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Search Results: 1 - 10 of 194 matches for " Devin Absher "
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Statistical Quantification of Methylation Levels by Next-Generation Sequencing
Guodong Wu,Nengjun Yi,Devin Absher,Degui Zhi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0021034
Abstract: Recently, next-generation sequencing-based technologies have enabled DNA methylation profiling at high resolution and low cost. Methyl-Seq and Reduced Representation Bisulfite Sequencing (RRBS) are two such technologies that interrogate methylation levels at CpG sites throughout the entire human genome. With rapid reduction of sequencing costs, these technologies will enable epigenotyping of large cohorts for phenotypic association studies. Existing quantification methods for sequencing-based methylation profiling are simplistic and do not deal with the noise due to the random sampling nature of sequencing and various experimental artifacts. Therefore, there is a need to investigate the statistical issues related to the quantification of methylation levels for these emerging technologies, with the goal of developing an accurate quantification method.
Characterization of X-Linked SNP genotypic variation in globally distributed human populations
Amanda M Casto, Jun Z Li, Devin Absher, Richard Myers, Sohini Ramachandran, Marcus W Feldman
Genome Biology , 2010, DOI: 10.1186/gb-2010-11-1-r10
Abstract: We found that X chromosomes tend to be more differentiated between human populations than autosomes, with several notable exceptions. Comparisons between genetically distant populations also showed an excess of X-linked SNPs with large allele frequency differences. Combining information about these SNPs with results from tests designed to detect selective sweeps, we identified two regions that were clear outliers from the rest of the X chromosome for haplotype structure and allele frequency distribution. We were also able to more precisely define the geographical extent of some previously described X-linked selective sweeps.The relationship between male and female demographic histories is likely to be complex as evidence supporting different conclusions can be found in the same dataset. Although demography may have contributed to the excess of SNPs with large allele frequency differences observed on the X chromosome, we believe that selection is at least partially responsible. Finally, our results reveal the geographical complexities of selective sweeps on the X chromosome and argue for the use of diverse populations in studies of selection.In humans, females typically carry two X chromosomes while males are haploid for almost all X-linked loci, complementing their one X chromosome with the smaller Y chromosome. This relatively small alteration to the standard of simple diploidy followed by all 22 autosomes has profound consequences for X-linked markers relative to their autosomal counterparts. Even under conditions of gender equality with respect to migration and population size, the smaller effective population size of the X chromosome means that drift may have a more profound influence upon it compared to the autosomes. Some repercussions of this are suggested by the results of Rosenberg et al. [1] and Ramachandran et al. [2], who observed that X chromosomes are generally more differentiated among human populations than are autosomes. On a worldwide scale, drift
Genome-Wide DNA Methylation Analysis of Systemic Lupus Erythematosus Reveals Persistent Hypomethylation of Interferon Genes and Compositional Changes to CD4+ T-cell Populations
Devin M. Absher ,Xinrui Li,Lindsay L. Waite,Andrew Gibson,Kevin Roberts,Jeffrey Edberg,W. Winn Chatham,Robert P. Kimberly
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003678
Abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease with known genetic, epigenetic, and environmental risk factors. To assess the role of DNA methylation in SLE, we collected CD4+ T-cells, CD19+ B-cells, and CD14+ monocytes from 49 SLE patients and 58 controls, and performed genome-wide DNA methylation analysis with Illumina Methylation450 microarrays. We identified 166 CpGs in B-cells, 97 CpGs in monocytes, and 1,033 CpGs in T-cells with highly significant changes in DNA methylation levels (p<1×10?8) among SLE patients. Common to all three cell-types were widespread and severe hypomethylation events near genes involved in interferon signaling (type I). These interferon-related changes were apparent in patients collected during active and quiescent stages of the disease, suggesting that epigenetically-mediated hypersensitivity to interferon persists beyond acute stages of the disease and is independent of circulating interferon levels. This interferon hypersensitivity was apparent in memory, na?ve and regulatory T-cells, suggesting that this epigenetic state in lupus patients is established in progenitor cell populations. We also identified a widespread, but lower amplitude shift in methylation in CD4+ T-cells (>16,000 CpGs at FDR<1%) near genes involved in cell division and MAPK signaling. These cell type-specific effects are consistent with disease-specific changes in the composition of the CD4+ population and suggest that shifts in the proportion of CD4+ subtypes can be monitored at CpGs with subtype-specific DNA methylation patterns.
Genomics of Post-Prandial Lipidomic Phenotypes in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study
Marguerite R. Irvin, Degui Zhi, Stella Aslibekyan, Steven A. Claas, Devin M. Absher, Jose M. Ordovas, Hemant K. Tiwari, Steve Watkins, Donna K. Arnett
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0099509
Abstract: Background Increased postprandial lipid (PPL) response to dietary fat intake is a heritable risk factor for cardiovascular disease (CVD). Variability in postprandial lipids results from the complex interplay of dietary and genetic factors. We hypothesized that detailed lipid profiles (eg, sterols and fatty acids) may help elucidate specific genetic and dietary pathways contributing to the PPL response. Methods and Results We used gas chromatography mass spectrometry to quantify the change in plasma concentration of 35 fatty acids and 11 sterols between fasting and 3.5 hours after the consumption of a high-fat meal (PPL challenge) among 40 participants from the GOLDN study. Correlations between sterols, fatty acids and clinical measures were calculated. Mixed linear regression was used to evaluate associations between lipidomic profiles and genomic markers including single nucleotide polymorphisms (SNPs) and methylation markers derived from the Affymetrix 6.0 array and the Illumina Methyl450 array, respectively. After the PPL challenge, fatty acids increased as well as sterols associated with cholesterol absorption, while sterols associated with cholesterol synthesis decreased. PPL saturated fatty acids strongly correlated with triglycerides, very low-density lipoprotein, and chylomicrons. Two SNPs (rs12247017 and rs12240292) in the sorbin and SH3 domain containing 1 (SORBS1) gene were associated with b-Sitosterol after correction for multiple testing (P≤4.5*10?10). SORBS1 has been linked to obesity and insulin signaling. No other markers reached the genome-wide significance threshold, yet several other biologically relevant loci are highlighted (eg, PRIC285, a co-activator of PPARa). Conclusions Integration of lipidomic and genomic data has the potential to identify new biomarkers of CVD risk.
The Role of Geography in Human Adaptation
Graham Coop equal contributor ,Joseph K. Pickrell equal contributor ,John Novembre,Sridhar Kudaravalli,Jun Li,Devin Absher,Richard M. Myers,Luigi Luca Cavalli-Sforza,Marcus W. Feldman,Jonathan K. Pritchard
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000500
Abstract: Various observations argue for a role of adaptation in recent human evolution, including results from genome-wide studies and analyses of selection signals at candidate genes. Here, we use genome-wide SNP data from the HapMap and CEPH-Human Genome Diversity Panel samples to study the geographic distributions of putatively selected alleles at a range of geographic scales. We find that the average allele frequency divergence is highly predictive of the most extreme FST values across the whole genome. On a broad scale, the geographic distribution of putatively selected alleles almost invariably conforms to population clusters identified using randomly chosen genetic markers. Given this structure, there are surprisingly few fixed or nearly fixed differences between human populations. Among the nearly fixed differences that do exist, nearly all are due to fixation events that occurred outside of Africa, and most appear in East Asia. These patterns suggest that selection is often weak enough that neutral processes—especially population history, migration, and drift—exert powerful influences over the fate and geographic distribution of selected alleles.
Sequential Use of Transcriptional Profiling, Expression Quantitative Trait Mapping, and Gene Association Implicates MMP20 in Human Kidney Aging
Heather E. Wheeler,E. Jeffrey Metter,Toshiko Tanaka,Devin Absher,John Higgins,Jacob M. Zahn,Julie Wilhelmy,Ronald W. Davis,Andrew Singleton,Richard M. Myers,Luigi Ferrucci,Stuart K. Kim
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000685
Abstract: Kidneys age at different rates, such that some people show little or no effects of aging whereas others show rapid functional decline. We sequentially used transcriptional profiling and expression quantitative trait loci (eQTL) mapping to narrow down which genes to test for association with kidney aging. We first performed whole-genome transcriptional profiling to find 630 genes that change expression with age in the kidney. Using two methods to detect eQTLs, we found 101 of these age-regulated genes contain expression-associated SNPs. We tested the eQTLs for association with kidney aging, measured by glomerular filtration rate (GFR) using combined data from the Baltimore Longitudinal Study of Aging (BLSA) and the InCHIANTI study. We found a SNP association (rs1711437 in MMP20) with kidney aging (uncorrected p = 3.6×10?5, empirical p = 0.01) that explains 1%–2% of the variance in GFR among individuals. The results of this sequential analysis may provide the first evidence for a gene association with kidney aging in humans.
Genome-Wide Association Studies of Quantitatively Measured Skin, Hair, and Eye Pigmentation in Four European Populations
Sophie I. Candille, Devin M. Absher, Sandra Beleza, Marc Bauchet, Brian McEvoy, Nanibaa’ A. Garrison, Jun Z. Li, Richard M. Myers, Gregory S. Barsh, Hua Tang, Mark D. Shriver
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048294
Abstract: Pigmentation of the skin, hair, and eyes varies both within and between human populations. Identifying the genes and alleles underlying this variation has been the goal of many candidate gene and several genome-wide association studies (GWAS). Most GWAS for pigmentary traits to date have been based on subjective phenotypes using categorical scales. But skin, hair, and eye pigmentation vary continuously. Here, we seek to characterize quantitative variation in these traits objectively and accurately and to determine their genetic basis. Objective and quantitative measures of skin, hair, and eye color were made using reflectance or digital spectroscopy in Europeans from Ireland, Poland, Italy, and Portugal. A GWAS was conducted for the three quantitative pigmentation phenotypes in 176 women across 313,763 SNP loci, and replication of the most significant associations was attempted in a sample of 294 European men and women from the same countries. We find that the pigmentation phenotypes are highly stratified along axes of European genetic differentiation. The country of sampling explains approximately 35% of the variation in skin pigmentation, 31% of the variation in hair pigmentation, and 40% of the variation in eye pigmentation. All three quantitative phenotypes are correlated with each other. In our two-stage association study, we reproduce the association of rs1667394 at the OCA2/HERC2 locus with eye color but we do not identify new genetic determinants of skin and hair pigmentation supporting the lack of major genes affecting skin and hair color variation within Europe and suggesting that not only careful phenotyping but also larger cohorts are required to understand the genetic architecture of these complex quantitative traits. Interestingly, we also see that in each of these four populations, men are more lightly pigmented in the unexposed skin of the inner arm than women, a fact that is underappreciated and may vary across the world.
Characterizing the admixed African ancestry of African Americans
Fouad Zakharia, Analabha Basu, Devin Absher, Themistocles L Assimes, Alan S Go, Mark A Hlatky, Carlos Iribarren, Joshua W Knowles, Jun Li, Balasubramanian Narasimhan, Steven Sidney, Audrey Southwick, Richard M Myers, Thomas Quertermous, Neil Risch, Hua Tang
Genome Biology , 2009, DOI: 10.1186/gb-2009-10-12-r141
Abstract: From cluster analysis, we found that all the African Americans are admixed in their African components of ancestry, with the majority contributions being from West and West-Central Africa, and only modest variation in these African-ancestry proportions among individuals. Furthermore, by principal components analysis, we found little evidence of genetic structure within the African component of ancestry in African Americans.These results are consistent with historic mating patterns among African Americans that are largely uncorrelated to African ancestral origins, and they cast doubt on the general utility of mtDNA or Y-chromosome markers alone to delineate the full African ancestry of African Americans. Our results also indicate that the genetic architecture of African Americans is distinct from that of Africans, and that the greatest source of potential genetic stratification bias in case-control studies of African Americans derives from the proportion of European ancestry.Numerous studies have estimated the rate of European admixture in African Americans; these studies have documented average admixture rates in the range of 10% to 20%, with some regional variation, but also with substantial variation among individuals [1]. For example, the largest study of African Americans to date, based on autosomal short tandem repeat (STR) markers, found an average of 14% European ancestry with a standard deviation of approximately 10%, and a range of near 0 to 65% [1], whereas another study based on ancestry informative markers (AIMs) found an average of 17.7% European ancestry with a standard deviation of 15.0% [2]. By using nine AIMs, Parra and colleagues [3] found substantial variation of European ancestry proportions in African-American populations across the United States, ranging from just over 10% in a Philadelphia group to more than 20% in a New Orleans population. Similar levels (11% to 15%) of European ancestry also were reported by Tishkoff and co-workers [4], base
Academic Success in College: Socioeconomic Status and Parental Influence as Predictors of Outcome  [PDF]
Devin L. Merritt, Walter Buboltz
Open Journal of Social Sciences (JSS) , 2015, DOI: 10.4236/jss.2015.35018
Abstract: Bandura (1986) postulated that beliefs about one’s ability (self-efficacy) were better predictors of achievement than ability itself [1]. Therefore, in academics, the higher the beliefs that a student develops regarding his or her ability to succeed in school, the greater the likelihood that he or she will attain academic success. Although academic goals vary among students, academic self-efficacy appears to be essential in order for academic aspirations to be achieved. Multiple factors, including socioeconomic status (SES) are related to academic self-efficacy. Past research has noted that SES influences academic attainment [2] [3]. Familial backgrounds, such as SES [4] and parental influence [5], have been found to impact academic achievement. This study examined the relationship between socioeconomic status, academic self-efficacy, and perceived success in college. A total of 298 undergraduate students from a southern university completed self-report measures that consisted of sociodemographic questions, the Multidimensional Scales of Perceived Self-Efficacy (MSPSE), and the Perceptions of Parental and Teacher Academic Involvement. Results indicated that SES was significantly related to self-efficacy, and parental influence was a significant predictor of academic self-efficacy. Results also showed that parental involvement mediated the relationship between familial SES and self-efficacy.
Post-Zygotic and Inter-Individual Structural Genetic Variation in a Presumptive Enhancer Element of the Locus between the IL10Rβ and IFNAR1 Genes
Hamid Reza Razzaghian, Lars A. Forsberg, Kancherla Reddy Prakash, Szymon Przerada, Hanna Paprocka, Anna Zywicka, Maxwell P. Westerman, Nancy L. Pedersen, Terrance P. O'Hanlon, Lisa G. Rider, Frederick W. Miller, Ewa Srutek, Michal Jankowski, Wojciech Zegarski, Arkadiusz Piotrowski, Devin Absher, Jan P. Dumanski
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0067752
Abstract: Although historically considered as junk-DNA, tandemly repeated sequence motifs can affect human phenotype. For example, variable number tandem repeats (VNTR) with embedded enhancers have been shown to regulate gene transcription. The post-zygotic variation is the presence of genetically distinct populations of cells in an individual derived from a single zygote, and this is an understudied aspect of genome biology. We report somatically variable VNTR with sequence properties of an enhancer, located upstream of IFNAR1. Initially, SNP genotyping of 63 monozygotic twin pairs and multiple tissues from 21 breast cancer patients suggested a frequent post-zygotic mosaicism. The VNTR displayed a repeated 32 bp core motif in the center of the repeat, which was flanked by similar variable motifs. A total of 14 alleles were characterized based on combinations of segments, which showed post-zygotic and inter-individual variation, with up to 6 alleles in a single subject. Somatic variation occurred in ~24% of cases. In this hypervariable region, we found a clustering of transcription factor binding sites with strongest sequence similarity to mouse Foxg1 transcription factor binding motif. This study describes a VNTR with sequence properties of an enhancer that displays post-zygotic and inter-individual genetic variation. This element is within a locus containing four related cytokine receptors: IFNAR2, IL10Rβ, IFNAR1 and IFNGR2, and we hypothesize that it might function in transcriptional regulation of several genes in this cluster. Our findings add another level of complexity to the variation among VNTR-based enhancers. Further work may unveil the normal function of this VNTR in transcriptional control and its possible involvement in diseases connected with these receptors, such as autoimmune conditions and cancer.
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