28659664

  19. Diversity and population-genetic properties of copy number variations and multicopy genes in cattle

    Bickhart, Derek M.; Xu, Lingyang; Hutchison, Jana L.; Cole, John B.; Null, Daniel J.; Schroeder, Steven G.; Song, Jiuzhou; Garcia, Jose Fernando; Sonstegard, Tad S.; Van Tassell, Curtis P.; Schnabel, Robert D.; Taylor, Jeremy F.; Lewin, Harris A.; Liu, George E.

    2016-01-01

    The diversity and population genetics of copy number variation (CNV) in domesticated animals are not well understood. In this study, we analysed 75 genomes of major taurine and indicine cattle breeds (including Angus, Brahman, Gir, Holstein, Jersey, Limousin, Nelore, and Romagnola), sequenced to 11-fold coverage to identify 1,853 non-redundant CNV regions. Supported by high validation rates in array comparative genomic hybridization (CGH) and qPCR experiments, these CNV regions accounted for 3.1% (87.5 Mb) of the cattle reference genome, representing a significant increase over previous estimates of the area of the genome that is copy number variable (∼2%). Further population genetics and evolutionary genomics analyses based on these CNVs revealed the population structures of the cattle taurine and indicine breeds and uncovered potential diversely selected CNVs near important functional genes, including AOX1, ASZ1, GAT, GLYAT, and KRTAP9-1. Additionally, 121 CNV gene regions were found to be either breed specific or differentially variable across breeds, such as RICTOR in dairy breeds and PNPLA3 in beef breeds. In contrast, clusters of the PRP and PAG genes were found to be duplicated in all sequenced animals, suggesting that subfunctionalization, neofunctionalization, or overdominance play roles in diversifying those fertility-related genes. These CNV results provide a new glimpse into the diverse selection histories of cattle breeds and a basis for correlating structural variation with complex traits in the future. PMID:27085184

  20. Sweet taste receptor gene variation and aspartame taste in primates and other species.

    Li, Xia; Bachmanov, Alexander A; Maehashi, Kenji; Li, Weihua; Lim, Raymond; Brand, Joseph G; Beauchamp, Gary K; Reed, Danielle R; Thai, Chloe; Floriano, Wely B

    2011-06-01

    Aspartame is a sweetener added to foods and beverages as a low-calorie sugar replacement. Unlike sugars, which are apparently perceived as sweet and desirable by a range of mammals, the ability to taste aspartame varies, with humans, apes, and Old World monkeys perceiving aspartame as sweet but not other primate species. To investigate whether the ability to perceive the sweetness of aspartame correlates with variations in the DNA sequence of the genes encoding sweet taste receptor proteins, T1R2 and T1R3, we sequenced these genes in 9 aspartame taster and nontaster primate species. We then compared these sequences with sequences of their orthologs in 4 other nontasters species. We identified 9 variant sites in the gene encoding T1R2 and 32 variant sites in the gene encoding T1R3 that distinguish aspartame tasters and nontasters. Molecular docking of aspartame to computer-generated models of the T1R2 + T1R3 receptor dimer suggests that species variation at a secondary, allosteric binding site in the T1R2 protein is the most likely origin of differences in perception of the sweetness of aspartame. These results identified a previously unknown site of aspartame interaction with the sweet receptor and suggest that the ability to taste aspartame might have developed during evolution to exploit a specialized food niche.

  1. Variations in testosterone pathway genes and susceptibility to testicular cancer in Norwegian men.

    Kristiansen, W; Aschim, E L; Andersen, J M; Witczak, O; Fosså, S D; Haugen, T B

    2012-12-01

    Imbalance between the oestrogen and androgen levels in utero is hypothesized to influence testicular cancer (TC) risk. Thus, variation in genes involved in the action of sex hormones may contribute to variability of an individual's susceptibility to TC. Mutations in testosterone pathway genes may alter the level of testosterone in vivo and hypothetically the risk of developing TC. Luteinizing hormone receptor (LHR), 5α-reductase II (SRD5A2) and androgen receptor (AR) are key elements in androgen action. A case-control study comprising 651 TC cases and 313 controls in a Norwegian population was conducted for investigation of polymorphisms in the LHR, SRD5A and AR genes and their possible association with TC. A statistical significant difference was observed in patients being heterozygous for the LHR Asn312Ser polymorphism when comparing genotypes between all TC cases and controls (OR = 0.66, 95% CI = 0.48-0.89, p(adj) = 0.049). No statistically significant difference between the histological subtypes seminoma and non-seminoma was observed. Our results may suggest a possible association between genetic variation in the LHR gene and the risk of developing TC. © 2012 The Authors. International Journal of Andrology © 2012 European Academy of Andrology.

  2. Identification and Characterization of Novel Variations in Platelet G-Protein Coupled Receptor (GPCR Genes in Patients Historically Diagnosed with Type 1 von Willebrand Disease.

    Jacqueline Stockley

    Full Text Available The clinical expression of type 1 von Willebrand disease may be modified by co-inheritance of other mild bleeding diatheses. We previously showed that mutations in the platelet P2Y12 ADP receptor gene (P2RY12 could contribute to the bleeding phenotype in patients with type 1 von Willebrand disease. Here we investigated whether variations in platelet G protein-coupled receptor genes other than P2RY12 also contributed to the bleeding phenotype. Platelet G protein-coupled receptor genes P2RY1, F2R, F2RL3, TBXA2R and PTGIR were sequenced in 146 index cases with type 1 von Willebrand disease and the potential effects of identified single nucleotide variations were assessed using in silico methods and heterologous expression analysis. Seven heterozygous single nucleotide variations were identified in 8 index cases. Two single nucleotide variations were detected in F2R; a novel c.-67G>C transversion which reduced F2R transcriptional activity and a rare c.1063C>T transition predicting a p.L355F substitution which did not interfere with PAR1 expression or signalling. Two synonymous single nucleotide variations were identified in F2RL3 (c.402C>G, p.A134 =; c.1029 G>C p.V343 =, both of which introduced less commonly used codons and were predicted to be deleterious, though neither of them affected PAR4 receptor expression. A third single nucleotide variation in F2RL3 (c.65 C>A; p.T22N was co-inherited with a synonymous single nucleotide variation in TBXA2R (c.6680 C>T, p.S218 =. Expression and signalling of the p.T22N PAR4 variant was similar to wild-type, while the TBXA2R variation introduced a cryptic splice site that was predicted to cause premature termination of protein translation. The enrichment of single nucleotide variations in G protein-coupled receptor genes among type 1 von Willebrand disease patients supports the view of type 1 von Willebrand disease as a polygenic disorder.

  3. Identification and Characterization of Novel Variations in Platelet G-Protein Coupled Receptor (GPCR) Genes in Patients Historically Diagnosed with Type 1 von Willebrand Disease.

    Stockley, Jacqueline; Nisar, Shaista P; Leo, Vincenzo C; Sabi, Essa; Cunningham, Margaret R; Eikenboom, Jeroen C; Lethagen, Stefan; Schneppenheim, Reinhard; Goodeve, Anne C; Watson, Steve P; Mundell, Stuart J; Daly, Martina E

    2015-01-01

    The clinical expression of type 1 von Willebrand disease may be modified by co-inheritance of other mild bleeding diatheses. We previously showed that mutations in the platelet P2Y12 ADP receptor gene (P2RY12) could contribute to the bleeding phenotype in patients with type 1 von Willebrand disease. Here we investigated whether variations in platelet G protein-coupled receptor genes other than P2RY12 also contributed to the bleeding phenotype. Platelet G protein-coupled receptor genes P2RY1, F2R, F2RL3, TBXA2R and PTGIR were sequenced in 146 index cases with type 1 von Willebrand disease and the potential effects of identified single nucleotide variations were assessed using in silico methods and heterologous expression analysis. Seven heterozygous single nucleotide variations were identified in 8 index cases. Two single nucleotide variations were detected in F2R; a novel c.-67G>C transversion which reduced F2R transcriptional activity and a rare c.1063C>T transition predicting a p.L355F substitution which did not interfere with PAR1 expression or signalling. Two synonymous single nucleotide variations were identified in F2RL3 (c.402C>G, p.A134 =; c.1029 G>C p.V343 =), both of which introduced less commonly used codons and were predicted to be deleterious, though neither of them affected PAR4 receptor expression. A third single nucleotide variation in F2RL3 (c.65 C>A; p.T22N) was co-inherited with a synonymous single nucleotide variation in TBXA2R (c.6680 C>T, p.S218 =). Expression and signalling of the p.T22N PAR4 variant was similar to wild-type, while the TBXA2R variation introduced a cryptic splice site that was predicted to cause premature termination of protein translation. The enrichment of single nucleotide variations in G protein-coupled receptor genes among type 1 von Willebrand disease patients supports the view of type 1 von Willebrand disease as a polygenic disorder.

  4. Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

    Purrington, Kristen S.; Slettedahl, Seth; Bolla, Manjeet K.; Michailidou, Kyriaki; Czene, Kamila; Nevanlinna, Heli; Bojesen, Stig E.; Andrulis, Irene L.; Cox, Angela; Hall, Per; Carpenter, Jane; Yannoukakos, Drakoulis; Haiman, Christopher A.; Fasching, Peter A.; Mannermaa, Arto; Winqvist, Robert; Brenner, Hermann; Lindblom, Annika; Chenevix-Trench, Georgia; Benitez, Javier; Swerdlow, Anthony; Kristensen, Vessela; Guénel, Pascal; Meindl, Alfons; Darabi, Hatef; Eriksson, Mikael; Fagerholm, Rainer; Aittomäki, Kristiina; Blomqvist, Carl; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Wang, Xianshu; Olswold, Curtis; Olson, Janet E.; Mulligan, Anna Marie; Knight, Julia A.; Tchatchou, Sandrine; Reed, Malcolm W.R.; Cross, Simon S.; Liu, Jianjun; Li, Jingmei; Humphreys, Keith; Clarke, Christine; Scott, Rodney; Fostira, Florentia; Fountzilas, George; Konstantopoulou, Irene; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Ekici, Arif B.; Hartmann, Arndt; Beckmann, Matthias W.; Hartikainen, Jaana M.; Kosma, Veli-Matti; Kataja, Vesa; Jukkola-Vuorinen, Arja; Pylkäs, Katri; Kauppila, Saila; Dieffenbach, Aida Karina; Stegmaier, Christa; Arndt, Volker; Margolin, Sara; Balleine, Rosemary; Arias Perez, Jose Ignacio; Pilar Zamora, M.; Menéndez, Primitiva; Ashworth, Alan; Jones, Michael; Orr, Nick; Arveux, Patrick; Kerbrat, Pierre; Truong, Thérèse; Bugert, Peter; Toland, Amanda E.; Ambrosone, Christine B.; Labrèche, France; Goldberg, Mark S.; Dumont, Martine; Ziogas, Argyrios; Lee, Eunjung; Dite, Gillian S.; Apicella, Carmel; Southey, Melissa C.; Long, Jirong; Shrubsole, Martha; Deming-Halverson, Sandra; Ficarazzi, Filomena; Barile, Monica; Peterlongo, Paolo; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Tollenaar, Robert A.E.M.; Seynaeve, Caroline; Brüning, Thomas; Ko, Yon-Dschun; Van Deurzen, Carolien H.M.; Martens, John W.M.; Kriege, Mieke; Figueroa, Jonine D.; Chanock, Stephen J.; Lissowska, Jolanta; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Schneeweiss, Andreas; Tapper, William J.; Gerty, Susan M.; Durcan, Lorraine; Mclean, Catriona; Milne, Roger L.; Baglietto, Laura; dos Santos Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Van'T Veer, Laura J.; Cornelissen, Sten; Försti, Asta; Torres, Diana; Rüdiger, Thomas; Rudolph, Anja; Flesch-Janys, Dieter; Nickels, Stefan; Weltens, Caroline; Floris, Giuseppe; Moisse, Matthieu; Dennis, Joe; Wang, Qin; Dunning, Alison M.; Shah, Mitul; Brown, Judith; Simard, Jacques; Anton-Culver, Hoda; Neuhausen, Susan L.; Hopper, John L.; Bogdanova, Natalia; Dörk, Thilo; Zheng, Wei; Radice, Paolo; Jakubowska, Anna; Lubinski, Jan; Devillee, Peter; Brauch, Hiltrud; Hooning, Maartje; García-Closas, Montserrat; Sawyer, Elinor; Burwinkel, Barbara; Marmee, Frederick; Eccles, Diana M.; Giles, Graham G.; Peto, Julian; Schmidt, Marjanka; Broeks, Annegien; Hamann, Ute; Chang-Claude, Jenny; Lambrechts, Diether; Pharoah, Paul D.P.; Easton, Douglas; Pankratz, V. Shane; Slager, Susan; Vachon, Celine M.; Couch, Fergus J.

    2014-01-01

    Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16–1.33, P = 4.2 × 10−10) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04–1.11, P = 8.7 × 10−6) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07–1.23, P = 7.9 × 10−5) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10−3). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer. PMID:24927736

  5. Association of interleukin-1 gene variations with moderate to severe chronic periodontitis in multiple ethnicities

    Wu, X; Offenbacher, S; Lόpez, N J; Chen, D; Wang, H-Y; Rogus, J; Zhou, J; Beck, J; Jiang, S; Bao, X; Wilkins, L; Doucette-Stamm, L; Kornman, K

    2015-01-01

    Background and Objective Genetic markers associated with disease are often non-functional and generally tag one or more functional “causative” variants in linkage disequilibrium. Markers may not show tight linkage to the causative variants across multiple ethnicities due to evolutionary divergence, and therefore may not be informative across different population groups. Validated markers of disease suggest causative variants exist in the gene and, if the causative variants can be identified, it is reasonable to hypothesize that such variants will be informative across diverse populations. The aim of this study was to test that hypothesis using functional Interleukin-1 (IL-1) gene variations across multiple ethnic populations to replace the non-functional markers originally associated with chronic adult periodontitis in Caucasians. Material and Methods Adult chronic periodontitis cases and controls from four ethnic groups (Caucasians, African Americans, Hispanics and Asians) were recruited in the USA, Chile and China. Genotypes of IL1B gene single nucleotide polymorphisms (SNPs), including three functional SNPs (rs16944, rs1143623, rs4848306) in the promoter and one intronic SNP (rs1143633), were determined using a single base extension method or TaqMan 5′ nuclease assay. Logistic regression and other statistical analyses were used to examine the association between moderate to severe periodontitis and IL1B gene variations, including SNPs, haplotypes and composite genotypes. Genotype patterns associated with disease in the discovery study were then evaluated in independent validation studies. Results Significant associations were identified in the discovery study, consisting of Caucasians and African Americans, between moderate to severe adult chronic periodontitis and functional variations in the IL1B gene, including a pattern of four IL1B SNPs (OR = 1.87, p < 0.0001). The association between the disease and this IL1B composite genotype pattern was validated

  6. Chitosan in Non-Viral Gene Delivery: Role of Structure, Characterization Methods, and Insights in Cancer and Rare Diseases Therapies

    Beatriz Santos-Carballal

    2018-04-01

    Full Text Available Non-viral gene delivery vectors have lagged far behind viral ones in the current pipeline of clinical trials of gene therapy nanomedicines. Even when non-viral nanovectors pose less safety risks than do viruses, their efficacy is much lower. Since the early studies to deliver pDNA, chitosan has been regarded as a highly attractive biopolymer to deliver nucleic acids intracellularly and induce a transgenic response resulting in either upregulation of protein expression (for pDNA, mRNA or its downregulation (for siRNA or microRNA. This is explained as the consequence of a multi-step process involving condensation of nucleic acids, protection against degradation, stabilization in physiological conditions, cellular internalization, release from the endolysosome (“proton sponge” effect, unpacking and enabling the trafficking of pDNA to the nucleus or the siRNA to the RNA interference silencing complex (RISC. Given the multiple steps and complexity involved in the gene transfection process, there is a dearth of understanding of the role of chitosan’s structural features (Mw and degree of acetylation, DA% on each step that dictates the net transfection efficiency and its kinetics. The use of fully characterized chitosan samples along with the utilization of complementary biophysical and biological techniques is key to bridging this gap of knowledge and identifying the optimal chitosans for delivering a specific gene. Other aspects such as cell type and administration route are also at play. At the same time, the role of chitosan structural features on the morphology, size and surface composition of synthetic virus-like particles has barely been addressed. The ongoing revolution brought about by the recent discovery of CRISPR-Cas9 technology will undoubtedly be a game changer in this field in the short term. In the field of rare diseases, gene therapy is perhaps where the greatest potential lies and we anticipate that chitosans will be key players

  7. Engineering and Validation of a Vector for Concomitant Expression of Rare Transfer RNA (tRNA and HIV-1 nef Genes in Escherichia coli.

    Siti Aisyah Mualif

    Full Text Available Relative ease in handling and manipulation of Escherichia coli strains make them primary candidate to express proteins heterologously. Overexpression of heterologous genes that contain codons infrequently used by E. coli is related with difficulties such as mRNA instability, early termination of transcription and/or translation, deletions and/or misincorporation, and cell growth inhibition. These codon bias -associated problems are addressed by co-expressing ColE1-compatible, rare tRNA expressing helper plasmids. However, this approach has inadequacies, which we have addressed by engineering an expression vector that concomitantly expresses the heterologous protein of interest, and rare tRNA genes in E. coli. The expression vector contains three (argU, ileY, leuW rare tRNA genes and a useful multiple cloning site for easy in-frame cloning. To maintain the overall size of the parental plasmid vector, the rare tRNA genes replaced the non-essential DNA segments in the vector. The cloned gene is expressed under the control of T7 promoter and resulting recombinant protein has a C-terminal 6His tag for IMAC-mediated purification. We have evaluated the usefulness of this expression vector by expressing three HIV-1 genes namely HIV-1 p27 (nef, HIV-1 p24 (ca, and HIV-1 vif in NiCo21(DE3 E.coli and demonstrated the advantages of using expression vector that concomitantly expresses rare tRNA and heterologous genes.

  8. A general scenario of Hox gene inventory variation among major sarcopterygian lineages

    Wang Chaolin

    2011-01-01

    Full Text Available Abstract Background Hox genes are known to play a key role in shaping the body plan of metazoans. Evolutionary dynamics of these genes is therefore essential in explaining patterns of evolutionary diversity. Among extant sarcopterygians comprising both lobe-finned fishes and tetrapods, our knowledge of the Hox genes and clusters has largely been restricted in several model organisms such as frogs, birds and mammals. Some evolutionary gaps still exist, especially for those groups with derived body morphology or occupying key positions on the tree of life, hindering our understanding of how Hox gene inventory varied along the sarcopterygian lineage. Results We determined the Hox gene inventory for six sarcopterygian groups: lungfishes, caecilians, salamanders, snakes, turtles and crocodiles by comprehensive PCR survey and genome walking. Variable Hox genes in each of the six sarcopterygian group representatives, compared to the human Hox gene inventory, were further validated for their presence/absence by PCR survey in a number of related species representing a broad evolutionary coverage of the group. Turtles, crocodiles, birds and placental mammals possess the same 39 Hox genes. HoxD12 is absent in snakes, amphibians and probably lungfishes. HoxB13 is lost in frogs and caecilians. Lobe-finned fishes, amphibians and squamate reptiles possess HoxC3. HoxC1 is only present in caecilians and lobe-finned fishes. Similar to coelacanths, lungfishes also possess HoxA14, which is only found in lobe-finned fishes to date. Our Hox gene variation data favor the lungfish-tetrapod, turtle-archosaur and frog-salamander relationships and imply that the loss of HoxD12 is not directly related to digit reduction. Conclusions Our newly determined Hox inventory data provide a more complete scenario for evolutionary dynamics of Hox genes along the sarcopterygian lineage. Limbless, worm-like caecilians and snakes possess similar Hox gene inventories to animals with

  9. Novel subtractive transcription-based amplification of mRNA (STAR method and its application in search of rare and differentially expressed genes in AD brains

    Walker P Roy

    2006-11-01

    Full Text Available Abstract Background Alzheimer's disease (AD is a complex disorder that involves multiple biological processes. Many genes implicated in these processes may be present in low abundance in the human brain. DNA microarray analysis identifies changed genes that are expressed at high or moderate levels. Complementary to this approach, we described here a novel technology designed specifically to isolate rare and novel genes previously undetectable by other methods. We have used this method to identify differentially expressed genes in brains affected by AD. Our method, termed Subtractive Transcription-based Amplification of mRNA (STAR, is a combination of subtractive RNA/DNA hybridization and RNA amplification, which allows the removal of non-differentially expressed transcripts and the linear amplification of the differentially expressed genes. Results Using the STAR technology we have identified over 800 differentially expressed sequences in AD brains, both up- and down- regulated, compared to age-matched controls. Over 55% of the sequences represent genes of unknown function and roughly half of them were novel and rare discoveries in the human brain. The expression changes of nearly 80 unique genes were further confirmed by qRT-PCR and the association of additional genes with AD and/or neurodegeneration was established using an in-house literature mining tool (LitMiner. Conclusion The STAR process significantly amplifies unique and rare sequences relative to abundant housekeeping genes and, as a consequence, identifies genes not previously linked to AD. This method also offers new opportunities to study the subtle changes in gene expression that potentially contribute to the development and/or progression of AD.

  10. Genomic variation and its impact on gene expression in Drosophila melanogaster.

    Andreas Massouras

    Full Text Available Understanding the relationship between genetic and phenotypic variation is one of the great outstanding challenges in biology. To meet this challenge, comprehensive genomic variation maps of human as well as of model organism populations are required. Here, we present a nucleotide resolution catalog of single-nucleotide, multi-nucleotide, and structural variants in 39 Drosophila melanogaster Genetic Reference Panel inbred lines. Using an integrative, local assembly-based approach for variant discovery, we identify more than 3.6 million distinct variants, among which were more than 800,000 unique insertions, deletions (indels, and complex variants (1 to 6,000 bp. While the SNP density is higher near other variants, we find that variants themselves are not mutagenic, nor are regions with high variant density particularly mutation-prone. Rather, our data suggest that the elevated SNP density around variants is mainly due to population-level processes. We also provide insights into the regulatory architecture of gene expression variation in adult flies by mapping cis-expression quantitative trait loci (cis-eQTLs for more than 2,000 genes. Indels comprise around 10% of all cis-eQTLs and show larger effects than SNP cis-eQTLs. In addition, we identified two-fold more gene associations in males as compared to females and found that most cis-eQTLs are sex-specific, revealing a partial decoupling of the genomic architecture between the sexes as well as the importance of genetic factors in mediating sex-biased gene expression. Finally, we performed RNA-seq-based allelic expression imbalance analyses in the offspring of crosses between sequenced lines, which revealed that the majority of strong cis-eQTLs can be validated in heterozygous individuals.

  11. Rare muscular variations identified in a single cadaveric upper limb: a four-headed biceps brachii and muscular elevator of the latissimus dorsi tendon.

    Moore, Colin W; Rice, Charles L

    2018-03-01

    Supernumerary or accessory heads of the biceps brachii are persistent muscular structures which can vary in number and location in the arm. Variations in other arm muscles, such as the coracobrachialis, can accompany supernumerary biceps brachii musculature in the upper limb. In this case report, we describe two rare muscular variants in a single adult male: a four-headed biceps brachii and the muscular elevator of the latissimus dorsi tendon. Additionally, accessory muscles of the brachialis and flexor digiti minimi brevis were identified in the upper limb. To our knowledge, the muscular variants identified here are considered rare, and their co-occurrence in a single upper limb has not been described previously. Also, a four-headed biceps brachii consisting of both the infero-medial and infero-lateral humeral heads has not been described previously to our knowledge. We postulate that the simultaneous appearance of several muscular variations may indicate a signaling disruption in embryogenesis during muscle patterning of the ventral limb bud. Knowledge of variant musculature in the arm is important for surgeons and clinicians as these muscles and their aberrant innervation patterns can complicate surgical procedures and may compress arteries and nerves producing upper limb pain and paresthesia. The clinical, functional and embryological implications of the upper limb variants are discussed.

  12. Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages

    Phelan, Jody E.

    2016-02-29

    Background Approximately 10 % of the Mycobacterium tuberculosis genome is made up of two families of genes that are poorly characterized due to their high GC content and highly repetitive nature. The PE and PPE families are typified by their highly conserved N-terminal domains that incorporate proline-glutamate (PE) and proline-proline-glutamate (PPE) signature motifs. They are hypothesised to be important virulence factors involved with host-pathogen interactions, but their high genetic variability and complexity of analysis means they are typically disregarded in genome studies. Results To elucidate the structure of these genes, 518 genomes from a diverse international collection of clinical isolates were de novo assembled. A further 21 reference M. tuberculosis complex genomes and long read sequence data were used to validate the approach. SNP analysis revealed that variation in the majority of the 168 pe/ppe genes studied was consistent with lineage. Several recombination hotspots were identified, notably pe_pgrs3 and pe_pgrs17. Evidence of positive selection was revealed in 65 pe/ppe genes, including epitopes potentially binding to major histocompatibility complex molecules. Conclusions This, the first comprehensive study of the pe and ppe genes, provides important insight into M. tuberculosis diversity and has significant implications for vaccine development.

  13. The Genetic Variation of Bali Cattle (Bos javanicus Based on Sex Related Y Chromosome Gene

    A Winaya

    2011-09-01

    Full Text Available Bali cattle is very popular Indonesian local beef related to their status in community living process of farmers in Indonesia, especially as providers of meat and exotic animal. Bali cattle were able to adapt the limited environment and becoming local livestock that existed until recently.  In our early study by microsatellites showed that Bali cattle have specific allele. In this study we analyzed the variance of partly sex related Y (SRY gene sequence in Bali cattle bull as a source of cement for Artificial Insemination (AI.  Blood from 17 two location of AI center, Singosari, Malang and Baturiti, Bali was collected and then extracted to get the DNA genome.  PCR reaction was done to amplify partially of SRY gene segment and followed by sequencing PCR products to get the DNA sequence of SRY gene. The SRY gene sequence was used to determine the genetic variation and phylogenetic relationship.  We found that Bali cattle bull from Singosari has relatively closed genetic relationship with Baturiti. It is also supported that in early data some Bali bulls of Singosari were came from Baturiti. It has been known that Baturiti is the one source of Bali cattle bull with promising genetic potential. While, in general that Bali bull where came from two areas were not different on reproductive performances. It is important to understand about the genetic variation of Bali cattle in molecular level related to conservation effort and maintaining the genetic characters of the local cattle. So, it will not become extinct or even decreased the genetic quality of Indonesian indigenous cattle.   Key Words : Bali cattle, SRY gene, artificial insemination, phylogenetic, allele   Animal Production 13(3:150-155 (2011

  14. Evaluation of bovine chemerin (RARRES2 gene variation on beef cattle production traits

    Amanda K Lindholm-Perry

    2012-03-01

    Full Text Available A previous study in cattle based on >48,000 markers identified markers on chromosome 4 near the chemerin gene associated with average daily feed intake (ADFI in steers (P<0.008. Chemerin is an adipokine associated with obesity and metabolic syndrome in humans, representing a strong candidate gene potentially underlying the observed association. To evaluate whether the bovine chemerin gene is involved in feed intake, 16 markers within and around the gene were tested for association in the same resource population. Eleven were nominally significant for ADFI (P<0.05 and two were significant after Bonferroni correction. Two and five SNP in this region were nominally significant for the related traits of average daily gain (ADG and residual feed intake (RFI, respectively. All markers were evaluated for effects on meat quality and carcass phenotypes. Many of the markers associated with ADFI were associated with hot carcass weight (HCW, adjusted fat thickness (AFT, and marbling (P<0.05. Marker alleles that were associated with lower ADFI were also associated with lower HCW, AFT, and marbling. Markers associated with ADFI were genotyped in a validation population of steers representing 14 breeds to determine predictive merit across populations. No consistent relationships for ADFI were detected. To determine whether cattle feed intake or growth phenotypes might be related to chemerin transcript abundance, the expression of chemerin was evaluated in adipose of 114 heifers that were siblings of the steers in the discovery population. Relative chemerin transcript abundance was not correlated with ADFI, ADG, or RFI, but associations with body condition score and yearling weight were observed. We conclude that variation in the chemerin gene may underlie observed association in the resource population, but that additional research is required to determine if this variation is widespread among breeds and to develop robust markers with predictive merit across

  15. Cholecystokinin A receptor (CCKAR gene variation is associated with language lateralization.

    Sebastian Ocklenburg

    Full Text Available Schizophrenia is a psychiatric disorder associated with atypical handedness and language lateralization. However, the molecular mechanisms underlying these functional changes are still poorly understood. Therefore, the present study was aimed at investigating whether variation in schizophrenia-related genes modulates individual lateralization patterns. To this end, we genotyped 16 single nucleotide polymorphisms that have previously been linked to schizophrenia on a meta-analysis level in a sample of 444 genetically unrelated healthy participants and examined the association of these polymorphisms with handedness, footedness and language lateralization. We found a significant association of the cholecystokinin-A receptor (CCKAR gene variation rs1800857 and language lateralization assessed using the dichotic listening task. Individuals carrying the schizophrenia risk allele C of this polymorphism showed a marked reduction of the typical left-hemispheric dominance for language processing. Since the cholecystokinin A receptor is involved in dopamine release in the central nervous system, these findings suggest that genetic variation in this receptor may modulate language lateralization due to its impact on dopaminergic pathways.

  16. Schooling and variation in the COMT gene: the devil is in the details.

    Campbell, Daniel; Bick, Johanna; Yrigollen, Carolyn M; Lee, Maria; Joseph, Antony; Chang, Joseph T; Grigorenko, Elena L

    2013-10-01

    Schooling is considered one of the major contributors to the development of intelligence within societies and individuals. Genetic variation might modulate the impact of schooling and explain, at least partially, the presence of individual differences in classrooms. We studied a sample of 1,502 children (mean age = 11.7 years) from Zambia. Approximately 57% of these children were enrolled in school, and the rest were not. To quantify genetic variation, we investigated a number of common polymorphisms in the catechol-O-methyltransferase (COMT) gene that controls the production of the protein thought to account for >60% of the dopamine degradation in the prefrontal cortex. Haplotype analyses generated results ranging from the presence to absence of significant interactions between a number of COMT haplotypes and indicators of schooling (i.e., in- vs. out-of-school and grade completed) in the prediction of nonverbal intelligence, depending on the parameter specification. However, an investigation of the distribution of corresponding p-values suggested that these positive results were false. Convincing evidence that the variation in the COMT gene is associated with individual differences in nonverbal intelligence either directly or through interactions with schooling was not found. p-values produced by the method of testing for haplotype effects employed here may be sensitive to parameter settings, invalid under default settings, and should be checked for validity through simulation. © 2013 The Authors. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health.

  17. Dietary Variation and Evolution of Gene Copy Number among Dog Breeds.

    Taylor Reiter

    Full Text Available Prolonged human interactions and artificial selection have influenced the genotypic and phenotypic diversity among dog breeds. Because humans and dogs occupy diverse habitats, ecological contexts have likely contributed to breed-specific positive selection. Prior to the advent of modern dog-feeding practices, there was likely substantial variation in dietary landscapes among disparate dog breeds. As such, we investigated one type of genetic variant, copy number variation, in three metabolic genes: glucokinase regulatory protein (GCKR, phytanol-CoA 2-hydroxylase (PHYH, and pancreatic α-amylase 2B (AMY2B. These genes code for proteins that are responsible for metabolizing dietary products that originate from distinctly different food types: sugar, meat, and starch, respectively. After surveying copy number variation among dogs with diverse dietary histories, we found no correlation between diet and positive selection in either GCKR or PHYH. Although it has been previously demonstrated that dogs experienced a copy number increase in AMY2B relative to wolves during or after the dog domestication process, we demonstrate that positive selection continued to act on amylase copy number in dog breeds that consumed starch-rich diets in time periods after domestication. Furthermore, we found that introgression with wolves is not responsible for deterioration of positive selection on AMY2B among diverse dog breeds. Together, this supports the hypothesis that the amylase copy number expansion is found universally in dogs.

  18. [Genetic variation analysis of canine parvovirus VP2 gene in China].

    Yi, Li; Cheng, Shi-Peng; Yan, Xi-Jun; Wang, Jian-Ke; Luo, Bin

    2009-11-01

    To recognize the molecular biology character, phylogenetic relationship and the state quo prevalent of Canine parvovirus (CPV), Faecal samnples from pet dogs with acute enteritis in the cities of Beijing, Wuhan, and Nanjing were collected and tested for CPV by PCR and other assay between 2006 and 2008. There was no CPV to FPV (MEV) variation by PCR-RFLP analysis in all samples. The complete ORFs of VP2 genes were obtained by PCR from 15 clinical CPVs and 2 CPV vaccine strains. All amplicons were cloned and sequenced. Analysis of the VP2 sequences showed that clinical CPVs both belong to CPV-2a subtype, and could be classified into a new cluster by amino acids contrasting which contains Tyr-->Ile (324) mutation. Besides the 2 CPV vaccine strains belong to CPV-2 subtype, and both of them have scattered variation in amino acids residues of VP2 protein. Construction of the phylogenetic tree based on CPV VP2 sequence showed these 15 CPV clinical strains were in close relationship with Korea strain K001 than CPV-2a isolates in other countries at early time, It is indicated that the canine parvovirus genetic variation was associated with location and time in some degree. The survey of CPV capsid protein VP2 gene provided the useful information for the identification of CPV types and understanding of their genetic relationship.

  19. Natural variation and gene regulatory basis for the responses of asparagus beans to soil drought

    Xu, Pei; Moshelion, Menachem; Wu, XiaoHua; Halperin, Ofer; Wang, BaoGen; Luo, Jie; Wallach, Rony; Wu, Xinyi; Lu, Zhongfu; Li, Guojing

    2015-01-01

    Asparagus bean (Vigna unguiculata ssp. sesquipedalis) is the Asian subspecies of cowpea, a drought-resistant legume crop native to Africa. In order to explore the genetic variation of drought responses in asparagus bean, we conducted multi-year phenotyping of drought resistance traits across the Chinese asparagus bean mini-core. The phenotypic distribution indicated that the ssp. sesquipedalis subgene pool has maintained high natural variation in drought responses despite known domestic bottleneck. Thirty-nine SNP loci were found to show an association with drought resistance via a genome-wide association study (GWAS). Whole-plant water relations were compared among four genotypes by lysimetric assay. Apparent genotypic differences in transpiration patterns and the critical soil water threshold in relation to dehydration avoidance were observed, indicating a delicate adaptive mechanism for each genotype to its own climate. Microarray gene expression analyses revealed that known drought resistance pathways such as the ABA and phosphate lipid signaling pathways are conserved between different genotypes, while differential regulation of certain aquaporin genes and hormonal genes may be important for the genotypic differences. Our results suggest that divergent sensitivity to soil water content is an important mechanism configuring the genotypic specific responses to water deficit. The SNP markers identified provide useful resources for marker-assisted breeding. PMID:26579145

  20. Natural variation and gene regulatory basis for the responses of asparagus beans to soil drought

    Pei eXu

    2015-10-01

    Full Text Available Asparagus bean (Vigna unguiculata ssp. sesquipedalis is the Asian subspecies of cowpea, a drought-resistant legume crop native to Africa. In order to explore the genetic variation of drought responses in asparagus bean, we conducted multi-year phenotyping of drought resistance traits across the Chinese asparagus bean mini-core. The phenotypic distribution indicated that the ssp. sesquipedalis subgene pool has maintained high natural variation in drought responses despite known domestic bottleneck. Thirty-nine SNP loci were found to show an association with drought resistance via a genome-wide association study (GWAS. Whole-plant water relations were compared among four genotypes by lysimetric assay. Apparent genotypic differences in transpiration patterns and the critical soil water threshold in relation to dehydration avoidance were observed, indicating a delicate adaptive mechanism for each genotype to its own climate. Microarray gene expression analyses revealed that known drought resistance pathways such as the ABA and phosphate lipid signaling pathways are conserved between genotypes, while differential regulation of certain aquaporin genes and hormonal genes may be important for the genotypic differences. Our results suggest that divergent sensitivity to soil water content is an important mechanism configuring the genotypic specific responses to water deficit. The SNP markers identified provide useful resources for marker-assisted breeding.

  1. Deep sequencing of the viral phoH gene reveals temporal variation, depth-specific composition, and persistent dominance of the same viral phoH genes in the Sargasso Sea

    Dawn B. Goldsmith

    2015-06-01

    Full Text Available Deep sequencing of the viral phoH gene, a host-derived auxiliary metabolic gene, was used to track viral diversity throughout the water column at the Bermuda Atlantic Time-series Study (BATS site in the summer (September and winter (March of three years. Viral phoH sequences reveal differences in the viral communities throughout a depth profile and between seasons in the same year. Variation was also detected between the same seasons in subsequent years, though these differences were not as great as the summer/winter distinctions. Over 3,600 phoH operational taxonomic units (OTUs; 97% sequence identity were identified. Despite high richness, most phoH sequences belong to a few large, common OTUs whereas the majority of the OTUs are small and rare. While many OTUs make sporadic appearances at just a few times or depths, a small number of OTUs dominate the community throughout the seasons, depths, and years.

  2. Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID.

    Steven M Offer

    Full Text Available BACKGROUND: Despite considerable effort, the genetic factors responsible for >90% of the antibody deficiency syndromes IgAD and CVID remain elusive. To produce a functionally diverse antibody repertoire B lymphocytes undergo class switch recombination. This process is initiated by AID-catalyzed deamination of cytidine to uridine in switch region DNA. Subsequently, these residues are recognized by the uracil excision enzyme UNG2 or the mismatch repair proteins MutSalpha (MSH2/MSH6 and MutLalpha (PMS2/MLH1. Further processing by ubiquitous DNA repair factors is thought to introduce DNA breaks, ultimately leading to class switch recombination and expression of a different antibody isotype. METHODOLOGY/PRINCIPAL FINDINGS: Defects in AID and UNG2 have been shown to result in the primary immunodeficiency hyper-IgM syndrome, leading us to hypothesize that additional, potentially more subtle, DNA repair gene variations may underlie the clinically related antibody deficiencies syndromes IgAD and CVID. In a survey of twenty-seven candidate DNA metabolism genes, markers in MSH2, RAD50, and RAD52 were associated with IgAD/CVID, prompting further investigation into these pathways. Resequencing identified four rare, non-synonymous alleles associated with IgAD/CVID, two in MLH1, one in RAD50, and one in NBS1. One IgAD patient carried heterozygous non-synonymous mutations in MLH1, MSH2, and NBS1. Functional studies revealed that one of the identified mutations, a premature RAD50 stop codon (Q372X, confers increased sensitivity to ionizing radiation. CONCLUSIONS: Our results are consistent with a class switch recombination model in which AID-catalyzed uridines are processed by multiple DNA repair pathways. Genetic defects in these DNA repair pathways may contribute to IgAD and CVID.

  3. Genetic variation of Taenia pisiformis collected from Sichuan, China, based on the mitochondrial cytochrome B gene.

    Yang, Deying; Ren, Yongjun; Fu, Yan; Xie, Yue; Nie, Huaming; Nong, Xiang; Gu, Xiaobin; Wang, Shuxian; Peng, Xuerong; Yang, Guangyou

    2013-08-01

    Taenia pisiformis is one of the most important parasites of canines and rabbits. T. pisiformis cysticercus (the larval stage) causes severe damage to rabbit breeding, which results in huge economic losses. In this study, the genetic variation of T. pisiformis was determined in Sichuan Province, China. Fragments of the mitochondrial cytochrome b (cytb) (922 bp) gene were amplified in 53 isolates from 8 regions of T. pisiformis. Overall, 12 haplotypes were found in these 53 cytb sequences. Molecular genetic variations showed 98.4% genetic variation derived from intra-region. FST and Nm values suggested that 53 isolates were not genetically differentiated and had low levels of genetic diversity. Neutrality indices of the cytb sequences showed the evolution of T. pisiformis followed a neutral mode. Phylogenetic analysis revealed no correlation between phylogeny and geographic distribution. These findings indicate that 53 isolates of T. pisiformis keep a low genetic variation, which provide useful knowledge for monitoring changes in parasite populations for future control strategies.

  4. Gene

    U.S. Department of Health & Human Services — Gene integrates information from a wide range of species. A record may include nomenclature, Reference Sequences (RefSeqs), maps, pathways, variations, phenotypes,...

  5. A Rare Cause of Short Stature: 3M Syndrome in a Patient with Novel Mutation in OBSL1 Gene.

    Keskin, Melikşah; Muratoğlu Şahin, Nursel; Kurnaz, Erdal; Bayramoğlu, Elvan; Savaş Erdeve, Şenay; Aycan, Zehra; Çetinkaya, Semra

    2017-03-01

    The Miller-McKusick-Malvaux (3M) syndrome is a rare autosomal disorder that can lead to short stature, dysmorphic features, and skeletal abnormalities with normal intelligence. A 16-month-old female patient had been referred to our clinic due to short stature. Case history revealed a birth weight of 1740 grams on the 39 th week of gestation, with a birth length of 42 cm and no prior hereditary conditions of clinical significance in her family. On physical examination, her length was 67 cm [-3.6 standard deviation (SD) score], weight 7.2 kg (-2.9 SD score), and head circumference 42 cm (below 3 rd percentile). She also had numerous characteristic physical features such as a triangular face, fleshy nose tip, a long philtrum, prominent mouth and lips, pointed chin, lumbar lordosis, and prominent heels. As her growth retardation had a prenatal onset and the physical examination results were suggestive of a characteristic profile, the diagnosis of 3M syndrome was strongly considered. Genetic assessment of the patient revealed a novel homozygous p.T45Nfs*40 mutation in the OBSL1 gene. It is recommended that physicians pay further attention to this condition in the differential diagnosis of children with severe short stature.

  6. The right vertebral artery originating from the right occipital artery and the absence of the transverse foramen: a rare anatomical variation.

    Öner, Zülal; Öner, Serkan; Kahraman, Ayşegül Sağır

    2017-12-01

    Variations in the origin of the vertebral artery (VA) is a congenital anomaly that occurs during embryological development. Multiple variations related to VA origin have been reported in the literature. Abnormal VA origin is usually determined as incidental findings during angiographic or postmortem anatomical studies. Although most of the cases are asymptomatic, in patients with VA anomaly symptoms such as dizziness have been described. The anomalous variation in the origin of the right VA is rare and separated into three categories: (1) originating from the aorta, (2) originating from the carotid arteries, (3) duplicated origin. In this case, we aimed to present the right VA originating from the right occipital artery and concomitant anomalies of the transverse foramen that have not been reported previously according to our knowledge in literature. In a 32-year-old female patient referred to our hospital because of dizziness, the right VA was not observed on magnetic resonance imaging and computed tomography angiography (CTA) examination was performed. CTA showed hypoplasia of the right transverse foramen at the levels of the C1, C5 and C6 vertebrae and aplasia of the right transverse foramen at the levels of the C2, C3 and C4 vertebrae. The right VA originating from the right occipital artery continues to its normal course by entering the cranium through the foramen magnum at the level of the atlantooccipital junction.

  7. Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

    Jim, Heather S L; Lin, Hui-Yi; Tyrer, Jonathan P

    2015-01-01

    where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine...... single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2......,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant...

  8. Natural Variation of Epstein-Barr Virus Genes, Proteins, and Primary MicroRNA.

    Correia, Samantha; Palser, Anne; Elgueta Karstegl, Claudio; Middeldorp, Jaap M; Ramayanti, Octavia; Cohen, Jeffrey I; Hildesheim, Allan; Fellner, Maria Dolores; Wiels, Joelle; White, Robert E; Kellam, Paul; Farrell, Paul J

    2017-08-01

    Viral gene sequences from an enlarged set of about 200 Epstein-Barr virus (EBV) strains, including many primary isolates, have been used to investigate variation in key viral genetic regions, particularly LMP1, Zp, gp350, EBNA1, and the BART microRNA (miRNA) cluster 2. Determination of type 1 and type 2 EBV in saliva samples from people from a wide range of geographic and ethnic backgrounds demonstrates a small percentage of healthy white Caucasian British people carrying predominantly type 2 EBV. Linkage of Zp and gp350 variants to type 2 EBV is likely to be due to their genes being adjacent to the EBNA3 locus, which is one of the major determinants of the type 1/type 2 distinction. A novel classification of EBNA1 DNA binding domains, named QCIGP, results from phylogeny analysis of their protein sequences but is not linked to the type 1/type 2 classification. The BART cluster 2 miRNA region is classified into three major variants through single-nucleotide polymorphisms (SNPs) in the primary miRNA outside the mature miRNA sequences. These SNPs can result in altered levels of expression of some miRNAs from the BART variant frequently present in Chinese and Indonesian nasopharyngeal carcinoma (NPC) samples. The EBV genetic variants identified here provide a basis for future, more directed analysis of association of specific EBV variations with EBV biology and EBV-associated diseases. IMPORTANCE Incidence of diseases associated with EBV varies greatly in different parts of the world. Thus, relationships between EBV genome sequence variation and health, disease, geography, and ethnicity of the host may be important for understanding the role of EBV in diseases and for development of an effective EBV vaccine. This paper provides the most comprehensive analysis so far of variation in specific EBV genes relevant to these diseases and proposed EBV vaccines. By focusing on variation in LMP1, Zp, gp350, EBNA1, and the BART miRNA cluster 2, new relationships with the known

  9. Genetic variation in the serotonin transporter gene influences ERP old/new effects during recognition memory.

    Ross, Robert S; Medrano, Paolo; Boyle, Kaitlin; Smolen, Andrew; Curran, Tim; Nyhus, Erika

    2015-11-01

    Recognition memory is defined as the ability to recognize a previously encountered stimulus and has been associated with spatially and temporally distinct event-related potentials (ERPs). Allelic variations of the serotonin transporter gene (SLC6A4) have recently been shown to impact memory performance. Common variants of the serotonin transporter-linked polymorphic region (5HTTLPR) of the SLC6A4 gene result in long (l) and short (s) allelic variants with carriers of the s allele having lowered transcriptional efficiency. Thus, the current study examines the effects polymorphisms of the SLC6A4 gene have on performance and ERP amplitudes commonly associated with recognition memory. Electroencephalogram (EEG), genetic, and behavioral data were collected from sixty participants as they performed an item and source memory recognition task. In both tasks, participants studied and encoded 200 words, which were then mixed with 200 new words during retrieval. Participants were monitored with EEG during the retrieval portion of each memory task. EEG electrodes were grouped into four ROIs, left anterior superior, right anterior superior, left posterior superior, and right posterior superior. ERP mean amplitudes during hits in the item and source memory task were compared to correctly recognizing new items (correct rejections). Results show that s-carriers have decreased mean hit amplitudes in both the right anterior superior ROI 1000-1500ms post stimulus during the source memory task and the left anterior superior ROI 300-500ms post stimulus during the item memory task. These results suggest that individual differences due to genetic variation of the serotonin transporter gene influences recognition memory. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Genetic Variation and Population Structure in Jamunapari Goats Using Microsatellites, Mitochondrial DNA, and Milk Protein Genes

    Rout, P. K.; Thangraj, K.; Mandal, A.; Roy, R.

    2012-01-01

    Jamunapari, a dairy goat breed of India, has been gradually declining in numbers in its home tract over the years. We have analysed genetic variation and population history in Jamunapari goats based on 17 microsatellite loci, 2 milk protein loci, mitochondrial hypervariable region I (HVRI) sequencing, and three Y-chromosomal gene sequencing. We used the mitochondrial DNA (mtDNA) mismatch distribution, microsatellite data, and bottleneck tests to infer the population history and demography. The mean number of alleles per locus was 9.0 indicating that the allelic variation was high in all the loci and the mean heterozygosity was 0.769 at nuclear loci. Although the population size is smaller than 8,000 individuals, the amount of variability both in terms of allelic richness and gene diversity was high in all the microsatellite loci except ILST 005. The gene diversity and effective number of alleles at milk protein loci were higher than the 10 other Indian goat breeds that they were compared to. Mismatch analysis was carried out and the analysis revealed that the population curve was unimodal indicating the expansion of population. The genetic diversity of Y-chromosome genes was low in the present study. The observed mean M ratio in the population was above the critical significance value (Mc) and close to one indicating that it has maintained a slowly changing population size. The mode-shift test did not detect any distortion of allele frequency and the heterozygosity excess method showed that there was no significant departure from mutation-drift equilibrium detected in the population. However, the effects of genetic bottlenecks were observed in some loci due to decreased heterozygosity and lower level of M ratio. There were two observed genetic subdivisions in the population supporting the observations of farmers in different areas. This base line information on genetic diversity, bottleneck analysis, and mismatch analysis was obtained to assist the conservation

  11. Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

    Purrington, Kristen S; Slettedahl, Seth; Bolla, Manjeet K

    2014-01-01

    polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10......Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide......(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene...

  12. Prevalence of variations in melanoma susceptibility genes among Slovenian melanoma families

    Besic Nikola

    2008-09-01

    Full Text Available Abstract Background Two high-risk genes have been implicated in the development of CM (cutaneous melanoma. Germline mutations of the CDKN2A gene are found in CDK4 gene reported to date. Beside those high penetrance genes, certain allelic variants of the MC1R gene modify the risk of developing the disease. The aims of our study were: to determine the prevalence of germline CDKN2A mutations and variants in members of families with familial CM and in patients with multiple primary CM; to search for possible CDK4 mutations, and to determine the frequency of variations in the MC1R gene. Methods From January 2001 until January 2007, 64 individuals were included in the study. The group included 28 patients and 7 healthy relatives belonging to 25 families, 26 patients with multiple primary tumors and 3 children with CM. Additionally 54 healthy individuals were included as a control group. Mutations and variants of the melanoma susceptibility genes were identified by direct sequencing. Results Seven families with CDKN2A mutations were discovered (7/25 or 28.0%. The L94Q mutation found in one family had not been previously reported in other populations. The D84N variant, with possible biological impact, was discovered in the case of patient without family history but with multiple primary CM. Only one mutation carrier was found in the control group. Further analysis revealed that c.540C>T heterozygous carriers were more common in the group of CM patients and their healthy relatives (11/64 vs. 2/54. One p14ARF variant was discovered in the control group and no mutations of the CDK4 gene were found. Most frequently found variants of the MC1R gene were T314T, V60L, V92M, R151C, R160W and R163Q with frequencies slightly higher in the group of patients and their relatives than in the group of controls, but the difference was statistically insignificant. Conclusion The present study has shown high prevalence of p16INK4A mutations in Slovenian population of

  13. Analysis of Copy Number Variation in the Abp Gene Regions of Two House Mouse Subspecies Suggests Divergence during the Gene Family Expansions.

    Pezer, Željka; Chung, Amanda G; Karn, Robert C; Laukaitis, Christina M

    2017-06-01

    The Androgen-binding protein ( Abp ) gene region of the mouse genome contains 64 genes, some encoding pheromones that influence assortative mating between mice from different subspecies. Using CNVnator and quantitative PCR, we explored copy number variation in this gene family in natural populations of Mus musculus domesticus ( Mmd ) and Mus musculus musculus ( Mmm ), two subspecies of house mice that form a narrow hybrid zone in Central Europe. We found that copy number variation in the center of the Abp gene region is very common in wild Mmd , primarily representing the presence/absence of the final duplications described for the mouse genome. Clustering of Mmd individuals based on this variation did not reflect their geographical origin, suggesting no population divergence in the Abp gene cluster. However, copy number variation patterns differ substantially between Mmd and other mouse taxa. Large blocks of Abp genes are absent in Mmm , Mus musculus castaneus and an outgroup, Mus spretus , although with differences in variation and breakpoint locations. Our analysis calls into question the reliance on a reference genome for interpreting the detailed organization of genes in taxa more distant from the Mmd reference genome. The polymorphic nature of the gene family expansion in all four taxa suggests that the number of Abp genes, especially in the central gene region, is not critical to the survival and reproduction of the mouse. However, Abp haplotypes of variable length may serve as a source of raw genetic material for new signals influencing reproductive communication and thus speciation of mice. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  14. A comprehensive review of the prevalence of beta globin gene variations and the co-inheritance of related gene variants in Saudi Arabians with beta-thalassemia

    Alaithan, Mousa A.; AbdulAzeez, Sayed; Borgio, J. Francis

    2018-01-01

    Beta-thalassemia is a genetic disorder that is caused by variations in the beta-hemoglobin (HBB) gene. Saudi Arabia is among the countries most affected by beta-thalassemia, and this is particularly problematic in the Eastern regions. This review article is an attempt to compile all the reported mutations to facilitate further national-level studies to prepare a Saudi repository of HBB gene variations. In Saudi Arabians, IVSI-5 (G>C) and Cd 39 (C>T) are the most prevalent HBB gene variations out of 42 variations. The coinheritance of HBB gene variations with ATRX, HBA1, HBA2, HBA12, AHSP, and KLF1 gene variations were observed to be common in the Saudi population. National surveys on the molecular nature of hemoglobinopathies should be set up through collaborations between research centers from various regions to create a well-documented molecular data bank. This data bank can be used to develop a premarital screening program and lead to the best treatment and prevention strategies for beta-thalassemia. PMID:29619482

  15. MHC class II genes in the European badger (Meles meles) : Characterization, patterns of variation, and transcription analysis

    Sin, Yung Wa; Dugdale, Hannah L.; Newman, Chris; Macdonald, David W.; Burke, Terry

    The major histocompatibility complex (MHC) comprises many genes, some of which are polymorphic with numerous alleles. Sequence variation among alleles is most pronounced in exon 2 of the class II genes, which encodes the alpha 1 and beta 1 domains that form the antigen-binding site (ABS) for the

  16. Allelic variation of the FRMD7 gene in congenital idiopathic nystagmus.

    Self, James E; Shawkat, Fatima; Malpas, Crispin T; Thomas, N Simon; Harris, Christopher M; Hodgkins, Peter R; Chen, Xiaoli; Trump, Dorothy; Lotery, Andrew J

    2007-09-01

    To perform a genotype-phenotype correlation study in an X-linked congenital idiopathic nystagmus pedigree (pedigree 1) and to assess the allelic variance of the FRMD7 gene in congenital idiopathic nystagmus. Subjects from pedigree 1 underwent detailed clinical examination including nystagmology. Screening of FRMD7 was undertaken in pedigree 1 and in 37 other congenital idiopathic nystagmus probands and controls. Direct sequencing confirmed sequence changes. X-inactivation studies were performed in pedigree 1. The nystagmus phenotype was extremely variable in pedigree 1. We identified 2 FRMD7 mutations. However, 80% of X-linked families and 96% of simplex cases showed no mutations. X-inactivation studies demonstrated no clear causal link between skewing and variable penetrance. We confirm profound phenotypic variation in X-linked congenital idiopathic nystagmus pedigrees. We demonstrate that other congenital nystagmus genes exist besides FRMD7. We show that the role of X inactivation in variable penetrance is unclear in congenital idiopathic nystagmus. Clinical Relevance We demonstrate that phenotypic variation of nystagmus occurs in families with FRMD7 mutations. While FRMD7 mutations may be found in some cases of X-linked congenital idiopathic nystagmus, the diagnostic yield is low. X-inactivation assays are unhelpful as a test for carrier status for this disease.

  17. Allelic variation of bile salt hydrolase genes in Lactobacillus salivarius does not determine bile resistance levels.

    Fang, Fang

    2009-09-01

    Commensal lactobacilli frequently produce bile salt hydrolase (Bsh) enzymes whose roles in intestinal survival are unclear. Twenty-six Lactobacillus salivarius strains from different sources all harbored a bsh1 allele on their respective megaplasmids. This allele was related to the plasmid-borne bsh1 gene of the probiotic strain UCC118. A second locus (bsh2) was found in the chromosomes of two strains that had higher bile resistance levels. Four Bsh1-encoding allele groups were identified, defined by truncations or deletions involving a conserved residue. In vitro analyses showed that this allelic variation was correlated with widely varying bile deconjugation phenotypes. Despite very low activity of the UCC118 Bsh1 enzyme, a mutant lacking this protein had significantly lower bile resistance, both in vitro and during intestinal transit in mice. However, the overall bile resistance phenotype of this and other strains was independent of the bsh1 allele type. Analysis of the L. salivarius transcriptome upon exposure to bile and cholate identified a multiplicity of stress response proteins and putative efflux proteins that appear to broadly compensate for, or mask, the effects of allelic variation of bsh genes. Bsh enzymes with different bile-degrading kinetics, though apparently not the primary determinants of bile resistance in L. salivarius, may have additional biological importance because of varying effects upon bile as a signaling molecule in the host.

  18. Constitutional sequence variation in the Fanconi anaemia group C (FANCC) gene in childhood acute myeloid leukaemia.

    Barber, Lisa M; McGrath, Helen E N; Meyer, Stefan; Will, Andrew M; Birch, Jillian M; Eden, Osborn B; Taylor, G Malcolm

    2003-04-01

    The extent to which genetic susceptibility contributes to the causation of childhood acute myeloid leukaemia (AML) is not known. The inherited bone marrow failure disorder Fanconi anaemia (FA) carries a substantially increased risk of AML, raising the possibility that constitutional variation in the FA (FANC) genes is involved in the aetiology of childhood AML. We have screened genomic DNA extracted from remission blood samples of 97 children with sporadic AML and 91 children with sporadic acute lymphoblastic leukaemia (ALL), together with 104 cord blood DNA samples from newborn children, for variations in the Fanconi anaemia group C (FANCC) gene. We found no evidence of known FANCC pathogenic mutations in children with AML, ALL or in the cord blood samples. However, we detected 12 different FANCC sequence variants, of which five were novel to this study. Among six FANCC variants leading to amino-acid substitutions, one (S26F) was present at a fourfold greater frequency in children with AML than in the cord blood samples (odds ratio: 4.09, P = 0.047; 95% confidence interval 1.08-15.54). Our results thus do not exclude the possibility that this polymorphic variant contributes to the risk of a small proportion of childhood AML.

  19. Nucleotide variation at the dopa decarboxylase (Ddc) gene in natural populations of Drosophila melanogaster.

    Tatarenkov, Andrey; Ayala, Francisco J

    2007-08-01

    We studied nucleotide sequence variation at the gene coding for dopa decarboxylase (Ddc) in seven populations of Drosophila melanogaster. Strength and pattern of linkage disequilibrium are somewhat distinct in the extensively sampled Spanish and Raleigh populations. In the Spanish population, a few sites are in strong positive association, whereas a large number of sites in the Raleigh population are associated nonrandomly but the association is not strong. Linkage disequilibrium analysis shows presence of two groups of haplotypes in the populations, each of which is fairly diverged, suggesting epistasis or inversion polymorphism. There is evidence of two forms of natural selection acting on Ddc. The McDonald-Kreitman test indicates a deficit of fixed amino acid differences between D. melanogaster and D. simulans, which may be due to negative selection. An excess of derived alleles at high frequency, significant according to the H-test, is consistent with the effect of hitchhiking. The hitchhiking may have been caused by directional selection downstream of the locus studied, as suggested by a gradual decrease of the polymorphism-to-divergence ratio. Altogether, the Ddc locus exhibits a complicated pattern of variation apparently due to several evolutionary forces. Such a complex pattern may be a result of an unusually high density of functionally important genes.

  20. Variation in the γ-glutamyltransferase 1 gene and risk of chronic pancreatitis.

    Brand, Harrison; Diergaarde, Brenda; O'Connell, Michael R; Whitcomb, David C; Brand, Randall E

    2013-07-01

    Individuals with chronic pancreatitis are at increased risk for pancreatic cancer. We hypothesized that genetic variation in the γ-glutamyltransferase 1 (GGT1) gene, which was recently reported associated with pancreatic cancer risk in a genome-wide association study, is also associated with risk of chronic pancreatitis. Associations between common polymorphisms in GGT1 and chronic pancreatitis were evaluated using data and samples from the North American Pancreatitis Study 2. Patients (n = 496) and control subjects (n = 465) were genotyped for 4 single-nucleotide polymorphisms: rs4820599, rs2017869, rs8135987, and rs5751901. Odds ratios (ORs) and corresponding 95% confidence intervals (95% CI) for chronic pancreatitis risk were calculated using multiple logistic regression models. Interactions with cigarette smoking and alcohol use were explored. Single-nucleotide polymorphisms rs8135987 and rs4820599 were both statistically significantly associated with risk of chronic pancreatitis; compared with common allele homozygotes, individuals with at least 1 minor allele were at increased risk (rs8135987: OR, 1.36; 95% CI, 1.03-1.80 [P(trend) = 0.01]; rs4820599: OR, 1.39; 95% CI, 1.04-1.84 [P(trend) = 0.0]; adjusted for age, sex, race, smoking status, and alcohol use). No significant interactions with cigarette smoking and alcohol use were observed. Our results suggest that common variation in the GGT1 gene may also affect risk of chronic pancreatitis.

  1. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.

    Chornokur, Ganna; Lin, Hui-Yi; Tyrer, Jonathan P; Lawrenson, Kate; Dennis, Joe; Amankwah, Ernest K; Qu, Xiaotao; Tsai, Ya-Yu; Jim, Heather S L; Chen, Zhihua; Chen, Ann Y; Permuth-Wey, Jennifer; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V; Bean, Yukie T; Beckmann, Matthias W; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bunker, Clareann H; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Dicks, Ed; Doherty, Jennifer A; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F; Eccles, Diana M; Edwards, Robert P; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goodman, Marc T; Gronwald, Jacek; Harrington, Patricia; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Claus K; Hogdall, Estrid; Hosono, Satoyo; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kelemen, Linda E; Kellar, Mellissa; Kiemeney, Lambertus A; Krakstad, Camilla; Kjaer, Susanne K; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; McNeish, Iain; Menon, Usha; Milne, Roger L; Modugno, Francesmary; Moysich, Kirsten B; Ness, Roberta B; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Paul, James; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M; Pike, Malcolm C; Poole, Elizabeth M; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schernhammer, Eva; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C; Spiewankiewicz, Beata; Sucheston, Lara; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Thomsen, Lotte; Tangen, Ingvild L; Tworoger, Shelley S; van Altena, Anne M; Vierkant, Robert A; Vergote, Ignace; Walsh, Christine S; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Wu, Anna H; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Hasmad, Hanis N; Berchuck, Andrew; Iversen, Edwin S; Schildkraut, Joellen M; Ramus, Susan J; Goode, Ellen L; Monteiro, Alvaro N A; Gayther, Simon A; Narod, Steven A; Pharoah, Paul D P; Sellers, Thomas A; Phelan, Catherine M

    2015-01-01

    Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons. The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). These results, generated on a large cohort of women, revealed associations between inherited cellular transport

  2. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC Risk.

    Ganna Chornokur

    Full Text Available Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC, we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC. Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS. SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020; this SNP was also associated with the borderline/low malignant potential (LMP tumors (P = 0.021. Other genes significantly associated with EOC histological subtypes (p<0.05 included the UGT1A (endometrioid, SLC25A45 (mucinous, SLC39A11 (low malignant potential, and SERPINA7 (clear cell carcinoma. In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4.These results, generated on a large cohort of women, revealed associations between inherited cellular

  3. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

    Chornokur, Ganna; Lin, Hui-Yi; Tyrer, Jonathan P.; Lawrenson, Kate; Dennis, Joe; Amankwah, Ernest K.; Qu, Xiaotao; Tsai, Ya-Yu; Jim, Heather S. L.; Chen, Zhihua; Chen, Ann Y.; Permuth-Wey, Jennifer; Aben, Katja KH.; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V.; Bean, Yukie T.; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bunker, Clareann H.; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F.; Eccles, Diana M.; Edwards, Robert P.; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goodman, Marc T.; Gronwald, Jacek; Harrington, Patricia; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A. T.; Hillemanns, Peter; Hogdall, Claus K.; Hogdall, Estrid; Hosono, Satoyo; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Kelemen, Linda E.; Kellar, Mellissa; Kiemeney, Lambertus A.; Krakstad, Camilla; Kjaer, Susanne K.; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F. A. G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Iain; Menon, Usha; Milne, Roger L.; Modugno, Francesmary; Moysich, Kirsten B.; Ness, Roberta B.; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Paul, James; Pearce, Celeste L.; Pejovic, Tanja; Pelttari, Liisa M.; Pike, Malcolm C.; Poole, Elizabeth M.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schernhammer, Eva; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Spiewankiewicz, Beata; Sucheston, Lara; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Thomsen, Lotte; Tangen, Ingvild L.; Tworoger, Shelley S.; van Altena, Anne M.; Vierkant, Robert A.; Vergote, Ignace; Walsh, Christine S.; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wu, Anna H.; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Hasmad, Hanis N.; Berchuck, Andrew; Iversen, Edwin S.; Schildkraut, Joellen M.; Ramus, Susan J.; Goode, Ellen L.; Monteiro, Alvaro N. A.; Gayther, Simon A.; Narod, Steven A.; Pharoah, Paul D. P.; Sellers, Thomas A.; Phelan, Catherine M.

    2015-01-01

    Background Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. Methods In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons. Results The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). Conclusion These results, generated on a large cohort of women, revealed associations

  4. Variation in the autism candidate gene GABRB3 modulates tactile sensitivity in typically developing children

    Tavassoli Teresa

    2012-07-01

    Full Text Available Abstract Background Autism spectrum conditions have a strong genetic component. Atypical sensory sensitivities are one of the core but neglected features of autism spectrum conditions. GABRB3 is a well-characterised candidate gene for autism spectrum conditions. In mice, heterozygous Gabrb3 deletion is associated with increased tactile sensitivity. However, no study has examined if tactile sensitivity is associated with GABRB3 genetic variation in humans. To test this, we conducted two pilot genetic association studies in the general population, analysing two phenotypic measures of tactile sensitivity (a parent-report and a behavioural measure for association with 43 SNPs in GABRB3. Findings Across both tactile sensitivity measures, three SNPs (rs11636966, rs8023959 and rs2162241 were nominally associated with both phenotypes, providing a measure of internal validation. Parent-report scores were nominally associated with six SNPs (P Conclusions This is the first human study to show an association between GABRB3 variation and tactile sensitivity. This provides support for the evidence from animal models implicating the role of GABRB3 variation in the atypical sensory sensitivity in autism spectrum conditions. Future research is underway to directly test this association in cases of autism spectrum conditions.

  5. Polymorphic genes of major effect: consequences for variation, selection and evolution in Arabidopsis thaliana.

    Stinchcombe, John R; Weinig, Cynthia; Heath, Katy D; Brock, Marcus T; Schmitt, Johanna

    2009-07-01

    The importance of genes of major effect for evolutionary trajectories within and among natural populations has long been the subject of intense debate. For example, if allelic variation at a major-effect locus fundamentally alters the structure of quantitative trait variation, then fixation of a single locus can have rapid and profound effects on the rate or direction of subsequent evolutionary change. Using an Arabidopsis thaliana RIL mapping population, we compare G-matrix structure between lines possessing different alleles at ERECTA, a locus known to affect ecologically relevant variation in plant architecture. We find that the allele present at ERECTA significantly alters G-matrix structure-in particular the genetic correlations between branch number and flowering time traits-and may also modulate the strength of natural selection on these traits. Despite these differences, however, when we extend our analysis to determine how evolution might differ depending on the ERECTA allele, we find that predicted responses to selection are similar. To compare responses to selection between allele classes, we developed a resampling strategy that incorporates uncertainty in estimates of selection that can also be used for statistical comparisons of G matrices.

  6. Natural Variation in Synthesis and Catabolism Genes Influences Dhurrin Content in Sorghum

    Chad M. Hayes

    2015-07-01

    Full Text Available Cyanogenic glucosides are natural compounds found in more than 1000 species of angiosperms that produce HCN and are deemed undesirable for agricultural use. However, these compounds are important components of the primary defensive mechanisms of many plant species. One of the best-studied cyanogenic glucosides is dhurrin [(--hydroxymandelonitrile-β--glucopyranoside], which is produced primarily in sorghum [ (L. Moench]. The biochemical basis for dhurrin metabolism is well established; however, little information is available on its genetic control. Here, we dissect the genetic control of leaf dhurrin content through a genome-wide association study (GWAS using a panel of 700 diverse converted sorghum lines (conversion panel previously subjected to pre-breeding and selected for short stature (∼1 m in height and photoperiod insensitivity. The conversion panel was grown for 2 yr in three environments. Wide variation for leaf dhurrin content was found in the sorghum conversion panel, with the Caudatum group exhibiting the highest dhurrin content and the Guinea group showing the lowest dhurrin content. A GWAS using a mixed linear model revealed significant associations (a false discovery rate [FDR] < 0.05 close to both UGT 185B1 in the canonical biosynthetic gene cluster on chromosome 1 and close to the catabolic dhurrinase loci on chromosome 8. Dhurrin content was associated consistently with biosynthetic genes in the two N-fertilized environments, while dhurrin content was associated with catabolic loci in the environment without supplemental N. These results suggest that genes for both biosynthesis and catabolism are important in determining natural variation for leaf dhurrin in sorghum in different environments.

  7. Genetic variation in hormone metabolizing genes and risk of testicular germ cell tumors.

    Figueroa, Jonine D; Sakoda, Lori C; Graubard, Barry I; Chanock, Stephen; Rubertone, Mark V; Erickson, R Loren; McGlynn, Katherine A

    2008-11-01

    Testicular germ cell tumors (TGCT) that arise in young men are composed of two histologic types, seminomas and nonseminomas. Risk patterns for the two types appear to be similar and may be related to either endogenous or exogenous hormonal exposures in utero. Why similar risk patterns would result in different histologic types is unclear, but could be related to varying genetic susceptibility profiles. Genetic variation in hormone metabolizing genes could potentially modify hormonal exposures, and thereby affect which histologic type a man develops. To examine this hypothesis, 33 single nucleotide polymorphisms (SNPs) in four hormone metabolism candidate genes (CYP1A1, CYP17A1, HSD17B1, HSD17B4) and the androgen receptor gene (AR) were genotyped. Associations with TGCT were evaluated among 577 TGCT cases (254 seminoma, 323 nonseminoma) and 707 controls from the US Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) study. There were no significant associations with TGCT overall based on a test using an additive model. However, compared to homozygotes of the most common allele, two nonredundant SNPs in CYP1A1 were inversely associated with nonseminoma: CYP1A1 promoter SNP rs4886605 OR = 0.75 (95% CI = 0.54-1.04) among the heterozygotes and OR = 0.37, 95% CI = 0.12-1.11 among the homozygotes with a p-value for trend = 0.02; rs2606345 intron 1 SNP, OR = 0.69 (95% CI = 0.51-0.93) among heterozygotes and OR = 0.70 (95% CI = 0.42-1.17) among homozygotes, with a p-value for trend = 0.02. Caution in interpretation is warranted until findings are replicated in other studies; however, the results suggest that genetic variation in CYP1A1 may be associated with nonseminoma.

  8. Whole-exome sequencing of a rare case of familial childhood acute lymphoblastic leukemia reveals putative predisposing mutations in Fanconi anemia genes.

    Spinella, Jean-François; Healy, Jasmine; Saillour, Virginie; Richer, Chantal; Cassart, Pauline; Ouimet, Manon; Sinnett, Daniel

    2015-07-23

    Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. While the multi-step model of pediatric leukemogenesis suggests interplay between constitutional and somatic genomes, the role of inherited genetic variability remains largely undescribed. Nonsyndromic familial ALL, although extremely rare, provides the ideal setting to study inherited contributions to ALL. Toward this goal, we sequenced the exomes of a childhood ALL family consisting of mother, father and two non-twinned siblings diagnosed with concordant pre-B hyperdiploid ALL and previously shown to have inherited a rare form of PRDM9, a histone H3 methyltransferase involved in crossing-over at recombination hotspots and Holliday junctions. We postulated that inheritance of additional rare disadvantaging variants in predisposing cancer genes could affect genomic stability and lead to increased risk of hyperdiploid ALL within this family. Whole exomes were captured using Agilent's SureSelect kit and sequenced on the Life Technologies SOLiD System. We applied a data reduction strategy to identify candidate variants shared by both affected siblings. Under a recessive disease model, we focused on rare non-synonymous or frame-shift variants in leukemia predisposing pathways. Though the family was nonsyndromic, we identified a combination of rare variants in Fanconi anemia (FA) genes FANCP/SLX4 (compound heterozygote - rs137976282/rs79842542) and FANCA (rs61753269) and a rare homozygous variant in the Holliday junction resolvase GEN1 (rs16981869). These variants, predicted to affect protein function, were previously identified in familial breast cancer cases. Based on our in-house database of 369 childhood ALL exomes, the sibs were the only patients to carry this particularly rare combination and only a single hyperdiploid patient was heterozygote at both FANCP/SLX4 positions, while no FANCA variant allele carriers were identified. FANCA is the most commonly mutated gene in FA and is essential for

  9. Clinical Relevance of Gene Copy Number Variation in Metastatic Clear Cell Renal Cell Carcinoma.

    Nouhaud, François-Xavier; Blanchard, France; Sesboue, Richard; Flaman, Jean-Michel; Sabourin, Jean-Christophe; Pfister, Christian; Di Fiore, Frédéric

    2018-02-23

    Gene copy number variations (CNVs) have been reported to be frequent in renal cell carcinoma (RCC), with potential prognostic value for some. However, their clinical utility, especially to guide treatment of metastatic disease remains to be established. Our objectives were to assess CNVs on a panel of selected genes and determine their clinical relevance in patients who underwent treatment of metastatic RCC. The genetic assessment was performed on frozen tissue samples of clear cell metastatic RCC using quantitative multiplex polymerase chain reaction of short fluorescent fragment method to detect CNVs on a panel of 14 genes of interest. The comparison of the electropherogram obtained from both tumor and normal renal adjacent tissue allowed for CNV identification. The clinical, biologic, and survival characteristics were assessed for their associations with the most frequent CNVs. Fifty patients with clear cell metastatic RCC were included. The CNV rate was 21.4%. The loss of CDKN2A and PLG was associated with a higher tumor stage (P relevance, especially those located on CDKN2A, PLG, and ALDOB, in a homogeneous cohort of patients with clear cell metastatic RCC. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Variations in KIR Genes: A Study in HIV-1 Serodiscordant Couples

    Vijay R. Chavan

    2014-01-01

    Full Text Available Background. NK cells have anti-HIV activity mediated through killer cell immunoglobulin-like receptors (KIRs. The current prospective cohort study evaluated whether variation in KIR genes is associated with HIV infection in discordant couples (DCs, where one spouse remains seronegative (HSN despite repeated exposure to the HIV. Methods. KIR was genotyped using PCR SSP. Viral load and CD4 counts were estimated using commercially available reagents. Data were analyzed using SPSS software. Results. Among the 47 DCs, HSN spouses had significantly (P=0.006 higher frequencies of KIR3DS1. Regression analysis revealed significant (P=0.009 association of KIR2DS1 with low viral load. KIR2DS4 variant was associated (P=0.032 with high viral load. Three pairs of KIR genes were in strong LD in HSNs and two pairs in HSPs. There were 60 KIR genotypes, and 16 are reported the first time in the Indian population. Exclusive genotypes were present either in HSPs (N=22, 11 unique genotypes or in HSNs (n=27, 9 unique genotypes. Conclusions. This study highlights for the first time in the Indian population an association of KIR genes in HIV infection where presence of exclusive and unique genotypes indicates possible association with either HIV infection or with protection.

  11. Progranulin gene variation affects serum progranulin levels differently in Danish bipolar individuals compared with healthy controls.

    Buttenschøn, Henriette N; Nielsen, Marit N; Thotakura, Gangadaar; Lee, Chris W; Nykjær, Anders; Mors, Ole; Glerup, Simon

    2017-06-01

    The identification of peripheral biomarkers for bipolar disorder is of great importance and has the potential to improve diagnosis, treatment and prognosis. Recent studies have reported lower plasma progranulin levels in bipolar individuals compared with controls and association with single nucleotide polymorphisms (SNPs) within the progranulin gene (GRN). In the present study, we investigated the effect of GRN and sortilin (SORT1) gene variation on serum progranulin levels in bipolar individuals and controls. In a Danish cohort of individuals with bipolar disorder and controls, we analysed the serum progranulin level (nbipolar=80, ncontrols=76) and five SNPs located within GRN and two SNPs near the SORT1 gene encoding sortilin, a progranulin scavenger receptor known to affect circulating progranulin levels (nbipolar=166, ncontrols=186). We observed no significant difference in the serum progranulin level between cases and controls and none of the analysed SNPs located within GRN or close to SORT1 were associated with bipolar disorder. Crude and adjusted (adjusted for case-control status, sex and age) linear regression analyses showed no effect of any SNPs on the serum progranulin level. However, we observed that the mean serum progranulin level in cases and controls is affected differently depending on the genotypes of two SNPs within GRN (rs2879096 and rs4792938). The sample size is relatively small and detailed information on medication and polarity of the disorder is not available. No correction for multiple testing was performed. Our study suggests that the potential of progranulin as a biomarker for bipolar disorder is genotype dependent.

  12. Variation in Cilia Protein Genes and Progression of Lung Disease in Cystic Fibrosis.

    Blue, Elizabeth; Louie, Tin L; Chong, Jessica X; Hebbring, Scott J; Barnes, Kathleen C; Rafaels, Nicholas M; Knowles, Michael R; Gibson, Ronald L; Bamshad, Michael J; Emond, Mary J

    2018-04-01

    Cystic fibrosis, like primary ciliary dyskinesia, is an autosomal recessive disorder characterized by abnormal mucociliary clearance and obstructive lung disease. We hypothesized that genes underlying the development or function of cilia may modify lung disease severity in persons with cystic fibrosis. To test this hypothesis, we compared variants in 93 candidate genes in both upper and lower tertiles of lung function in a large cohort of children and adults with cystic fibrosis with those of a population control dataset. Variants within candidate genes were tested for association using the SKAT-O test, comparing cystic fibrosis cases defined by poor (n = 127) or preserved (n = 127) lung function with population controls (n = 3,269 or 3,148, respectively). Associated variants were then tested for association with related phenotypes in independent datasets. Variants in DNAH14 and DNAAF3 were associated with poor lung function in cystic fibrosis, whereas variants in DNAH14 and DNAH6 were associated with preserved lung function in cystic fibrosis. Associations between DNAH14 and lung function were replicated in disease-related phenotypes characterized by obstructive lung disease in adults. Genetic variants within DNAH6, DNAH14, and DNAAF3 are associated with variation in lung function among persons with cystic fibrosis.

  13. Genetic variation in DNA repair gene XRCC7 (G6721T) and susceptibility to breast cancer.

    Nasiri, Meysam; Saadat, Iraj; Omidvari, Shahpour; Saadat, Mostafa

    2012-08-15

    The human XRCC7 is a DNA double-strand break (DSBs) repair gene, involved in non-homologous end joining (NHEJ). It is speculated that DNA DSBs repair have an important role during development of breast cancer. The human XRCC7 is a NHEJ DSBs repair gene. Genetic variation G6721T of XRCC7 (rs7003908) is located in the intron 8 of the gene. This polymorphism may regulate splicing and cause mRNA instability. In the present study, we specifically investigated whether common G6721T genetic variant of XRCC7 was associated with an altered risk of breast cancer. The present study included 362 females with breast cancer. Age frequency-matched controls (362 persons) were randomly selected from the healthy female blood donors, according to the age distribution of the cases. Using RFLP-PCR based method, the polymorphism of XRCC7 was determined. The TG (OR=1.20, 95% CI: 0.83-1.74, P=0.320) and TT (OR=1.01, 95% CI: 0.67-1.53, P=0.933) genotypes had no significant effect on risk of breast cancer, in comparison with the GG genotype. Our present findings indicate that the TT and TG genotypes were not associated with an altered breast cancer risk. Copyright © 2012 Elsevier B.V. All rights reserved.

  14. Attachment style and oxytocin receptor gene variation interact in influencing social anxiety.

    Notzon, S; Domschke, K; Holitschke, K; Ziegler, C; Arolt, V; Pauli, P; Reif, A; Deckert, J; Zwanzger, P

    2016-01-01

    Social anxiety has been suggested to be promoted by an insecure attachment style. Oxytocin is discussed as a mediator of trust and social bonding as well as a modulator of social anxiety. Applying a gene-environment (G × E) interaction approach, in the present pilot study the main and interactive effects of attachment styles and oxytocin receptor (OXTR) gene variation were probed in a combined risk factor model of social anxiety in healthy probands. Participants (N = 388; 219 females, 169 males; age 24.7 ± 4.7 years) were assessed for anxiety in social situations (Social Phobia and Anxiety Inventory) depending on attachment style (Adult Attachment Scale, AAS) and OXTR rs53576 A/G genotype. A less secure attachment style was significantly associated with higher social anxiety. This association was partly modulated by OXTR genotype, with a stronger negative influence of a less secure attachment style on social anxiety in A allele carriers as compared to GG homozygotes. The present pilot data point to a strong association of less secure attachment and social anxiety as well as to a gene-environment interaction effect of OXTR rs53576 genotype and attachment style on social anxiety possibly constituting a targetable combined risk marker of social anxiety disorder.

  15. Genetic variation at hair length candidate genes in elephants and the extinct woolly mammoth

    Tisdale Michele

    2009-09-01

    Full Text Available Abstract Background Like humans, the living elephants are unusual among mammals in being sparsely covered with hair. Relative to extant elephants, the extinct woolly mammoth, Mammuthus primigenius, had a dense hair cover and extremely long hair, which likely were adaptations to its subarctic habitat. The fibroblast growth factor 5 (FGF5 gene affects hair length in a diverse set of mammalian species. Mutations in FGF5 lead to recessive long hair phenotypes in mice, dogs, and cats; and the gene has been implicated in hair length variation in rabbits. Thus, FGF5 represents a leading candidate gene for the phenotypic differences in hair length notable between extant elephants and the woolly mammoth. We therefore sequenced the three exons (except for the 3' UTR and a portion of the promoter of FGF5 from the living elephantid species (Asian, African savanna and African forest elephants and, using protocols for ancient DNA, from a woolly mammoth. Results Between the extant elephants and the mammoth, two single base substitutions were observed in FGF5, neither of which alters the amino acid sequence. Modeling of the protein structure suggests that the elephantid proteins fold similarly to the human FGF5 protein. Bioinformatics analyses and DNA sequencing of another locus that has been implicated in hair cover in humans, type I hair keratin pseudogene (KRTHAP1, also yielded negative results. Interestingly, KRTHAP1 is a pseudogene in elephantids as in humans (although fully functional in non-human primates. Conclusion The data suggest that the coding sequence of the FGF5 gene is not the critical determinant of hair length differences among elephantids. The results are discussed in the context of hairlessness among mammals and in terms of the potential impact of large body size, subarctic conditions, and an aquatic ancestor on hair cover in the Proboscidea.

  16. Novel rare missense variations and risk of autism spectrum disorder: whole-exome sequencing in two families with affected siblings and a two-stage follow-up study in a Japanese population.

    Jun Egawa

    Full Text Available Rare inherited variations in multiplex families with autism spectrum disorder (ASD are suggested to play a major role in the genetic etiology of ASD. To further investigate the role of rare inherited variations, we performed whole-exome sequencing (WES in two families, each with three affected siblings. We also performed a two-stage follow-up case-control study in a Japanese population. WES of the six affected siblings identified six novel rare missense variations. Among these variations, CLN8 R24H was inherited in one family by three affected siblings from an affected father and thus co-segregated with ASD. In the first stage of the follow-up study, we genotyped the six novel rare missense variations identified by WES in 241 patients and 667 controls (the Niigata sample. Only CLN8 R24H had higher mutant allele frequencies in patients (1/482 compared with controls (1/1334. In the second stage, this variation was further genotyped, yet was not detected in a sample of 309 patients and 350 controls (the Nagoya sample. In the combined Niigata and Nagoya samples, there was no significant association (odds ratio = 1.8, 95% confidence interval = 0.1-29.6. These results suggest that CLN8 R24H plays a role in the genetic etiology of ASD, at least in a subset of ASD patients.

  17. Molecular variation at a candidate gene implicated in the regulation of fire ant social behavior.

    Dietrich Gotzek

    2007-11-01

    Full Text Available The fire ant Solenopsis invicta and its close relatives display an important social polymorphism involving differences in colony queen number. Colonies are headed by either a single reproductive queen (monogyne form or multiple queens (polygyne form. This variation in social organization is associated with variation at the gene Gp-9, with monogyne colonies harboring only B-like allelic variants and polygyne colonies always containing b-like variants as well. We describe naturally occurring variation at Gp-9 in fire ants based on 185 full-length sequences, 136 of which were obtained from S. invicta collected over much of its native range. While there is little overall differentiation between most of the numerous alleles observed, a surprising amount is found in the coding regions of the gene, with such substitutions usually causing amino acid replacements. This elevated coding-region variation may result from a lack of negative selection acting to constrain amino acid replacements over much of the protein, different mutation rates or biases in coding and non-coding sequences, negative selection acting with greater strength on non-coding than coding regions, and/or positive selection acting on the protein. Formal selection analyses provide evidence that the latter force played an important role in the basal b-like lineages coincident with the emergence of polygyny. While our data set reveals considerable paraphyly and polyphyly of S. invicta sequences with respect to those of other fire ant species, the b-like alleles of the socially polymorphic species are monophyletic. An expanded analysis of colonies containing alleles of this clade confirmed the invariant link between their presence and expression of polygyny. Finally, our discovery of several unique alleles bearing various combinations of b-like and B-like codons allows us to conclude that no single b-like residue is completely predictive of polygyne behavior and, thus, potentially causally

  18. Genetic variation of clock genes and cancer risk: a field synopsis and meta-analysis.

    Benna, Clara; Helfrich-Förster, Charlotte; Rajendran, Senthilkumar; Monticelli, Halenya; Pilati, Pierluigi; Nitti, Donato; Mocellin, Simone

    2017-04-04

    The number of studies on the association between clock genes' polymorphisms and cancer susceptibility has increased over the last years but the results are often conflicting and no comprehensive overview and quantitative summary of the evidence in this field is available. Literature search identified 27 eligible studies comprising 96756 subjects (cases: 38231) and investigating 687 polymorphisms involving 14 clock genes. Overall, 1025 primary and subgroup meta-analyses on 366 gene variants were performed. Study distribution by tumor was as follows: breast cancer (n=15), prostate cancer (n=3), pancreatic cancer (n=2), non-Hodgkin's lymphoma (n=2), glioma (n=1), chronic lymphocytic leukemia (n=1), colorectal cancer (n=1), non-small cell lung cancer (n=1) and ovarian cancer (n=1).We identified 10 single nucleotide polymorphisms (SNPs) significantly associated with cancer risk: NPAS2 rs10165970 (mixed and breast cancer shiftworkers), rs895520 (mixed), rs17024869 (breast) and rs7581886 (breast); CLOCK rs3749474 (breast) and rs11943456 (breast); RORA rs7164773 (breast and breast cancer postmenopausal), rs10519097 (breast); RORB rs7867494 (breast cancer postmenopausal), PER3 rs1012477 (breast cancer subgroups) and assessed the level of quality evidence to be intermediate. We also identified polymorphisms with lower quality statistically significant associations (n=30). Our work supports the hypothesis that genetic variation of clock genes might affect cancer risk. These findings also highlight the need for more efforts in this research field in order to fully establish the contribution of clock gene variants to the risk of developing cancer. We conducted a systematic review and meta-analysis of the evidence on the association between clock genes' germline variants and the risk of developing cancer. To assess result credibility, summary evidence was graded according to the Venice criteria and false positive report probability (FPRP) was calculated to further validate

  19. Novel sequence variations in LAMA2 and SGCG genes modulating cis-acting regulatory elements and RNA secondary structure

    Olfa Siala

    2010-01-01

    Full Text Available In this study, we detected new sequence variations in LAMA2 and SGCG genes in 5 ethnic populations, and analysed their effect on enhancer composition and mRNA structure. PCR amplification and DNA sequencing were performed and followed by bioinformatics analyses using ESEfinder as well as MFOLD software. We found 3 novel sequence variations in the LAMA2 (c.3174+22_23insAT and c.6085 +12delA and SGCG (c.*102A/C genes. These variations were present in 210 tested healthy controls from Tunisian, Moroccan, Algerian, Lebanese and French populations suggesting that they represent novel polymorphisms within LAMA2 and SGCG genes sequences. ESEfinder showed that the c.*102A/C substitution created a new exon splicing enhancer in the 3'UTR of SGCG genes, whereas the c.6085 +12delA deletion was situated in the base pairing region between LAMA2 mRNA and the U1snRNA spliceosomal components. The RNA structure analyses showed that both variations modulated RNA secondary structure. Our results are suggestive of correlations between mRNA folding and the recruitment of spliceosomal components mediating splicing, including SR proteins. The contribution of common sequence variations to mRNA structural and functional diversity will contribute to a better study of gene expression.

  20. MAINTENANCE OF ECOLOGICALLY SIGNIFICANT GENETIC VARIATION IN THE TIGER SWALLOWTAIL BUTTERFLY THROUGH DIFFERENTIAL SELECTION AND GENE FLOW.

    Bossart, J L; Scriber, J M

    1995-12-01

    Differential selection in a heterogeneous environment is thought to promote the maintenance of ecologically significant genetic variation. Variation is maintained when selection is counterbalanced by the homogenizing effects of gene flow and random mating. In this study, we examine the relative importance of differential selection and gene flow in maintaining genetic variation in Papilio glaucus. Differential selection on traits contributing to successful use of host plants (oviposition preference and larval performance) was assessed by comparing the responses of southern Ohio, north central Georgia, and southern Florida populations of P. glaucus to three hosts: Liriodendron tulipifera, Magnolia virginiana, and Prunus serotina. Gene flow among populations was estimated using allozyme frequencies from nine polymorphic loci. Significant genetic differentiation was observed among populations for both oviposition preference and larval performance. This differentiation was interpreted to be the result of selection acting on Florida P. glaucus for enhanced use of Magnolia, the prevalent host in Florida. In contrast, no evidence of population differentiation was revealed by allozyme frequencies. F ST -values were very small and Nm, an estimate of the relative strengths of gene flow and genetic drift, was large, indicating that genetic exchange among P. glaucus populations is relatively unrestricted. The contrasting patterns of spatial differentiation for host-use traits and lack of differentiation for electrophoretically detectable variation implies that differential selection among populations will be counterbalanced by gene flow, thereby maintaining genetic variation for host-use traits. © 1995 The Society for the Study of Evolution.

  1. High natural gene expression variation in the reef-building coral Acropora millepora: potential for acclimative and adaptive plasticity.

    Granados-Cifuentes, Camila; Bellantuono, Anthony J; Ridgway, Tyrone; Hoegh-Guldberg, Ove; Rodriguez-Lanetty, Mauricio

    2013-04-08

    Ecosystems worldwide are suffering the consequences of anthropogenic impact. The diverse ecosystem of coral reefs, for example, are globally threatened by increases in sea surface temperatures due to global warming. Studies to date have focused on determining genetic diversity, the sequence variability of genes in a species, as a proxy to estimate and predict the potential adaptive response of coral populations to environmental changes linked to climate changes. However, the examination of natural gene expression variation has received less attention. This variation has been implicated as an important factor in evolutionary processes, upon which natural selection can act. We acclimatized coral nubbins from six colonies of the reef-building coral Acropora millepora to a common garden in Heron Island (Great Barrier Reef, GBR) for a period of four weeks to remove any site-specific environmental effects on the physiology of the coral nubbins. By using a cDNA microarray platform, we detected a high level of gene expression variation, with 17% (488) of the unigenes differentially expressed across coral nubbins of the six colonies (jsFDR-corrected, p natural variation between reef corals when assessing experimental gene expression differences. The high transcriptional variation detected in this study is interpreted and discussed within the context of adaptive potential and phenotypic plasticity of reef corals. Whether this variation will allow coral reefs to survive to current challenges remains unknown.

  2. Considerations in the construction of an instrument to assess attitudes regarding critical illness gene variation research.

    Freeman, Bradley D; Kennedy, Carie R; Bolcic-Jankovic, Dragana; Eastman, Alexander; Iverson, Ellen; Shehane, Erica; Celious, Aaron; Barillas, Jennifer; Clarridge, Brian

    2012-02-01

    Clinical studies conducted in intensive care units are associated with logistical and ethical challenges. Diseases investigated are precipitous and life-threatening, care is highly technological, and patients are often incapacitated and decision-making is provided by surrogates. These investigations increasingly involve collection of genetic data. The manner in which the exigencies of critical illness impact attitudes regarding genetic data collection is unstudied. Given interest in understanding stakeholder preferences as a foundation for the ethical conduct of research, filling this knowledge gap is timely. The conduct of opinion research in the critical care arena is novel. This brief report describes the development of parallel patient/surrogate decision-maker quantitative survey instruments for use in this environment. Future research employing this instrument or a variant of it with diverse populations promises to inform research practices in critical illness gene variation research.

  3. Intra and Interspecific Variations of Gene Expression Levels in Yeast Are Largely Neutral: (Nei Lecture, SMBE 2016, Gold Coast).

    Yang, Jian-Rong; Maclean, Calum J; Park, Chungoo; Zhao, Huabin; Zhang, Jianzhi

    2017-09-01

    It is commonly, although not universally, accepted that most intra and interspecific genome sequence variations are more or less neutral, whereas a large fraction of organism-level phenotypic variations are adaptive. Gene expression levels are molecular phenotypes that bridge the gap between genotypes and corresponding organism-level phenotypes. Yet, it is unknown whether natural variations in gene expression levels are mostly neutral or adaptive. Here we address this fundamental question by genome-wide profiling and comparison of gene expression levels in nine yeast strains belonging to three closely related Saccharomyces species and originating from five different ecological environments. We find that the transcriptome-based clustering of the nine strains approximates the genome sequence-based phylogeny irrespective of their ecological environments. Remarkably, only ∼0.5% of genes exhibit similar expression levels among strains from a common ecological environment, no greater than that among strains with comparable phylogenetic relationships but different environments. These and other observations strongly suggest that most intra and interspecific variations in yeast gene expression levels result from the accumulation of random mutations rather than environmental adaptations. This finding has profound implications for understanding the driving force of gene expression evolution, genetic basis of phenotypic adaptation, and general role of stochasticity in evolution. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  4. Ancestral Variations of the PCDHG Gene Cluster Predispose to Dyslexia in a Multiplex Family

    Teesta Naskar

    2018-02-01

    Full Text Available Dyslexia is a heritable neurodevelopmental disorder characterized by difficulties in reading and writing. In this study, we describe the identification of a set of 17 polymorphisms located across 1.9 Mb region on chromosome 5q31.3, encompassing genes of the PCDHG cluster, TAF7, PCDH1 and ARHGAP26, dominantly inherited with dyslexia in a multi-incident family. Strikingly, the non-risk form of seven variations of the PCDHG cluster, are preponderant in the human lineage, while risk alleles are ancestral and conserved across Neanderthals to non-human primates. Four of these seven ancestral variations (c.460A > C [p.Ile154Leu], c.541G > A [p.Ala181Thr], c.2036G > C [p.Arg679Pro] and c.2059A > G [p.Lys687Glu] result in amino acid alterations. p.Ile154Leu and p.Ala181Thr are present at EC2: EC3 interacting interface of γA3-PCDH and γA4-PCDH respectively might affect trans-homophilic interaction and hence neuronal connectivity. p.Arg679Pro and p.Lys687Glu are present within the linker region connecting trans-membrane to extracellular domain. Sequence analysis indicated the importance of p.Ile154, p.Arg679 and p.Lys687 in maintaining class specificity. Thus the observed association of PCDHG genes encoding neural adhesion proteins reinforces the hypothesis of aberrant neuronal connectivity in the pathophysiology of dyslexia. Additionally, the striking conservation of the identified variants indicates a role of PCDHG in the evolution of highly specialized cognitive skills critical to reading.

  5. The architecture of gene regulatory variation across multiple human tissues: the MuTHER study.

    Alexandra C Nica

    2011-02-01

    Full Text Available While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL, skin, and fat. The samples (156 LCL, 160 skin, 166 fat were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes. In addition, we apply factor analysis (FA to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes. The unique study design (Matched Co-Twin Analysis--MCTA permits immediate replication of eQTLs using co-twins (93%-98% and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20% have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.

  6. Rare MDM4 gene amplification in colorectal cancer: The principle of a mutually exclusive relationship between MDM alteration and TP53 inactivation is not applicable.

    Suda, Tetsuji; Yoshihara, Mitsuyo; Nakamura, Yoshiyasu; Sekiguchi, Hironobu; Godai, Ten-I; Sugano, Nobuhiro; Tsuchida, Kazuhito; Shiozawa, Manabu; Sakuma, Yuji; Tsuchiya, Eiju; Kameda, Yoichi; Akaike, Makoto; Matsukuma, Shoichi; Miyagi, Yohei

    2011-07-01

    MDM4, a homolog of MDM2, is considered a key negative regulator of p53. Gene amplification of MDM4 has been identified in a variety of tumors. MDM2 or MDM4 gene amplification is only associated with the wild-type TP53 gene in retinoblastomas, thus the amplification of the two genes is mutually exclusive. Previously, we demonstrated that MDM2 amplification and TP53 alteration were not mutually exclusive in colorectal cancer, and we identified a subset of colorectal cancer patients without alterations in either the TP53 or the MDM2 gene. In this study, we investigated the gene amplification status of MDM4 in the same set of colorectal cancer cases. Unexpectedly, MDM4 amplification was rare, detected in only 1.4% (3 out of 211) of colorectal cancer cases. All the three gene-amplified tumors also harbored TP53-inactivating mutations. This contradicts the simple mutually exclusive relationship observed in retinoblastomas. Surprisingly, two of the three MDM4-amplified tumors also demonstrated MDM2 amplification. Paradoxically, the MDM4 protein levels were decreased in the tumor tissue of the gene-amplified cases compared with levels in the matched normal mucosa. We speculate that MDM4 might play a role in colorectal carcinogenesis that is not limited to negative regulation of p53 in combination with MDM2. The functional significance of MDM4 is still unclear and further studies are needed.

  7. Rare mutations and potentially damaging missense variants in genes encoding fibrillar collagens and proteins involved in their production are candidates for risk for preterm premature rupture of membranes.

    Modi, Bhavi P; Teves, Maria E; Pearson, Laurel N; Parikh, Hardik I; Chaemsaithong, Piya; Sheth, Nihar U; York, Timothy P; Romero, Roberto; Strauss, Jerome F

    2017-01-01

    Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth with ~ 40% of preterm births being associated with PPROM and occurs in 1% - 2% of all pregnancies. We hypothesized that multiple rare variants in fetal genes involved in extracellular matrix synthesis would associate with PPROM, based on the assumption that impaired elaboration of matrix proteins would reduce fetal membrane tensile strength, predisposing to unscheduled rupture. We performed whole exome sequencing (WES) on neonatal DNA derived from pregnancies complicated by PPROM (49 cases) and healthy term deliveries (20 controls) to identify candidate mutations/variants. Genotyping for selected variants from the WES study was carried out on an additional 188 PPROM cases and 175 controls. All mothers were self-reported African Americans, and a panel of ancestry informative markers was used to control for genetic ancestry in all genetic association tests. In support of the primary hypothesis, a statistically significant genetic burden (all samples combined, SKAT-O p-value = 0.0225) of damaging/potentially damaging rare variants was identified in the genes of interest-fibrillar collagen genes, which contribute to fetal membrane strength and integrity. These findings suggest that the fetal contribution to PPROM is polygenic, and driven by an increased burden of rare variants that may also contribute to the disparities in rates of preterm birth among African Americans.

  8. Variation in oxytocin receptor gene (OXTR) polymorphisms is associated with emotional and behavioral reactions to betrayal.

    Tabak, Benjamin A; McCullough, Michael E; Carver, Charles S; Pedersen, Eric J; Cuccaro, Michael L

    2014-06-01

    Variations in the gene that encodes the oxytocin receptor (OXTR) have been associated with many aspects of social cognition as well as several prosocial behaviors. However, potential associations of OXTR variants with reactions to betrayals of trust while cooperating for mutual benefit have not yet been explored. We examined how variations in 10 single-nucleotide polymorphisms on OXTR were associated with behavior and emotional reactions after a betrayal of trust in an iterated Prisoner's Dilemma Game. After correction for multiple testing, one haplotype (C-rs9840864, T-rs2268494) was significantly associated with faster retaliation post-betrayal-an association that appeared to be due to this haplotype's intermediate effect of exacerbating people's anger after they had been betrayed. Furthermore, a second haplotype (A-rs237887, C-rs2268490) was associated with higher levels of post-betrayal satisfaction, and a third haplotype (G-rs237887, C-rs2268490) was associated with lower levels of post-betrayal satisfaction. © The Author (2013). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  9. Antigenic variation of Anaplasma marginale msp2 occurs by combinatorial gene conversion.

    Brayton, Kelly A; Palmer, Guy H; Lundgren, Anna; Yi, Jooyoung; Barbet, Anthony F

    2002-03-01

    The rickettsial pathogen Anaplasma marginale establishes lifelong persistent infection in the mammalian reservoir host, during which time immune escape variants continually arise in part because of variation in the expressed copy of the immunodominant outer membrane protein MSP2. A key question is how the small 1.2 Mb A. marginale genome generates sufficient variants to allow long-term persistence in an immunocompetent reservoir host. The recombination of whole pseudogenes into the single msp2 expression site has been previously identified as one method of generating variants, but is inadequate to generate the number of variants required for persistent infection. In the present study, we demonstrate that recombination of a whole pseudogene is followed by a second level of variation in which small segments of pseudogenes recombine into the expression site by gene conversion. Evidence for four short sequential changes in the hypervariable region of msp2 coupled with the identification of nine pseudogenes from a single strain of A. marginale provides for a combinatorial number of possible expressed MSP2 variants sufficient for lifelong persistence.

  10. Endostatin gene variation and protein levels in breast cancer susceptibility and severity

    Balasubramanian, Sabapathy P; Cross, Simon S; Globe, Jenny; Cox, Angela; Brown, Nicola J; Reed, Malcolm W

    2007-01-01

    Endostatin is a potent endogenous anti-angiogenic agent which inhibits tumour growth. A non-synonymous coding polymorphism in the Endostatin gene is thought to affect Endostatin activity. We aimed to determine the role of this Endostatin polymorphism in breast cancer pathogenesis and any influence on serum Endostatin levels in healthy volunteers. Endostatin protein expression on a breast cancer micro array was also studied to determine any relationship to genotype and to breast cancer prognosis. The 4349G > A (coding non-synonymous) polymorphism in exon 42 of the Endostatin gene was genotyped in approximately 846 breast cancer cases and 707 appropriate controls. In a separate healthy cohort of 57 individuals, in addition to genotyping, serum Endostatin levels were measured using enzyme linked immunosorbant assay (ELISA). A semi-quantitative assessment of Endostatin protein expression on immunostained tissue micro arrays (TMA) constructed from breast cancer samples of patients with genotype data was performed. The rare allele (A) was significantly associated with invasive breast cancers compared to non-invasive tumours (p = 0.03), but there was no association with tumour grade, nodal status, vascular invasion or overall survival. There was no association with breast cancer susceptibility. Serum Endostatin levels and Endostatin protein expression on the tissue micro array were not associated with genotype. The Endostatin 4349A allele is associated with invasive breast cancer. The Endostatin 4349G > A polymorphism however does not appear to be associated with breast cancer susceptibility or severity in invasive disease. By studying circulating levels and tumour Endostatin protein expression, we have shown that any influence of this polymorphism is unlikely to be through an effect on the levels of protein produced

  11. The DNA methylation status alteration of two steroidogenic genes in gonads of rare minnow after bisphenol A exposure.

    Zhang, Ting; Liu, Yan; Chen, Hong; Gao, Jiancao; Zhang, Yingying; Yuan, Cong; Wang, Zaizhao

    2017-08-01

    Both cytochrome P450c17 (CYP17A1) and P-450 side chain cleavage (CYP11A1) play important roles in steroid biosynthesis. According to our previous studies, bisphenol A (BPA) could regulate the mRNA expression of cyp17a1 and cyp11a1 in rare minnow Gobiocypris rarus. However, the potential mechanism of the regulation is barely understood. In the present study, aiming to explore how BPA affects the mRNA expression of cyp17a1 and cyp11a1 in testes and ovaries of G. rarus, we firstly cloned 340-bp fragment of 5' flanking region of cyp11a1 and then detected the methylation level of CpG loci involved in 5' flanking of cyp11a1 and cyp17a1 and their mRNA expression levels. Results showed that exposure to BPA significantly increased serum estradiol (E2) and 11-ketotesterone (11-KT) concentrations. Ovarian mRNA expression of cyp17a1 and cyp11a1 were significantly decreased after BPA exposure 7- for and 14-days. However, transcriptions of testicular cyp17a1 and cyp11a1 were significantly increased and decreased respectively after BPA treatment for 14days. The DNA methylation levels of cyp17a1 were decreased in ovaries on day 7 and increased in ovaries and decreased in testes respectively on day 14. The methylation levels of cyp11a1 were increased in ovaries on day 7 and both ovaries and testes on day 14. There were a significant correlation between DNA methylation at specific CpG loci and cyp17a1 and cyp11a1 genes transcription levels. In conclusion, the CpG loci methylation in 5' flanking region appears to involve in the regulation of mRNA expression of cyp17a1 and cyp11a1 mediated by BPA. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Molecular genetic variations in vitamin D receptor gene with risk of osteoporosis in postmenopausal women

    Zahid, S.; Tahir, M.; Ahmed, S.

    2017-01-01

    To investigate the association of Vitamin D receptor (VDR) gene polymorphisms and development of osteoporosis. Methodology: This case-control study was conducted at Sir Ganga Hospital and Sheikh Zayed Hospital, Lahore, Pakistan from January 2015 to August 2015. A total of 136 postmenopausal women between 46-75 years of age were included in the study while women with serious internal disease and premature (surgical) menopause before the age of 45 years were excluded. Genotyping of VDR ApaI, TaqI and BsmI loci was done using polymerase chain reaction-restriction fragment length polymorphism. Levels of ionized calcium, C-reactive protein, alkaline phosphatase were measured and body mass index was calculated. Statistical analysis was done by using SPSS version 16.0. Results: Percentage of AA genotype was higher (28%) as compared to controls (16.6%). The postmenopausal cases showed 54% TT, 42%Tt and 4% tt genotype. The Bb genotype (42.6 %) was most frequent in both cases and controls. Postmenopausal cases and controls showed non-significant difference in alkaline phosphatase, C-reactive protein and ionized calcium levels. Conclusions: Findings explained the earlier inconsistent association results and no particular genetic variation in Vitamin D receptor gene had pronounced effect in predisposition to osteoporosis. (author)

  13. Association between ghrelin gene variations and blood pressure in subjects with impaired glucose tolerance.

    Mager, Ursula; Kolehmainen, Marjukka; Lindström, Jaana; Eriksson, Johan G; Valle, Timo T; Hämäläinen, Helena; Ilanne-Parikka, Pirjo; Keinänen-Kiukaanniemi, Sirkka; Tuomilehto, Jaakko O; Pulkkinen, Leena; Uusitupa, Matti I

    2006-09-01

    Ghrelin is a gut-brain hormone, which stimulates food intake and controls energy balance. Recently, it has been shown that ghrelin may also play a role in the regulation of blood pressure (BP) by acting at the sympathetic nervous system. In the present study we genotyped six variants of the ghrelin gene and its promoter, and tested whether these single nucleotide polymorphisms (SNPs) were associated with BP levels in participants of the Finnish Diabetes Prevention Study. The Finnish Diabetes Prevention Study was a longitudinal study where 522 subjects with impaired glucose tolerance were randomized into either an intervention or control group. DNA was available from 507 subjects (mean body mass index [BMI] 31.2+/-4.5 kg/m2, age 55+/-7 years). All six SNPs were screened by the restriction fragment length polymorphism method. Subjects with the most common genotype combination of the following four SNPs, -604G/A, -501A/C, Leu72Met, and Gln90Leu, had the lowest systolic (131+/-11 v 137+/-13 mm Hg, P=.003) and diastolic BP levels (79+/-7 v 83+/-7 mm Hg, P=.004) at the baseline of the study and during 3 years of follow-up compared to all other genotypes. Adjustments for age, gender, antihypertensive medication, BMI, waist circumference, and alcohol intake did not change this association. Several ghrelin gene variations were associated with BP levels in subjects with impaired glucose tolerance.

  14. Application of heteroduplex analysis for detecting variation within the growth hormone 2 gene in Salmo trutta L. (brown trout).

    Gross, R; Nilsson, J

    1995-03-01

    A new method to detect variation at a single copy nuclear gene in brown trout, Salmo trutta L., is provided. The technique entails (i) selective gene amplification by the polymerase chain reaction (PCR), (ii) digestion of amplification products by restriction endonucleases to obtain fragments of suitable size, (iii) hybridization with heterologous DNA followed by denaturation and reannealing to obtain heteroduplex molecules, and (iv) screening for variation in polyacrylamide gels. Variation was studied within a growth hormone 2 gene 1489 bp segment and polymorphism was detected in two HinfI-digested fragments. Formation of different heteroduplex patterns in experimental mixtures of digested amplification products from brown trout and Atlantic salmon, Salmo salar L., allowed us to determine the genotype of the brown trout. Polymorphism was observed in four out of six studied populations.

  15. Drug Metabolizing Enzyme and Transporter Gene Variation, Nicotine Metabolism, Prospective Abstinence, and Cigarette Consumption.

    Andrew W Bergen

    Full Text Available The Nicotine Metabolite Ratio (NMR, ratio of trans-3'-hydroxycotinine and cotinine, has previously been associated with CYP2A6 activity, response to smoking cessation treatments, and cigarette consumption. We searched for drug metabolizing enzyme and transporter (DMET gene variation associated with the NMR and prospective abstinence in 2,946 participants of laboratory studies of nicotine metabolism and of clinical trials of smoking cessation therapies. Stage I was a meta-analysis of the association of 507 common single nucleotide polymorphisms (SNPs at 173 DMET genes with the NMR in 449 participants of two laboratory studies. Nominally significant associations were identified in ten genes after adjustment for intragenic SNPs; CYP2A6 and two CYP2A6 SNPs attained experiment-wide significance adjusted for correlated SNPs (CYP2A6 PACT=4.1E-7, rs4803381 PACT=4.5E-5, rs1137115, PACT=1.2E-3. Stage II was mega-regression analyses of 10 DMET SNPs with pretreatment NMR and prospective abstinence in up to 2,497 participants from eight trials. rs4803381 and rs1137115 SNPs were associated with pretreatment NMR at genome-wide significance. In post-hoc analyses of CYP2A6 SNPs, we observed nominally significant association with: abstinence in one pharmacotherapy arm; cigarette consumption among all trial participants; and lung cancer in four case:control studies. CYP2A6 minor alleles were associated with reduced NMR, CPD, and lung cancer risk. We confirmed the major role that CYP2A6 plays in nicotine metabolism, and made novel findings with respect to genome-wide significance and associations with CPD, abstinence and lung cancer risk. Additional multivariate analyses with patient variables and genetic modeling will improve prediction of nicotine metabolism, disease risk and smoking cessation treatment prognosis.

  16. Gene expression patterns of chicken neuregulin 3 in association with copy number variation and frameshift deletion.

    Abe, Hideaki; Aoya, Daiki; Takeuchi, Hiro-Aki; Inoue-Murayama, Miho

    2017-07-21

    Neuregulin 3 (NRG3) plays a key role in central nervous system development and is a strong candidate for human mental disorders. Thus, genetic variation in NRG3 may have some impact on a variety of phenotypes in non-mammalian vertebrates. Recently, genome-wide screening for short insertions and deletions in chicken (Gallus gallus) genomes has provided useful information about structural variation in functionally important genes. NRG3 is one such gene that has a putative frameshift deletion in exon 2, resulting in premature termination of translation. Our aims were to characterize the structure of chicken NRG3 and to compare expression patterns between NRG3 isoforms. Depending on the presence or absence of the 2-bp deletion in chicken NRG3, 3 breeds (red junglefowl [RJF], Boris Brown [BB], and Hinai-jidori [HJ]) were genotyped using flanking primers. In the commercial breeds (BB and HJ), approximately 45% of individuals had at least one exon 2 allele with the 2-bp deletion, whereas there was no deletion allele in RJF. The lack of a homozygous mutant indicated the existence of duplicated NRG3 segments in the chicken genome. Indeed, highly conserved elements consisting of exon 1, intron 1, exon 2, and part of intron 2 were found in the reference RJF genome, and quantitative PCR detected copy number variation (CNV) between breeds as well as between individuals. The copy number of conserved elements was significantly higher in chicks harboring the 2-bp deletion in exon 2. We identified 7 novel transcript variants using total mRNA isolated from the amygdala. Novel isoforms were found to lack the exon 2 cassette, which probably harbored the premature termination codon. The relative transcription levels of the newly identified isoforms were almost the same between chick groups with and without the 2-bp deletion, while chicks with the deletion showed significant suppression of the expression of previously reported isoforms. A putative frameshift deletion and CNV in chicken

  17. Melanopsin gene variations interact with season to predict sleep onset and chronotype.

    Roecklein, Kathryn A; Wong, Patricia M; Franzen, Peter L; Hasler, Brant P; Wood-Vasey, W Michael; Nimgaonkar, Vishwajit L; Miller, Megan A; Kepreos, Kyle M; Ferrell, Robert E; Manuck, Stephen B

    2012-10-01

    The human melanopsin gene has been reported to mediate risk for seasonal affective disorder (SAD), which is hypothesized to be caused by decreased photic input during winter when light levels fall below threshold, resulting in differences in circadian phase and/or sleep. However, it is unclear if melanopsin increases risk of SAD by causing differences in sleep or circadian phase, or if those differences are symptoms of the mood disorder. To determine if melanopsin sequence variations are associated with differences in sleep-wake behavior among those not suffering from a mood disorder, the authors tested associations between melanopsin gene polymorphisms and self-reported sleep timing (sleep onset and wake time) in a community sample (N = 234) of non-Hispanic Caucasian participants (age 30-54 yrs) with no history of psychological, neurological, or sleep disorders. The authors also tested the effect of melanopsin variations on differences in preferred sleep and activity timing (i.e., chronotype), which may reflect differences in circadian phase, sleep homeostasis, or both. Daylength on the day of assessment was measured and included in analyses. DNA samples were genotyped for melanopsin gene polymorphisms using fluorescence polarization. P10L genotype interacted with daylength to predict self-reported sleep onset (interaction p sleep onset among those with the TT genotype was later in the day when individuals were assessed on longer days and earlier in the day on shorter days, whereas individuals in the other genotype groups (i.e., CC and CT) did not show this interaction effect. P10L genotype also interacted in an analogous way with daylength to predict self-reported morningness (interaction p sleep onset and chronotype as a function of daylength, whereas other genotypes at P10L do not seem to have effects that vary by daylength. A better understanding of how melanopsin confers heightened responsivity to daylength may improve our understanding of a broad range of

  18. RARE TRIPLE ANATOMICAL VARIATION OF THE CEREBRAL ARTERIAL CIRCLE; Rara triple variación del círculo arterial cerebral.

    Joaquín García Pisón

    2017-04-01

    Full Text Available Se reporta la rara asociación de un aneurisma de arteria trigeminal persistente lateral derecha (Tipo II de Saltzman, aplasia del segmento pre-comunicante de ambas arterias cerebrales posteriores y la presencia de arterias cerebrales posteriores fetales en forma bilateral, en una mujer de 64 años que consultó de diplopía y parálisis del nervio abducens derecho, probablemente debida a compresión del nervio en el espacio latero-celar. Se realizó con éxito la embolización endovascular con coils, sin complicaciones inmediatas. Los hallazgos de CT, RM y angiografía son presentados. Aunque cada una de estas variaciones son infrecuentes en forma individual, la combinación de las mismas no ha sido reportada en la literatura hasta nuestro conocimiento, siendo de enorme importancia en el manejo diagnóstico y terapéutico de pacientes con stroke de mecanismo embolico, así como para la planificación de procedimientos endovasculares diagnósticos y terapéuticos. We report the rare association of an aneurysm of a lateral right persistent trigeminal artery (Saltzman type II, bilateral aplasia of the pre-communicating segment of both posterior cerebral arteries and bilateral fetal posterior cerebral arteries, in a 64 years old woman who suffered from progressive diplopia and right abducens nerve palsy, most likely due to nerve compression in the latero-cellar space. Successful endovascular coils embolization of the aneurysm was performed, with no immediate complications. CT, MR and angiographic findings are presented. Although infrequent as single variations, the association of these three arterial variations has not been reported in literature to our knowledge, having special importance in the diagnostic workup and therapeutic procedures in a patient with an embolic stroke, as well as in the planification of intracranial endovascular diagnostic and therapeutic procedures.

  19. Genetic variations of MMP9 gene and intracerebral hemorrhage susceptibility: a case-control study in Chinese Han population.

    Yang, Jie; Wu, Bo; Lin, Sen; Zhou, Junshan; Li, Yingbin; Dong, Wei; Arima, Hisatomi; Zhang, Chanfei; Liu, Yukai; Liu, Ming

    2014-06-15

    To investigate the association between genetic variations of matrix metalloproteinase 9 (MMP9) gene and intracerebral hemorrhage (ICH) susceptibility in Chinese Han population. The clinical data and peripheral blood samples from the patients with ICH and hypertension, and controlled subjects with hypertension only, were collected. MassARRAY Analyzer was used to genotype the tagger single nucleotide polymorphism (SNP) of MMP9 gene. Haploview4.2 and Unphased3.1.7 were employed to construct haplotypes and to analyze the association between genetic variations (alleles, genotypes and haplotypes) of MMP9 gene and ICH susceptibility. 181 patients with ICH and hypertension, and 197 patients with hypertension only, were recruited between Sep 2009 and Oct 2010. Patients in the ICH group were younger (61.80 ± 13.27 vs. 72.44 ± 12.71 years, ppopulation. Our logistical regression analysis showed that there were no significant associations between genetic variations of the MPP9 gene and ICH susceptibility (all p>0.05). The genetic variations of MMP9 gene were not significantly associated with ICH susceptibility in the Chinese Han population. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Variation in extracellular matrix genes is associated with weight regain after weight loss in a sex-specific manner

    Roumans, Nadia J T; Vink, Roel G; Gielen, Marij

    2015-01-01

    The extracellular matrix (ECM) of adipocytes is important for body weight regulation. Here, we investigated whether genetic variation in ECM-related genes is associated with weight regain among participants of the European DiOGenes study. Overweight and obese subjects (n = 469, 310 females, 159 m.......40-5.63). Concluding, variants of ECM genes are associated with weight regain after weight loss in a sex-specific manner....

  1. Protein translation and cell death: the role of rare tRNAs in biofilm formation and in activating dormant phage killer genes.

    Rodolfo García-Contreras

    2008-06-01

    Full Text Available We discovered previously that the small Escherichia coli proteins Hha (hemolysin expression modulating protein and the adjacent, poorly-characterized YbaJ are important for biofilm formation; however, their roles have been nebulous. Biofilms are intricate communities in which cell signaling often converts single cells into primitive tissues. Here we show that Hha decreases biofilm formation dramatically by repressing the transcription of rare codon tRNAs which serves to inhibit fimbriae production and by repressing to some extent transcription of fimbrial genes fimA and ihfA. In vivo binding studies show Hha binds to the rare codon tRNAs argU, ileX, ileY, and proL and to two prophage clusters D1P12 and CP4-57. Real-time PCR corroborated that Hha represses argU and proL, and Hha type I fimbriae repression is abolished by the addition of extra copies of argU, ileY, and proL. The repression of transcription of rare codon tRNAs by Hha also leads to cell lysis and biofilm dispersal due to activation of prophage lytic genes rzpD, yfjZ, appY, and alpA and due to induction of ClpP/ClpX proteases which activate toxins by degrading antitoxins. YbaJ serves to mediate the toxicity of Hha. Hence, we have identified that a single protein (Hha can control biofilm formation by limiting fimbriae production as well as by controlling cell death. The mechanism used by Hha is the control of translation via the availability of rare codon tRNAs which reduces fimbriae production and activates prophage lytic genes. Therefore, Hha acts as a toxin in conjunction with co-transcribed YbaJ (TomB that attenuates Hha toxicity.

  2. Seasonal and spatial variations of rare earth elements in rainwaters, river waters and total suspended particles in air in South Korea

    Ryu, J.S.; Lee, K.S.; Lee, S.G.; Lee, D.; Chang, H.W.

    2007-01-01

    In order to investigate the seasonal and spatial variations of rare earth element (REE) concentrations in natural waters in the central part of South Korea, rain and river waters were collected during 2003-2004. Total suspended particles (TSP) in air were also sampled to investigate the effect of the Asian dust (the Yellow sand) on the chemistry of rainwaters. All samples showed that the absolute concentrations of the light REEs (LREEs) were higher than those of the heavy REEs (HREEs). The post-Archean Australian shale (PAAS)-normalized REE patterns indicate that the REEs in TSP and rainwaters were affected by Asian dust and anthropogenic contaminant, whereas those of river waters were mainly controlled by the geology of their drainage basin and seasonal changes in water regime. The calculated fluxes and yields of total REEs (REEs plus Y) in the South Han River were much greater than those in the North Han River due to the more widespread distribution of sedimentary rocks in the drainage area and more efficient chemical weathering

  3. Assessing the spectrum of germline variation in Fanconi anemia genes among patients with head and neck carcinoma before age 50.

    Chandrasekharappa, Settara C; Chinn, Steven B; Donovan, Frank X; Chowdhury, Naweed I; Kamat, Aparna; Adeyemo, Adebowale A; Thomas, James W; Vemulapalli, Meghana; Hussey, Caroline S; Reid, Holly H; Mullikin, James C; Wei, Qingyi; Sturgis, Erich M

    2017-10-15

    Patients with Fanconi anemia (FA) have an increased risk for head and neck squamous cell carcinoma (HNSCC). The authors sought to determine the prevalence of undiagnosed FA and FA carriers among patients with HNSCC as well as an age cutoff for FA genetic screening. Germline DNA samples from 417 patients with HNSCC aged <50 years were screened for sequence variants by targeted next-generation sequencing of the entire length of 16 FA genes. The sequence revealed 194 FA gene variants in 185 patients (44%). The variant spectrum was comprised of 183 nonsynonymous point mutations, 9 indels, 1 large deletion, and 1 synonymous variant that was predicted to effect splicing. One hundred eight patients (26%) had at least 1 rare variant that was predicted to be damaging, and 57 (14%) had at least 1 rare variant that was predicted to be damaging and had been previously reported. Fifteen patients carried 2 rare variants or an X-linked variant in an FA gene. Overall, an age cutoff for FA screening was not identified among young patients with HNSCC, because there were no significant differences in mutation rates when patients were stratified by age, tumor site, ethnicity, smoking status, or human papillomavirus status. However, an increased burden, or mutation load, of FA gene variants was observed in carriers of the genes FA complementation group D2 (FANCD2), FANCE, and FANCL in the HNSCC patient cohort relative to the 1000 Genomes population. FA germline functional variants offer a novel area of study in HNSCC tumorigenesis. FANCE and FANCL, which are components of the core complex, are known to be responsible for the recruitment and ubiquitination, respectively, of FANCD2, a critical step in the FA DNA repair pathway. In the current cohort, the increased mutation load of FANCD2, FANCE, and FANCL variants among younger patients with HNSCC indicates the importance of the FA pathway in HNSCC. Cancer 2017;123:3943-54. © 2017 American Cancer Society. © 2017 American Cancer Society.

  4. Ovine leukocyte profiles do not associate with variation in the prion gene, but are breed-dependent

    Prion genotype in sheep confer resistance to scrapie. In cattle, lymphocyte profile has been found to be associated with prion genotype. Therefore, the aim of this study was to determine if variations in the sheep prion gene were associated with leukocyte populations as measured by complete blood ce...

  5. Common Variation in the NOS1AP Gene Is Associated With Drug-Induced QT Prolongation and Ventricular Arrhythmia

    Jamshidi, Yalda; Nolte, Ilja M.; Dalageorgou, Chrysoula; Zheng, Dongling; Johnson, Toby; Bastiaenen, Rachel; Ruddy, Suzanne; Talbott, Daniel; Norris, Kris J.; Snieder, Harold; George, Alfred L.; Marshall, Vanessa; Shakir, Saad; Kannankeril, Prince J.; Munroe, Patricia B.; Camm, A. John; Jeffery, Steve; Roden, Dan M.; Behr, Elijah R.

    2012-01-01

    Objectives This study sought to determine whether variations in NOS1AP affect drug-induced long QT syndrome (LQTS). Background Use of antiarrhythmic drugs is limited by the high incidence of serious adverse events including QT prolongation and torsades de pointes. NOS1AP gene variants play a role in

  6. Analysis of Temporal-spatial Co-variation within Gene Expression Microarray Data in an Organogenesis Model

    Ehler, Martin; Rajapakse, Vinodh; Zeeberg, Barry; Brooks, Brian; Brown, Jacob; Czaja, Wojciech; Bonner, Robert F.

    The gene networks underlying closure of the optic fissure during vertebrate eye development are poorly understood. We used a novel clustering method based on Laplacian Eigenmaps, a nonlinear dimension reduction method, to analyze microarray data from laser capture microdissected (LCM) cells at the site and developmental stages (days 10.5 to 12.5) of optic fissure closure. Our new method provided greater biological specificity than classical clustering algorithms in terms of identifying more biological processes and functions related to eye development as defined by Gene Ontology at lower false discovery rates. This new methodology builds on the advantages of LCM to isolate pure phenotypic populations within complex tissues and allows improved ability to identify critical gene products expressed at lower copy number. The combination of LCM of embryonic organs, gene expression microarrays, and extracting spatial and temporal co-variations appear to be a powerful approach to understanding the gene regulatory networks that specify mammalian organogenesis.

  7. Genetic variation in selenoprotein genes, lifestyle, and risk of colon and rectal cancer.

    Martha L Slattery

    Full Text Available BACKGROUND: Associations between selenium and cancer have directed attention to role of selenoproteins in the carcinogenic process. METHODS: We used data from two population-based case-control studies of colon (n = 1555 cases, 1956 controls and rectal (n = 754 cases, 959 controls cancer. We evaluated the association between genetic variation in TXNRD1, TXNRD2, TXNRD3, C11orf31 (SelH, SelW, SelN1, SelS, SepX, and SeP15 with colorectal cancer risk. RESULTS: After adjustment for multiple comparisons, several associations were observed. Two SNPs in TXNRD3 were associated with rectal cancer (rs11718498 dominant OR 1.42 95% CI 1.16,1.74 pACT 0.0036 and rs9637365 recessive 0.70 95% CI 0.55,0.90 pACT 0.0208. Four SNPs in SepN1 were associated with rectal cancer (rs11247735 recessive OR 1.30 95% CI 1.04,1.63 pACT 0.0410; rs2072749 GGvsAA OR 0.53 95% CI 0.36,0.80 pACT 0.0159; rs4659382 recessive OR 0.58 95% CI 0.39,0.86 pACT 0.0247; rs718391 dominant OR 0.76 95% CI 0.62,0.94 pACT 0.0300. Interaction between these genes and exposures that could influence these genes showed numerous significant associations after adjustment for multiple comparisons. Two SNPs in TXNRD1 and four SNPs in TXNRD2 interacted with aspirin/NSAID to influence colon cancer; one SNP in TXNRD1, two SNPs in TXNRD2, and one SNP in TXNRD3 interacted with aspirin/NSAIDs to influence rectal cancer. Five SNPs in TXNRD2 and one in SelS, SeP15, and SelW1 interacted with estrogen to modify colon cancer risk; one SNP in SelW1 interacted with estrogen to alter rectal cancer risk. Several SNPs in this candidate pathway influenced survival after diagnosis with colon cancer (SeP15 and SepX1 increased HRR and rectal cancer (SepX1 increased HRR. CONCLUSIONS: Findings support an association between selenoprotein genes and colon and rectal cancer development and survival after diagnosis. Given the interactions observed, it is likely that the impact of cancer susceptibility from genotype is

  8. Variations in host genes encoding adhesion molecules and susceptibility to falciparum malaria in India

    Tyagi Prajesh K

    2008-12-01

    Full Text Available Abstract Background Host adhesion molecules play a significant role in the pathogenesis of Plasmodium falciparum malaria and changes in their structure or levels in individuals can influence the outcome of infection. The aim of this study was to investigate the association of SNPs of three adhesion molecule genes, ICAM1, PECAM1 and CD36, with severity of falciparum malaria in a malaria-endemic and a non-endemic region of India. Methods The frequency distribution of seven selected SNPs of ICAM1, PECAM1 and CD36 was determined in 552 individuals drawn from 24 populations across India. SNP-disease association was analysed in a case-control study format. Genotyping of the population panel was performed by Sequenom mass spectroscopy and patient/control samples were genotyped by SNaPshot method. Haplotypes and linkage disequilibrium (LD plots were generated using PHASE and Haploview, respectively. Odds-ratio (OR for risk assessment was estimated using EpiInfo™ version 3.4. Results Association of the ICAM1 rs5498 (exon 6 G allele and the CD36 exon 1a A allele with increased risk of severe malaria was observed (severe versus control, OR = 1.91 and 2.66, P = 0.02 and 0.0012, respectively. The CD36 rs1334512 (-53 T allele as well as the TT genotype associated with protection from severe disease (severe versus control, TT versus GG, OR = 0.37, P = 0.004. Interestingly, a SNP of the PECAM1 gene (rs668, exon 3, C/G with low minor allele frequency in populations of the endemic region compared to the non-endemic region exhibited differential association with disease in these regions; the G allele was a risk factor for malaria in the endemic region, but exhibited significant association with protection from disease in the non-endemic region. Conclusion The data highlights the significance of variations in the ICAM1, PECAM1 and CD36 genes in the manifestation of falciparum malaria in India. The PECAM1 exon 3 SNP exhibits altered association with disease in the

  9. Longevity is independent of common variations in genes associated with cardiovascular risk

    Bladbjerg, E M; Andersen-Ranberg, K; Maat, M de

    1999-01-01

    Do extremely old persons have a genetically favourable profile which has protected them from cardiovascular death? We have tried to answer this question by measuring DNA polymorphisms of selected cardiovascular risk indicators [factor VII, FVII (R/Q353, intron 7 (37bp)n, and -323ins10), beta fibr......, ACE (intron 16 ins287), and angiotensinogen (M/T235)]. Blood was collected from 187 unselected Danish centenarians, and 201 healthy Danish blood donors, aged 20-64 years (mean age 42 years). Genomic DNA was amplified using PCR and the genotype was determined by RFLP methods or allele.......33; for ACE 0.52; and for angiotensinogen 0.36. Comparable frequencies were observed in the blood donors. Subgroup analysis of men and women separately gave similar results. The genotype frequencies in the centenarians and the blood donors were similar for all polymorphisms, and this study suggests...... that common variations in genes associated with cardiovascular risk do not contribute significantly to longevity....

  10. Natural variation in rosette size under salt stress conditions corresponds to developmental differences between Arabidopsis accessions and allelic variation in the LRR-KISS gene

    Julkowska, Magdalena

    2016-02-11

    Natural variation among Arabidopsis accessions is an important genetic resource to identify mechanisms underlying plant development and stress tolerance. To evaluate the natural variation in salinity stress tolerance, two large-scale experiments were performed on two populations consisting of 160 Arabidopsis accessions each. Multiple traits, including projected rosette area, and fresh and dry weight were collected as an estimate for salinity tolerance. Our results reveal a correlation between rosette size under salt stress conditions and developmental differences between the accessions grown in control conditions, suggesting that in general larger plants were more salt tolerant. This correlation was less pronounced when plants were grown under severe salt stress conditions. Subsequent genome wide association study (GWAS) revealed associations with novel candidate genes for salinity tolerance such as LRR-KISS (At4g08850), flowering locus KH-domain containing protein and a DUF1639-containing protein. Accessions with high LRR-KISS expression developed larger rosettes under salt stress conditions. Further characterization of allelic variation in candidate genes identified in this study will provide more insight into mechanisms of salt stress tolerance due to enhanced shoot growth.

  11. Ecological and population genetics of locally rare plants: A review

    Simon A. Lei

    2001-01-01

    Plant species with limited dispersal ability, narrow geographical and physiological tolerance ranges, as well as with specific habitat and ecological requirements are likely to be rare. Small and isolated populations and species contain low levels of within-population genetic variation in many plant species. The gene pool of plants is a product of phenotype-environment...

  12. [Association of the genetic variations of bone morphogenetic protein 7 gene with diabetes and insulin resistance in Xinjiang Uygur population].

    Yan, Zhi-tao; Li, Nan-fang; Guo, Yan-ying; Yao, Xiao-guang; Wang, Hong-mei; Hu, Jun-li

    2011-06-01

    To investigate the association between the genetic variations of the functional region in bone morphogenetic protein gene (BMP7) with type 2 diabetes mellitus in Chinese Uygur individuals. A case-control study was conducted based on epidemiological investigation. A total of 717 Uygur subjects (276 males and 441 females) were selected and divided into two groups: diabetes mellitus group (n = 502, 191 males and 311 females) and control group (n = 215, 85 males and 130 females). All exons, flanking introns and the promoter regions of (BMP7) gene were sequenced in 48 Uygur diabetics. Representative variations were selected according to the minor allele frequency (MAF) and linkage disequilibrium and genotyped using the TaqMan polymerase chain reaction method in 717 Uygur individuals, a relatively isolated general population in a relatively homogeneous environment and a case-control study was conducted to test the association between the genetic variations of (BMP7) gene and type 2 diabetes mellitus. Five novel and 8 known variations in the (BMP7) gene were identified. All genotype distributions were tested for deviations from Hardy-Weinberg equilibrium (P> 0.05). There was significant difference of genotype distribution of rs6025422 between type 2 diabetes mellitus and control groups in the male population (P 0.05), but there was no difference in total and female population (P> 0.05). And the means of fasting blood glucose (FBG), fasting insulin and HOMA-index significantly decreased in individuals with AA, AG and GG genotypes of rs6025422 in male population (Ppopulation (P> 0.05). The logistic regression analysis showed that GG genotype of rs6025422 variation might be a protective factor for diabetes in male (OR= 0.637, 95% confidence interval 0.439-0.923, P< 0.05). The present study suggests that the rs6025422 polymorphism in (BMP7) gene may be associated with diabetes mellitus and insulin resistance in Uygur men.

  13. Random phenotypic variation of yeast (Saccharomyces cerevisiae) single-gene knockouts fits a double pareto-lognormal distribution.

    Graham, John H; Robb, Daniel T; Poe, Amy R

    2012-01-01

    Distributed robustness is thought to influence the buffering of random phenotypic variation through the scale-free topology of gene regulatory, metabolic, and protein-protein interaction networks. If this hypothesis is true, then the phenotypic response to the perturbation of particular nodes in such a network should be proportional to the number of links those nodes make with neighboring nodes. This suggests a probability distribution approximating an inverse power-law of random phenotypic variation. Zero phenotypic variation, however, is impossible, because random molecular and cellular processes are essential to normal development. Consequently, a more realistic distribution should have a y-intercept close to zero in the lower tail, a mode greater than zero, and a long (fat) upper tail. The double Pareto-lognormal (DPLN) distribution is an ideal candidate distribution. It consists of a mixture of a lognormal body and upper and lower power-law tails. If our assumptions are true, the DPLN distribution should provide a better fit to random phenotypic variation in a large series of single-gene knockout lines than other skewed or symmetrical distributions. We fit a large published data set of single-gene knockout lines in Saccharomyces cerevisiae to seven different probability distributions: DPLN, right Pareto-lognormal (RPLN), left Pareto-lognormal (LPLN), normal, lognormal, exponential, and Pareto. The best model was judged by the Akaike Information Criterion (AIC). Phenotypic variation among gene knockouts in S. cerevisiae fits a double Pareto-lognormal (DPLN) distribution better than any of the alternative distributions, including the right Pareto-lognormal and lognormal distributions. A DPLN distribution is consistent with the hypothesis that developmental stability is mediated, in part, by distributed robustness, the resilience of gene regulatory, metabolic, and protein-protein interaction networks. Alternatively, multiplicative cell growth, and the mixing of

  14. Effects of vertebral number variations on carcass traits and genotyping of Vertnin candidate gene in Kazakh sheep

    Zhifeng Zhang

    2017-09-01

    Full Text Available Objective The vertebral number is associated with body length and carcass traits, which represents an economically important trait in farm animals. The variation of vertebral number has been observed in a few mammalian species. However, the variation of vertebral number and quantitative trait loci in sheep breeds have not been well addressed. Methods In our investigation, the information including gender, age, carcass weight, carcass length and the number of thoracic and lumbar vertebrae from 624 China Kazakh sheep was collected. The effect of vertebral number variation on carcass weight and carcass length was estimated by general linear model. Further, the polymorphic sites of Vertnin (VRTN gene were identified by sequencing, and the association of the genotype and vertebral number variation was analyzed by the one-way analysis of variance model. Results The variation of thoracolumbar vertebrae number in Kazakh sheep (18 to 20 was smaller than that in Texel sheep (17 to 21. The individuals with 19 thoracolumbar vertebrae (T13L6 were dominant in Kazakh sheep (79.2%. The association study showed that the numbers of thoracolumbar vertebrae were positively correlated with the carcass length and carcass weight, statistically significant with carcass length. To investigate the association of thoracolumbar vertebrae number with VRTN gene, we genotyped the VRTN gene. A total of 9 polymorphic sites were detected and only a single nucleotide polymorphism (SNP (rs426367238 was suggested to associate with thoracic vertebral number statistically. Conclusion The variation of thoracolumbar vertebrae number positively associated with the carcass length and carcass weight, especially with the carcass length. VRTN gene polymorphism of the SNP (rs426367238 with significant effect on thoracic vertebral number could be as a candidate marker to further evaluate its role in influence of thoracolumbar vertebral number.

  15. Effects of vertebral number variations on carcass traits and genotyping of Vertnin candidate gene in Kazakh sheep.

    Zhang, Zhifeng; Sun, Yawei; Du, Wei; He, Sangang; Liu, Mingjun; Tian, Changyan

    2017-09-01

    The vertebral number is associated with body length and carcass traits, which represents an economically important trait in farm animals. The variation of vertebral number has been observed in a few mammalian species. However, the variation of vertebral number and quantitative trait loci in sheep breeds have not been well addressed. In our investigation, the information including gender, age, carcass weight, carcass length and the number of thoracic and lumbar vertebrae from 624 China Kazakh sheep was collected. The effect of vertebral number variation on carcass weight and carcass length was estimated by general linear model. Further, the polymorphic sites of Vertnin ( VRTN ) gene were identified by sequencing, and the association of the genotype and vertebral number variation was analyzed by the one-way analysis of variance model. The variation of thoracolumbar vertebrae number in Kazakh sheep (18 to 20) was smaller than that in Texel sheep (17 to 21). The individuals with 19 thoracolumbar vertebrae (T13L6) were dominant in Kazakh sheep (79.2%). The association study showed that the numbers of thoracolumbar vertebrae were positively correlated with the carcass length and carcass weight, statistically significant with carcass length. To investigate the association of thoracolumbar vertebrae number with VRTN gene, we genotyped the VRTN gene. A total of 9 polymorphic sites were detected and only a single nucleotide polymorphism (SNP) (rs426367238) was suggested to associate with thoracic vertebral number statistically. The variation of thoracolumbar vertebrae number positively associated with the carcass length and carcass weight, especially with the carcass length. VRTN gene polymorphism of the SNP (rs426367238) with significant effect on thoracic vertebral number could be as a candidate marker to further evaluate its role in influence of thoracolumbar vertebral number.

  16. Patterns of gene variation in central and marginal populations of Drosophila robusta.

    Prakash, S

    1973-10-01

    follows: (1) The allele frequencies are similar in all populations at the XDH, Pep-1 and Hex-1 loci. (2) The alleles at the Est-1, Est-2, Amy loci and the AP-4(1.0) and the LAP-1(.90) alleles show north south clinal change in frequency. (3) There is north south and east west differentiation at the Pt-5, Pt-8 and Pt-9 loci and the allele AP-4(.81). (4) Polymorphism at loci such as Fum, B.Ox, Hex-8, Pep-2 and Pep-3 are restricted to only one or two of the populations. (5) Allele frequencies at the MDH and ODH loci fluctuate between populations. (6) Allele frequencies at many polymorphic loci such as Est-1, Est-2, LAP-1, AP-4, Pt-5, Pt-8, Pt-9, Pt-16, MDH, Fum change clinally within a gene arrangement. The pattern of gene variation in D. robusta is very complex and cannot be easily explained due to migration of neutral alleles between once-isolated populations or to semi-isolation of neutral alleles. The observations of the pattern of allele variation in different populations, high levels of polymorphism in the marginal populations which have small population size and low levels of polymorphism of the X chromosome loci all support the argument in favor of balancing selection as the main mechanism for the maintenance of these polymorphisms. Environmental factors must play a role in the maintenance of a great deal of these polymorphisms, since we observe clinal allele frequency changes even within a given inversion type.

  17. Seasonal and spatial variations in rare earth elements and yttrium of dissolved load in the middle, lower reaches and estuary of the Minjiang River, southeastern China

    Zhu, Xuxu; Gao, Aiguo; Lin, Jianjie; Jian, Xing; Yang, Yufeng; Zhang, Yanpo; Hou, Yuting; Gong, Songbai

    2017-09-01

    With the aim of elucidating the spatial and seasonal behaviors of rare earth elements (REEs), we investigated the dissolved REE concentrations of surface water collected during four seasons from middle, lower reaches and estuary of the Minjiang River, southeastern China. The results display that the REE abundances in Minjiang River, ranging from 3.3-785.9 ng/L, were higher than those of many of the major global rivers. The total REE concentrations (ΣREE) were seasonally variable, averaging in 5 937.30, 863.79, 825.65 and 1 065.75 ng/L during second highest flow (SHF), normal flow (NF), low flow (LF) and high flow (HF) season, respectively. The R (L/M) and R (H/M) ratios reveal the spatial and temporal variations of REE patterns, and particularly vary apparently in the maximum turbidity zone and estuary. REE patterns of dissolved loads are characterized by progressing weaker LREEs-enrichment and stronger HREEs-enrichment downstream from middle reaches to estuary during all four seasons. Comparing with NF and LF seasons, in which REE patterns are relatively flat, samples of SHF season have more LREE-enriched and HREE-depleted patterns that close to parent rocks, while samples of HF season are more LREEs-depleted and HREE-enriched. REE fractionations from the middle to lower reaches are stronger in the SHF and HF seasons than those in NF and LF seasons. Generally, spatial and seasonal variations in REE abundance and pattern are presumably due to several factors, such as chemical weathering, mixture with rainfall and groundwater, estuarine mixing, runoff, biological production and mountain river characters, such as strong hydrodynamic forces and steep slopes. The highest Gd/Gd* always occurs at north ports during all four seasons, where most of the large hospitals are located. This suggests Gd anomalies are depended on the density of modern medical facilities. Y/Ho ratios fluctuate and positively correlate to salinity in estuary, probably because of the geochemical

  18. Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles.

    Ella R Thompson

    2012-09-01

    Full Text Available Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome-sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families.

  19. Whole Exome Sequencing Identified a Novel Heterozygous Mutation in HMBS Gene in a Chinese Patient With Acute Intermittent Porphyria With Rare Type of Mild Anemia

    Yongjiang Zheng

    2018-04-01

    Full Text Available Acute intermittent porphyria (AIP is a rare hereditary metabolic disease with an autosomal dominant mode of inheritance. Germline mutations of HMBS gene causes AIP. Mutation of HMBS gene results into the partial deficiency of the heme biosynthetic enzyme hydroxymethylbilane synthase. AIP is clinically manifested with abdominal pain, vomiting, and neurological complaints. Additionally, an extreme phenotypic heterogeneity has been reported in AIP patients with mutations in HMBS gene. Here, we investigated a Chinese patient with AIP. The proband is a 28-year-old Chinese male manifested with severe stomach ache, constipation, nausea and depression. Proband’s father and mother is normal. Proband’s blood sample was collected and genomic DNA was extracted. Whole exome sequencing and Sanger sequencing identified a heterozygous novel single nucleotide deletion (c.809delC in exon 12 of HMBS gene in the proband. This mutation leads to frameshift followed by formation of a truncated (p.Ala270Valfs∗2 HMBS protein with 272 amino acids comparing with the wild type HMBS protein of 361 amino acids. This mutation has not been found in proband’s unaffected parents as well as in 100 healthy normal control. According to the variant interpretation guidelines of American College of Medical Genetics and Genomics (ACMG, this variant is classified as “likely pathogenic” variant. Our findings expand the mutational spectra of HMBS gene related AIP which are significant for screening and genetic diagnosis for AIP.

  20. Gene expression profiles deciphering rice phenotypic variation between Nipponbare (Japonica and 93-11 (Indica during oxidative stress.

    Fengxia Liu

    Full Text Available Rice is a very important food staple that feeds more than half the world's population. Two major Asian cultivated rice (Oryza sativa L. subspecies, japonica and indica, show significant phenotypic variation in their stress responses. However, the molecular mechanisms underlying this phenotypic variation are still largely unknown. A common link among different stresses is that they produce an oxidative burst and result in an increase of reactive oxygen species (ROS. In this study, methyl viologen (MV as a ROS agent was applied to investigate the rice oxidative stress response. We observed that 93-11 (indica seedlings exhibited leaf senescence with severe lesions under MV treatment compared to Nipponbare (japonica. Whole-genome microarray experiments were conducted, and 1,062 probe sets were identified with gene expression level polymorphisms between the two rice cultivars in addition to differential expression under MV treatment, which were assigned as Core Intersectional Probesets (CIPs. These CIPs were analyzed by gene ontology (GO and highlighted with enrichment GO terms related to toxin and oxidative stress responses as well as other responses. These GO term-enriched genes of the CIPs include glutathine S-transferases (GSTs, P450, plant defense genes, and secondary metabolism related genes such as chalcone synthase (CHS. Further insertion/deletion (InDel and regulatory element analyses for these identified CIPs suggested that there may be some eQTL hotspots related to oxidative stress in the rice genome, such as GST genes encoded on chromosome 10. In addition, we identified a group of marker genes individuating the japonica and indica subspecies. In summary, we developed a new strategy combining biological experiments and data mining to study the possible molecular mechanism of phenotypic variation during oxidative stress between Nipponbare and 93-11. This study will aid in the analysis of the molecular basis of quantitative traits.

  1. Genetic variation in the HSD17B1 gene and risk of prostate cancer.

    Peter Kraft

    2005-11-01

    Full Text Available Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17beta-hydroxysteroid dehydrogenase 1, an enzyme that converts dihydroepiandrosterone to the testosterone precursor Delta5-androsterone-3beta,17beta-diol and converts estrone to estradiol. The Breast and Prostate Cancer Cohort Consortium researchers systematically characterized variation in HSD17B1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,290 prostate cancer cases and 9,367 study-, age-, and ethnicity-matched controls. We found no evidence that HSD17B1 htSNPs (including the nonsynonymous coding SNP S312G or htSNP haplotypes were associated with risk of prostate cancer or tumor stage in the pooled multiethnic sample or in U.S. and European whites. Analyses stratified by age, body mass index, and family history of disease found no subgroup-specific associations between these HSD17B1 htSNPs and prostate cancer. We found significant evidence of heterogeneity in associations between HSD17B1 haplotypes and prostate cancer across ethnicity: one haplotype had a significant (p < 0.002 inverse association with risk of prostate cancer in Latinos and Japanese Americans but showed no evidence of association in African Americans, Native Hawaiians, or whites. However, the smaller numbers of Latinos and Japanese Americans in this study makes

  2. Variation in the MC4R gene is associated with bone phenotypes in elderly Swedish women.

    Gaurav Garg

    Full Text Available Osteoporosis is characterized by reduced bone mineral density (BMD and increased fracture risk. Fat mass is a determinant of bone strength and both phenotypes have a strong genetic component. In this study, we examined the association between obesity associated polymorphisms (SNPs with body composition, BMD, Ultrasound (QUS, fracture and biomarkers (Homocysteine (Hcy, folate, Vitamin D and Vitamin B12 for obesity and osteoporosis. Five common variants: rs17782313 and rs1770633 (melanocortin 4 receptor (MC4R; rs7566605 (insulin induced gene 2 (INSIG2; rs9939609 and rs1121980 (fat mass and obesity associated (FTO were genotyped in 2 cohorts of Swedish women: PEAK-25 (age 25, n = 1061 and OPRA (age 75, n = 1044. Body mass index (BMI, total body fat and lean mass were strongly positively correlated with QUS and BMD in both cohorts (r(2 = 0.2-0.6. MC4R rs17782313 was associated with QUS in the OPRA cohort and individuals with the minor C-allele had higher values compared to T-allele homozygotes (TT vs. CT vs.100 vs. 103 vs. 103; p = 0.002; (SOS: 1521 vs. 1526 vs. 1524; p = 0.008; (Stiffness index: 69 vs. 73 vs. 74; p = 0.0006 after adjustment for confounders. They also had low folate (18 vs. 17 vs. 16; p = 0.03 and vitamin D (93 vs. 91 vs. 90; p = 0.03 and high Hcy levels (13.7 vs 14.4 vs. 14.5; p = 0.06. Fracture incidence was lower among women with the C-allele, (52% vs. 58%; p = 0.067. Variation in MC4R was not associated with BMD or body composition in either OPRA or PEAK-25. SNPs close to FTO and INSIG2 were not associated with any bone phenotypes in either cohort and FTO SNPs were only associated with body composition in PEAK-25 (p≤0.001. Our results suggest that genetic variation close to MC4R is associated with quantitative ultrasound and risk of fracture.

  3. Immune gene expression in Bombus terrestris: signatures of infection despite strong variation among populations, colonies, and sister workers.

    Franziska S Brunner

    Full Text Available Ecological immunology relies on variation in resistance to parasites. Colonies of the bumblebee Bombus terrestris vary in their susceptibility to the trypanosome gut parasite Crithidia bombi, which reduces colony fitness. To understand the possible origin of this variation in resistance we assayed the expression of 28 immunologically important genes in foraging workers. We deliberately included natural variation of the host "environment" by using bees from colonies collected in two locations and sampling active foraging workers that were not age controlled. Immune gene expression patterns in response to C. bombi showed remarkable variability even among genetically similar sisters. Nevertheless, expression varied with parasite exposure, among colonies and, perhaps surprisingly, strongly among populations (collection sites. While only the antimicrobial peptide abaecin is universally up regulated upon exposure, linear discriminant analysis suggests that the overall exposure effect is driven by a combination of several immune pathways and further immune functions such as ROS regulation. Also, the differences among colonies in their immune gene expression profiles provide clues to the mechanistic basis of well-known inter-colony variation in susceptibility to this parasite. Our results show that transcriptional responses to parasite exposure can be detected in ecologically heterogeneous groups despite strong background noise.

  4. Colony-level behavioural variation correlates with differences in expression of the foraging gene in red imported fire ants.

    Bockoven, Alison A; Coates, Craig J; Eubanks, Micky D

    2017-11-01

    Among social insects, colony-level variation is likely to be widespread and has significant ecological consequences. Very few studies, however, have documented how genetic factors relate to behaviour at the colony level. Differences in expression of the foraging gene have been associated with differences in foraging and activity of a wide variety of organisms. We quantified expression of the red imported fire ant foraging gene (sifor) in workers from 21 colonies collected across the natural range of Texas fire ant populations, but maintained under standardized, environmentally controlled conditions. Colonies varied significantly in their behaviour. The most active colonies had up to 10 times more active foragers than the least active colony and more than 16 times as many workers outside the nest. Expression differences among colonies correlated with this colony-level behavioural variation. Colonies with higher sifor expression in foragers had, on average, significantly higher foraging activity, exploratory activity and recruitment to nectar than colonies with lower expression. Expression of sifor was also strongly correlated with worker task (foraging vs. working in the interior of the nest). These results provide insight into the genetic and physiological processes underlying collective differences in social behaviour. Quantifying variation in expression of the foraging gene may provide an important tool for understanding and predicting the ecological consequences of colony-level behavioural variation. © 2017 John Wiley & Sons Ltd.

  5. Variations and classification of toxic epitopes related to celiac disease among α-gliadin genes from four Aegilops genomes.

    Li, Jie; Wang, Shunli; Li, Shanshan; Ge, Pei; Li, Xiaohui; Ma, Wujun; Zeller, F J; Hsam, Sai L K; Yan, Yueming

    2012-07-01

    The α-gliadins are associated with human celiac disease. A total of 23 noninterrupted full open reading frame α-gliadin genes and 19 pseudogenes were cloned and sequenced from C, M, N, and U genomes of four diploid Aegilops species. Sequence comparison of α-gliadin genes from Aegilops and Triticum species demonstrated an existence of extensive allelic variations in Gli-2 loci of the four Aegilops genomes. Specific structural features were found including the compositions and variations of two polyglutamine domains (QI and QII) and four T cell stimulatory toxic epitopes. The mean numbers of glutamine residues in the QI domain in C and N genomes and the QII domain in C, N, and U genomes were much higher than those in Triticum genomes, and the QI domain in C and N genomes and the QII domain in C, M, N, and U genomes displayed greater length variations. Interestingly, the types and numbers of four T cell stimulatory toxic epitopes in α-gliadins from the four Aegilops genomes were significantly less than those from Triticum A, B, D, and their progenitor genomes. Relationships between the structural variations of the two polyglutamine domains and the distributions of four T cell stimulatory toxic epitopes were found, resulting in the α-gliadin genes from the Aegilops and Triticum genomes to be classified into three groups.

  6. GeneYenta: a phenotype-based rare disease case matching tool based on online dating algorithms for the acceleration of exome interpretation.

    Gottlieb, Michael M; Arenillas, David J; Maithripala, Savanie; Maurer, Zachary D; Tarailo Graovac, Maja; Armstrong, Linlea; Patel, Millan; van Karnebeek, Clara; Wasserman, Wyeth W

    2015-04-01

    Advances in next-generation sequencing (NGS) technologies have helped reveal causal variants for genetic diseases. In order to establish causality, it is often necessary to compare genomes of unrelated individuals with similar disease phenotypes to identify common disrupted genes. When working with cases of rare genetic disorders, finding similar individuals can be extremely difficult. We introduce a web tool, GeneYenta, which facilitates the matchmaking process, allowing clinicians to coordinate detailed comparisons for phenotypically similar cases. Importantly, the system is focused on phenotype annotation, with explicit limitations on highly confidential data that create barriers to participation. The procedure for matching of patient phenotypes, inspired by online dating services, uses an ontology-based semantic case matching algorithm with attribute weighting. We evaluate the capacity of the system using a curated reference data set and 19 clinician entered cases comparing four matching algorithms. We find that the inclusion of clinician weights can augment phenotype matching. © 2015 WILEY PERIODICALS, INC.

  7. Variation in MHC class II B genes in marbled murrelets: implications for delineating conservation units

    C. Vásquez-Carrillo; V. Friesen; L. Hall; M.Z. Peery

    2013-01-01

    Conserving genetic variation is critical for maintaining the evolutionary potential and viability of a species. Genetic studies seeking to delineate conservation units, however, typically focus on characterizing neutral genetic variation and may not identify populations harboring local adaptations. Here, variation at two major histocompatibility complex (MHC) class II...

  8. Sequence variation in mitochondrial cox1 and nad1 genes of ascaridoid nematodes in cats and dogs from Iran.

    Mikaeili, F; Mirhendi, H; Mohebali, M; Hosseini, M; Sharbatkhori, M; Zarei, Z; Kia, E B

    2015-07-01

    The study was conducted to determine the sequence variation in two mitochondrial genes, namely cytochrome c oxidase 1 (pcox1) and NADH dehydrogenase 1 (pnad1) within and among isolates of Toxocara cati, Toxocara canis and Toxascaris leonina. Genomic DNA was extracted from 32 isolates of T. cati, 9 isolates of T. canis and 19 isolates of T. leonina collected from cats and dogs in different geographical areas of Iran. Mitochondrial genes were amplified by polymerase chain reaction (PCR) and sequenced. Sequence data were aligned using the BioEdit software and compared with published sequences in GenBank. Phylogenetic analysis was performed using Bayesian inference and maximum likelihood methods. Based on pairwise comparison, intra-species genetic diversity within Iranian isolates of T. cati, T. canis and T. leonina amounted to 0-2.3%, 0-1.3% and 0-1.0% for pcox1 and 0-2.0%, 0-1.7% and 0-2.6% for pnad1, respectively. Inter-species sequence variation among the three ascaridoid nematodes was significantly higher, being 9.5-16.6% for pcox1 and 11.9-26.7% for pnad1. Sequence and phylogenetic analysis of the pcox1 and pnad1 genes indicated that there is significant genetic diversity within and among isolates of T. cati, T. canis and T. leonina from different areas of Iran, and these genes can be used for studying genetic variation of ascaridoid nematodes.

  9. Sequence Variation in Rhoptry Neck Protein 10 Gene among Toxoplasma gondii Isolates from Different Hosts and Geographical Locations.

    Zhao, Yu; Zhou, Donghui; Chen, Jia; Sun, Xiaolin

    2017-01-01

    Toxoplasma gondii, as a eukaryotic parasite of the phylum Apicomplexa, can infect almost all the warm-blooded animals and humans, causing toxoplasmosis. Rhoptry neck proteins (RONs) play a key role in the invasion process of T. gondii and are potential vaccine candidate molecules against toxoplasmosis. The present study examined sequence variation in the rhoptry neck protein 10 (TgRON10) gene among 10 T. gondii isolates from different hosts and geographical locations from Lanzhou province during 2014, and compared with the corresponding sequences of strains ME49 and VEG obtained from the ToxoDB database, using polymerase chain reaction (PCR) amplification, sequence analysis, and phylogenetic reconstruction by Bayesian inference (BI) and maximum parsimony (MP). Analysis of all the 12 TgRON10 genomic and cDNA sequences revealed 7 exons and 6 introns in the TgRON10 gDNA. The complete genomic sequence of the TgRON10 gene ranged from 4759 bp to 4763 bp, and sequence variation was 0-0.6% among the 12 T. gondii isolates, indicating a low sequence variation in TgRON10 gene. Phylogenetic analysis of TgRON10 sequences showed that the cluster of the 12 T. gondii isolates was not completely consistent with their respective genotypes. TgRON10 gene is not a suitable genetic marker for the differentiation of T. gondii isolates from different hosts and geographical locations, but may represent a potential vaccine candidate against toxoplasmosis, worth further studies.

  10. Characterization of genomic variations in SNPs of PE_PGRS genes reveals deletions and insertions in extensively drug resistant (XDR) M. tuberculosis strains from Pakistan

    Kanji, Akbar; Hasan, Zahra; Ali, Asho; McNerney, Ruth; Mallard, Kim; Coll, Francesc; Hill-Cawthorne, Grant A.; Nair, Mridul; Clark, Taane G.; Zaver, Ambreen; Jafri, Sana; Hasan, Rumina

    2015-01-01

    Genetic diversity in PE_PGRS genes contributes to antigenic variability and may result in increased immunogenicity of strains. This is the first study identifying variations in nsSNPs and INDELs in the PE_PGRS genes of XDR-TB strains from Pakistan. It highlights common genetic variations which may contribute to persistence.

  11. Sex bias in copy number variation of olfactory receptor gene family depends on ethnicity

    Farideh eShadravan

    2013-03-01

    Full Text Available Gender plays a pivotal role in the human genetic identity and is also manifested in many genetic disorders particularly mental retardation. In this study its effect on copy number variation (CNV, known to cause genetic disorders was explored. As the olfactory receptor (OR repertoire comprises the largest human gene family, it was selected for this study, which was carried out within and between three populations, derived from 150 individuals from the 1000 Genome Project. Analysis of 3872 CNVs detected among 791 OR loci, in which 307 loci showed CNV, revealed the following novel findings: Sex bias in CNV was significantly more prevalent in uncommon than common CNV variants of OR pseudogenes, in which the male genome showed more CNVs; and in one-copy number loss compared to complete deletion of OR pseudogenes; both findings implying a more recent evolutionary role for gender. Sex bias in copy number gain was also detected. Another novel finding was that the observed six bias was largely dependent on ethnicity and was in general absent in East Asians. Using a CNV public database for sick children (ISCA the application of these findings for improving clinical molecular diagnostics is discussed by showing an example of sex bias in CNV among kids with autism. Additional clinical relevance is discussed, as the most polymorphic CNV-enriched OR cluster in the human genome, located on chr 15q11.2, is found near the PWS/AS bi-directionally imprinted region associated with two well-known mental retardation syndromes. As olfaction represents the primitive cognition in most mammals, arguably in competition with the development of a larger brain, the extensive retention of OR pseudogenes in females of this study, might point to a parent-of-origin indirect regulatory role for OR pseudogenes in the embryonic development of human brain. Thus any perturbation in the temporal regulation of olfactory system could lead to developmental delay disorders including

  12. Quantitative variation in obesity-related traits and insulin precursors linked to the OB gene region on human chromosome 7

    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.

  13. Candidate genes revealed by a genome scan for mosquito resistance to a bacterial insecticide: sequence and gene expression variations

    David Jean-Philippe

    2009-11-01

    Full Text Available Abstract Background Genome scans are becoming an increasingly popular approach to study the genetic basis of adaptation and speciation, but on their own, they are often helpless at identifying the specific gene(s or mutation(s targeted by selection. This shortcoming is hopefully bound to disappear in the near future, thanks to the wealth of new genomic resources that are currently being developed for many species. In this article, we provide a foretaste of this exciting new era by conducting a genome scan in the mosquito Aedes aegypti with the aim to look for candidate genes involved in resistance to Bacillus thuringiensis subsp. israelensis (Bti insecticidal toxins. Results The genome of a Bti-resistant and a Bti-susceptible strains was surveyed using about 500 MITE-based molecular markers, and the loci showing the highest inter-strain genetic differentiation were sequenced and mapped on the Aedes aegypti genome sequence. Several good candidate genes for Bti-resistance were identified in the vicinity of these highly differentiated markers. Two of them, coding for a cadherin and a leucine aminopeptidase, were further examined at the sequence and gene expression levels. In the resistant strain, the cadherin gene displayed patterns of nucleotide polymorphisms consistent with the action of positive selection (e.g. an excess of high compared to intermediate frequency mutations, as well as a significant under-expression compared to the susceptible strain. Conclusion Both sequence and gene expression analyses agree to suggest a role for positive selection in the evolution of this cadherin gene in the resistant strain. However, it is unlikely that resistance to Bti is conferred by this gene alone, and further investigation will be needed to characterize other genes significantly associated with Bti resistance in Ae. aegypti. Beyond these results, this article illustrates how genome scans can build on the body of new genomic information (here, full

  14. Identification of Rare Variants in TNNI3 with Atrial Fibrillation in a Chinese GeneID Population

    Wang, Chuchu; Wu, Manman; Qian, Jin; Li, Bin; Tu, Xin; Xu, Chengqi; Li, Sisi; Chen, Shanshan; Zhao, Yuanyuan; Huang, Yufeng; Shi, Lisong; Cheng, Xiang; Liao, Yuhua; Chen, Qiuyun; Xia, Yunlong; Yao, Wei; Wu, Gang; Cheng, Mian; Wang, Qing K.

    2015-01-01

    Despite advances by genome-wide association studies (GWAS), much of heritability of common human diseases remains missing, a phenomenon referred to as ‘missing heritability’. One potential cause for ‘missing heritability’ is the rare susceptibility variants overlooked by GWAS. Atrial fibrillation (AF) is the most common arrhythmia seen at hospitals and increases risk of stroke by 5-fold and doubles risk of heart failure and sudden death. Here we studied one large Chinese family with AF and hypertrophic cardiomyopathy (HCM). Whole-exome sequencing analysis identified a mutation in TNNI3, R186Q, that co-segregated with the disease in the family, but did not exist in >1,583 controls, suggesting that R186Q causes AF and HCM. High-resolution melting curve analysis and direct DNA sequence analysis were then used to screen mutations in all exons and exon-intron boundaries of TNNI3 in a panel of 1,127 unrelated AF patients and 1,583 non-AF subjects. Four novel missense variants were identified in TNNI3, including E64G, M154L, E187G and D196G in four independent AF patients, but no variant was found in 1,583 non-AF subjects. All variants were not found in public databases, including the ExAC Browser database with 60,706 exomes. These data suggests that rare TNNI3 variants are associated with AF (P=0.03). TNNI3 encodes troponin I, a key regulator of the contraction-relaxation function of cardiac muscle and was not previously implicated in AF. Thus, this study may identify a new biological pathway for the pathogenesis of AF and provides evidence to support the rare variant hypothesis for missing heritability. PMID:26169204

  15. [Association between variations in protocadherin 15 gene and occupational noise-induced hearing loss].

    Xu, X R; Yang, Q Y; Jiao, J; Zheng, Y X; He, L H; Yu, S F; Gu, G Z; Chen, G S; Zhou, W H; Wu, H; Li, Y H; Zhang, H L; Zhang, Z R

    2017-01-06

    or CNE when the noise exposure level was>85 dB (A), compared with cases with the AA genotype of rs10825113, individuals with the GA/GG genotype had a 2.63-fold increased risk of NIHL (95% CI: 1.12- 6.14). When the CNE was ≤ 98 dB(A), compared with cases with the TT genotype of rs11004085, individuals with the CC/CT genotype had a 2.96-fold increased risk of NIHL (95% CI: 1.33- 6.56). However, these differences were not significant after Bonferroni correction had been applied. Conclusions: The results confirmed that genetic variation within the PCDH15 gene may affect the susceptibility to NIHL.

  16. Uncovering genomic causes of co-morbidity in epilepsy: gene-driven phenotypic characterization of rare microdeletions.

    Dalia Kasperavičiūtė

    Full Text Available Patients with epilepsy often suffer from other important conditions. The existence of such co-morbidities is frequently not recognized and their relationship with epilepsy usually remains unexplained.We describe three patients with common, sporadic, non-syndromic epilepsies in whom large genomic microdeletions were found during a study of genetic susceptibility to epilepsy. We performed detailed gene-driven clinical investigations in each patient. Disruption of the function of genes in the deleted regions can explain co-morbidities in these patients.Co-morbidities in patients with epilepsy can be part of a genomic abnormality even in the absence of (known congenital malformations or intellectual disabilities. Gene-driven phenotype examination can also reveal clinically significant unsuspected condition.

  17. Copy number variation in VEGF gene as a biomarker of susceptibility to age-related macular degeneration

    Norshakimah Md Bakri

    2018-07-01

    Full Text Available Background: Several studies in various populations have been conducted to determine candidate genes that could contribute to age-related macular degeneration (AMD pathogenesis. Objective: The present study was undertaken to determine the association of high temperature requirement A-1 (HTRA1, vascular endothelial growth factor (VEGF and very-low-density receptor (VLDR genes with wet AMD subjects in Malaysia. Methods: A total of 125 subjects with wet AMD and 120 subjects without AMD from the Malaysian population were selected for this study. Genomic DNA was extracted and copy number variations (CNVs were determined using quantitative real-time Polymerase Chain Reaction (qPCR and comparison between the two groups was done. The demographic characteristics were also recorded. Statistical analysis was carried out using software where a level of P  0.05. Conclusion: Observations of an association between CNVs of VEGF gene and wet AMD have revealed that the CNVs of VEGF gene appears to be a possible contributor to wet AMD subjects in Malaysia. Keywords: Age-related macular degeneration, Copy number variations, VEGF, HTRA1, VLDR genes and Malaysia

  18. Leveraging long sequencing reads to investigate R-gene clustering and variation in sugar beet

    Host-pathogen interactions are of prime importance to modern agriculture. Plants utilize various types of resistance genes to mitigate pathogen damage. Identification of the specific gene responsible for a specific resistance can be difficult due to duplication and clustering within R-gene families....

  19. Mutations of the Spliceosome Complex Genes Occur In Adult Patients but Are Very Rare In Children with Myeloid Neoplasia

    Hirabayashi, Shinsuke; Moetter, Jessica; Yoshida, Kenichi

    -protein complexes that remove noncoding introns from precursor mRNA. We hypothesized that the disruption of the spliceosome complex might play a driving role in the leukemogenesis in pediatric MDS. Using targeted re-sequencing we investigated the 3 exclusive hotspots of 2 spliceosome genes that were found...... negative. The drastically reduced frequency of spliceosome mutations in pediatric compared to adult myeloid malignancies suggests a different pathogenetic mechanism in childhood disease, and fits well with previous reports that somatic mutations of non-Ras-pathway genes, such as DNMT3A, are less prevalent...

  20. Investigation of the effect of ionizing radiation on gene expression variation by the 'DNA chips': feasibility of a biological dosimeter

    Gruel, G.

    2005-01-01

    After having described the different biological effects of ionizing radiation and the different approaches to biological dosimetry, and introduced 'DNA chips' or DNA micro-arrays, the author reports the characterization of gene expression variations in the response of cells to a gamma irradiation. Both main aspects of the use DNA chips are investigated: fundamental research and diagnosis. This research thesis thus proposes an analysis of the effect of ionizing radiation using DNA chips, notably by comparing gene expression modifications measured in mouse irradiated lung, heart and kidney. It reports a feasibility study of bio-dosimeter based on expression profiles

  1. Sequence variation in the alpha-toxin encoding plc gene of Clostridium perfringens strains isolated from diseased and healthy chickens

    Abildgaard, L; Engberg, RM; Pedersen, Karl

    2009-01-01

    The aim of the present study was to analyse the genetic diversity of the alpha-toxin encoding plc gene and the variation in a-toxin production of Clostridium perfringens type A strains isolated from presumably healthy chickens and chickens suffering from either necrotic enteritis (NE) or cholangio......-hepatitis. The a-toxin encoding plc genes from 60 different pulsed-field gel electrophoresis (PFGE) types (strains) of C perfringens were sequenced and translated in silico to amino acid sequences and the a-toxin production was investigated in batch cultures of 45 of the strains using an enzyme...

  2. Genetic Variation and Divergence of Genes Involved in Leaf Adaxial-abaxial Polarity Establishment in Brassica rapa

    Jianli eLiang

    2016-02-01

    Full Text Available Alterations in leaf adaxial–abaxial (ad-ab polarity are one of the main factors that are responsible for leaf curvature. In Chinese cabbage, to form a leafy head, leaf incurvature is an essential prerequisite. Identifying ad-ab patterning genes and investigating its genetic variations will facilitate in elucidating the mechanism underlying leaf incurvature during head formation. In the present study we conducted comparative genomic analysis of the identification of 45 leaf ad-ab patterning genes in Brassica rapa based on 26 homologs in Arabidopsis thaliana, indicating that these genes underwent expansion and were retained after whole genome triplication (WGT. We also assessed the nucleotide diversity and selection footprints of these 45 genes in a collection of 94 Brassica rapa accessions that were composed of heading and non-heading morphotypes. Six of the 45 genes showed significant negative Tajima’s D indices and nucleotide diversity reduction in heading accessions compared to that in non-heading accessions, indicating that these underwent purifying selection. Further testing of the BrARF3.1 gene, which was one of the selection signals from a larger collection, confirmed that purifying selection did occur. Our results provide genetic evidence that ad-ab patterning genes are involved in leaf incurvature that is associated in the formation of a leafy head, as well as promote an understanding of the genetic mechanism underlying leafy head formation in Chinese cabbage.

  3. Robust assignment of cancer subtypes from expression data using a uni-variate gene expression average as classifier

    Lauss, Martin; Frigyesi, Attila; Ryden, Tobias; Höglund, Mattias

    2010-01-01

    Genome wide gene expression data is a rich source for the identification of gene signatures suitable for clinical purposes and a number of statistical algorithms have been described for both identification and evaluation of such signatures. Some employed algorithms are fairly complex and hence sensitive to over-fitting whereas others are more simple and straight forward. Here we present a new type of simple algorithm based on ROC analysis and the use of metagenes that we believe will be a good complement to existing algorithms. The basis for the proposed approach is the use of metagenes, instead of collections of individual genes, and a feature selection using AUC values obtained by ROC analysis. Each gene in a data set is assigned an AUC value relative to the tumor class under investigation and the genes are ranked according to these values. Metagenes are then formed by calculating the mean expression level for an increasing number of ranked genes, and the metagene expression value that optimally discriminates tumor classes in the training set is used for classification of new samples. The performance of the metagene is then evaluated using LOOCV and balanced accuracies. We show that the simple uni-variate gene expression average algorithm performs as well as several alternative algorithms such as discriminant analysis and the more complex approaches such as SVM and neural networks. The R package rocc is freely available at http://cran.r-project.org/web/packages/rocc/index.html

  4. The Role of a Novel TRMT1 Gene Mutation and Rare GRM1 Gene Defect in Intellectual Disability in Two Azeri Families.

    Davarniya, Behzad; Hu, Hao; Kahrizi, Kimia; Musante, Luciana; Fattahi, Zohreh; Hosseini, Masoumeh; Maqsoud, Fariba; Farajollahi, Reza; Wienker, Thomas F; Ropers, H Hilger; Najmabadi, Hossein

    2015-01-01

    Cognitive impairment or intellectual disability (ID) is a widespread neurodevelopmental disorder characterized by low IQ (below 70). ID is genetically heterogeneous and is estimated to affect 1-3% of the world's population. In affected children from consanguineous families, autosomal recessive inheritance is common, and identifying the underlying genetic cause is an important issue in clinical genetics. In the framework of a larger project, aimed at identifying candidate genes for autosomal recessive intellectual disorder (ARID), we recently carried out single nucleotide polymorphism-based genome-wide linkage analysis in several families from Ardabil province in Iran. The identification of homozygosity-by-descent loci in these families, in combination with whole exome sequencing, led us to identify possible causative homozygous changes in two families. In the first family, a missense variant was found in GRM1 gene, while in the second family, a frameshift alteration was identified in TRMT1, both of which were found to co-segregate with the disease. GRM1, a known causal gene for autosomal recessive spinocerebellar ataxia (SCAR13, MIM#614831), encodes the metabotropic glutamate receptor1 (mGluR1). This gene plays an important role in synaptic plasticity and cerebellar development. Conversely, the TRMT1 gene encodes a tRNA methyltransferase that dimethylates a single guanine residue at position 26 of most tRNAs using S-adenosyl methionine as the methyl group donor. We recently presented TRMT1 as a candidate gene for ARID in a consanguineous Iranian family (Najmabadi et al., 2011). We believe that this second Iranian family with a biallelic loss-of-function mutation in TRMT1 gene supports the idea that this gene likely has function in development of the disorder.

  5. The Role of a Novel TRMT1 Gene Mutation and Rare GRM1 Gene Defect in Intellectual Disability in Two Azeri Families.

    Behzad Davarniya

    Full Text Available Cognitive impairment or intellectual disability (ID is a widespread neurodevelopmental disorder characterized by low IQ (below 70. ID is genetically heterogeneous and is estimated to affect 1-3% of the world's population. In affected children from consanguineous families, autosomal recessive inheritance is common, and identifying the underlying genetic cause is an important issue in clinical genetics. In the framework of a larger project, aimed at identifying candidate genes for autosomal recessive intellectual disorder (ARID, we recently carried out single nucleotide polymorphism-based genome-wide linkage analysis in several families from Ardabil province in Iran. The identification of homozygosity-by-descent loci in these families, in combination with whole exome sequencing, led us to identify possible causative homozygous changes in two families. In the first family, a missense variant was found in GRM1 gene, while in the second family, a frameshift alteration was identified in TRMT1, both of which were found to co-segregate with the disease. GRM1, a known causal gene for autosomal recessive spinocerebellar ataxia (SCAR13, MIM#614831, encodes the metabotropic glutamate receptor1 (mGluR1. This gene plays an important role in synaptic plasticity and cerebellar development. Conversely, the TRMT1 gene encodes a tRNA methyltransferase that dimethylates a single guanine residue at position 26 of most tRNAs using S-adenosyl methionine as the methyl group donor. We recently presented TRMT1 as a candidate gene for ARID in a consanguineous Iranian family (Najmabadi et al., 2011. We believe that this second Iranian family with a biallelic loss-of-function mutation in TRMT1 gene supports the idea that this gene likely has function in development of the disorder.

  6. The Role of a Novel TRMT1 Gene Mutation and Rare GRM1 Gene Defect in Intellectual Disability in Two Azeri Families

    Kahrizi, Kimia; Musante, Luciana; Fattahi, Zohreh; Hosseini, Masoumeh; Maqsoud, Fariba; Farajollahi, Reza; Wienker, Thomas F.; Ropers, H. Hilger; Najmabadi, Hossein

    2015-01-01

    Cognitive impairment or intellectual disability (ID) is a widespread neurodevelopmental disorder characterized by low IQ (below 70). ID is genetically heterogeneous and is estimated to affect 1–3% of the world’s population. In affected children from consanguineous families, autosomal recessive inheritance is common, and identifying the underlying genetic cause is an important issue in clinical genetics. In the framework of a larger project, aimed at identifying candidate genes for autosomal recessive intellectual disorder (ARID), we recently carried out single nucleotide polymorphism-based genome-wide linkage analysis in several families from Ardabil province in Iran. The identification of homozygosity-by-descent loci in these families, in combination with whole exome sequencing, led us to identify possible causative homozygous changes in two families. In the first family, a missense variant was found in GRM1 gene, while in the second family, a frameshift alteration was identified in TRMT1, both of which were found to co-segregate with the disease. GRM1, a known causal gene for autosomal recessive spinocerebellar ataxia (SCAR13, MIM#614831), encodes the metabotropic glutamate receptor1 (mGluR1). This gene plays an important role in synaptic plasticity and cerebellar development. Conversely, the TRMT1 gene encodes a tRNA methyltransferase that dimethylates a single guanine residue at position 26 of most tRNAs using S-adenosyl methionine as the methyl group donor. We recently presented TRMT1 as a candidate gene for ARID in a consanguineous Iranian family (Najmabadi et al., 2011). We believe that this second Iranian family with a biallelic loss-of-function mutation in TRMT1 gene supports the idea that this gene likely has function in development of the disorder. PMID:26308914

  7. Rare germline alterations in cancer-related genes associated with the risk of multiple primary tumor development

    Villacis, Rolando A. R.; Basso, Tatiane R; Canto, Luisa M

    2017-01-01

    Multiple primary tumors (MPT) have been described in carriers of inherited cancer predisposition genes. However, the genetic etiology of a large proportion of MPT cases remains unclear. We reviewed 267 patients with hereditary cancer predisposition syndromes (HCPS) that underwent genetic counseli...

  8. Dispersal and gene flow in the rare, parasitic Large Blue butterfly Maculinea arion

    Ugelvig, Line Vej; Andersen, Anne; Boomsma, Jacobus Jan

    2012-01-01

    decline throughout Europe and extinction in Britain followed by reintroduction of a seed population from the Swedish island of Öland. We find that populations are highly structured genetically, but that gene flow occurs over distances 15 times longer than the maximum distance recorded from mark...

  9. Molecular Evolution and Genetic Variation of G2-Like Transcription Factor Genes in Maize.

    Fang Liu

    Full Text Available The productivity of maize (Zea mays L. depends on the development of chloroplasts, and G2-like transcription factors play a central role in regulating chloroplast development. In this study, we identified 59 G2-like genes in the B73 maize genome and systematically analyzed these genes at the molecular and evolutionary levels. Based on gene structure character, motif compositions and phylogenetic analysis, maize G2-like genes (ZmG1- ZmG59 were divided into seven groups (I-VII. By synteny analysis, 18 collinear gene pairs and strongly conserved microsyntny among regions hosting G2-like genes across maize and sorghum were found. Here, we showed that the vast majority of ZmG gene duplications resulted from whole genome duplication events rather than tandem duplications. After gene duplication events, some ZmG genes were silenced. The functions of G2-like genes were multifarious and most genes that are expressed in green tissues may relate to maize photosynthesis. The qRT-PCR showed that the expression of these genes was sensitive to low temperature and drought. Furthermore, we analyzed differences of ZmGs specific to cultivars in temperate and tropical regions at the population level. Interestingly, the single nucleotide polymorphism (SNP analysis revealed that nucleotide polymorphism associated with different temperature zones. Above all, G2-like genes were highly conserved during evolution, but polymorphism could be caused due to a different geographical location. Moreover, G2-like genes might be related to cold and drought stresses.

  10. Gene set of nuclear-encoded mitochondrial regulators is enriched for common inherited variation in obesity.

    Nadja Knoll

    Full Text Available There are hints of an altered mitochondrial function in obesity. Nuclear-encoded genes are relevant for mitochondrial function (3 gene sets of known relevant pathways: (1 16 nuclear regulators of mitochondrial genes, (2 91 genes for oxidative phosphorylation and (3 966 nuclear-encoded mitochondrial genes. Gene set enrichment analysis (GSEA showed no association with type 2 diabetes mellitus in these gene sets. Here we performed a GSEA for the same gene sets for obesity. Genome wide association study (GWAS data from a case-control approach on 453 extremely obese children and adolescents and 435 lean adult controls were used for GSEA. For independent confirmation, we analyzed 705 obesity GWAS trios (extremely obese child and both biological parents and a population-based GWAS sample (KORA F4, n = 1,743. A meta-analysis was performed on all three samples. In each sample, the distribution of significance levels between the respective gene set and those of all genes was compared using the leading-edge-fraction-comparison test (cut-offs between the 50(th and 95(th percentile of the set of all gene-wise corrected p-values as implemented in the MAGENTA software. In the case-control sample, significant enrichment of associations with obesity was observed above the 50(th percentile for the set of the 16 nuclear regulators of mitochondrial genes (p(GSEA,50 = 0.0103. This finding was not confirmed in the trios (p(GSEA,50 = 0.5991, but in KORA (p(GSEA,50 = 0.0398. The meta-analysis again indicated a trend for enrichment (p(MAGENTA,50 = 0.1052, p(MAGENTA,75 = 0.0251. The GSEA revealed that weak association signals for obesity might be enriched in the gene set of 16 nuclear regulators of mitochondrial genes.

  11. Genetic Variation in Cardiomyopathy and Cardiovascular Disorders.

    McNally, Elizabeth M; Puckelwartz, Megan J

    2015-01-01

    With the wider deployment of massively-parallel, next-generation sequencing, it is now possible to survey human genome data for research and clinical purposes. The reduced cost of producing short-read sequencing has now shifted the burden to data analysis. Analysis of genome sequencing remains challenged by the complexity of the human genome, including redundancy and the repetitive nature of genome elements and the large amount of variation in individual genomes. Public databases of human genome sequences greatly facilitate interpretation of common and rare genetic variation, although linking database sequence information to detailed clinical information is limited by privacy and practical issues. Genetic variation is a rich source of knowledge for cardiovascular disease because many, if not all, cardiovascular disorders are highly heritable. The role of rare genetic variation in predicting risk and complications of cardiovascular diseases has been well established for hypertrophic and dilated cardiomyopathy, where the number of genes that are linked to these disorders is growing. Bolstered by family data, where genetic variants segregate with disease, rare variation can be linked to specific genetic variation that offers profound diagnostic information. Understanding genetic variation in cardiomyopathy is likely to help stratify forms of heart failure and guide therapy. Ultimately, genetic variation may be amenable to gene correction and gene editing strategies.

  12. Gene expression variation resolves species and individual strains among coral-associated dinoflagellates within the genus Symbiodinium

    Parkinson, John Everett

    2016-02-11

    Reef-building corals depend on symbiotic mutualisms with photosynthetic dinoflagellates in the genus Symbiodinium. This large microalgal group comprises many highly divergent lineages (“Clades A-I”) and hundreds of undescribed species. Given their ecological importance, efforts have turned to genomic approaches to characterize the functional ecology of Symbiodinium. To date, investigators have only compared gene expression between representatives from separate clades—the equivalent of contrasting genera or families in other dinoflagellate groups—making it impossible to distinguish between clade-level and species-level functional differences. Here, we examined the transcriptomes of four species within one Symbiodinium clade (Clade B) at ~20,000 orthologous genes, as well as multiple isoclonal cell lines within species (i.e. cultured strains). These species span two major adaptive radiations within Clade B, each encompassing both host-specialized and ecologically cryptic taxa. Species-specific expression differences were consistently enriched for photosynthesis-related genes, likely reflecting selection pressures driving niche diversification. Transcriptional variation among strains involved fatty acid metabolism and biosynthesis pathways. Such differences among individuals are potentially a major source of physiological variation, contributing to the functional diversity of coral holobionts composed of unique host-symbiont genotype pairings. Our findings expand the genomic resources available for this important symbiont group and emphasize the power of comparative transcriptomics as a method for studying speciation processes and inter-individual variation in non-model organisms.

  13. Gene expression variation resolves species and individual strains among coral-associated dinoflagellates within the genus Symbiodinium

    Parkinson, John Everett; Baumgarten, Sebastian; Michell, Craig; Baums, Iliana B.; LaJeunesse, Todd C.; Voolstra, Christian R.

    2016-01-01

    Reef-building corals depend on symbiotic mutualisms with photosynthetic dinoflagellates in the genus Symbiodinium. This large microalgal group comprises many highly divergent lineages (“Clades A-I”) and hundreds of undescribed species. Given their ecological importance, efforts have turned to genomic approaches to characterize the functional ecology of Symbiodinium. To date, investigators have only compared gene expression between representatives from separate clades—the equivalent of contrasting genera or families in other dinoflagellate groups—making it impossible to distinguish between clade-level and species-level functional differences. Here, we examined the transcriptomes of four species within one Symbiodinium clade (Clade B) at ~20,000 orthologous genes, as well as multiple isoclonal cell lines within species (i.e. cultured strains). These species span two major adaptive radiations within Clade B, each encompassing both host-specialized and ecologically cryptic taxa. Species-specific expression differences were consistently enriched for photosynthesis-related genes, likely reflecting selection pressures driving niche diversification. Transcriptional variation among strains involved fatty acid metabolism and biosynthesis pathways. Such differences among individuals are potentially a major source of physiological variation, contributing to the functional diversity of coral holobionts composed of unique host-symbiont genotype pairings. Our findings expand the genomic resources available for this important symbiont group and emphasize the power of comparative transcriptomics as a method for studying speciation processes and inter-individual variation in non-model organisms.

  14. A nine-nucleotide deletion and splice variation in the coding region of the interferon induced ISG12 gene

    Smidt, Kamille; Hansen, Lise Lotte; Søgaard, T Max M

    2003-01-01

    distributed between ISG12 and ISG12-S in breast carcinoma cells, in cancer cell lines and in cervical cytobrush material with neoplastic lesions. In addition, we have found a nine-nucleotide deletion situated in exon 4 of the ISG12 gene. This deletion leads to a three-amino-acid deletion (AMA) in the putative...... ISG12 gene products, ISG12Δ and ISG12-SΔ. We have determined the prevalence of the deletion ISG12Δ in normal and neoplastic cells. Homozygosity ISG12(0/0) and ISG12(Δ/Δ), and heterozygosity ISG12(0/Δ) were found, although the ISG12(Δ/Δ) genotype was rare. In heterozygous cells from cytobrush material...

  15. Differentially expressed genes linked to natural variation in long-term memory formation in Cotesia parasitic wasps

    Joke J. F. A. Van Vugt

    2015-09-01

    Full Text Available Even though learning and memory are universal traits in the Animal Kingdom, closely related species reveal substantial variation in learning rate and memory dynamics. To determine the genetic background of this natural variation, we studied two congeneric parasitic wasp species, Cotesia glomerata and C. rubecula, which lay their eggs in caterpillars of the large and small cabbage white butterfly. A successful egg laying event serves as an unconditioned stimulus in a classical conditioning paradigm, where plant odors become associated to the encounter of a suitable host caterpillar. Depending on the host species, the number of conditioning trials and the parasitic wasp species, three different types of transcription-dependent long-term memory (LTM and one type of transcription-independent, anesthesia-resistant memory (ARM can be distinguished. To identify transcripts underlying these differences in memory formation, we isolated mRNA from parasitic wasp heads at three different time points between induction and consolidation of each of the four memory types, and for each sample three biological replicates, where after strand-specific paired-end 100 bp deep sequencing. Transcriptomes were assembled de novo and differential expression was determined for each memory type and time point after conditioning, compared to unconditioned wasps. Most differentially expressed (DE genes and antisense transcripts were only DE in one of the LTM types. Among the DE genes that were DE in two or more LTM types, were many protein kinases and phosphatases, small GTPases, receptors and ion channels. Some genes were DE in opposing directions between any of the LTM memory types and ARM, suggesting that ARM in Cotesia requires the transcription of genes inhibiting LTM or vice versa. We discuss our findings in the context of neuronal functioning, including RNA splicing and transport, epigenetic regulation, neurotransmitter/peptide synthesis and antisense transcription. In

  16. Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia.

    Gu, Fangyi; Zhang, Han; Hyland, Paula L; Berndt, Sonja; Gapstur, Susan M; Wheeler, William; Ellipse Consortium, The; Amos, Christopher I; Bezieau, Stephane; Bickeböller, Heike; Brenner, Hermann; Brennan, Paul; Chang-Claude, Jenny; Conti, David V; Doherty, Jennifer Anne; Gruber, Stephen B; Harrison, Tabitha A; Hayes, Richard B; Hoffmeister, Michael; Houlston, Richard S; Hung, Rayjean J; Jenkins, Mark A; Kraft, Peter; Lawrenson, Kate; McKay, James; Markt, Sarah; Mucci, Lorelei; Phelan, Catherine M; Qu, Conghui; Risch, Angela; Rossing, Mary Anne; Wichmann, H-Erich; Shi, Jianxin; Schernhammer, Eva; Yu, Kai; Landi, Maria Teresa; Caporaso, Neil E

    2017-11-01

    Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (p pathway  circadian rhythm pathway in GAME-ON (p pathway  = 0.021); this association was not confirmed in GECCO (p pathway  = 0.76) or the combined data (p pathway  = 0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms. © 2017 UICC.

  17. Social context-induced song variation affects female behavior and gene expression.

    Sarah C Woolley

    2008-03-01

    Full Text Available Social cues modulate the performance of communicative behaviors in a range of species, including humans, and such changes can make the communication signal more salient. In songbirds, males use song to attract females, and song organization can differ depending on the audience to which a male sings. For example, male zebra finches (Taeniopygia guttata change their songs in subtle ways when singing to a female (directed song compared with when they sing in isolation (undirected song, and some of these changes depend on altered neural activity from a specialized forebrain-basal ganglia circuit, the anterior forebrain pathway (AFP. In particular, variable activity in the AFP during undirected song is thought to actively enable syllable variability, whereas the lower and less-variable AFP firing during directed singing is associated with more stereotyped song. Consequently, directed song has been suggested to reflect a "performance" state, and undirected song a form of vocal motor "exploration." However, this hypothesis predicts that directed-undirected song differences, despite their subtlety, should matter to female zebra finches, which is a question that has not been investigated. We tested female preferences for this natural variation in song in a behavioral approach assay, and we found that both mated and socially naive females could discriminate between directed and undirected song-and strongly preferred directed song. These preferences, which appeared to reflect attention especially to aspects of song variability controlled by the AFP, were enhanced by experience, as they were strongest for mated females responding to their mate's directed songs. We then measured neural activity using expression of the immediate early gene product ZENK, and found that social context and song familiarity differentially modulated the number of ZENK-expressing cells in telencephalic auditory areas. Specifically, the number of ZENK-expressing cells in the

  18. Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of monogenic diabetes

    Torsvik, Janniche; Johansson, Stefan; Johansen, Anders

    2009-01-01

    of the VNTR, and determined the VNTR-length of each allele. When blindly testing 56 members of the two families with known single-base deletions in the CEL VNTR, the method correctly assessed the mutation carriers. Screening of 241 probands from suspected maturity-onset diabetes of the young (MODY) families...... negative for mutations in known MODY genes (95 individuals from Denmark and 146 individuals from UK) revealed no deletions in the proximal repeats of the CEL VNTR. However, we found one Danish patient with a short, novel CEL allele containing only three VNTR repeats (normal range 7-23 in healthy controls......). This allele co-segregated with diabetes or impaired glucose tolerance in the patient's family as six of seven mutation carriers were affected. We also identified individuals who had three copies of a complete CEL VNTR. In conclusion, the CEL gene is highly polymorphic, but mutations in CEL are likely...

  19. Genetic variations in the MCT1 (SLC16A1) gene in the Chinese population of Singapore.

    Lean, Choo Bee; Lee, Edmund Jon Deoon

    2009-01-01

    MCT1(SLC16A1) is the first member of the monocarboxylate transporter (MCT) and its family is involved in the transportation of metabolically important monocarboxylates such as lactate, pyruvate, acetate and ketone bodies. This study identifies genetic variations in SLC16A1 in the ethnic Chinese group of the Singaporean population (n=95). The promoter, coding region and exon-intron junctions of the SLC16A1 gene encoding the MCT1 transporter were screened for genetic variation in the study population by DNA sequencing. Seven genetic variations of SLC16A1, including 4 novel ones, were found: 2 in the promoter region, 2 in the coding exons (both nonsynonymous variations), 2 in the 3' untranslated region (3'UTR) and 1 in the intron. Of the two mutations detected in the promoter region, the -363-855T>C is a novel mutation. The 1282G>A (Val(428)Ile) is a novel SNP and was found as heterozygotic in 4 subjects. The 1470T>A (Asp(490)Glu) was found to be a common polymorphism in this study. Lastly, IVS3-17A>C in intron 3 and 2258 (755)A>G in 3'UTR are novel mutations found to be common polymorphisms in the local Chinese population. To our knowledge, this is the first report of a comprehensive analysis on the MCT1 gene in any population.

  20. Gene expression variations during Drosophila metamorphosis in space: The GENE experiment in the Spanish cervantes missions to the ISS

    Herranz, Raul; Benguria, Alberto; Medina, Javier; Gasset, Gilbert; van Loon, Jack J.; Zaballos, Angel; Marco, Roberto

    2005-08-01

    The ISS expedition 8, a Soyuz Mission, flew to the International Space Station (ISS) to replace the two- member ISS crew during October 2003. During this crew exchanging flight, the Spanish Cervantes Scientific Mission took place. In it some biological experiments were performed among them three proposed by our Team. The third member of the expedition, the Spanish born ESA astronaut Pedro Duque, returned within the Soyuz 7 capsule carrying the experiment containing transport box after almost 11 days in microgravity. In one of the three experiments, the GENE experiment, we intended to determine how microgravity affects the gene expression pattern of Drosophila with one of the current more powerful technologies , a complete Drosophila melanogaster genome microarray (AffymetrixTM, version 1.0). Due to the constrains in the current ISS experiments, we decided to limit our experiment to the organism rebuilding processes that occurs during Drosophila metamorphosis. In addition to the ISS samples, several control experiments have been performed including a 1g Ground control parallel to the ISS flight samples, a Random Position Machine microgravity simulated control and a parallel Hypergravity (10g) experiment. Extracted RNA from the samples was used to test the differences in gene expression during Drosophila development. A preliminary analysis of the results indicates that around five hundred genes change their expression profiles, many of them belonging to particular ontology classification groups.

  1. Multi-allelic major effect genes interact with minor effect QTLs to control adaptive color pattern variation in Heliconius erato.

    Riccardo Papa

    Full Text Available Recent studies indicate that relatively few genomic regions are repeatedly involved in the evolution of Heliconius butterfly wing patterns. Although this work demonstrates a number of cases where homologous loci underlie both convergent and divergent wing pattern change among different Heliconius species, it is still unclear exactly how many loci underlie pattern variation across the genus. To address this question for Heliconius erato, we created fifteen independent crosses utilizing the four most distinct color pattern races and analyzed color pattern segregation across a total of 1271 F2 and backcross offspring. Additionally, we used the most variable brood, an F2 cross between H. himera and the east Ecuadorian H. erato notabilis, to perform a quantitative genetic analysis of color pattern variation and produce a detailed map of the loci likely involved in the H. erato color pattern radiation. Using AFLP and gene based markers, we show that fewer major genes than previously envisioned control the color pattern variation in H. erato. We describe for the first time the genetic architecture of H. erato wing color pattern by assessing quantitative variation in addition to traditional linkage mapping. In particular, our data suggest three genomic intervals modulate the bulk of the observed variation in color. Furthermore, we also identify several modifier loci of moderate effect size that contribute to the quantitative wing pattern variation. Our results are consistent with the two-step model for the evolution of mimetic wing patterns in Heliconius and support a growing body of empirical data demonstrating the importance of major effect loci in adaptive change.

  2. Associations of GBP2 gene copy number variations with growth traits and transcriptional expression in Chinese cattle.

    Zhang, Gui-Min; Zheng, Li; He, Hua; Song, Cheng-Chuang; Zhang, Zi-Jing; Cao, Xiu-Kai; Lei, Chu-Zhao; Lan, Xian-Yong; Qi, Xing-Lei; Chen, Hong; Huang, Yong-Zhen

    2018-03-20

    Copy number variations (CNVs) recently have been recognized as another important genetic variability followed single nucleotide polymorphisms (SNPs). The guanylate binding protein 2 (GBP2) gene plays an important role in cell proliferation. This study was performed to determine the presence of GBP2 CNV (relative to Angus cattle) in 466 individuals representing six main cattle breeds from China, identify its relationship with growth, and explore the biological effects of gene expression. There were two CNV regions in the GBP2 gene, for three types, CNV1 loss type (relative to Angus cattle) was more frequent in XN than other breeds, and CNV2 loss type (relative to Angus cattle) was more frequent in XN and CDM than other breeds. Though the GBP2 gene copy number presented no correlation with the transcriptional expression of JX (P > .05), but the transcriptional expression in heart is higher than other tissues, and the copy number in muscles and fat of JX is higher than others breeds. Statistical analysis revealed that the GBP2 gene CNV1 and CNV2 were significantly associated with growth traits (P cattle breeds, and our results suggested that the CNVs in GBP2 gene may be considered markers for the molecular breeding of Chinese beef cattle. Copyright © 2018. Published by Elsevier B.V.

  3. AIRE variations in Addison's disease and autoimmune polyendocrine syndromes (APS): partial gene deletions contribute to APS I.

    Bøe Wolff, A S; Oftedal, B; Johansson, S; Bruland, O; Løvås, K; Meager, A; Pedersen, C; Husebye, E S; Knappskog, P M

    2008-03-01

    Autoimmune Addison's disease (AAD) is often associated with other components in autoimmune polyendocrine syndromes (APS). Whereas APS I is caused by mutations in the AIRE gene, the susceptibility genes for AAD and APS II are unclear. In the present study, we investigated whether polymorphisms or copy number variations in the AIRE gene were associated with AAD and APS II. First, nine SNPs in the AIRE gene were analyzed in 311 patients with AAD and APS II and 521 healthy controls, identifying no associated risk. Second, in a subgroup of 25 of these patients, AIRE sequencing revealed three novel polymorphisms. Finally, the AIRE copy number was determined by duplex quantitative PCR in 14 patients with APS I, 161 patients with AAD and APS II and in 39 healthy subjects. In two Scandinavian APS I patients previously reported to be homozygous for common AIRE mutations, we identified large deletions of the AIRE gene covering at least exon 2 to exon 8. We conclude that polymorphisms in the AIRE gene are not associated with AAD and APS II. We further suggest that DNA analysis of the parents of patients found to be homozygous for mutations in AIRE, always should be performed.

  4. Novel Nucleotide Variations, Haplotypes Structure and Associations with Growth Related Traits of Goat AT Motif-Binding Factor ( Gene

    Xiaoyan Zhang

    2015-10-01

    Full Text Available The AT motif-binding factor (ATBF1 not only interacts with protein inhibitor of activated signal transducer and activator of transcription 3 (STAT3 (PIAS3 to suppress STAT3 signaling regulating embryo early development and cell differentiation, but is required for early activation of the pituitary specific transcription factor 1 (Pit1 gene (also known as POU1F1 critically affecting mammalian growth and development. The goal of this study was to detect novel nucleotide variations and haplotypes structure of the ATBF1 gene, as well as to test their associations with growth-related traits in goats. Herein, a total of seven novel single nucleotide polymorphisms (SNPs (SNP 1-7 within this gene were found in two well-known Chinese native goat breeds. Haplotypes structure analysis demonstrated that there were four haplotypes in Hainan black goat while seventeen haplotypes in Xinong Saanen dairy goat, and both breeds only shared one haplotype (hap1. Association testing revealed that the SNP2, SNP5, SNP6, and SNP7 loci were also found to significantly associate with growth-related traits in goats, respectively. Moreover, one diplotype in Xinong Saanen dairy goats significantly linked to growth related traits. These preliminary findings not only would extend the spectrum of genetic variations of the goat ATBF1 gene, but also would contribute to implementing marker-assisted selection in genetics and breeding in goats.

  5. No Association between Variation in Longevity Candidate Genes and Aging-related Phenotypes in Oldest-old Danes

    Sørensen, Mette; Nygaard, Marianne; Debrabant, Birgit

    2016-01-01

    additional genes repeatedly considered as candidates for human longevity: APOE, APOA4, APOC3, ACE, CETP, HFE, IL6, IL6R, MTHFR, TGFB1, SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. Altogether, 1,049 single nucleotide polymorphisms (SNPs) were genotyped in 1,088 oldest-old (age 92-93 years) Danes and analysed......In this study we explored the association between aging-related phenotypes previously reported to predict survival in old age and variation in 77 genes from the DNA repair pathway, 32 genes from the growth hormone 1/ insulin-like growth factor 1/insulin (GH/IGF-1/INS) signalling pathway and 16...... in the relevant phenotype over time (7 years of follow-up) and none of the SNPs could be confirmed in a replication sample of 1,281 oldest-old Danes (age 94-100). Hence, our study does not support association between common variation in the investigated longevity candidate genes and aging-related phenotypes...

  6. No Association between Variation in Longevity Candidate Genes and Aging-related Phenotypes in Oldest-old Danes.

    Soerensen, Mette; Nygaard, Marianne; Debrabant, Birgit; Mengel-From, Jonas; Dato, Serena; Thinggaard, Mikael; Christensen, Kaare; Christiansen, Lene

    2016-06-01

    In this study we explored the association between aging-related phenotypes previously reported to predict survival in old age and variation in 77 genes from the DNA repair pathway, 32 genes from the growth hormone 1/ insulin-like growth factor 1/insulin (GH/IGF-1/INS) signalling pathway and 16 additional genes repeatedly considered as candidates for human longevity: APOE, APOA4, APOC3, ACE, CETP, HFE, IL6, IL6R, MTHFR, TGFB1, SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. Altogether, 1,049 single nucleotide polymorphisms (SNPs) were genotyped in 1,088 oldest-old (age 92-93 years) Danes and analysed with phenotype data on physical functioning (hand grip strength), cognitive functioning (mini mental state examination and a cognitive composite score), activity of daily living and self-rated health. Five SNPs showed association to one of the phenotypes; however, none of these SNPs were associated with a change in the relevant phenotype over time (7 years of follow-up) and none of the SNPs could be confirmed in a replication sample of 1,281 oldest-old Danes (age 94-100). Hence, our study does not support association between common variation in the investigated longevity candidate genes and aging-related phenotypes consistently shown to predict survival. It is possible that larger sample sizes are needed to robustly reveal associations with small effect sizes. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Fine Physical Bin Mapping of the Powdery Mildew Resistance Gene Pm21 Based on Chromosomal Structural Variations in Wheat

    Shanying Zhu

    2018-02-01

    Full Text Available Pm21, derived from wheat wild relative Dasypyrum villosum, is one of the most effective powdery mildew resistance genes and has been widely applied in wheat breeding in China. Mapping and cloning Pm21 are of importance for understanding its resistance mechanism. In the present study, physical mapping was performed using different genetic stocks involving in structural variations of chromosome 6VS carrying Pm21. The data showed that 6VS could be divided into eight distinguishable chromosomal bins, and Pm21 was mapped to the bin FLb4–b5/b6 closely flanked by the markers 6VS-08.6 and 6VS-10.2. Comparative genomic mapping indicated that the orthologous regions of FLb4–b5/b6 carrying Pm21 were narrowed to a 117.7 kb genomic region harboring 19 genes in Brachypodium and a 37.7 kb region harboring 5 genes in rice, respectively. The result was consistent with that given by recent genetic mapping in diploid D. villosum. In conclusion, this study demonstrated that physical mapping based on chromosomal structural variations is an efficient method for locating alien genes in wheat background.

  8. Variation of antibiotic resistance genes in municipal wastewater treatment plant with A(2)O-MBR system.

    Du, Jing; Geng, Jinju; Ren, Hongqiang; Ding, Lili; Xu, Ke; Zhang, Yan

    2015-03-01

    The variation of five antibiotic resistance genes (ARGs)-tetG, tetW, tetX, sul1, and intI1-in a full-scale municipal wastewater treatment plant with A(2)O-MBR system was studied. The concentrations of five resistance genes both in influent and in membrane bioreactor (MBR) effluent decreased as sul1 > intI1 > tetX > tetG > tetW, and an abundance of sul1 was statistically higher than three other tetracycline resistance genes (tetG, tetW, and tetX) (p MBR effluent. The reduction of tetW, intI1, and sul1 was all significantly positively correlated with the reduction of 16S ribosomal DNA (rDNA) in the wastewater treatment process (p MBR was observed for all ARGs.

  9. Association between genetic variation in the oxytocin receptor gene and emotional withdrawal, but not between oxytocin pathway genes and diagnosis in psychotic disorders.

    Marit eHaram

    2015-01-01

    Full Text Available Social dysfunction is common in patients with psychotic disorders. Oxytocin is a neuropeptide with a central role in social behaviour. This study aims to explore the relationship between oxytocin pathway genes and symptoms related to social dysfunction in patients with psychotic disorders. We performed association analyses between four oxytocin pathway genes (OXT, OXTR, AVP, CD38 and four areas of social behaviour-related psychopathology as measured by Positive and Negative Syndrome Scale (PANSS. For this purpose, we used both a polygenic risk score (PGRS and single OXTR candidate SNPs previously reported in the literature (rs53576, rs237902, rs2254298. A total of 734 subjects with DSM-IV psychotic spectrum disorders and 420 healthy controls were included. Oxytocin pathway PGRSs were calculated based on the independent Psychiatric Genomics Consortium study sample. There was a significant association between symptom of Emotional Withdrawal and the previously reported OXTR risk allele A in rs53576. No significant associations between oxytocin pathway gene variants and a diagnosis of psychotic disorder were found. Our findings indicate that while oxytocin pathway genes do not appear to contribute to the susceptibility to psychotic disorders, variations in the OXTR gene might play a role in the development of impaired social behaviour.

  10. Balancing Selection at the Tomato RCR3 Guardee Gene Family Maintains Variation in Strength of Pathogen Defense

    Hörger, Anja C.; Ilyas, Muhammad; Stephan, Wolfgang; Tellier, Aurélien; van der Hoorn, Renier A. L.; Rose, Laura E.

    2012-01-01

    Coevolution between hosts and pathogens is thought to occur between interacting molecules of both species. This results in the maintenance of genetic diversity at pathogen antigens (or so-called effectors) and host resistance genes such as the major histocompatibility complex (MHC) in mammals or resistance (R) genes in plants. In plant–pathogen interactions, the current paradigm posits that a specific defense response is activated upon recognition of pathogen effectors via interaction with their corresponding R proteins. According to the “Guard-Hypothesis,” R proteins (the “guards”) can sense modification of target molecules in the host (the “guardees”) by pathogen effectors and subsequently trigger the defense response. Multiple studies have reported high genetic diversity at R genes maintained by balancing selection. In contrast, little is known about the evolutionary mechanisms shaping the guardee, which may be subject to contrasting evolutionary forces. Here we show that the evolution of the guardee RCR3 is characterized by gene duplication, frequent gene conversion, and balancing selection in the wild tomato species Solanum peruvianum. Investigating the functional characteristics of 54 natural variants through in vitro and in planta assays, we detected differences in recognition of the pathogen effector through interaction with the guardee, as well as substantial variation in the strength of the defense response. This variation is maintained by balancing selection at each copy of the RCR3 gene. Our analyses pinpoint three amino acid polymorphisms with key functional consequences for the coevolution between the guardee (RCR3) and its guard (Cf-2). We conclude that, in addition to coevolution at the “guardee-effector” interface for pathogen recognition, natural selection acts on the “guard-guardee” interface. Guardee evolution may be governed by a counterbalance between improved activation in the presence and prevention of auto

  11. Balancing selection at the tomato RCR3 Guardee gene family maintains variation in strength of pathogen defense.

    Anja C Hörger

    Full Text Available Coevolution between hosts and pathogens is thought to occur between interacting molecules of both species. This results in the maintenance of genetic diversity at pathogen antigens (or so-called effectors and host resistance genes such as the major histocompatibility complex (MHC in mammals or resistance (R genes in plants. In plant-pathogen interactions, the current paradigm posits that a specific defense response is activated upon recognition of pathogen effectors via interaction with their corresponding R proteins. According to the "Guard-Hypothesis," R proteins (the "guards" can sense modification of target molecules in the host (the "guardees" by pathogen effectors and subsequently trigger the defense response. Multiple studies have reported high genetic diversity at R genes maintained by balancing selection. In contrast, little is known about the evolutionary mechanisms shaping the guardee, which may be subject to contrasting evolutionary forces. Here we show that the evolution of the guardee RCR3 is characterized by gene duplication, frequent gene conversion, and balancing selection in the wild tomato species Solanum peruvianum. Investigating the functional characteristics of 54 natural variants through in vitro and in planta assays, we detected differences in recognition of the pathogen effector through interaction with the guardee, as well as substantial variation in the strength of the defense response. This variation is maintained by balancing selection at each copy of the RCR3 gene. Our analyses pinpoint three amino acid polymorphisms with key functional consequences for the coevolution between the guardee (RCR3 and its guard (Cf-2. We conclude that, in addition to coevolution at the "guardee-effector" interface for pathogen recognition, natural selection acts on the "guard-guardee" interface. Guardee evolution may be governed by a counterbalance between improved activation in the presence and prevention of auto-immune responses in

  12. High frequency of rare copy number variants affecting functionally related genes in patients with structural brain malformations

    Kariminejad, Roxana; Lind-Thomsen, Allan; Tümer, Zeynep

    2011-01-01

    ) to investigate copy number variants (CNVs) in a cohort of 169 patients with various structural brain malformations including lissencephaly, polymicrogyria, focal cortical dysplasia, and corpus callosum agenesis. The majority of the patients had intellectual disabilities (ID) and suffered from symptomatic...... that genes involved in "axonal transport," "cation transmembrane transporter activity," and the "c-Jun N-terminal kinase (JNK) cascade" play a significant role in the etiology of brain malformations. This is to the best of our knowledge the first systematic study of CNVs in patients with structural brain...

  13. The G to C polymorphism at -174 of the interleukin-6 gene is rare in a Southern Chinese population

    Zhai, R.H.; Liu, G.; Yang, C.M.; Huang, C.H.; Wu, C.R.; Christiani, D.C. [Harvard University, Boston, MA (United States). School of Public Health, Occupational Health Programme, Dept. of Environmental Health

    2001-11-01

    Interleukin-6 is thought to be involved in the pathogenesis of coal workers' pneumoconiosis. Recently, a functional G to C polymorphism at position -174 of the promoter of the IL-6 gene has been described. The -174 polymorphisms in 259 retired Chinese men from Guangxi province (all retired coal miners) were examined. Only one GC heterozygous and no CC homozygous variants were found. Our results suggest that the frequency of the C allele in this Chinese population is lower than in Caucasian and east Indian populations.

  14. A comprehensive candidate gene approach identifies genetic variation associated with osteosarcoma

    Mirabello, Lisa; Grotmol, Tom; Douglass, Chester; Hayes, Richard B; Hoover, Robert N; Savage, Sharon A; Yu, Kai; Berndt, Sonja I; Burdett, Laurie; Wang, Zhaoming; Chowdhury, Salma; Teshome, Kedest; Uzoka, Arinze; Hutchinson, Amy

    2011-01-01

    Osteosarcoma (OS) is a bone malignancy which occurs primarily in adolescents. Since it occurs during a period of rapid growth, genes important in bone formation and growth are plausible modifiers of risk. Genes involved in DNA repair and ribosomal function may contribute to OS pathogenesis, because they maintain the integrity of critical cellular processes. We evaluated these hypotheses in an OS association study of genes from growth/hormone, bone formation, DNA repair, and ribosomal pathways. We evaluated 4836 tag-SNPs across 255 candidate genes in 96 OS cases and 1426 controls. Logistic regression models were used to estimate the odds ratios (OR) and 95% confidence intervals (CI). Twelve SNPs in growth or DNA repair genes were significantly associated with OS after Bonferroni correction. Four SNPs in the DNA repair gene FANCM (ORs 1.9-2.0, P = 0.003-0.004) and 2 SNPs downstream of the growth hormone gene GH1 (OR 1.6, P = 0.002; OR 0.5, P = 0.0009) were significantly associated with OS. One SNP in the region of each of the following genes was significant: MDM2, MPG, FGF2, FGFR3, GNRH2, and IGF1. Our results suggest that several SNPs in biologically plausible pathways are associated with OS. Larger studies are required to confirm our findings

  15. Variation of DNA methylation patterns associated with gene expression in rice (Oryza sativa) exposed to cadmium.

    Feng, Sheng Jun; Liu, Xue Song; Tao, Hua; Tan, Shang Kun; Chu, Shan Shan; Oono, Youko; Zhang, Xian Duo; Chen, Jian; Yang, Zhi Min

    2016-12-01

    We report genome-wide single-base resolution maps of methylated cytosines and transcriptome change in Cd-exposed rice. Widespread differences were identified in CG and non-CG methylation marks between Cd-exposed and Cd-free rice genomes. There are 2320 non-redundant differentially methylated regions detected in the genome. RNA sequencing revealed 2092 DNA methylation-modified genes differentially expressed under Cd exposure. More genes were found hypermethylated than those hypomethylated in CG, CHH and CHG (where H is A, C or T) contexts in upstream, gene body and downstream regions. Many of the genes were involved in stress response, metal transport and transcription factors. Most of the DNA methylation-modified genes were transcriptionally altered under Cd stress. A subset of loss of function mutants defective in DNA methylation and histone modification activities was used to identify transcript abundance of selected genes. Compared with wide type, mutation of MET1 and DRM2 resulted in general lower transcript levels of the genes under Cd stress. Transcripts of OsIRO2, OsPR1b and Os09g02214 in drm2 were significantly reduced. A commonly used DNA methylation inhibitor 5-azacytidine was employed to investigate whether DNA demethylation affected physiological consequences. 5-azacytidine provision decreased general DNA methylation levels of selected genes, but promoted growth of rice seedlings and Cd accumulation in rice plant. © 2016 John Wiley & Sons Ltd.

  16. Variation in sequence and location of the fumonisin mycotoxin niosynthetic gene cluster in Fusarium

    Proctor, R.H.; Hove, van F.; Susca, A.; Stea, A.; Busman, M.; Lee, van der T.A.J.; Waalwijk, C.; Moretti, A.

    2010-01-01

    In Fusarium, the ability to produce fumonisins is governed by a 17-gene fumonisin biosynthetic gene (FUM) cluster. Here, we examined the cluster in F. oxysporum strain O-1890 and nine other species selected to represent a wide range of the genetic diversity within the GFSC.

  17. Variation in the DNA methylation pattern of expressed and nonexpressed genes in chicken.

    Cooper, D N; Errington, L H; Clayton, R M

    1983-01-01

    Using methyl-sensitive and -insensitive restriction enzymes, Hpa II and Msp I, the methylation status of various chicken genes was examined in different tissues and developmental stages. Tissue-specific differences in methylation were found for the delta-crystallin, beta-tubulin, G3PDH, rDNA, and actin genes but not for the histone genes. Developmental decreases in methylation were noted for the delta-crystallin and actin genes in chicken kidney between embryo and adult. Since most of the sequences examined were housekeeping genes, transcriptional differences are apparently not a necessary accompaniment to changes in DNA methylation at the CpG sites examined. The only exception is sperm DNA where the delta-crystallin, beta-tubulin, and actin genes are highly methylated and almost certainly not transcribed. However the G3PDH genes are no more highly methylated in sperm than in other somatic tissues. Many sequences homologous to the rDNA and histone probes used are unmethylated in all tissues examined including sperm, but a methylated rDNA subfraction is more heavily methylated in sperm than in other tissues. We speculate as to the significance of these differences in sperm DNA methylation in the light of possible requirements for early gene activation and the probable deleterious mutagenic effects of heavy methylation within coding sequences.

  18. Association of the gene expression variation of tumor necrosis factor-α and expressions changes of dopamine receptor genes in progression of diabetic severe foot ulcers

    Hajar Vaseghi

    2017-11-01

    Full Text Available Objective(s:Regulation of pro-inflammatory factors such as TNF-, which are secreted by the immune cells through induction of their several receptors including dopamine receptors (especially DRD2 and DRD3 is one of the noticeable problems in diabetic severe foot ulcer healing. This study was conducted to evaluate the alteration of TNF- in plasma as well as DRD2 and DRD3 changes in PBMCs of diabetics with severe foot ulcers. Materials and Methods: Peripheral blood samples were collected from 31 subjects with ulcers, 29 without ulcers, and 25 healthy individuals. Total mRNA was extracted from PBMCs for the study of DRD2, DRD3, and TNF- gene expression variations. Expression patterns of these genes were evaluated by real-time PCR. Consequently, concentration of TNF- was investigated in plasma. Results: Significant decrease in gene expression and plasma concentration of TNF- in PBMCs was observed in both patient groups at P Conclusion: We concluded that DRD2 and DRD3 expression alteration and presence of new DRD3 transcripts can be effective in reduction of TNF-α expression as a pro-inflammatory factor. Performing complementary studies, may explain that variations in DRD2 and DRD3 are prognostic and effective markers attributed to the development of diabetes severe foot ulcers.

  19. Removal of unwanted variation reveals novel patterns of gene expression linked to sleep homeostasis in murine cortex

    Jason R. Gerstner

    2016-10-01

    Full Text Available Abstract Background Why we sleep is still one of the most perplexing mysteries in biology. Strong evidence indicates that sleep is necessary for normal brain function and that sleep need is a tightly regulated process. Surprisingly, molecular mechanisms that determine sleep need are incompletely described. Moreover, very little is known about transcriptional changes that specifically accompany the accumulation and discharge of sleep need. Several studies have characterized differential gene expression changes following sleep deprivation. Much less is known, however, about changes in gene expression during the compensatory response to sleep deprivation (i.e. recovery sleep. Results In this study we present a comprehensive analysis of the effects of sleep deprivation and subsequent recovery sleep on gene expression in the mouse cortex. We used a non-traditional analytical method for normalization of genome-wide gene expression data, Removal of Unwanted Variation (RUV. RUV improves detection of differential gene expression following sleep deprivation. We also show that RUV normalization is crucial to the discovery of differentially expressed genes associated with recovery sleep. Our analysis indicates that the majority of transcripts upregulated by sleep deprivation require 6 h of recovery sleep to return to baseline levels, while the majority of downregulated transcripts return to baseline levels within 1–3 h. We also find that transcripts that change rapidly during recovery (i.e. within 3 h do so on average with a time constant that is similar to the time constant for the discharge of sleep need. Conclusions We demonstrate that proper data normalization is essential to identify changes in gene expression that are specifically linked to sleep deprivation and recovery sleep. Our results provide the first evidence that recovery sleep is comprised of two waves of transcriptional regulation that occur at different times and affect functionally

  20. Variation in the Williams syndrome GTF2I gene and anxiety proneness interactively affect prefrontal cortical response to aversive stimuli.

    Jabbi, M; Chen, Q; Turner, N; Kohn, P; White, M; Kippenhan, J S; Dickinson, D; Kolachana, B; Mattay, V; Weinberger, D R; Berman, K F

    2015-08-18

    Characterizing the molecular mechanisms underlying the heritability of complex behavioral traits such as human anxiety remains a challenging endeavor for behavioral neuroscience. Copy-number variation (CNV) in the general transcription factor gene, GTF2I, located in the 7q11.23 chromosomal region that is hemideleted in Williams syndrome and duplicated in the 7q11.23 duplication syndrome (Dup7), is associated with gene-dose-dependent anxiety in mouse models and in both Williams syndrome and Dup7. Because of this recent preclinical and clinical identification of a genetic influence on anxiety, we examined whether sequence variation in GTF2I, specifically the single-nucleotide polymorphism rs2527367, interacts with trait and state anxiety to collectively impact neural response to anxiety-laden social stimuli. Two hundred and sixty healthy adults completed the Tridimensional Personality Questionnaire Harm Avoidance (HA) subscale, a trait measure of anxiety proneness, and underwent functional magnetic resonance imaging (fMRI) while matching aversive (fearful or angry) facial identity. We found an interaction between GTF2I allelic variations and HA that affects brain response: in individuals homozygous for the major allele, there was no correlation between HA and whole-brain response to aversive cues, whereas in heterozygotes and individuals homozygous for the minor allele, there was a positive correlation between HA sub-scores and a selective dorsolateral prefrontal cortex (DLPFC) responsivity during the processing of aversive stimuli. These results demonstrate that sequence variation in the GTF2I gene influences the relationship between trait anxiety and brain response to aversive social cues in healthy individuals, supporting a role for this neurogenetic mechanism in anxiety.

  1. Sequence Variation in Rhoptry Neck Protein 10 Gene among Toxoplasma gondii Isolates from Different Hosts and Geographical Locations

    Yu ZHAO

    2017-09-01

    Full Text Available Background: Toxoplasma gondii, as a eukaryotic parasite of the phylum Apicomplexa, can infect almost all the warm-blooded animals and humans, causing toxoplasmosis. Rhoptry neck proteins (RONs play a key role in the invasion process of T. gondii and are potential vaccine candidate molecules against toxoplasmosis.Methods: The present study examined sequence variation in the rhoptry neck protein 10 (TgRON10 gene among 10 T. gondii isolates from different hosts and geographical locations from Lanzhou province during 2014, and compared with the corresponding sequences of strains ME49 and VEG obtained from the ToxoDB database, using polymerase chain reaction (PCR amplification, sequence analysis, and phylogenetic reconstruction by Bayesian inference (BI and maximum parsimony (MP. Results: Analysis of all the 12 TgRON10 genomic and cDNA sequences revealed 7 exons and 6 introns in the TgRON10 gDNA. The complete genomic sequence of the TgRON10 gene ranged from 4759 bp to 4763 bp, and sequence variation was 0-0.6% among the 12 T. gondii isolates, indicating a low sequence variation in TgRON10 gene. Phylogenetic analysis of TgRON10 sequences showed that the cluster of the 12 T. gondii isolates was not completely consistent with their respective genotypes.Conclusion: TgRON10 gene is not a suitable genetic marker for the differentiation of T. gondii isolates from different hosts and geographical locations, but may represent a potential vaccine candidate against toxoplasmosis, worth further studies.

  2. Identification of Raoultella terrigena as a Rare Causative Agent of Subungual Abscess Based on 16S rRNA and Housekeeping Gene Sequencing

    Yu Wang

    2016-01-01

    Full Text Available A 63-year-old-man was admitted to our hospital with severe subungual abscess. Bacteria were isolated from pus samples, and an inconsistent identification was shown by VITEK 2 system and MALDI-TOF mass spectrometry as Raoultella planticola and Raoultella terrigena, respectively. Molecular identification by 16S rRNA sequencing suggested that the isolate is R. terrigena, and this was further demonstrated by sequencing three housekeeping genes (rpoB, gyrA, and parC with phylogenetic analysis. To our knowledge, this is the first report of subungual abscess caused by R. terrigena, a rare case of human infection due to soil bacterium. Our study highlights the technique importance on this pathogen identification.

  3. No association between type 1 diabetes and genetic variation in vitamin D metabolism genes

    Thorsen, Steffen U; Mortensen, Henrik B; Carstensen, Bendix

    2014-01-01

    BACKGROUND: Vitamin D, certain single nucleotide polymorphisms (SNPs) in the vitamin D-receptor (VDR) gene and vitamin D metabolism genes have been associated with type 1 diabetes (T1D). OBJECTIVE: We wanted to examine if the most widely studied SNPs in genes important for production, transport......, and action of vitamin D were associated with T1D or to circulating levels of vitamin D 25-hydroxyvitamin D [25(OH)D] in a juvenile Danish population. METHODS: We genotyped eight SNPs in five vitamin D metabolism genes in 1467 trios. 25(OH)D status were analyzed in 1803 children (907 patients and 896 siblings......). RESULTS: We did not demonstrate association with T1D for SNPs in the following genes: CYP27B1, VDR, GC, CYP2R1, DHCR7, and CYP24A1. Though, variants in the GC gene were significantly associated with 25(OH)D levels in the joint model. CONCLUSION: Some of the most examined SNPs in vitamin D metabolism genes...

  4. Supplementary Material for: Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages

    Phelan, Jody

    2016-01-01

    Abstract Background Approximately 10 % of the Mycobacterium tuberculosis genome is made up of two families of genes that are poorly characterized due to their high GC content and highly repetitive nature. The PE and PPE families are typified by their highly conserved N-terminal domains that incorporate proline-glutamate (PE) and proline-proline-glutamate (PPE) signature motifs. They are hypothesised to be important virulence factors involved with host-pathogen interactions, but their high genetic variability and complexity of analysis means they are typically disregarded in genome studies. Results To elucidate the structure of these genes, 518 genomes from a diverse international collection of clinical isolates were de novo assembled. A further 21 reference M. tuberculosis complex genomes and long read sequence data were used to validate the approach. SNP analysis revealed that variation in the majority of the 168 pe/ppe genes studied was consistent with lineage. Several recombination hotspots were identified, notably pe_pgrs3 and pe_pgrs17. Evidence of positive selection was revealed in 65 pe/ppe genes, including epitopes potentially binding to major histocompatibility complex molecules. Conclusions This, the first comprehensive study of the pe and ppe genes, provides important insight into M. tuberculosis diversity and has significant implications for vaccine development.

  5. Interactions Between Variation in Candidate Genes and Environmental Factors in the Etiology of Schizophrenia and Bipolar Disorder: a Systematic Review.

    Misiak, Błażej; Stramecki, Filip; Gawęda, Łukasz; Prochwicz, Katarzyna; Sąsiadek, Maria M; Moustafa, Ahmed A; Frydecka, Dorota

    2017-08-18

    Schizophrenia and bipolar disorder (BD) are complex and multidimensional disorders with high heritability rates. The contribution of genetic factors to the etiology of these disorders is increasingly being recognized as the action of multiple risk variants with small effect sizes, which might explain only a minor part of susceptibility. On the other site, numerous environmental factors have been found to play an important role in their causality. Therefore, in recent years, several studies focused on gene × environment interactions that are believed to bridge the gap between genetic underpinnings and environmental insults. In this article, we performed a systematic review of studies investigating gene × environment interactions in BD and schizophrenia spectrum phenotypes. In the majority of studies from this field, interacting effects of variation in genes encoding catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), and FK506-binding protein 5 (FKBP5) have been explored. Almost consistently, these studies revealed that polymorphisms in COMT, BDNF, and FKBP5 genes might interact with early life stress and cannabis abuse or dependence, influencing various outcomes of schizophrenia spectrum disorders and BD. Other interactions still require further replication in larger clinical and non-clinical samples. In addition, future studies should address the direction of causality and potential mechanisms of the relationship between gene × environment interactions and various categories of outcomes in schizophrenia and BD.

  6. Characterization of a rare variant (c.2635-2A>G) of the MSH2 gene in a family with Lynch syndrome.

    Cariola, Filomena; Disciglio, Vittoria; Valentini, Anna M; Lotesoriere, Claudio; Fasano, Candida; Forte, Giovanna; Russo, Luciana; Di Carlo, Antonio; Guglielmi, Floranna; Manghisi, Andrea; Lolli, Ivan; Caruso, Maria L; Simone, Cristiano

    2018-04-01

    Lynch syndrome is caused by germline mutations in one of the mismatch repair genes ( MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. Lynch syndrome is defined on the basis of clinical, pathological, and genetic findings. Accordingly, the identification of predisposing genes allows for accurate risk assessment and tailored screening protocols. Here, we report a family case with three family members manifesting the Lynch syndrome phenotype, all of which harbor the rare variant c.2635-2A>G affecting the splice site consensus sequence of intron 15 of the MSH2 gene. This mutation was previously described only in one family with Lynch syndrome, in which mismatch repair protein expression in tumor tissues was not assessed. In this study, we report for the first time the molecular characterization of the MSH2 c.2635-2A>G variant through in silico prediction analysis, microsatellite instability, and mismatch repair protein expression experiments on tumor tissues of Lynch syndrome patients. The potential effect of the splice site variant was revealed by three splicing prediction bioinformatics tools, which suggested the generation of a new cryptic splicing site. The potential pathogenic role of this variant was also revealed by the presence of microsatellite instability and the absence of MSH2/MSH6 heterodimer protein expression in the tumor cells of cancer tissues of the affected family members. We provide compelling evidence in favor of the pathogenic role of the MSH2 variant c.2635-2A>G, which could induce an alteration of the canonical splice site and consequently an aberrant form of the protein product (MSH2).

  7. Frequent genes in rare diseases: panel-based next generation sequencing to disclose causal mutations in hereditary neuropathies.

    Dohrn, Maike F; Glöckle, Nicola; Mulahasanovic, Lejla; Heller, Corina; Mohr, Julia; Bauer, Christine; Riesch, Erik; Becker, Andrea; Battke, Florian; Hörtnagel, Konstanze; Hornemann, Thorsten; Suriyanarayanan, Saranya; Blankenburg, Markus; Schulz, Jörg B; Claeys, Kristl G; Gess, Burkhard; Katona, Istvan; Ferbert, Andreas; Vittore, Debora; Grimm, Alexander; Wolking, Stefan; Schöls, Ludger; Lerche, Holger; Korenke, G Christoph; Fischer, Dirk; Schrank, Bertold; Kotzaeridou, Urania; Kurlemann, Gerhard; Dräger, Bianca; Schirmacher, Anja; Young, Peter; Schlotter-Weigel, Beate; Biskup, Saskia

    2017-12-01

    Hereditary neuropathies comprise a wide variety of chronic diseases associated to more than 80 genes identified to date. We herein examined 612 index patients with either a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a customized multigene panel based on the next generation sequencing technique. In 121 cases (19.8%), we identified at least one putative pathogenic mutation. Of these, 54.4% showed an autosomal dominant, 33.9% an autosomal recessive, and 11.6% an X-linked inheritance. The most frequently affected genes were PMP22 (16.4%), GJB1 (10.7%), MPZ, and SH3TC2 (both 9.9%), and MFN2 (8.3%). We further detected likely or known pathogenic variants in HINT1, HSPB1, NEFL, PRX, IGHMBP2, NDRG1, TTR, EGR2, FIG4, GDAP1, LMNA, LRSAM1, POLG, TRPV4, AARS, BIC2, DHTKD1, FGD4, HK1, INF2, KIF5A, PDK3, REEP1, SBF1, SBF2, SCN9A, and SPTLC2 with a declining frequency. Thirty-four novel variants were considered likely pathogenic not having previously been described in association with any disorder in the literature. In one patient, two homozygous mutations in HK1 were detected in the multigene panel, but not by whole exome sequencing. A novel missense mutation in KIF5A was considered pathogenic because of the highly compatible phenotype. In one patient, the plasma sphingolipid profile could functionally prove the pathogenicity of a mutation in SPTLC2. One pathogenic mutation in MPZ was identified after being previously missed by Sanger sequencing. We conclude that panel based next generation sequencing is a useful, time- and cost-effective approach to assist clinicians in identifying the correct diagnosis and enable causative treatment considerations. © 2017 International Society for Neurochemistry.

  8. Inter- and intra-individual variation in allele-specific DNA methylation and gene expression in children conceived using assisted reproductive technology.

    Nahid Turan

    2010-07-01

    Full Text Available Epidemiological studies have reported a higher incidence of rare disorders involving imprinted genes among children conceived using assisted reproductive technology (ART, suggesting that ART procedures may be disruptive to imprinted gene methylation patterns. We examined intra- and inter-individual variation in DNA methylation at the differentially methylated regions (DMRs of the IGF2/H19 and IGF2R loci in a population of children conceived in vitro or in vivo. We found substantial variation in allele-specific methylation at both loci in both groups. Aberrant methylation of the maternal IGF2/H19 DMR was more common in the in vitro group, and the overall variance was also significantly greater in the in vitro group. We estimated the number of trophoblast stem cells in each group based on approximation of the variance of the binomial distribution of IGF2/H19 methylation ratios, as well as the distribution of X chromosome inactivation scores in placenta. Both of these independent measures indicated that placentas of the in vitro group were derived from fewer stem cells than the in vivo conceived group. Both IGF2 and H19 mRNAs were significantly lower in placenta from the in vitro group. Although average birth weight was lower in the in vitro group, we found no correlation between birth weight and IGF2 or IGF2R transcript levels or the ratio of IGF2/IGF2R transcript levels. Our results show that in vitro conception is associated with aberrant methylation patterns at the IGF2/H19 locus. However, very little of the inter- or intra-individual variation in H19 or IGF2 mRNA levels can be explained by differences in maternal DMR DNA methylation, in contrast to the expectations of current transcriptional imprinting models. Extraembryonic tissues of embryos cultured in vitro appear to be derived from fewer trophoblast stem cells. It is possible that this developmental difference has an effect on placental and fetal growth.

  9. Transcription through the eye of a needle: daily and annual cyclic gene expression variation in Douglas-fir needles.

    Cronn, Richard; Dolan, Peter C; Jogdeo, Sanjuro; Wegrzyn, Jill L; Neale, David B; St Clair, J Bradley; Denver, Dee R

    2017-07-24

    Perennial growth in plants is the product of interdependent cycles of daily and annual stimuli that induce cycles of growth and dormancy. In conifers, needles are the key perennial organ that integrates daily and seasonal signals from light, temperature, and water availability. To understand the relationship between seasonal cycles and seasonal gene expression responses in conifers, we examined diurnal and circannual needle mRNA accumulation in Douglas-fir (Pseudotsuga menziesii) needles at diurnal and circannual scales. Using mRNA sequencing, we sampled 6.1 × 10 9 reads from 19 trees and constructed a de novo pan-transcriptome reference that includes 173,882 tree-derived transcripts. Using this reference, we mapped RNA-Seq reads from 179 samples that capture daily and annual variation. We identified 12,042 diurnally-cyclic transcripts, 9299 of which showed homology to annotated genes from other plant genomes, including angiosperm core clock genes. Annual analysis revealed 21,225 circannual transcripts, 17,335 of which showed homology to annotated genes from other plant genomes. The timing of maximum gene expression is associated with light intensity at diurnal scales and photoperiod at annual scales, with approximately half of transcripts reaching maximum expression +/- 2 h from sunrise and sunset, and +/- 20 days from winter and summer solstices. Comparisons with published studies from other conifers shows congruent behavior in clock genes with Japanese cedar (Cryptomeria), and a significant preservation of gene expression patterns for 2278 putative orthologs from Douglas-fir during the summer growing season, and 760 putative orthologs from spruce (Picea) during the transition from fall to winter. Our study highlight the extensive diurnal and circannual transcriptome variability demonstrated in conifer needles. At these temporal scales, 29% of expressed transcripts show a significant diurnal cycle, and 58.7% show a significant circannual cycle. Remarkably

  10. Balancing selection and recombination as evolutionary forces caused population genetic variations in golden pheasant MHC class I genes.

    Zeng, Qian-Qian; He, Ke; Sun, Dan-Dan; Ma, Mei-Ying; Ge, Yun-Fa; Fang, Sheng-Guo; Wan, Qiu-Hong

    2016-02-18

    The major histocompatibility complex (MHC) genes are vital partners in the acquired immune processes of vertebrates. MHC diversity may be directly associated with population resistance to infectious pathogens. Here, we screened for polymorphisms in exons 2 and 3 of the IA1 and IA2 genes in 12 golden pheasant populations across the Chinese mainland to characterize their genetic variation levels, to understand the effects of historical positive selection and recombination in shaping class I diversity, and to investigate the genetic structure of wild golden pheasant populations. Among 339 individual pheasants, we identified 14 IA1 alleles in exon 2 (IA1-E2), 11 IA1-E3 alleles, 27 IA2-E2 alleles, and 28 IA2-E3 alleles. The non-synonymous substitution rate was significantly greater than the synonymous substitution rate at sequences in the IA2 gene encoding putative peptide-binding sites but not in the IA1 gene; we also found more positively selected sites in IA2 than in IA1. Frequent recombination events resulted in at least 9 recombinant IA2 alleles, in accordance with the intermingling pattern of the phylogenetic tree. Although some IA alleles are widely shared among studied populations, large variation occurs in the number of IA alleles across these populations. Allele frequency analysis across 2 IA loci showed low levels of genetic differentiation among populations on small geographic scales; however, significant genetic differentiation was observed between pheasants from the northern and southern regions of the Yangtze River. Both STRUCTURE analysis and F-statistic (F ST ) value comparison classified those populations into 2 major groups: the northern region of the Yangtze River (NYR) and the southern region of the Yangtze River (SYR). More extensive polymorphisms in IA2 than IA1 indicate that IA2 has undergone much stronger positive-selection pressure during evolution. Moreover, the recombination events detected between the genes and the intermingled phylogenetic

  11. Spatial and temporal variation in selection of genes associated with pearl millet varietal quantitative traits in situ

    Cedric Mariac

    2016-07-01

    Full Text Available Ongoing global climate changes imply new challenges for agriculture. Whether plants and crops can adapt to such rapid changes is still a widely debated question. We previously showed adaptation in the form of earlier flowering in pearl millet at the scale of a whole country over three decades. However, this analysis did not deal with variability of year to year selection. To understand and possibly manage plant and crop adaptation, we need more knowledge of how selection acts in situ. Is selection gradual, abrupt, and does it vary in space and over time? In the present study, we tracked the evolution of allele frequency in two genes associated with pearl millet phenotypic variation in situ. We sampled 17 populations of cultivated pearl millet over a period of two years. We tracked changes in allele frequencies in these populations by genotyping more than seven thousand individuals. We demonstrate that several allele frequencies changes are compatible with selection, by correcting allele frequency changes associated with genetic drift. We found marked variation in allele frequencies from year to year, suggesting a variable selection effect in space and over time. We estimated the strength of selection associated with variations in allele frequency. Our results suggest that the polymorphism maintained at the genes we studied is partially explained by the spatial and temporal variability of selection. In response to environmental changes, traditional pearl millet varieties could rapidly adapt thanks to this available functional variability.

  12. The effect of genetic variation of the serotonin 1B receptor gene on impulsive aggressive behavior and suicide.

    Zouk, Hana; McGirr, Alexander; Lebel, Véronique; Benkelfat, Chawky; Rouleau, Guy; Turecki, Gustavo

    2007-12-05

    Impulsive-aggressive behaviors (IABs) are regarded as possible suicide intermediate phenotypes, mediating the relationship between genes and suicide outcome. In this study, we aimed to investigate the putative relationship between genetic variation at the 5-HT1B receptor gene, which in animal models is involved in impulse-aggression control, IABs, and suicide risk. We investigated the relationship of variation at five 5-HT1B loci and IAB measures in a sample of 696 subjects, including 338 individuals who died by suicide and 358 normal epidemiological controls. We found that variation at the 5-HT1B promoter A-161T locus had a significant effect on levels of IABs, as measured by the Buss-Durkee Hostility Inventory (BDHI). Suicides also differed from controls in distribution of variants at this locus. The A-161T locus, which seems to impact 5-HT1B transcription, could play a role in suicide predisposition by means of mediating impulsive-aggressive behaviors. 2007 Wiley-Liss, Inc.

  13. Wild rodents as a model to discover genes and pathways underlying natural variation in infectious disease susceptibility.

    Turner, A K; Paterson, S

    2013-11-01

    Individuals vary in their susceptibility to infectious disease, and it is now well established that host genetic factors form a major component of this variation. The discovery of genes underlying susceptibility has the potential to lead to improved disease control, through the identification and management of vulnerable individuals and the discovery of novel therapeutic targets. Laboratory rodents have proved invaluable for ascertaining the function of genes involved in immunity to infection. However, these captive animals experience conditions very different to the natural environment, lacking the genetic diversity and environmental pressures characteristic of natural populations, including those of humans. It has therefore often proved difficult to translate basic laboratory research to the real world. In order to further our understanding of the genetic basis of infectious disease resistance, and the evolutionary forces that drive variation in susceptibility, we propose that genetic research traditionally conducted on laboratory animals is expanded to the more ecologically valid arena of natural populations. In this article, we highlight the potential of using wild rodents as a new resource for biomedical research, to link the functional genetic knowledge gained from laboratory rodents with the variation in infectious disease susceptibility observed in humans and other natural populations. © 2013 John Wiley & Sons Ltd.

  14. Variation of gene effects of six agronomic traits with water regimes in ...

    yahia

    2013-04-10

    Apr 10, 2013 ... generations mean analyses revealed that gene effects were ... fluctuation of precipitations and absence of tolerant ... excellent grain protein content (P2). ... and arc-sine of square root had no effect on data distribution or in.

  15. Lack of variation of ATTCT pentanucleotide repeats at ATXN10 gene ...

    ized incoordination of gait, speech and limb movements. (Tang et ... ataxia (SCA); ATXN10 gene; nucleotide repeat; mutation detection; capillary electrophoresis; human genetics. ... Southern blot analysis using EcoRI was performed to distin-.

  16. Diversity from genes to ecosystems: A unifying framework to study variation across biological metrics and scales

    Biological diversity is a key concept in the life sciences and plays a fundamental role in many ecological and evolutionary processes. Although biodiversity is inherently a hierarchical concept covering different levels of organization (genes, population, species, ecological communities and ecosyst...

  17. Genetic variation of Pit-1 gene in Chinese indigenous and Western ...

    STORAGESEVER

    2009-07-20

    Jul 20, 2009 ... regulates pituitary development and expression of the growth hormone, prolactin and thyrotropin β- submit genes. Pit-1 ... mice (Camper et al., 1990), as well as including the .... logy Company, Shanghai, China). Statistical ...

  18. Rare earths

    Cranstone, D A

    1979-01-01

    Rare earth elements are commonly extracted from the minerals monazite, bastnaesite, and xenotine. New uses for these elements are constantly developing; they have found applications in glass polishing, television tube phosphors, high-strength low-alloy steels, magnets, catalysts, refractory ceramics, and hydrogen sponge alloys. In Canada, rare earths have been produced as byproducts of the uranium mining industry, but there was no production of rare earths in 1978 or 1979. The world sources of and markets for the rare earth elements are discussed.

  19. Genetic Variation in the Matrix Metalloproteinase Genes and Diabetic Nephropathy in Type 1 Diabetes

    Kure, Masahiko; Pezzolesi, Marcus G.; Poznik, G. David; Katavetin, Pisut; Skupien, Jan; Dunn, Jonathon S.; Mychaleckyj, Josyf C.; Warram, James H.; Krolewski, Andrzej S.

    2011-01-01

    Genetic data support the notion that polymorphisms in members of the matrix metalloproteinase (MMP) family of genes play an important role in extracellular matrix remodeling and contribute to the pathogenesis of vascular disease. To identify novel genetic markers for diabetic nephropathy (DN), we examined the relationship between MMP gene polymorphisms and DN in the Genetics of Kidneys in Diabetes (GoKinD) population. Genotypic data from the Genetic Association Information Network (GAIN) type...

  20. Genetic variation in a DNA double strand break repair gene in saudi population: a comparative study with worldwide ethnic groups.

    Areeshi, Mohammed Yahya

    2013-01-01

    DNA repair capacity is crucial in maintaining cellular functions and homeostasis. However, it can be altered based on DNA sequence variations in DNA repair genes and this may lead to the development of many diseases including malignancies. Identification of genetic polymorphisms responsible for reduced DNA repair capacity is necessary for better prevention. Homologous recombination (HR), a major double strand break repair pathway, plays a critical role in maintaining the genome stability. The present study was performed to determine the frequency of the HR gene XRCC3 Exon 7 (C18067T, rs861539) polymorphisms in Saudi Arabian population in comparison with epidemiological studies by "MEDLINE" search to equate with global populations. The variant allelic (T) frequency of XRCC3 (C>T) was found to be 39%. Our results suggest that frequency of XRCC3 (C>T) DNA repair gene exhibits distinctive patterns compared with the Saudi Arabian population and this might be attributed to ethnic variation. The present findings may help in high-risk screening of humans exposed to environmental carcinogens and cancer predisposition in different ethnic groups.

  1. SLC26A4 gene copy number variations in Chinese patients with non-syndromic enlarged vestibular aqueduct

    Zhao Jiandong

    2012-05-01

    Full Text Available Abstract Background Many patients with enlarged vestibular aqueduct (EVA have either only one allelic mutant of the SLC26A4 gene or lack any detectable mutation. In this study, multiplex ligation-dependent probe amplification (MLPA was used to screen for copy number variations (CNVs of SLC26A4 and to reveal the pathogenic mechanisms of non-syndromic EVA (NSEVA. Methods Between January 2003 and March 2010, 923 Chinese patients (481 males, 442 females with NSEVA were recruited. Among these, 68 patients (7.4% were found to carry only one mutant allele of SLC26A4 and 39 patients (4.2% lacked any detectable mutation in SLC26A4; these 107 patients without double mutant alleles were assigned to the patient group. Possible copy number variations in SLC26A4 were detected by SALSA MLPA. Results Using GeneMapper, no significant difference was observed between the groups, as compared with the standard probe provided in the assay. The results of the capillary electrophoresis showed no significant difference between the patients and controls. Conclusion Our results suggest that CNVs and the exon deletion in SLC26A4 are not important factors in NSEVA. However, it would be premature to conclude that CNVs have no role in EVA. Genome-wide studies to explore CNVs within non-coding regions of the SLC26A4 gene and neighboring regions are warranted, to elucidate their roles in NSEVA etiology.

  2. Unraveling the effects of selection and demography on immune gene variation in free-ranging plains zebra (Equus quagga) populations.

    Kamath, Pauline L; Getz, Wayne M

    2012-01-01

    Demography, migration and natural selection are predominant processes affecting the distribution of genetic variation among natural populations. Many studies use neutral genetic markers to make inferences about population history. However, the investigation of functional coding loci, which directly reflect fitness, is critical to our understanding of species' ecology and evolution. Immune genes, such as those of the Major Histocompatibility Complex (MHC), play an important role in pathogen recognition and provide a potent model system for studying selection. We contrasted diversity patterns of neutral data with MHC loci, ELA-DRA and -DQA, in two southern African plains zebra (Equus quagga) populations: Etosha National Park, Namibia, and Kruger National Park, South Africa. Results from neutrality tests, along with observations of elevated diversity and low differentiation across populations, supported previous genus-level evidence for balancing selection at these loci. Despite being low, MHC divergence across populations was significant and may be attributed to drift effects typical of geographically separated populations experiencing little to no gene flow, or alternatively to shifting allele frequency distributions driven by spatially variable and fluctuating pathogen communities. At the DRA, zebra exhibited geographic differentiation concordant with microsatellites and reduced levels of diversity in Etosha due to highly skewed allele frequencies that could not be explained by demography, suggestive of spatially heterogeneous selection and local adaptation. This study highlights the complexity in which selection affects immune gene diversity and warrants the need for further research on the ecological mechanisms shaping patterns of adaptive variation among natural populations.

  3. Unraveling the effects of selection and demography on immune gene variation in free-ranging plains zebra (Equus quagga populations.

    Pauline L Kamath

    Full Text Available Demography, migration and natural selection are predominant processes affecting the distribution of genetic variation among natural populations. Many studies use neutral genetic markers to make inferences about population history. However, the investigation of functional coding loci, which directly reflect fitness, is critical to our understanding of species' ecology and evolution. Immune genes, such as those of the Major Histocompatibility Complex (MHC, play an important role in pathogen recognition and provide a potent model system for studying selection. We contrasted diversity patterns of neutral data with MHC loci, ELA-DRA and -DQA, in two southern African plains zebra (Equus quagga populations: Etosha National Park, Namibia, and Kruger National Park, South Africa. Results from neutrality tests, along with observations of elevated diversity and low differentiation across populations, supported previous genus-level evidence for balancing selection at these loci. Despite being low, MHC divergence across populations was significant and may be attributed to drift effects typical of geographically separated populations experiencing little to no gene flow, or alternatively to shifting allele frequency distributions driven by spatially variable and fluctuating pathogen communities. At the DRA, zebra exhibited geographic differentiation concordant with microsatellites and reduced levels of diversity in Etosha due to highly skewed allele frequencies that could not be explained by demography, suggestive of spatially heterogeneous selection and local adaptation. This study highlights the complexity in which selection affects immune gene diversity and warrants the need for further research on the ecological mechanisms shaping patterns of adaptive variation among natural populations.

  4. Allelic Variations at Four Major Maturity E Genes and Transcriptional Abundance of the E1 Gene Are Associated with Flowering Time and Maturity of Soybean Cultivars

    Wang, Yueqiang; Chen, Xin; Ren, Haixiang; Yang, Jiayin; Cheng, Wen; Zong, Chunmei; Gu, Heping; Qiu, Hongmei; Wu, Hongyan; Zhang, Xingzheng; Cui, Tingting; Xia, Zhengjun

    2014-01-01

    The time to flowering and maturity are ecologically and agronomically important traits for soybean landrace and cultivar adaptation. As a typical short-day crop, long day conditions in the high-latitude regions require soybean cultivars with photoperiod insensitivity that can mature before frost. Although the molecular basis of four major E loci (E1 to E4) have been deciphered, it is not quite clear whether, or to what degree, genetic variation and the expression level of the four E genes are associated with the time to flowering and maturity of soybean cultivars. In this study, we genotyped 180 cultivars at E1 to E4 genes, meanwhile, the time to flowering and maturity of those cultivars were investigated at six geographic locations in China from 2011 to 2012 and further confirmed in 2013. The percentages of recessive alleles at E1, E2, E3 and E4 loci were 38.34%, 84.45%, 36.33%, and 7.20%, respectively. Statistical analysis showed that allelic variations at each of four loci had a significant effect on flowering time as well as maturity. We classified the 180 cultivars into eight genotypic groups based on allelic variations of the four major E loci. The genetic group of e1-nf representing dysfunctional alleles at the E1 locus flowered earliest in all the geographic locations. In contrast, cultivars in the E1E2E3E4 group originated from the southern areas flowered very late or did not flower before frost at high latitude locations. The transcriptional abundance of functional E1 gene was significantly associated with flowering time. However, the ranges of time to flowering and maturity were quite large within some genotypic groups, implying the presence of some other unknown genetic factors that are involved in control of flowering time or maturity. Known genes (e.g. E3 and E4) and other unknown factors may function, at least partially, through regulation of the expression of the E1 gene. PMID:24830458

  5. Expression profiles of sugarcane under drought conditions: Variation in gene regulation

    Júlio César Farias de Andrade

    2015-01-01

    Full Text Available AbstractDrought is a major factor in decreased sugarcane productivity because of the resulting morphophysiological effects that it causes. Gene expression studies that have examined the influence of water stress in sugarcane have yielded divergent results, indicating the absence of a fixed pattern of changes in gene expression. In this work, we investigated the expression profiles of 12 genes in the leaves of a drought-tolerant genotype (RB72910 of sugarcane and compared the results with those of other studies. The genotype was subjected to 80–100% water availability (control condition and 0–20% water availability (simulated drought. To analyze the physiological status, the SPAD index, Fv/Fm ratio, net photosynthesis (A, stomatal conductance (gs and stomatal transpiration (E were measured. Total RNA was extracted from leaves and the expression of SAMDC, ZmPIP2-1 protein, ZmTIP4-2 protein, WIP protein, LTP protein, histone H3, DNAj, ferredoxin I, β-tubulin, photosystem I, gene 1 and gene 2 was analyzed by quantitative real-time PCR (RT-PCR. Important differences in the expression profiles of these genes were observed when compared with other genotypes, suggesting that complex defense mechanisms are activated in response to water stress. However, there was no recognizable pattern for the changes in expression of the different proteins associated with tolerance to drought stress.

  6. The association of telomere length and genetic variation in telomere biology genes.

    Mirabello, Lisa; Yu, Kai; Kraft, Peter; De Vivo, Immaculata; Hunter, David J; Prescott, Jennifer; Wong, Jason Y Y; Chatterjee, Nilanjan; Hayes, Richard B; Savage, Sharon A

    2010-09-01

    Telomeres cap chromosome ends and are critical for genomic stability. Many telomere-associated proteins are important for telomere length maintenance. Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in genes encoding telomere-associated proteins (RTEL1 and TERT-CLPTM1) as markers of cancer risk. We conducted an association study of telomere length and 743 SNPs in 43 telomere biology genes. Telomere length in peripheral blood DNA was determined by Q-PCR in 3,646 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and Nurses' Health Study. We investigated associations by SNP, gene, and pathway (functional group). We found no associations between telomere length and SNPs in TERT-CLPTM1L or RTEL1. Telomere length was not significantly associated with specific functional groups. Thirteen SNPs from four genes (MEN1, MRE11A, RECQL5, and TNKS) were significantly associated with telomere length. The strongest findings were in MEN1 (gene-based P=0.006), menin, which associates with the telomerase promoter and may negatively regulate telomerase. This large association study did not find strong associations with telomere length. The combination of limited diversity and evolutionary conservation suggest that these genes may be under selective pressure. More work is needed to explore the role of genetic variants in telomere length regulation. Published 2010 Wiley-Liss, Inc.

  7. Gene expression variation to predict 10-year survival in lymph-node-negative breast cancer

    Karlsson, Elin; Delle, Ulla; Danielsson, Anna; Olsson, Björn; Abel, Frida; Karlsson, Per; Helou, Khalil

    2008-01-01

    It is of great significance to find better markers to correctly distinguish between high-risk and low-risk breast cancer patients since the majority of breast cancer cases are at present being overtreated. 46 tumours from node-negative breast cancer patients were studied with gene expression microarrays. A t-test was carried out in order to find a set of genes where the expression might predict clinical outcome. Two classifiers were used for evaluation of the gene lists, a correlation-based classifier and a Voting Features Interval (VFI) classifier. We then evaluated the predictive accuracy of this expression signature on tumour sets from two similar studies on lymph-node negative patients. They had both developed gene expression signatures superior to current methods in classifying node-negative breast tumours. These two signatures were also tested on our material. A list of 51 genes whose expression profiles could predict clinical outcome with high accuracy in our material (96% or 89% accuracy in cross-validation, depending on type of classifier) was developed. When tested on two independent data sets, the expression signature based on the 51 identified genes had good predictive qualities in one of the data sets (74% accuracy), whereas their predictive value on the other data set were poor, presumably due to the fact that only 23 of the 51 genes were found in that material. We also found that previously developed expression signatures could predict clinical outcome well to moderately well in our material (72% and 61%, respectively). The list of 51 genes derived in this study might have potential for clinical utility as a prognostic gene set, and may include candidate genes of potential relevance for clinical outcome in breast cancer. According to the predictions by this expression signature, 30 of the 46 patients may have benefited from different adjuvant treatment than they recieved. The research on these tumours was approved by the Medical Faculty Research

  8. Variation in the fumonisin biosynthetic gene cluster in fumonisin-producing and nonproducing black aspergilli.

    Susca, Antonia; Proctor, Robert H; Butchko, Robert A E; Haidukowski, Miriam; Stea, Gaetano; Logrieco, Antonio; Moretti, Antonio

    2014-12-01

    The ability to produce fumonisin mycotoxins varies among members of the black aspergilli. Previously, analyses of selected genes in the fumonisin biosynthetic gene (fum) cluster in black aspergilli from California grapes indicated that fumonisin-nonproducing isolates of Aspergillus welwitschiae lack six fum genes, but nonproducing isolates of Aspergillus niger do not. In the current study, analyses of black aspergilli from grapes from the Mediterranean Basin indicate that the genomic context of the fum cluster is the same in isolates of A. niger and A. welwitschiae regardless of fumonisin-production ability and that full-length clusters occur in producing isolates of both species and nonproducing isolates of A. niger. In contrast, the cluster has undergone an eight-gene deletion in fumonisin-nonproducing isolates of A. welwitschiae. Phylogenetic analyses suggest each species consists of a mixed population of fumonisin-producing and nonproducing individuals, and that existence of both production phenotypes may provide a selective advantage to these species. Differences in gene content of fum cluster homologues and phylogenetic relationships of fum genes suggest that the mutation(s) responsible for the nonproduction phenotype differs, and therefore arose independently, in the two species. Partial fum cluster homologues were also identified in genome sequences of four other black Aspergillus species. Gene content of these partial clusters and phylogenetic relationships of fum sequences indicate that non-random partial deletion of the cluster has occurred multiple times among the species. This in turn suggests that an intact cluster and fumonisin production were once more widespread among black aspergilli. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Population genetic implications from sequence variation in four Y chromosome genes.

    Shen, P; Wang, F; Underhill, P A; Franco, C; Yang, W H; Roxas, A; Sung, R; Lin, A A; Hyman, R W; Vollrath, D; Davis, R W; Cavalli-Sforza, L L; Oefner, P J

    2000-06-20

    Some insight into human evolution has been gained from the sequencing of four Y chromosome genes. Primary genomic sequencing determined gene SMCY to be composed of 27 exons that comprise 4,620 bp of coding sequence. The unfinished sequencing of the 5' portion of gene UTY1 was completed by primer walking, and a total of 20 exons were found. By using denaturing HPLC, these two genes, as well as DBY and DFFRY, were screened for polymorphic sites in 53-72 representatives of the five continents. A total of 98 variants were found, yielding nucleotide diversity estimates of 2.45 x 10(-5), 5. 07 x 10(-5), and 8.54 x 10(-5) for the coding regions of SMCY, DFFRY, and UTY1, respectively, with no variant having been observed in DBY. In agreement with most autosomal genes, diversity estimates for the noncoding regions were about 2- to 3-fold higher and ranged from 9. 16 x 10(-5) to 14.2 x 10(-5) for the four genes. Analysis of the frequencies of derived alleles for all four genes showed that they more closely fit the expectation of a Luria-Delbrück distribution than a distribution expected under a constant population size model, providing evidence for exponential population growth. Pairwise nucleotide mismatch distributions date the occurrence of population expansion to approximately 28,000 years ago. This estimate is in accord with the spread of Aurignacian technology and the disappearance of the Neanderthals.

  10. Genetic and molecular analyses of natural variation indicate CBF2 as a candidate gene for underlying a freezing tolerance quantitative trait locus in Arabidopsis

    Alonso-Blanco, C.; Gomez-Mena, C.; Llorente, F.; Koornneef, M.; Salinas, J.; Martinez-Zapater, J.M.

    2005-01-01

    Natural variation for freezing tolerance is a major component of adaptation and geographic distribution of plant species. However, little is known about the genes and molecular mechanisms that determine its naturally occurring diversity. We have analyzed the intraspecific freezing tolerance

  11. A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration.

    Rivera, A; White, K; Stöhr, H; Steiner, K; Hemmrich, N; Grimm, T; Jurklies, B; Lorenz, B; Scholl, H P; Apfelstedt-Sylla, E; Weber, B H

    2000-10-01

    Stargardt disease (STGD) is a common autosomal recessive maculopathy of early and young-adult onset and is caused by alterations in the gene encoding the photoreceptor-specific ATP-binding cassette (ABC) transporter (ABCA4). We have studied 144 patients with STGD and 220 unaffected individuals ascertained from the German population, to complete a comprehensive, population-specific survey of the sequence variation in the ABCA4 gene. In addition, we have assessed the proposed role for ABCA4 in age-related macular degeneration (AMD), a common cause of late-onset blindness, by studying 200 affected individuals with late-stage disease. Using a screening strategy based primarily on denaturing gradient gel electrophoresis, we have identified in the three study groups a total of 127 unique alterations, of which 90 have not been previously reported, and have classified 72 as probable pathogenic mutations. Of the 288 STGD chromosomes studied, mutations were identified in 166, resulting in a detection rate of approximately 58%. Eight different alleles account for 61% of the identified disease alleles, and at least one of these, the L541P-A1038V complex allele, appears to be a founder mutation in the German population. When the group with AMD and the control group were analyzed with the same methodology, 18 patients with AMD and 12 controls were found to harbor possible disease-associated alterations. This represents no significant difference between the two groups; however, for detection of modest effects of rare alleles in complex diseases, the analysis of larger cohorts of patients may be required.

  12. Identification of a rare point mutation at C-terminus of merozoite surface antigen-1 gene of Plasmodium falciparum in eastern Indian isolates.

    Raj, Dipak Kumar; Das, Bibhu Ranjan; Dash, A P; Supakar, Prakash C

    2004-01-01

    Merozoite surface antigen-1 (MSA-1) of Plasmodium falciparum is highly immunogenic in human. Several studies suggest that MSA-1 protein is an effective target for a protective immune response. Attempt has been made to find new point mutations by analyzing 244 bp [codon 1655(R) to 1735 (I)] relatively conserved C-terminus region of MSA-1 gene in 125 isolates. This region contains two EGF like domains, which are involved in generating protective immune response in human. Point mutations in this region are very much important in view of vaccine development. Searching of mutational hot spots in MSA-1 protein by sequencing method in a representative number of isolates is quite critical and expensive. Therefore, in this study slot blot and PCR-SSCP method have been used to find out new mutations in the individual isolates showing alterations in the mobility of DNA fragment. Sequencing of the altered bands from the SSCP gel shows a rare non-synonymous point mutation in 7 (5.6%) of the 125 isolates at amino acid position 1704 of MSA-1 gene where isoleucine is replaced by valine.

  13. Contribution of Myostatin gene polymorphisms to normal variation in lean mass, fat mass and peak BMD in Chinese male offspring

    Hua YUE; Miao LI; Yu-juan LIU; Song-hua WU; Zhen-lin ZHANG; Jin-wei HE; Hao ZHANG; Chun WANG; Wei-wei HU; Jie-mei GU; Yao-hua KE; Wen-zhen FU; Yun-qiu HU

    2012-01-01

    Myostatin gene is a member of the transforming growth factor-β (TGF-β) family that negatively regulates skeletal muscle growth.Genetic polymorphisms in Myostatin were found to be associated with the peak bone mineral density (BMD) in Chinese women.The purpose of this study was to investigate whether Myostatin played a role in the normal variation in peak BMD,lean mass (LM),and fat mass (FM) of Chinese men.Methods:Four hundred male-offspring nuclear families of Chinese Han ethnic group were recruited.Anthropometric measurements,includingthe peak BMD,body LM and FM were measured using dual-energy X-ray absorptiometry (DXA).The single nucleotide polymorphisms (SNPs) studied were tag-SNPs selected by sequencing.Both rs2293284 and +2278G>A were genotyped using TaqMan assay,and rs3791783 was genotyped with PCR-restriction fragment length polymorphism (RFLP) analysis.The associations of the SNPs with anthropometfic variations were analyzed using the quantitative transmission disequilibrium test (QTDT).Results:Using QTDT to detect within-family associations,neither single SNP nor haplotype was found to be associated with peak BMD at any bone site.However,rs3791783 was found to be significantly associated with fat mass of the trunk (P<0.001).Moreover,for within-family associations,haplotypes AGG,AAA,and TGG were found to be significantly associated with the trunk fat mass (all P<0.001).Conclusion:Our results suggest that genetic variation within Myostatin may play a role in regulating the variation in fat mass in Chinese males.Additionally,the Myostatin gene may be a candidate that determines body fat mass in Chinese men.

  14. Common genetic variations in the CYP2R1 and GC genes are determinants of vitamin D status in Danes

    Nissen, Ioanna

    Vitamin D is considered a key fat-soluble vitamin critically important for good bone- and overall health throughout life. Vitamin D deficiency increases the risk of developing rickets, osteomalacia and osteoporosis, and moreover increases the risk of various non-skeletal adverse health outcomes......), after 6 months intake of vitamin D3-fortified bread and milk (paper II) and in 92 participants in the VitDgen study after artificial UVB irradiation during winter (paper III). Common genetic variations in the CYP2R1 and GC genes were found to be important determinants of vitamin D status in three out...

  15. Endocannabinoid receptor 1 gene variations increase risk for obesity and modulate body mass index in European populations

    Benzinou, Michael; Chèvre, Jean-Claude; Ward, Kirsten J

    2008-01-01

    The therapeutic effects of cannabinoid receptor blockade on obesity-associated phenotypes underline the importance of the endocannabinoid pathway on the energy balance. Using a staged-approach, we examined the contribution of the endocannabinoid receptor 1 gene (CNR1) on obesity and body mass ind...... variations increase the risk for obesity and modulate BMI in our European population. As CB1 is a drug target for obesity, a pharmacogenetic analysis of the endocannabinoid blockade obesity treatment may be of interest to identify best responders....

  16. Plasticity of the Leishmania genome leading to gene copy number variations and drug resistance [version 1; referees: 5 approved

    Marie-Claude N. Laffitte

    2016-09-01

    Full Text Available Leishmania has a plastic genome, and drug pressure can select for gene copy number variation (CNV. CNVs can apply either to whole chromosomes, leading to aneuploidy, or to specific genomic regions. For the latter, the amplification of chromosomal regions occurs at the level of homologous direct or inverted repeated sequences leading to extrachromosomal circular or linear amplified DNAs. This ability of Leishmania to respond to drug pressure by CNVs has led to the development of genomic screens such as Cos-Seq, which has the potential of expediting the discovery of drug targets for novel promising drug candidates.

  17. Porcine MYF6 gene: sequence, homology analysis, and variation in the promoter region.

    Wyszyńska-Koko, J; Kurył, J

    2004-01-01

    MYF6 gene codes for the bHLH transcription factor belonging to MyoD family. Its expression accompanies the processes of differentiation and maturation of myotubes during embriogenesis and continues on a relatively high level after birth, affecting the muscle phenotype. The porcine MYF6 gene was amplified and sequenced and compared with MYF6 gene sequences of other species. The amino acid sequence was deduced and an interspecies homology analysis was performed. Myf-6 protein shows a high conservation among species of 99 and 97% identity when comparing pig with cow and human, respectively, and of 93% when comparing pig with mouse and rat. The single nucleotide polymorphism (SNP) was revealed within the promoter region, which appeared to be T --> C transition recognized by a MspI restriction enzyme.

  18. Variation at the Calpain 3 gene is associated with meat tenderness in zebu and composite breeds of cattle

    Bunch Rowan J

    2008-07-01

    Full Text Available Abstract Background Quantitative Trait Loci (QTL affecting meat tenderness have been reported on Bovine chromosome 10. Here we examine variation at the Calpain 3 (CAPN3 gene in cattle, a gene located within the confidence interval of the QTL, and which is a positional candidate gene based on the biochemical activity of the protein. Results We identified single nucleotide polymorphisms (SNP in the genomic sequence of the CAPN3 gene and tested three of these in a sample of 2189 cattle. Of the three SNP genotyped, the CAPN3:c.1538+225G>T had the largest significant additive effect, with an allele substitution effect in the Brahman of α = -0.144 kg, SE = 0.060, P = 0.016, and the polymorphism explained 1.7% of the residual phenotypic variance in that sample of the breed. Significant haplotype substitution effects were found for all three breeds, the Brahman, the Belmont Red, and the Santa Gertrudis. For the common haplotype, the haplotype substitution effect in the Brahman was α = 0.169 kg, SE = 0.056, P = 0.003. The effect of this gene was compared to Calpastatin in the same sample. The SNP show negligible frequencies in taurine breeds and low to moderate minor allele frequencies in zebu or composite animals. Conclusion These associations confirm the location of a QTL for meat tenderness in this region of bovine chromosome 10. SNP in or near this gene may be responsible for part of the overall difference between taurine and zebu breeds in meat tenderness, and the greater variability in meat tenderness found in zebu and composite breeds. The evidence provided so far suggests that none of these tested SNP are causative mutations.

  19. Diversity and population-genetic properties of copy number variations and multicopy genes in cattle

    The diversity and population-genetics of copy number variation (CNV) in domesticated animals are not well understood. In this study, we analyzed 75 genomes of major taurine and indicine cattle breeds (including Angus, Brahman, Gir, Holstein, Jersey, Limousin, Nelore, Romagnola), sequenced to 11-fold...

  20. Analysis of indel variations in the human disease-associated genes ...

    Keywords. insertion–deletion variations; haematological disease; tumours; human genetics. Journal of Genetics ... domly selected healthy Korean individuals using a blood genomic DNA ... Bioinformatics annotation and 3-D protein structure analysis. In this study ..... 2009 A genome-wide meta-analysis identifies. Journal of ...

  1. Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes

    Jetten, M.J.A.; Blanco Garcia, Ainhoa; Coonen, M.L.J.; Claessen, Sandra; Herwijnen, van M.H.M.; Lommen, Arjen; Delft, van J.H.M.; Peijnenburg, A.A.C.M.; Kleinjans, J.C.S.

    2016-01-01

    Acetaminophen (APAP) is a readily available over-the-counter drug and is one of the most commonly used analgesics/antipyretics worldwide. Large interindividual variation in susceptibility toward APAP-induced liver failure has been reported. However, the exact underlying factors causing this

  2. Schooling and Variation in the "COMT" Gene: The Devil Is in the Details

    Campbell, Daniel; Bick, Johanna; Yrigollen, Carolyn M.; Lee, Maria; Joseph, Antony; Chang, Joseph T.; Grigorenko, Elena L.

    2013-01-01

    Background: Schooling is considered one of the major contributors to the development of intelligence within societies and individuals. Genetic variation might modulate the impact of schooling and explain, at least partially, the presence of individual differences in classrooms. Method: We studied a sample of 1,502 children (mean age = 11.7 years)…

  3. Structural defects and variations in the HIV-1 nef gene from rapid, slow and non-progressor children.

    Casartelli, Nicoletta; Di Matteo, Gigliola; Argentini, Claudio; Cancrini, Caterina; Bernardi, Stefania; Castelli, Guido; Scarlatti, Gabriella; Plebani, Anna; Rossi, Paolo; Doria, Margherita

    2003-06-13

    Evaluation of sequence evolution as well as structural defects and mutations of the human immunodeficiency virus-type 1 (HIV-1) nef gene in relation to disease progression in infected children. We examined a large number of nef alleles sequentially derived from perinatally HIV-1-infected children with different rates of disease progression: six non-progressors (NPs), four rapid progressors (RPs), and three slow progressors (SPs). Nef alleles (182 total) were isolated from patients' peripheral blood mononuclear cells (PBMCs), sequenced and analysed for their evolutionary pattern, frequency of mutations and occurrence of amino acid variations associated with different stages of disease. The evolution rate of the nef gene apparently correlated with CD4+ decline in all progression groups. Evidence for rapid viral turnover and positive selection for changes were found only in two SPs and two RPs respectively. In NPs, a higher proportion of disrupted sequences and mutations at various functional motifs were observed. Furthermore, NP-derived Nef proteins were often changed at residues localized in the folded core domain at cytotoxic T lymphocytes (CTL) epitopes (E(105), K(106), E(110), Y(132), K(164), and R(200)), while other residues outside the core domain are more often changed in RPs (A(43)) and SPs (N(173) and Y(214)). Our results suggest a link between nef gene functions and the progression rate in HIV-1-infected children. Moreover, non-progressor-associated variations in the core domain of Nef, together with the genetic analysis, suggest that nef gene evolution is shaped by an effective immune system in these patients.

  4. Genetic Variation of Goat Interferon Regulatory Factor 3 Gene and Its Implication in Goat Evolution.

    Okpeku, Moses; Esmailizadeh, Ali; Adeola, Adeniyi C; Shu, Liping; Zhang, Yesheng; Wang, Yangzi; Sanni, Timothy M; Imumorin, Ikhide G; Peters, Sunday O; Zhang, Jiajin; Dong, Yang; Wang, Wen

    2016-01-01

    The immune systems are fundamentally vital for evolution and survival of species; as such, selection patterns in innate immune loci are of special interest in molecular evolutionary research. The interferon regulatory factor (IRF) gene family control many different aspects of the innate and adaptive immune responses in vertebrates. Among these, IRF3 is known to take active part in very many biological processes. We assembled and evaluated 1356 base pairs of the IRF3 gene coding region in domesticated goats from Africa (Nigeria, Ethiopia and South Africa) and Asia (Iran and China) and the wild goat (Capra aegagrus). Five segregating sites with θ value of 0.0009 for this gene demonstrated a low diversity across the goats' populations. Fu and Li tests were significantly positive but Tajima's D test was significantly negative, suggesting its deviation from neutrality. Neighbor joining tree of IRF3 gene in domesticated goats, wild goat and sheep showed that all domesticated goats have a closer relationship than with the wild goat and sheep. Maximum likelihood tree of the gene showed that different domesticated goats share a common ancestor and suggest single origin. Four unique haplotypes were observed across all the sequences, of which, one was particularly common to African goats (MOCH-K14-0425, Poitou and WAD). In assessing the evolution mode of the gene, we found that the codon model dN/dS ratio for all goats was greater than one. Phylogenetic Analysis by Maximum Likelihood (PAML) gave a ω0 (dN/dS) value of 0.067 with LnL value of -6900.3 for the first Model (M1) while ω2 = 1.667 in model M2 with LnL value of -6900.3 with positive selection inferred in 3 codon sites. Mechanistic empirical combination (MEC) model for evaluating adaptive selection pressure on particular codons also confirmed adaptive selection pressure in three codons (207, 358 and 408) in IRF3 gene. Positive diversifying selection inferred with recent evolutionary changes in domesticated goat IRF3

  5. Homoeologous exchange is a major cause of gene presence/absence variation in the amphidiploid Brassica napus.

    Hurgobin, Bhavna; Golicz, Agnieszka A; Bayer, Philipp E; Chan, Chon-Kit Kenneth; Tirnaz, Soodeh; Dolatabadian, Aria; Schiessl, Sarah V; Samans, Birgit; Montenegro, Juan D; Parkin, Isobel A P; Pires, J Chris; Chalhoub, Boulos; King, Graham J; Snowdon, Rod; Batley, Jacqueline; Edwards, David

    2018-07-01

    Homoeologous exchanges (HEs) have been shown to generate novel gene combinations and phenotypes in a range of polyploid species. Gene presence/absence variation (PAV) is also a major contributor to genetic diversity. In this study, we show that there is an association between these two events, particularly in recent Brassica napus synthetic accessions, and that these represent a novel source of genetic diversity, which can be captured for the improvement of this important crop species. By assembling the pangenome of B. napus, we show that 38% of the genes display PAV behaviour, with some of these variable genes predicted to be involved in important agronomic traits including flowering time, disease resistance, acyl lipid metabolism and glucosinolate metabolism. This study is a first and provides a detailed characterization of the association between HEs and PAVs in B. napus at the pangenome level. © 2017 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

  6. Gene therapy in rare diseases: the benefits and challenges of developing a patient-centric registry for Strimvelis in ADA-SCID.

    Stirnadel-Farrant, Heide; Kudari, Mahesh; Garman, Nadia; Imrie, Jessica; Chopra, Bikramjit; Giannelli, Stefania; Gabaldo, Michela; Corti, Ambra; Zancan, Stefano; Aiuti, Alessandro; Cicalese, Maria Pia; Batta, Rohit; Appleby, Jonathan; Davinelli, Mario; Ng, Pauline

    2018-04-06

    Strimvelis (autologous CD34+ cells transduced to express adenosine deaminase [ADA]) is the first ex vivo stem cell gene therapy approved by the European Medicines Agency (EMA), indicated as a single treatment for patients with ADA-severe combined immunodeficiency (ADA-SCID) who lack a suitable matched related bone marrow donor. Existing primary immunodeficiency registries are tailored to transplantation outcomes and do not capture the breadth of safety and efficacy endpoints required by the EMA for the long-term monitoring of gene therapies. Furthermore, for extended monitoring of Strimvelis, the young age of children treated, small patient numbers, and broad geographic distribution of patients all increase the risk of loss to follow-up before sufficient data have been collected. Establishing individual investigator sites would be impractical and uneconomical owing to the small number of patients from each location receiving Strimvelis. An observational registry has been established to monitor the safety and effectiveness of Strimvelis in up to 50 patients over a minimum of 15 years. To address the potential challenges highlighted above, data will be collected by a single investigator site at Ospedale San Raffaele (OSR), Milan, Italy, and entered into the registry via a central electronic platform. Patients/families and the patient's local physician will also be able to submit healthcare information directly to the registry using a uniquely designed electronic platform. Data entry will be monitored by a Gene Therapy Registry Centre (funded by GlaxoSmithKline) who will ensure that necessary information is collected and flows between OSR, the patient/family and the patient's local healthcare provider. The Strimvelis registry sets a precedent for the safety monitoring of future gene therapies. A unique, patient-focused design has been implemented to address the challenges of long-term follow-up of patients treated with gene therapy for a rare disease. Strategies to

  7. Serotonin and Early Cognitive Development: Variation in the Tryptophan Hydroxylase 2 Gene Is Associated with Visual Attention in 7-Month-Old Infants

    Leppanen, Jukka M.; Peltola, Mikko J.; Puura, Kaija; Mantymaa, Mirjami; Mononen, Nina; Lehtimaki, Terho

    2011-01-01

    Background: Allelic variation in the promoter region of a gene that encodes tryptophan hydroxylase isoform 2 (TPH2), a rate-limiting enzyme of serotonin synthesis in the central nervous system, has been associated with variations in cognitive function and vulnerability to affective spectrum disorders. Little is known about the effects of this gene…

  8. Genetic Variation in the Leptin Receptor Gene, Leptin, and Weight Gain in Young Dutch Adults

    Rossum, van C.T.M.; Hoebee, B.; Baak, van M.A.; Mars, M.; Saris, W.H.M.; Seidell, J.C.

    2003-01-01

    Objective: To investigate the association between leptin levels, polymorphisms in the leptin receptor (LEPR) gene, and weight gain. Research Methods and Procedures: From two large prospective cohorts in The Netherlands (n = 17, 500), we compared the baseline leptin of 259 subjects who had gained an

  9. Molecular cloning and variation of ω-gliadin genes from a somatic ...

    repetitive domain, which hampers cloning. Further analysis of ω-gliadins at the DNA level would provide more informa- tion to define the evolution and function of this gene family. (Hassania et al. 2008). ∗For correspondence. E-mail: fanguo2002@sdu.edu.cn. Agropyron elongatum (Host) Nevishi (syn. Thinopyrum ponticum ...

  10. Natural variation of histone modification and its impact on gene expression in the rat genome

    Rintisch, Carola; Heinig, Matthias; Bauerfeind, Anja; Schafer, Sebastian; Mieth, Christin; Patone, Giannino; Hummel, Oliver; Chen, Wei; Cook, Stuart; Cuppen, Edwin; Colomé-Tatché, Maria; Johannes, Frank; Jansen, Ritsert C; Neil, Helen; Werner, Michel; Pravenec, Michal; Vingron, Martin; Hubner, Norbert

    Histone modifications are epigenetic marks that play fundamental roles in many biological processes including the control of chromatin-mediated regulation of gene expression. Little is known about interindividual variability of histone modification levels across the genome and to what extent they

  11. Variations in estrogen receptor ? gene and risk of dementia, and brain volumes on MRI.

    S.C.E. Schuit (Stephanie); A. Hofman (Albert); P.J. Koudstaal (Peter Jan); C.M. van Duijn (Cornelia); A.G. Uitterlinden (André); H.A.P. Pols (Huib); M.M.B. Breteler (Monique); J.B.J. van Meurs (Joyce); T. den Heijer (Tom)

    2004-01-01

    textabstractThe role of estrogens in Alzheimer's disease (AD) is controversial. We investigated the association between well-recognized, and potentially functional, polymorphisms in the estrogen receptor (ER) gene and the risk of AD in a prospective study of 6056 Caucasian older men and women aged

  12. Dopamine Receptor D4 Gene Variation Predicts Preschoolers' Developing Theory of Mind

    Lackner, Christine; Sabbagh, Mark A.; Hallinan, Elizabeth; Liu, Xudong; Holden, Jeanette J. A.

    2012-01-01

    Individual differences in preschoolers' understanding that human action is caused by internal mental states, or representational theory of mind (RTM), are heritable, as are developmental disorders such as autism in which RTM is particularly impaired. We investigated whether polymorphisms of genes affecting dopamine (DA) utilization and metabolism…

  13. Variation of gene effects of six agronomic traits with water regimes in ...

    Separate generations mean analyses revealed that gene effects were dependent upon water regime. Under irrigated regime, only additive and dominance effects were implicated in inheritance of all traits, except plant height in the two crosses and grains per spike in the cross Razzek × Chili. However, under rainfed ...

  14. Variation in genes related to hepatic lipid metabolism and changes in waist circumference and body weight

    Meidtner, Karina; Fisher, Eva; Angquist, Lars

    2014-01-01

    We analysed single nucleotide polymorphisms (SNPs) tagging the genetic variability of six candidate genes (ATF6, FABP1, LPIN2, LPIN3, MLXIPL and MTTP) involved in the regulation of hepatic lipid metabolism, an important regulatory site of energy balance for associations with body mass index (BMI...

  15. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

    Chornokur, G.; Lin, H.Y.; Tyrer, J.P.; Lawrenson, K.; Dennis, J.; Amankwah, E.K.; Qu, X.; Tsai, Y.Y.; Jim, H.S.; Chen, Z.; Chen, A.Y.; Permuth-Wey, J.; Aben, K.; Anton-Culver, H.; Antonenkova, N.; Bruinsma, F.; Bandera, E.V.; Bean, Y.T.; Beckmann, M.W.; Bisogna, M.; Bjorge, L.; Bogdanova, N.; Brinton, L.A.; Brooks-Wilson, A.; Bunker, C.H.; Butzow, R.; Campbell, I.G.; Carty, K.; Chang-Claude, J.; Cook, L.S.; Cramer, D.W; Cunningham, J.M.; Cybulski, C.; Dansonka-Mieszkowska, A.; Bois, A. du; Despierre, E.; Dicks, E.; Doherty, J.A.; Dork, T.; Durst, M.; Easton, D.F.; Eccles, D.M.; Edwards, R.P.; Ekici, A.B.; Fasching, P.A.; Fridley, B.L.; Gao, Y.T.; Gentry-Maharaj, A.; Giles, G.G.; Glasspool, R.; Goodman, M.T.; Gronwald, J.; Harrington, P.; Harter, P.; Hein, A.; Heitz, F.; Hildebrandt, M.A.T.; Hillemanns, P.; Hogdall, C.K.; Hogdall, E.; Hosono, S.; Jakubowska, A.; Jensen, A.; Ji, B.T.; Karlan, B.Y.; Kelemen, L.E.; Kellar, M.; Kiemeney, L.A.L.M.; Krakstad, C.; Kjaer, S.K.; Kupryjanczyk, J.; Lambrechts, D.; Lambrechts, S.; Le, N.D.; Lee, A.W.; Lele, S.; Leminen, A.; Lester, J.; Levine, D.A.; Liang, D.; Lim, B.K.; Lissowska, J.; Lu, K.; Lubinski, J.; Lundvall, L.; Massuger, L.F.A.G.; Matsuo, K.; McGuire, V.; McLaughlin, J.R.; McNeish, I.; Menon, U.; Milne, R.L.; Modugno, F.; Moysich, K.B.; Ness, R.B.; Nevanlinna, H.; Eilber, U.; Odunsi, K.; Olson, S.H.; Orlow, I., et al.

    2015-01-01

    BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As

  16. Association Mapping and Nucleotide Sequence Variation in Five Drought Tolerance Candidate Genes in Spring Wheat

    Erena A. Edae

    2013-07-01

    Full Text Available Functional markers are needed for key genes involved in drought tolerance to improve selection for crop yield under moisture stress conditions. The objectives of this study were to (i characterize five drought tolerance candidate genes, namely dehydration responsive element binding 1A (, enhanced response to abscisic acid ( and , and fructan 1-exohydrolase ( and , in wheat ( L. for nucleotide and haplotype diversity, Tajima’s D value, and linkage disequilibrium (LD and (ii associate within-gene single nucleotide polymorphisms (SNPs with phenotypic traits in a spring wheat association mapping panel ( = 126. Field trials were grown under contrasting moisture regimes in Greeley, CO, and Melkassa, Ethiopia, in 2010 and 2011. Genome-specific amplification and DNA sequence analysis of the genes identified SNPs and revealed differences in nucleotide and haplotype diversity, Tajima’s D, and patterns of LD. showed associations (false discovery rate adjusted probability value = 0.1 with normalized difference vegetation index, heading date, biomass, and spikelet number. Both and were associated with harvest index, flag leaf width, and leaf senescence. was associated with grain yield, and was associated with thousand kernel weight and test weight. If validated in relevant genetic backgrounds, the identified marker–trait associations may be applied to functional marker-assisted selection.

  17. Genetic variation among the Mapuche Indians from the Patagonian region of Argentina: mitochondrial DNA sequence variation and allele frequencies of several nuclear genes.

    Ginther, C; Corach, D; Penacino, G A; Rey, J A; Carnese, F R; Hutz, M H; Anderson, A; Just, J; Salzano, F M; King, M C

    1993-01-01

    DNA samples from 60 Mapuche Indians, representing 39 maternal lineages, were genetically characterized for (1) nucleotide sequences of the mtDNA control region; (2) presence or absence of a nine base duplication in mtDNA region V; (3) HLA loci DRB1 and DQA1; (4) variation at three nuclear genes with short tandem repeats; and (5) variation at the polymorphic marker D2S44. The genetic profile of the Mapuche population was compared to other Amerinds and to worldwide populations. Two highly polymorphic portions of the mtDNA control region, comprising 650 nucleotides, were amplified by the polymerase chain reaction (PCR) and directly sequenced. The 39 maternal lineages were defined by two or three generation families identified by the Mapuches. These 39 lineages included 19 different mtDNA sequences that could be grouped into four classes. The same classes of sequences appear in other Amerinds from North, Central, and South American populations separated by thousands of miles, suggesting that the origin of the mtDNA patterns predates the migration to the Americas. The mtDNA sequence similarity between Amerind populations suggests that the migration throughout the Americas occurred rapidly relative to the mtDNA mutation rate. HLA DRB1 alleles 1602 and 1402 were frequent among the Mapuches. These alleles also occur at high frequency among other Amerinds in North and South America, but not among Spanish, Chinese or African-American populations. The high frequency of these alleles throughout the Americas, and their specificity to the Americas, supports the hypothesis that Mapuches and other Amerind groups are closely related.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Investigating the potential role of genetic and epigenetic variation of DNA methyltransferase genes in hyperplastic polyposis syndrome.

    Musa Drini

    2011-02-01

    Full Text Available Hyperplastic Polyposis Syndrome (HPS is a condition associated with multiple serrated polyps, and an increased risk of colorectal cancer (CRC. At least half of CRCs arising in HPS show a CpG island methylator phenotype (CIMP, potentially linked to aberrant DNA methyltransferase (DNMT activity. CIMP is associated with methylation of tumor suppressor genes including regulators of DNA mismatch repair (such as MLH1, MGMT, and negative regulators of Wnt signaling (such as WIF1. In this study, we investigated the potential for interaction of genetic and epigenetic variation in DNMT genes, in the aetiology of HPS.We utilized high resolution melting (HRM analysis to screen 45 cases with HPS for novel sequence variants in DNMT1, DNMT3A, DNMT3B, and DNMT3L. 21 polyps from 13 patients were screened for BRAF and KRAS mutations, with assessment of promoter methylation in the DNMT1, DNMT3A, DNMT3B, DNMT3L MLH1, MGMT, and WIF1 gene promoters.No pathologic germline mutations were observed in any DNA-methyltransferase gene. However, the T allele of rs62106244 (intron 10 of DNMT1 gene was over-represented in cases with HPS (p<0.01 compared with population controls. The DNMT1, DNMT3A and DNMT3B promoters were unmethylated in all instances. Interestingly, the DNMT3L promoter showed low levels of methylation in polyps and normal colonic mucosa relative to matched disease free cells with methylation level negatively correlated to expression level in normal colonic tissue. DNMT3L promoter hypomethylation was more often found in polyps harbouring KRAS mutations (p = 0.0053. BRAF mutations were common (11 out of 21 polyps, whilst KRAS mutations were identified in 4 of 21 polyps.Genetic or epigenetic alterations in DNMT genes do not appear to be associated with HPS, but further investigation of genetic variation at rs62106244 is justified given the high frequency of the minor allele in this case series.

  19. Rare earths

    1984-01-01

    The conference was held from September 12 to 13, 1984 in Jetrichovice, Czechoslovakia. The participants heard 16 papers of which 4 were inputted in INIS. These papers dealt with industrial separation processes of rare earths, the use of chemical methods of separation from the concentrate of apatite and bastnesite, the effect of the relative permittivity of solvents in the elution of rare earth elements from a cation exchanger, and the determination of the content of different rare earth elements using X-ray fluorescence analysis and atomic absorption spectroscopy. (E.S.)

  20. Sequence Variation of MHC Class II DQB Gene in Bottlenose Dolphin (Tursiops truncatus from Taiwanese Waters

    Wei-Cheng Yang

    2008-03-01

    Full Text Available The major histocompatibility complex (MHC is a large multigene coding for glycoproteins that play a key role in the initiation of immune responses in vertebrates. For a better understanding of the immunologic diversity in thriving marine mammal species, the sequence variation of the exon 2 region of MHC DQB locus was analyzed in 42 bottlenose dolphins (Tursiops truncatus collected from strandings and fishery bycatch in Taiwanese waters. The 172 bp sequences amplified showed no more than two alleles in each individual. The high proportion of non-synonymous nucleotide substitutions and the moderate amount of variation suggest positive selection pressure on this locus, arguing against a reduction in the marine environment selection pressure. The phylogenetic relationship among DQB exon 2 sequences of T. truncatus and other cetaceans did not coincide with taxonomic relationship, indicating a trans-species evolutionary pattern.

  1. Common variation in the autism risk gene CNTNAP2, brain structural connectivity and multisensory speech integration.

    Ross, Lars A; Del Bene, Victor A; Molholm, Sophie; Jae Woo, Young; Andrade, Gizely N; Abrahams, Brett S; Foxe, John J

    2017-11-01

    Three lines of evidence motivated this study. 1) CNTNAP2 variation is associated with autism risk and speech-language development. 2) CNTNAP2 variations are associated with differences in white matter (WM) tracts comprising the speech-language circuitry. 3) Children with autism show impairment in multisensory speech perception. Here, we asked whether an autism risk-associated CNTNAP2 single nucleotide polymorphism in neurotypical adults was associated with multisensory speech perception performance, and whether such a genotype-phenotype association was mediated through white matter tract integrity in speech-language circuitry. Risk genotype at rs7794745 was associated with decreased benefit from visual speech and lower fractional anisotropy (FA) in several WM tracts (right precentral gyrus, left anterior corona radiata, right retrolenticular internal capsule). These structural connectivity differences were found to mediate the effect of genotype on audiovisual speech perception, shedding light on possible pathogenic pathways in autism and biological sources of inter-individual variation in audiovisual speech processing in neurotypicals. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Deep Sequencing of 71 Candidate Genes to Characterize Variation Associated with Alcohol Dependence.

    Clark, Shaunna L; McClay, Joseph L; Adkins, Daniel E; Kumar, Gaurav; Aberg, Karolina A; Nerella, Srilaxmi; Xie, Linying; Collins, Ann L; Crowley, James J; Quackenbush, Corey R; Hilliard, Christopher E; Shabalin, Andrey A; Vrieze, Scott I; Peterson, Roseann E; Copeland, William E; Silberg, Judy L; McGue, Matt; Maes, Hermine; Iacono, William G; Sullivan, Patrick F; Costello, Elizabeth J; van den Oord, Edwin J

    2017-04-01

    Previous genomewide association studies (GWASs) have identified a number of putative risk loci for alcohol dependence (AD). However, only a few loci have replicated and these replicated variants only explain a small proportion of AD risk. Using an innovative approach, the goal of this study was to generate hypotheses about potentially causal variants for AD that can be explored further through functional studies. We employed targeted capture of 71 candidate loci and flanking regions followed by next-generation deep sequencing (mean coverage 78X) in 806 European Americans. Regions included in our targeted capture library were genes identified through published GWAS of alcohol, all human alcohol and aldehyde dehydrogenases, reward system genes including dopaminergic and opioid receptors, prioritized candidate genes based on previous associations, and genes involved in the absorption, distribution, metabolism, and excretion of drugs. We performed single-locus tests to determine if any single variant was associated with AD symptom count. Sets of variants that overlapped with biologically meaningful annotations were tested for association in aggregate. No single, common variant was significantly associated with AD in our study. We did, however, find evidence for association with several variant sets. Two variant sets were significant at the q-value <0.10 level: a genic enhancer for ADHFE1 (p = 1.47 × 10 -5 ; q = 0.019), an alcohol dehydrogenase, and ADORA1 (p = 5.29 × 10 -5 ; q = 0.035), an adenosine receptor that belongs to a G-protein-coupled receptor gene family. To our knowledge, this is the first sequencing study of AD to examine variants in entire genes, including flanking and regulatory regions. We found that in addition to protein coding variant sets, regulatory variant sets may play a role in AD. From these findings, we have generated initial functional hypotheses about how these sets may influence AD. Copyright © 2017 by the Research Society on

  3. Allelic Variation of Bile Salt Hydrolase Genes in Lactobacillus salivarius Does Not Determine Bile Resistance Levels▿ †

    Fang, Fang; Li, Yin; Bumann, Mario; Raftis, Emma J.; Casey, Pat G.; Cooney, Jakki C.; Walsh, Martin A.; O'Toole, Paul W.

    2009-01-01

    Commensal lactobacilli frequently produce bile salt hydrolase (Bsh) enzymes whose roles in intestinal survival are unclear. Twenty-six Lactobacillus salivarius strains from different sources all harbored a bsh1 allele on their respective megaplasmids. This allele was related to the plasmid-borne bsh1 gene of the probiotic strain UCC118. A second locus (bsh2) was found in the chromosomes of two strains that had higher bile resistance levels. Four Bsh1-encoding allele groups were identified, defined by truncations or deletions involving a conserved residue. In vitro analyses showed that this allelic variation was correlated with widely varying bile deconjugation phenotypes. Despite very low activity of the UCC118 Bsh1 enzyme, a mutant lacking this protein had significantly lower bile resistance, both in vitro and during intestinal transit in mice. However, the overall bile resistance phenotype of this and other strains was independent of the bsh1 allele type. Analysis of the L. salivarius transcriptome upon exposure to bile and cholate identified a multiplicity of stress response proteins and putative efflux proteins that appear to broadly compensate for, or mask, the effects of allelic variation of bsh genes. Bsh enzymes with different bile-degrading kinetics, though apparently not the primary determinants of bile resistance in L. salivarius, may have additional biological importance because of varying effects upon bile as a signaling molecule in the host. PMID:19592587

  4. Variations among Japanese of the factor IX gene (F9) detected by PCR-denaturing gradient gel electrophoresis

    Satoh, Chiyoko; Takahashi, Norio; Asakawa, Junichi; Hiyama, Keiko; Kodaira, Meiko (Radiation Effects Research Foundation, Hiroshima (Japan))

    1993-01-01

    In the course of feasibility studies to examine the efficiencies and practicalities of various techniques for screening for genetic variations, the human coagulation factor IX (F9) genes of 63 Japanese families were examined by PCR-denaturing gradient gel electrophoresis (PCR-DGGE). Four target sequences with lengths of 983-2,891 bp from the F9 genes of 126 unrelated individuals from Hiroshima and their 100 children were amplified by PCR, digested with restriction enzymes to approximately 500-bp fragments, and examined by DGGE - a total of 6,724 bp being examined per individual. GC-rich sequences (GC-clamps) of 40 bp were attached to both ends of the target sequences, as far as was feasible. Eleven types of new nucleotide substitutions were detected in the population, none of which produced RFLPs or caused hemophilia B. By examining two target sequences in a single lane, approximately 8,000 bp in a diploid individual could be examined. This approach is very effective for the detection of variations in DNA and is applicable to large-scale population studies. 46 refs., 3 figs., 1 tab.

  5. Mechanism and Effect of Temperature on Variations in Antibiotic Resistance Genes during Anaerobic Digestion of Dairy Manure

    Sun, Wei; Qian, Xun; Gu, Jie; Wang, Xiao-Juan; Duan, Man-Li

    2016-07-01

    Animal manure comprises an important reservoir for antibiotic resistance genes (ARGs), but the variation in ARGs during anaerobic digestion at various temperatures and its underlying mechanism remain unclear. Thus, we performed anaerobic digestion using dairy manure at three temperature levels (moderate: 20 °C, mesophilic: 35 °C, and thermophilic: 55 °C), to analyze the dynamics of ARGs and bacterial communities by quantitative PCR and 16S rRNA gene sequencing. We found that 8/10 detected ARGs declined and 5/10 decreased more than 1.0 log during thermophilic digestion, whereas only four and five ARGs decreased during moderate and mesophilic digestion, respectively. The changes in ARGs and bacterial communities were similar under the moderate and mesophilic treatments, but distinct from those in the thermophilic system. Potential pathogens such as Bacteroidetes, Proteobacteria, and Corynebacterium were removed by thermophilic digestion but not by moderate and mesophilic digestion. The bacterial community succession was the dominant mechanism that influenced the variation in ARGs and integrons during anaerobic digestion. Thermophilic digestion decreased the amount of mesophilic bacteria (Bacteroidetes and Proteobacteria) carrying ARGs. Anaerobic digestion generally decreased the abundance of integrons by eliminating the aerobic hosts of integrons (Actinomycetales and Bacilli). Thermophilic anaerobic digestion is recommended for the treatment and reuse of animal manure.

  6. Mechanism and Effect of Temperature on Variations in Antibiotic Resistance Genes during Anaerobic Digestion of Dairy Manure.

    Sun, Wei; Qian, Xun; Gu, Jie; Wang, Xiao-Juan; Duan, Man-Li

    2016-07-22

    Animal manure comprises an important reservoir for antibiotic resistance genes (ARGs), but the variation in ARGs during anaerobic digestion at various temperatures and its underlying mechanism remain unclear. Thus, we performed anaerobic digestion using dairy manure at three temperature levels (moderate: 20 °C, mesophilic: 35 °C, and thermophilic: 55 °C), to analyze the dynamics of ARGs and bacterial communities by quantitative PCR and 16S rRNA gene sequencing. We found that 8/10 detected ARGs declined and 5/10 decreased more than 1.0 log during thermophilic digestion, whereas only four and five ARGs decreased during moderate and mesophilic digestion, respectively. The changes in ARGs and bacterial communities were similar under the moderate and mesophilic treatments, but distinct from those in the thermophilic system. Potential pathogens such as Bacteroidetes, Proteobacteria, and Corynebacterium were removed by thermophilic digestion but not by moderate and mesophilic digestion. The bacterial community succession was the dominant mechanism that influenced the variation in ARGs and integrons during anaerobic digestion. Thermophilic digestion decreased the amount of mesophilic bacteria (Bacteroidetes and Proteobacteria) carrying ARGs. Anaerobic digestion generally decreased the abundance of integrons by eliminating the aerobic hosts of integrons (Actinomycetales and Bacilli). Thermophilic anaerobic digestion is recommended for the treatment and reuse of animal manure.

  7. Mechanism and Effect of Temperature on Variations in Antibiotic Resistance Genes during Anaerobic Digestion of Dairy Manure

    Sun, Wei; Qian, Xun; Gu, Jie; Wang, Xiao-Juan; Duan, Man-Li

    2016-01-01

    Animal manure comprises an important reservoir for antibiotic resistance genes (ARGs), but the variation in ARGs during anaerobic digestion at various temperatures and its underlying mechanism remain unclear. Thus, we performed anaerobic digestion using dairy manure at three temperature levels (moderate: 20 °C, mesophilic: 35 °C, and thermophilic: 55 °C), to analyze the dynamics of ARGs and bacterial communities by quantitative PCR and 16S rRNA gene sequencing. We found that 8/10 detected ARGs declined and 5/10 decreased more than 1.0 log during thermophilic digestion, whereas only four and five ARGs decreased during moderate and mesophilic digestion, respectively. The changes in ARGs and bacterial communities were similar under the moderate and mesophilic treatments, but distinct from those in the thermophilic system. Potential pathogens such as Bacteroidetes, Proteobacteria, and Corynebacterium were removed by thermophilic digestion but not by moderate and mesophilic digestion. The bacterial community succession was the dominant mechanism that influenced the variation in ARGs and integrons during anaerobic digestion. Thermophilic digestion decreased the amount of mesophilic bacteria (Bacteroidetes and Proteobacteria) carrying ARGs. Anaerobic digestion generally decreased the abundance of integrons by eliminating the aerobic hosts of integrons (Actinomycetales and Bacilli). Thermophilic anaerobic digestion is recommended for the treatment and reuse of animal manure. PMID:27444518

  8. Association between variations in the disrupted in schizophrenia 1 gene and schizophrenia: A meta-analysis.

    Xu, Yiliang; Ren, Jun; Ye, Haihong

    2018-04-20

    Schizophrenia is a severe psychiatric disorder. Genetic and functional studies have strongly implicated the disrupted in schizophrenia 1 gene (DISC1) as a candidate susceptibility gene for schizophrenia. Moreover, recent association studies have indicated that several DISC1 single nucleotide polymorphisms (SNPs) are associated with schizophrenia. However, the association is hardly replicate in different ethnic group. Here, we performed a meta-analysis of the association between DISC1 SNPs and schizophrenia in which the samples were divided into subgroups according to ethnicity. Both rs3738401 and rs821616 showed not significantly association with schizophrenia in the Caucasian, Asian, Japanese or Han Chinese populations. Copyright © 2018 Elsevier B.V. All rights reserved.

  9. Genes and genetic variations involved in the development of hypertension: focusing on a Greek patient cohort.

    Kouremenos, Nikolaos; Zacharopoulou, Ioanna V; Triantafyllidi, Helen; Zacharopoulos, Georgios V; Mornos, Cristian; Filippatos, Gerasimos; Lekakis, John; Kremastinos, Dimitrios; Manolis, Athanasios I; Gavras, Haralambos

    2014-01-01

    Essential hypertension (HTN) is a multifactorial disease involving environmental, genetic and other factors. Over the past years, genetic studies of essential HTN have increased dramatically but the molecular mechanisms involved are still unknown. As part of a research program coordinated by Boston university (USA), we studied the role of various genes and single nucleotide polymorphisms (SNPs) in the inheritance or the onset of HTN in African-American, Caucasian-American and Greek families. Among 128 Greek families with a history of HTN, we studied 1474 people. Of the total examined, 273 men and 286 women were hypertensive. Based on 410 DNA samples from the hypertensive subjects, different SNPs were examined. An overall meta-analysis of the results from the Greek families, as well as a comparison with the 2 other groups (African-Americans and Caucasian-Americans), was performed. We report SNPs that are associated with the inheritance of HTN and are located either at the promoters of N-methyltransferase and catalase genes, or within the coding region of NEDD4L ubiquitin ligase gene, or SNPs in mitochondrial DNA of hypertensive probands. Furthermore, we clarified the role of hereditary predisposition in the development of HTN, showing that the presence of maternal HTN was significantly higher in African-Americans and Greeks compared to Caucasian-Americans (81.7%, 84.8%, and 65%), while the paternal HTN showed no such difference (50%, 48.3% and 44.9%), respectively. Although genetic factors that were correlated with HTN were identified, it was not possible to identify a single gene that should be targeted for the treatment of HTN. Nevertheless, the important role of the maternal hereditary predisposition to HTN in the Greek patients and the responsible genetic factors involved should be further examined.

  10. Natural variation of histone modification and its impact on gene expression in the rat genome

    Rintisch, C.; Heinig, M.; Bauerfeind, A.; Schafer, S.; Mieth, Ch.; Patone, G.; Hummel, O.; Chen, W.; Cook, S.; Cuppen, E.; Colomé-Tatché, M.; Johannes, F.; Jansen, R. C.; Neil, H.; Werner, M.; Pravenec, Michal; Vingron, M.; Hubner, N.

    2014-01-01

    Roč. 24, JUN (2014), s. 942-953 ISSN 1088-9051 R&D Projects: GA MŠk(CZ) 7E10067; GA ČR(CZ) GAP301/10/0290; GA MŠk(CZ) LL1204 Institutional support: RVO:67985823 Keywords : ChIP-seq * histone modification * gene expression * genetic linkage analysis Subject RIV: EB - Genetic s ; Molecular Biology Impact factor: 14.630, year: 2014

  11. Global and disease-associated genetic variation in the human Fanconi anemia gene family

    Rogers, Kai J.; Fu, Wenqing; Akey, Joshua M.; Monnat, Raymond J.

    2014-01-01

    Fanconi anemia (FA) is a human recessive genetic disease resulting from inactivating mutations in any of 16 FANC (Fanconi) genes. Individuals with FA are at high risk of developmental abnormalities, early bone marrow failure and leukemia. These are followed in the second and subsequent decades by a very high risk of carcinomas of the head and neck and anogenital region, and a small continuing risk of leukemia. In order to characterize base pair-level disease-associated (DA) and population gen...

  12. Genetic variations and haplotype diversity of the UGT1 gene cluster in the Chinese population.

    Jing Yang

    Full Text Available Vertebrates require tremendous molecular diversity to defend against numerous small hydrophobic chemicals. UDP-glucuronosyltransferases (UGTs are a large family of detoxification enzymes that glucuronidate xenobiotics and endobiotics, facilitating their excretion from the body. The UGT1 gene cluster contains a tandem array of variable first exons, each preceded by a specific promoter, and a common set of downstream constant exons, similar to the genomic organization of the protocadherin (Pcdh, immunoglobulin, and T-cell receptor gene clusters. To assist pharmacogenomics studies in Chinese, we sequenced nine first exons, promoter and intronic regions, and five common exons of the UGT1 gene cluster in a population sample of 253 unrelated Chinese individuals. We identified 101 polymorphisms and found 15 novel SNPs. We then computed allele frequencies for each polymorphism and reconstructed their linkage disequilibrium (LD map. The UGT1 cluster can be divided into five linkage blocks: Block 9 (UGT1A9, Block 9/7/6 (UGT1A9, UGT1A7, and UGT1A6, Block 5 (UGT1A5, Block 4/3 (UGT1A4 and UGT1A3, and Block 3' UTR. Furthermore, we inferred haplotypes and selected their tagSNPs. Finally, comparing our data with those of three other populations of the HapMap project revealed ethnic specificity of the UGT1 genetic diversity in Chinese. These findings have important implications for future molecular genetic studies of the UGT1 gene cluster as well as for personalized medical therapies in Chinese.

  13. Variations in mismatch repair genes and colorectal cancer risk and clinical outcome

    Vymetálková, Veronika; Pardini, B.; Rosa, F.; Di Gaetano, C.; Novotný, J.; Levý, M.; Buchler, T.; Slyšková, Jana; Vodičková, Ludmila; Naccarati, Alessio; Vodička, Pavel

    2014-01-01

    Roč. 29, č. 4 (2014), s. 259-265 ISSN 0267-8357 R&D Projects: GA ČR GPP304/11/P715; GA ČR GAP304/10/1286; GA MZd NT12025 Institutional support: RVO:68378041 Keywords : colorectal cancer , , * mismatch repair genes * miRNA Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.793, year: 2014

  14. Intragenomic sequence variation at the ITS1 - ITS2 region and at the 18S and 28S nuclear ribosomal DNA genes of the New Zealand mud snail, Potamopyrgus antipodarum (Hydrobiidae: mollusca)

    Hoy, Marshal S.; Rodriguez, Rusty J.

    2013-01-01

    Molecular genetic analysis was conducted on two populations of the invasive non-native New Zealand mud snail (Potamopyrgus antipodarum), one from a freshwater ecosystem in Devil's Lake (Oregon, USA) and the other from an ecosystem of higher salinity in the Columbia River estuary (Hammond Harbor, Oregon, USA). To elucidate potential genetic differences between the two populations, three segments of nuclear ribosomal DNA (rDNA), the ITS1-ITS2 regions and the 18S and 28S rDNA genes were cloned and sequenced. Variant sequences within each individual were found in all three rDNA segments. Folding models were utilized for secondary structure analysis and results indicated that there were many sequences which contained structure-altering polymorphisms, which suggests they could be nonfunctional pseudogenes. In addition, analysis of molecular variance (AMOVA) was used for hierarchical analysis of genetic variance to estimate variation within and among populations and within individuals. AMOVA revealed significant variation in the ITS region between the populations and among clones within individuals, while in the 5.8S rDNA significant variation was revealed among individuals within the two populations. High levels of intragenomic variation were found in the ITS regions, which are known to be highly variable in many organisms. More interestingly, intragenomic variation was also found in the 18S and 28S rDNA, which has rarely been observed in animals and is so far unreported in Mollusca. We postulate that in these P. antipodarum populations the effects of concerted evolution are diminished due to the fact that not all of the rDNA genes in their polyploid genome should be essential for sustaining cellular function. This could lead to a lessening of selection pressures, allowing mutations to accumulate in some copies, changing them into variant sequences.                   

  15. Genetic variation and epigenetic modification of the prodynorphin gene in peripheral blood cells in alcoholism.

    D'Addario, Claudio; Shchetynsky, Klementy; Pucci, Mariangela; Cifani, Carlo; Gunnar, Agneta; Vukojević, Vladana; Padyukov, Leonid; Terenius, Lars

    2017-06-02

    Dynorphins are critically involved in the development, maintenance and relapse of alcoholism. Alcohol-induced changes in the prodynorphin gene expression may be influenced by both gene polymorphisms and epigenetic modifications. The present study of human alcoholics aims to evaluate DNA methylation patterns in the prodynorphin gene (PDYN) promoter and to identify single nucleotide polymorphisms (SNPs) associated with alcohol dependence and with altered DNA methylation. Genomic DNA was isolated from peripheral blood cells of alcoholics and healthy controls, and DNA methylation was studied in the PDYN promoter by bisulfite pyrosequencing. In alcoholics, DNA methylation increased in three of the seven CpG sites investigated, as well as in the average of the seven CpG sites. Data stratification showed lower increase in DNA methylation levels in individuals reporting craving and with higher levels of alcohol consumption. Association with alcoholism was observed for rs2235751 and the presence of the minor allele G was associated with reduced DNA methylation at PDYN promoter in females and younger subjects. Genetic and epigenetic factors within PDYN are related to risk for alcoholism, providing further evidence of its involvement on ethanol effects. These results might be of relevance for developing new biomarkers to predict disease trajectories and therapeutic outcome. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Gene expression profiling in the Cynomolgus macaque Macaca fascicularis shows variation within the normal birth range

    Vickers Mark H

    2011-10-01

    Full Text Available Abstract Background Although an adverse early-life environment has been linked to an increased risk of developing the metabolic syndrome, the molecular mechanisms underlying altered disease susceptibility as well as their relevance to humans are largely unknown. Importantly, emerging evidence suggests that these effects operate within the normal range of birth weights and involve mechanisms of developmental palsticity rather than pathology. Method To explore this further, we utilised a non-human primate model Macaca fascicularis (Cynomolgus macaque which shares with humans the same progressive history of the metabolic syndrome. Using microarray we compared tissues from neonates in the average birth weight (50-75th centile to those of lower birth weight (5-25th centile and studied the effect of different growth trajectories within the normal range on gene expression levels in the umbilical cord, neonatal liver and skeletal muscle. Results We identified 1973 genes which were differentially expressed in the three tissue types between average and low birth weight animals (P Conclusion These differences in gene expression levels between animals in the upper and lower percentiles of the normal birth weight range may point towards early life metabolic adaptations that in later life result in differences in disease risk.

  17. Comparative metabolomics in primates reveals the effects of diet and gene regulatory variation on metabolic divergence.

    Blekhman, Ran; Perry, George H; Shahbaz, Sevini; Fiehn, Oliver; Clark, Andrew G; Gilad, Yoav

    2014-07-28

    Human diets differ from those of non-human primates. Among few obvious differences, humans consume more meat than most non-human primates and regularly cook their food. It is hypothesized that a dietary shift during human evolution has been accompanied by molecular adaptations in metabolic pathways. Consistent with this notion, comparative studies of gene expression levels in primates have found that the regulation of genes with metabolic functions tend to evolve rapidly in the human lineage. The metabolic consequences of these regulatory differences, however, remained unknown. To address this gap, we performed a comparative study using a combination of gene expression and metabolomic profiling in livers from humans, chimpanzees, and rhesus macaques. We show that dietary differences between species have a strong effect on metabolic concentrations. In addition, we found that differences in metabolic concentration across species are correlated with inter-species differences in the expression of the corresponding enzymes, which control the same metabolic reaction. We identified a number of metabolic compounds with lineage-specific profiles, including examples of human-species metabolic differences that may be directly related to dietary differences.