PLoS Articles

User Collection Public
UNC logo

UNC-authored articles published by the Public Library of Science (PLoS)

Works (2111)

View results as:
List List Masonry Masonry Slideshow Slideshow
Sort the listing of items  

1581. Genome-Wide Association Analysis of Incident Coronary Heart Disease (CHD) in African Americans: A Short Report

Title Tesim:
Genome-Wide Association Analysis of Incident Coronary Heart Disease (CHD) in African Americans: A Short Report
Creator:
Reiner, Alex P., Wu, Chunyuan, Couper, David, Heiss, Gerardo, Mosley, Thomas, Franceschini, Nora, Eaton, Charles B., Hixson, James E., Barbalic, Maja, and Boerwinkle, Eric
Date of publication:
2011
Abstract Tesim:
African Americans have the highest rate of mortality due to coronary heart disease (CHD). Although multiple loci have been identified influencing CHD risk in European-Americans using a genome-wide association (GWAS) approach, no GWAS of incident CHD has been reported for African Americans. We performed a GWAS for incident CHD events collected during 19 years of follow-up in 2,905 African Americans from the Atherosclerosis Risk in Communities (ARIC) study. We identified a genome-wide significant SNP (rs1859023, MAF = 31%) located at 7q21 near the PFTK1 gene (HR = 0.57, 95% CI 0.46 to 0.69, p = 1.86×10−08), which replicated in an independent sample of over 8,000 African American women from the Women's Health Initiative (WHI) (HR = 0.81, 95% CI 0.70 to 0.93, p = 0.005). PFTK1 encodes a serine/threonine-protein kinase, PFTAIRE-1, that acts as a cyclin-dependent kinase regulating cell cycle progression and cell proliferation. This is the first finding of incident CHD locus identified by GWAS in African Americans.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/x23y-9397
Identifier:
Publisher DOI: https://doi.org/10.1371/journal.pgen.1002199, PMCID: PMC3150445, Onescience id: 1cb2035105b70dbe6929968927d166db3879470e, and PMID: 21829389
ISSN:
1553-7390 and 1553-7404
Journal Issue:
8
Journal Title:
PLoS Genetics
Journal Volume:
7
Keyword:
Middle Aged, Male, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Risk Factors, Gene Expression Regulation, Genetic Loci, Humans, Aged, African Americans, Coronary Disease, and Female
Language Label:
English
Page Start:
e1002199
Person:
Reiner, Alex P., Wu, Chunyuan, Couper, David, Heiss, Gerardo, Mosley, Thomas, Franceschini, Nora, Eaton, Charles B., Hixson, James E., Barbalic, Maja, and Boerwinkle, Eric
Rights Statement Label:
In Copyright
Source:
tm70n3273

1582. Genetic Determinants of Lipid Traits in Diverse Populations from the Population Architecture using Genomics and Epidemiology (PAGE) Study

Title Tesim:
Genetic Determinants of Lipid Traits in Diverse Populations from the Population Architecture using Genomics and Epidemiology (PAGE) Study
Creator:
Dumitrescu, Logan, Johnson, Karen C., Quibrera, Miguel, Shohet, Ralph V., Duggan, Dave, Lee, Elisa T., Fornage, Myriam, Anderson, Garnet, Schumacher, Fredrick R., Eaton, Charles B., Bůžková, Petra, Taylor, Kira, Cole, Shelley A., Pendergrass, Sarah A., Best, Lyle G., Haiman, Christopher A., Hindorff, Lucia A., Franceschini, Nora, Howard, Barbara V., Laston, Sandra, Carlson, Christopher S., Devereux, Richard B., Cochran, Barbara, Ambite, José L., Haessler, Jeff, Carty, Cara L., Kolonel, Laurence N., Wilkens, Lynne R., MacCluer, Jean W., Le Marchand, Loïc, Brown-Gentry, Kristin, and Manolio, Teri A.
Date of publication:
2011
Abstract Tesim:
For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS–identified variants in diverse population-based studies. We genotyped 49 GWAS–identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (∼20,000), African American (∼9,000), American Indian (∼6,000), Mexican American/Hispanic (∼2,500), Japanese/East Asian (∼690), and Pacific Islander/Native Hawaiian (∼175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/3pkd-qx31
Identifier:
Onescience id: 14b81d335b188193c927d870bff176b16693d411, PMID: 21738485, Publisher DOI: https://doi.org/10.1371/journal.pgen.1002138, and PMCID: PMC3128106
ISSN:
1553-7390 and 1553-7404
Journal Issue:
6
Journal Title:
PLoS Genetics
Journal Volume:
7
Keyword:
Humans, Adult, Molecular Epidemiology, Genetics, Population, Aged, Male, Lipoproteins, LDL, Female, Genome-Wide Association Study, Linkage Disequilibrium, Middle Aged, Continental Population Groups, Lipid Metabolism, Lipoproteins, HDL, Gene Frequency, Aged, 80 and over, and Adolescent
Language Label:
English
Page Start:
e1002138
Person:
Dumitrescu, Logan, Johnson, Karen C., Quibrera, Miguel, Shohet, Ralph V., Duggan, Dave, Lee, Elisa T., Fornage, Myriam, Anderson, Garnet, Schumacher, Fredrick R., Eaton, Charles B., Bůžková, Petra, Taylor, Kira, Cole, Shelley A., Pendergrass, Sarah A., Best, Lyle G., Haiman, Christopher A., Hindorff, Lucia A., Franceschini, Nora, Howard, Barbara V., Laston, Sandra, Carlson, Christopher S., Devereux, Richard B., Cochran, Barbara, Ambite, José L., Haessler, Jeff, Carty, Cara L., Kolonel, Laurence N., Wilkens, Lynne R., MacCluer, Jean W., Le Marchand, Loïc, Brown-Gentry, Kristin, and Manolio, Teri A.
Rights Statement Label:
In Copyright
Source:
1v53k530c

1583. Genetic Association for Renal Traits among Participants of African Ancestry Reveals New Loci for Renal Function

Title Tesim:
Genetic Association for Renal Traits among Participants of African Ancestry Reveals New Loci for Renal Function
Creator:
Garnaas, Maija K., Wyatt, Sharon, Reilly, Muredach P., Adeyemo, Adebowale, Rotimi, Charles N., Mosley, Thomas H., Peralta, Carmen A., Liu, Ching-Ti, Liu, Yongmei, Turner, Stephen T., Coresh, Josef, Li, Man, Kardia, Sharon L. R., Atkinson, Elizabeth, Akylbekova, Ermeg, Harris, Tamara B., Franceschini, Nora, Mychaleckjy, Josef, Nalls, Michael, Bibbins-Domingo, Kirsten, Zonderman, Alan B., Siscovick, David, Astor, Brad, Shriner, Daniel, de Andrade, Mariza, Ding, Jingzhong, Townsend, Raymond R., Tin, Adrienne, Kottgen, Anna, de Boer, Ian H., Kutlar, Abdullah, and Lu, Xiaoning
Date of publication:
2011
Abstract Tesim:
Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m2), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10−7) and FNDC1 (p-value = 3.0×10−7) for UACR, and KCNQ1 with eGFR (p = 3.6×10−6). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/1t9q-g098
Identifier:
PMCID: PMC3169523, Onescience id: 4a4d5b302d2c513b555f75824aed62a8e45c87b7, PMID: 21931561, and Publisher DOI: https://doi.org/10.1371/journal.pgen.1002264
ISSN:
1553-7404 and 1553-7390
Journal Issue:
9
Journal Title:
PLoS Genetics
Journal Volume:
7
Keyword:
Humans, KCNQ1 Potassium Channel, Genetic Loci, Gene Knockdown Techniques, African Continental Ancestry Group, Kidney, Male, Glomerular Filtration Rate, Adaptor Proteins, Vesicular Transport, Kidney Failure, Chronic, Adult, Genome-Wide Association Study, Animals, Genetic Association Studies, Aged, Female, and Middle Aged
Language Label:
English
Page Start:
e1002264
Person:
Garnaas, Maija K., Wyatt, Sharon, Reilly, Muredach P., Adeyemo, Adebowale, Rotimi, Charles N., Mosley, Thomas H., Peralta, Carmen A., Liu, Ching-Ti, Liu, Yongmei, Turner, Stephen T., Coresh, Josef, Li, Man, Kardia, Sharon L. R., Atkinson, Elizabeth, Akylbekova, Ermeg, Harris, Tamara B., Franceschini, Nora, Mychaleckjy, Josef, Nalls, Michael, Bibbins-Domingo, Kirsten, Zonderman, Alan B., Siscovick, David, Astor, Brad, Shriner, Daniel, de Andrade, Mariza, Ding, Jingzhong, Townsend, Raymond R., Tin, Adrienne, Kottgen, Anna, de Boer, Ian H., Kutlar, Abdullah, and Lu, Xiaoning
Rights Statement Label:
In Copyright
Source:
9593v365r

1584. Enhanced Statistical Tests for GWAS in Admixed Populations: Assessment using African Americans from CARe and a Breast Cancer Consortium

Title Tesim:
Enhanced Statistical Tests for GWAS in Admixed Populations: Assessment using African Americans from CARe and a Breast Cancer Consortium
Creator:
Bernstein, Leslie, Siscovick, David S., John, Esther M., Akylbekova, Ermeg L., Zhu, Xiaofeng, Hu, Jennifer J., Ingles, Sue A., Zaitlen, Noah, Press, Michael F., Li, Mingyao, Papanicolaou, George J., Chanock, Stephen J., Bandera, Elisa V., Tandon, Arti, Lettre, Guillaume, Mychaleckyj, Joe, Divers, Jasmin, Musani, Solomon K., Pasaniuc, Bogdan, Larkin, Emma, Zheng, Wei, Nyante, Sarah J., Ruczinski, Ingo, Ambrosone, Christine B., Lange, Leslie A., Chen, Gary K., Ziegler, Regina G., Millikan, Robert C., Kao, W. H. Linda, Yang, Qiong, Fornage, Myriam, and Cupples, L. Adrienne
Date of publication:
2011
Abstract Tesim:
While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/3jdw-6426
Identifier:
Publisher DOI: https://doi.org/10.1371/journal.pgen.1001371, PMID: 21541012, PMCID: PMC3080860, and Onescience id: 7fe81b03482d7051112c1366adac28f6f62ea179
ISSN:
1553-7404 and 1553-7390
Journal Issue:
4
Journal Title:
PLoS Genetics
Journal Volume:
7
Keyword:
Genotype, Male, Chromosome Mapping, Receptor, Fibroblast Growth Factor, Type 2, Genetic Variation, Linkage Disequilibrium, African Americans, Coronary Disease, Gene Frequency, Breast Neoplasms, Female, Phenotype, Genome-Wide Association Study, Algorithms, Genome, Human, Polymorphism, Single Nucleotide, Humans, Genetics, Population, Principal Component Analysis, Diabetes Mellitus, Type 2, Software, and Odds Ratio
Language Label:
English
Page Start:
e1001371
Person:
Bernstein, Leslie, Siscovick, David S., John, Esther M., Akylbekova, Ermeg L., Zhu, Xiaofeng, Hu, Jennifer J., Ingles, Sue A., Zaitlen, Noah, Press, Michael F., Li, Mingyao, Papanicolaou, George J., Chanock, Stephen J., Bandera, Elisa V., Tandon, Arti, Lettre, Guillaume, Mychaleckyj, Joe, Divers, Jasmin, Musani, Solomon K., Pasaniuc, Bogdan, Larkin, Emma, Zheng, Wei, Nyante, Sarah J., Ruczinski, Ingo, Ambrosone, Christine B., Lange, Leslie A., Chen, Gary K., Ziegler, Regina G., Millikan, Robert C., Kao, W. H. Linda, Yang, Qiong, Fornage, Myriam, and Cupples, L. Adrienne
Rights Statement Label:
In Copyright
Source:
w3763f588

1585. A Phenomics-Based Strategy Identifies Loci on APOC1, BRAP, and PLCG1 Associated with Metabolic Syndrome Phenotype Domains

Title Tesim:
A Phenomics-Based Strategy Identifies Loci on APOC1, BRAP, and PLCG1 Associated with Metabolic Syndrome Phenotype Domains
Creator:
Fornage, Myriam, Kooperberg, Charles, Psaty, Bruce M., Rotter, Jerome I., He, Qianchuan, Lin, Dan Yu, Pankow, James S., Ambite, Jose L., Avery, Christy L., Hindorff, Lucia A., North, Kari E., Heiss, Gerardo, Boerwinkle, Eric, Pendergrass, Sarah A., Ritchie, Marylyn D., Wilkens, Lynne R., Taylor, Kent D., and Meigs, James B.
Date of publication:
2011
Abstract Tesim:
Despite evidence of the clustering of metabolic syndrome components, current approaches for identifying unifying genetic mechanisms typically evaluate clinical categories that do not provide adequate etiological information. Here, we used data from 19,486 European American and 6,287 African American Candidate Gene Association Resource Consortium participants to identify loci associated with the clustering of metabolic phenotypes. Six phenotype domains (atherogenic dyslipidemia, vascular dysfunction, vascular inflammation, pro-thrombotic state, central obesity, and elevated plasma glucose) encompassing 19 quantitative traits were examined. Principal components analysis was used to reduce the dimension of each domain such that >55% of the trait variance was represented within each domain. We then applied a statistically efficient and computational feasible multivariate approach that related eight principal components from the six domains to 250,000 imputed SNPs using an additive genetic model and including demographic covariates. In European Americans, we identified 606 genome-wide significant SNPs representing 19 loci. Many of these loci were associated with only one trait domain, were consistent with results in African Americans, and overlapped with published findings, for instance central obesity and FTO. However, our approach, which is applicable to any set of interval scale traits that is heritable and exhibits evidence of phenotypic clustering, identified three new loci in or near APOC1, BRAP, and PLCG1, which were associated with multiple phenotype domains. These pleiotropic loci may help characterize metabolic dysregulation and identify targets for intervention.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/j176-x981
Identifier:
Publisher DOI: https://doi.org/10.1371/journal.pgen.1002322, PMID: 22022282, Onescience id: f56f81c5a7e1e37f5e284652fe302be876adfaf3, and PMCID: PMC3192835
ISSN:
1553-7390 and 1553-7404
Journal Issue:
10
Journal Title:
PLoS Genetics
Journal Volume:
7
Keyword:
Vascular Diseases, Quantitative Trait, Human, Dyslipidemias, Phospholipase C gamma, Genetic Association Studies, Heritable, European Continental Ancestry Group, Genome, Genetic Predisposition to Disease, Blood Glucose, Humans, Polymorphism, Phenotype, Abdominal, Obesity, African Americans, Metabolic Syndrome X, Single Nucleotide, Ubiquitin-Protein Ligases, and Apolipoprotein C-I
Language Label:
English
Page Start:
e1002322
Person:
Fornage, Myriam, Kooperberg, Charles, Psaty, Bruce M., Rotter, Jerome I., He, Qianchuan, Lin, Dan Yu, Pankow, James S., Ambite, Jose L., Avery, Christy L., Hindorff, Lucia A., North, Kari E., Heiss, Gerardo, Boerwinkle, Eric, Pendergrass, Sarah A., Ritchie, Marylyn D., Wilkens, Lynne R., Taylor, Kent D., and Meigs, James B.
Rights Statement Label:
In Copyright
Source:
70795h09n

1586. A Conserved PHD Finger Protein and Endogenous RNAi Modulate Insulin Signaling in Caenorhabditis elegans

Title Tesim:
A Conserved PHD Finger Protein and Endogenous RNAi Modulate Insulin Signaling in Caenorhabditis elegans
Creator:
Lieb, Jason D., Mansisidor, Andres R., Tan, Man-Wah, Cecere, Germano, Grishok, Alla, Kawli, Trupti, Kennedy, Lisa M., Chavez, Violeta, Hoersch, Sebastian, and Jensen, Morten B.
Date of publication:
2011
Abstract Tesim:
Insulin signaling has a profound effect on longevity and the oxidative stress resistance of animals. Inhibition of insulin signaling results in the activation of DAF-16/FOXO and SKN-1/Nrf transcription factors and increased animal fitness. By studying the biological functions of the endogenous RNA interference factor RDE-4 and conserved PHD zinc finger protein ZFP-1 (AF10), which regulate overlapping sets of genes in Caenorhabditis elegans, we identified an important role for these factors in the negative modulation of transcription of the insulin/PI3 signaling-dependent kinase PDK-1. Consistently, increased expression of pdk-1 in zfp-1 and rde-4 mutants contributed to their reduced lifespan and sensitivity to oxidative stress and pathogens due to the reduction in the expression of DAF-16 and SKN-1 targets. We found that the function of ZFP-1 in modulating pdk-1 transcription was important for the extended lifespan of the age-1(hx546) reduction-of-function PI3 kinase mutant, since the lifespan of the age-1; zfp-1 double mutant strain was significantly shorter compared to age-1(hx546). We further demonstrate that overexpression of ZFP-1 caused an increased resistance to oxidative stress in a DAF-16–dependent manner. Our findings suggest that epigenetic regulation of key upstream signaling components in signal transduction pathways through chromatin and RNAi may have a large impact on the outcome of signaling and expression of numerous downstream genes.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/vtnb-yf02
Identifier:
Onescience id: 185343b491c2fd021f713fa8e57eb603b62fef64, PMCID: PMC3183084, Publisher DOI: https://doi.org/10.1371/journal.pgen.1002299, and PMID: 21980302
ISSN:
1553-7390 and 1553-7404
Journal Issue:
9
Journal Title:
PLoS Genetics
Journal Volume:
7
Keyword:
Paraquat, Animals, RNA-Binding Proteins, RNA Interference, Epigenesis, Genetic, Insulin, Phosphatidylinositol 3-Kinases, Oxidative Stress, Gene Expression Regulation, Caenorhabditis elegans Proteins, Caenorhabditis elegans, Forkhead Transcription Factors, and Longevity
Language Label:
English
Page Start:
e1002299
Person:
Lieb, Jason D., Mansisidor, Andres R., Tan, Man-Wah, Cecere, Germano, Grishok, Alla, Kawli, Trupti, Kennedy, Lisa M., Chavez, Violeta, Hoersch, Sebastian, and Jensen, Morten B.
Rights Statement Label:
In Copyright
Source:
fx719v28k

1587. The Histone H3K36 Methyltransferase MES-4 Acts Epigenetically to Transmit the Memory of Germline Gene Expression to Progeny

Title Tesim:
The Histone H3K36 Methyltransferase MES-4 Acts Epigenetically to Transmit the Memory of Germline Gene Expression to Progeny
Creator:
Phippen, Taryn M., Ercan, Sevinc, Strome, Susan, Lieb, Jason D., Wang, Wenchao, Rechtsteiner, Andreas, Kimura, Hiroshi, Egelhofer, Thea A., and Takasaki, Teruaki
Date of publication:
2010
Abstract Tesim:
Methylation of histone H3K36 in higher eukaryotes is mediated by multiple methyltransferases. Set2-related H3K36 methyltransferases are targeted to genes by association with RNA Polymerase II and are involved in preventing aberrant transcription initiation within the body of genes. The targeting and roles of the NSD family of mammalian H3K36 methyltransferases, known to be involved in human developmental disorders and oncogenesis, are not known. We used genome-wide chromatin immunoprecipitation (ChIP) to investigate the targeting and roles of the Caenorhabditis elegans NSD homolog MES-4, which is maternally provided to progeny and is required for the survival of nascent germ cells. ChIP analysis in early C. elegans embryos revealed that, consistent with immunostaining results, MES-4 binding sites are concentrated on the autosomes and the leftmost ∼2% (300 kb) of the X chromosome. MES-4 overlies the coding regions of approximately 5,000 genes, with a modest elevation in the 5′ regions of gene bodies. Although MES-4 is generally found over Pol II-bound genes, analysis of gene sets with different temporal-spatial patterns of expression revealed that Pol II association with genes is neither necessary nor sufficient to recruit MES-4. In early embryos, MES-4 associates with genes that were previously expressed in the maternal germ line, an interaction that does not require continued association of Pol II with those loci. Conversely, Pol II association with genes newly expressed in embryos does not lead to recruitment of MES-4 to those genes. These and other findings suggest that MES-4, and perhaps the related mammalian NSD proteins, provide an epigenetic function for H3K36 methylation that is novel and likely to be unrelated to ongoing transcription. We propose that MES-4 transmits the memory of gene expression in the parental germ line to offspring and that this memory role is critical for the PGCs to execute a proper germline program.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/pzej-m054
Identifier:
Onescience id: f2242daf7921c1954c09c81a8816d89c912c6e10, Publisher DOI: https://doi.org/10.1371/journal.pgen.1001091, PMID: 20824077, and PMCID: PMC2932692
ISSN:
1553-7404 and 1553-7390
Journal Issue:
9
Journal Title:
PLoS Genetics
Journal Volume:
6
Keyword:
Caenorhabditis elegans, Histone-Lysine N-Methyltransferase, Lysine, Animals, Binding Sites, Female, Epigenesis, Genetic, Genes, Helminth, Germ Cells, Biocatalysis, Caenorhabditis elegans Proteins, Histones, Embryo, Nonmammalian, and Gene Expression Regulation, Developmental
Language Label:
English
Page Start:
e1001091
Person:
Phippen, Taryn M., Ercan, Sevinc, Strome, Susan, Lieb, Jason D., Wang, Wenchao, Rechtsteiner, Andreas, Kimura, Hiroshi, Egelhofer, Thea A., and Takasaki, Teruaki
Rights Statement Label:
In Copyright
Source:
4f16c9541

1588. The CYCLIN-A CYCA1;2/TAM Is Required for the Meiosis I to Meiosis II Transition and Cooperates with OSD1 for the Prophase to First Meiotic Division Transition

Title Tesim:
The CYCLIN-A CYCA1;2/TAM Is Required for the Meiosis I to Meiosis II Transition and Cooperates with OSD1 for the Prophase to First Meiotic Division Transition
Creator:
Jolivet, Sylvie, Cromer, Laurence, Mercier, Raphael, Sun, Yujin, Horlow, Christine, To, Jennifer P. C., Girard, Chloé, Berchowitz, Luke E., d'Erfurth, Isabelle, and Copenhaver, Gregory P.
Date of publication:
2010
Abstract Tesim:
Meiosis halves the chromosome number because its two divisions follow a single round of DNA replication. This process involves two cell transitions, the transition from prophase to the first meiotic division (meiosis I) and the unique meiosis I to meiosis II transition. We show here that the A-type cyclin CYCA1;2/TAM plays a major role in both transitions in Arabidopsis. A series of tam mutants failed to enter meiosis II and thus produced diploid spores and functional diploid gametes. These diploid gametes had a recombined genotype produced through the single meiosis I division. In addition, by combining the tam-2 mutation with AtSpo11-1 and Atrec8, we obtained plants producing diploid gametes through a mitotic-like division that were genetically identical to their parents. Thus tam alleles displayed phenotypes very similar to that of the previously described osd1 mutant. Combining tam and osd1 mutations leads to a failure in the prophase to meiosis I transition during male meiosis and to the production of tetraploid spores and gametes. This suggests that TAM and OSD1 are involved in the control of both meiotic transitions.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/hf21-nw07
Identifier:
PMID: 20585549, PMCID: PMC2887465, Onescience id: 32a16362e67279575064c6cbf4c3c42fd7ce41de, and Publisher DOI: https://doi.org/10.1371/journal.pgen.1000989
ISSN:
1553-7390 and 1553-7404
Journal Issue:
6
Journal Title:
PLoS Genetics
Journal Volume:
6
Keyword:
Pollen, Chromosome Segregation, Gene Expression Regulation, Plant, Cell Cycle Proteins, Arabidopsis Proteins, Meiosis, Arabidopsis, Alleles, Diploidy, Mutation, Cyclin A1, and Prophase
Language Label:
English
Page Start:
e1000989
Person:
Jolivet, Sylvie, Cromer, Laurence, Mercier, Raphael, Sun, Yujin, Horlow, Christine, To, Jennifer P. C., Girard, Chloé, Berchowitz, Luke E., d'Erfurth, Isabelle, and Copenhaver, Gregory P.
Rights Statement Label:
In Copyright
Source:
st74cz372

1589. The Caenorhabditis elegans Homolog of Gen1/Yen1 Resolvases Links DNA Damage Signaling to DNA Double-Strand Break Repair

Title Tesim:
The Caenorhabditis elegans Homolog of Gen1/Yen1 Resolvases Links DNA Damage Signaling to DNA Double-Strand Break Repair
Creator:
Déclais, Anne-Cécile, Lilley, David M. J., Freeman, Alasdair, Hall, Julie, Bailly, Aymeric P., Alpi, Arno, Gartner, Anton, and Ahmed, Shawn
Date of publication:
2010
Abstract Tesim:
DNA double-strand breaks (DSBs) can be repaired by homologous recombination (HR), which can involve Holliday junction (HJ) intermediates that are ultimately resolved by nucleolytic enzymes. An N-terminal fragment of human GEN1 has recently been shown to act as a Holliday junction resolvase, but little is known about the role of GEN-1 in vivo. Holliday junction resolution signifies the completion of DNA repair, a step that may be coupled to signaling proteins that regulate cell cycle progression in response to DNA damage. Using forward genetic approaches, we identified a Caenorhabditis elegans dual function DNA double-strand break repair and DNA damage signaling protein orthologous to the human GEN1 Holliday junction resolving enzyme. GEN-1 has biochemical activities related to the human enzyme and facilitates repair of DNA double-strand breaks, but is not essential for DNA double-strand break repair during meiotic recombination. Mutational analysis reveals that the DNA damage-signaling function of GEN-1 is separable from its role in DNA repair. GEN-1 promotes germ cell cycle arrest and apoptosis via a pathway that acts in parallel to the canonical DNA damage response pathway mediated by RPA loading, CHK1 activation, and CEP-1/p53–mediated apoptosis induction. Furthermore, GEN-1 acts redundantly with the 9-1-1 complex to ensure genome stability. Our study suggests that GEN-1 might act as a dual function Holliday junction resolvase that may coordinate DNA damage signaling with a late step in DNA double-strand break repair.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/6fk6-rb06
Identifier:
Onescience id: ed7bfd9648dd8150c2e3b47ea248b90651eecc40, PMID: 20661466, PMCID: PMC2908289, and Publisher DOI: https://doi.org/10.1371/journal.pgen.1001025
ISSN:
1553-7404 and 1553-7390
Journal Issue:
7
Journal Title:
PLoS Genetics
Journal Volume:
6
Keyword:
Holliday Junction Resolvases, Genomic Instability, DNA Breaks, Double-Stranded, Caenorhabditis elegans, Animals, Cell Cycle, Apoptosis, Signal Transduction, DNA Repair, Germ Cells, DNA Damage, GEN1 protein, human, and Meiosis
Language Label:
English
Page Start:
e1001025
Person:
Déclais, Anne-Cécile, Lilley, David M. J., Freeman, Alasdair, Hall, Julie, Bailly, Aymeric P., Alpi, Arno, Gartner, Anton, and Ahmed, Shawn
Rights Statement Label:
In Copyright
Source:
ft849023b

1590. Genome-Wide Meta-Analysis for Serum Calcium Identifies Significantly Associated SNPs near the Calcium-Sensing Receptor (CASR) Gene

Title Tesim:
Genome-Wide Meta-Analysis for Serum Calcium Identifies Significantly Associated SNPs near the Calcium-Sensing Receptor (CASR) Gene
Creator:
Holm, Hilma, Sigurdsson, Gunnar, Waeber, Gérard, Stefansson, Kari, Ferrucci, Luigi, Zhang, Weihua, Guralnik, Jack M., DiIorio, Angelo, Li, Yun, Kooner, Jaspal S., Mooser, Vincent, Waterworth, Dawn, Chambers, John, DeSilva, Ranil, Scott, James, Bjornsdottir, Unnur S., Gudbjartsson, Daniel F., Bandinelli, Stefania, Beckmann, Noam D., Sehmi, Joban, Milaneschi, Yuri, Hernandez, Dena G., Marek, Diana, Johnson, Toby, Eyjolfsson, Gudmundur I., Thorsteinsdottir, Unnur, Elliott, Paul, Kapur, Karen, Kutalik, Zoltán, Singleton, Andrew B., Tanaka, Toshiko, and Styrkarsdottir, Unnur
Date of publication:
2010
Abstract Tesim:
Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3×10-37 is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1×10-21), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02×10-4). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/3aw7-xt71
Identifier:
Onescience id: a5365165d89a036d64d035740b627f897d035bb0, PMID: 20661308, PMCID: PMC2908705, and Publisher DOI: https://doi.org/10.1371/journal.pgen.1001035
ISSN:
1553-7390 and 1553-7404
Journal Issue:
7
Journal Title:
PLoS Genetics
Journal Volume:
6
Keyword:
LOCI, CORONARY-HEART-DISEASE, Genetics & Heredity, Polymorphism, Receptors, COMMON VARIANT, CARDIOVASCULAR MORTALITY, Genome-Wide Association Study, Life Sciences & Biomedicine, European Continental Ancestry Group, PRIMARY HYPERPARATHYROIDISM, Science & Technology, Humans, A986S POLYMORPHISM, ADULT, HYPOCALCIURIC HYPERCALCEMIA, Calcium, Calcium-Sensing, Human, MYOCARDIAL-INFARCTION, GENETICS & HEREDITY, Genome, Single Nucleotide, and BONE-MINERAL DENSITY
Language Label:
English
Page Start:
e1001035
Person:
Holm, Hilma, Sigurdsson, Gunnar, Waeber, Gérard, Stefansson, Kari, Ferrucci, Luigi, Zhang, Weihua, Guralnik, Jack M., DiIorio, Angelo, Li, Yun, Kooner, Jaspal S., Mooser, Vincent, Waterworth, Dawn, Chambers, John, DeSilva, Ranil, Scott, James, Bjornsdottir, Unnur S., Gudbjartsson, Daniel F., Bandinelli, Stefania, Beckmann, Noam D., Sehmi, Joban, Milaneschi, Yuri, Hernandez, Dena G., Marek, Diana, Johnson, Toby, Eyjolfsson, Gudmundur I., Thorsteinsdottir, Unnur, Elliott, Paul, Kapur, Karen, Kutalik, Zoltán, Singleton, Andrew B., Tanaka, Toshiko, and Styrkarsdottir, Unnur
Rights Statement Label:
In Copyright
Source:
8049gd455