Carolina Center for Genome science

Chapel Hill, NC, United States

Carolina Center for Genome science

Chapel Hill, NC, United States
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Jabara C.B.,Center for Research | Jabara C.B.,University of North Carolina at Chapel Hill | Jabara C.B.,Abbott Laboratories | Hu F.,Center for Research | And 15 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

HIV coinfection accelerates disease progression in chronic hepatitis C and reduces sustained antiviral responses (SVR) to interferon- based therapy. New direct-acting antivirals (DAAs) promise higher SVR rates, but the selection of preexisting resistanceassociated variants (RAVs) may lead to virologic breakthrough or relapse. Thus, pretreatment frequencies of RAVs are likely determinants of treatment outcome but typically are below levels at which the viral sequence can be accurately resolved. Moreover, it is not known how HIV coinfection influences RAV frequency. We adopted an accurate high-throughput sequencing strategy to compare nucleotide diversity in HCV NS3 protease-coding sequences in 20 monoinfected and 20 coinfected subjects with well-controlled HIV infection. Differences in mean pairwise nucleotide diversity (π), Tajima's D statistic, and Shannon entropy index suggested that the genetic diversity of HCV is reduced in coinfection. Among coinfected subjects, diversity correlated positively with increases in CD4± T cells on antiretroviral therapy, suggesting T cell responses are important determinants of diversity. At a median sequencing depth of 0.084%, preexisting RAVs were readily identified. Q80K, which negatively impacts clinical responses to simeprevir, was encoded by more than 99% of viral RNAs in 17 of the 40 subjects. RAVs other than Q80K were identified in 39 of 40 subjects, mostly at frequencies near 0.1%. RAV frequency did not differ significantly between monoinfected and coinfected subjects. We conclude that HCV genetic diversity is reduced in patients with well-controlled HIV infection, likely reflecting impaired T cell immunity. However, RAV frequency is not increased and should not adversely influence the outcome of DAA therapy. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Franceschini N.,University of North Carolina at Chapel Hill | Shara N.M.,MedStar Research Institute | Shara N.M.,Georgetown and Howard Universities | Wang H.,MedStar Research Institute | And 15 more authors.
Kidney International | Year: 2012

Type 2 diabetes is highly prevalent and is the major cause of progressive chronic kidney disease in American Indians. Genome-wide association studies identified several loci associated with diabetes but their impact on susceptibility to diabetic complications is unknown. We studied the association of 18 type 2 diabetes genome-wide association single-nucleotide polymorphisms (SNPs) with estimated glomerular filtration rate (eGFR; MDRD equation) and urine albumin-to-creatinine ratio in 6958 Strong Heart Study family and cohort participants. Center-specific residuals of eGFR and log urine albumin-to-creatinine ratio, obtained from linear regression models adjusted for age, sex, and body mass index, were regressed onto SNP dosage using variance component models in family data and linear regression in unrelated individuals. Estimates were then combined across centers. Four diabetic loci were associated with eGFR and one locus with urine albumin-to-creatinine ratio. A SNP in the WFS1 gene (rs10010131) was associated with higher eGFR in younger individuals and with increased albuminuria. SNPs in the FTO, KCNJ11, and TCF7L2 genes were associated with lower eGFR, but not albuminuria, and were not significant in prospective analyses. Our findings suggest a shared genetic risk for type 2 diabetes and its kidney complications, and a potential role for WFS1 in early-onset diabetic nephropathy in American Indian populations. © 2012 International Society of Nephrology.

Bartoli C.,University of Tuscia | Bartoli C.,French National Institute for Agricultural Research | Berge O.,French National Institute for Agricultural Research | Monteil C.L.,French National Institute for Agricultural Research | And 9 more authors.
Environmental Microbiology | Year: 2014

As a species complex, Pseudomonas syringae exists in both agriculture and natural aquatic habitats. P.viridiflava, a member of this complex, has been reported to be phenotypically largely homogenous. We characterized strains from different habitats, selected based on their genetic similarity to previously described P.viridiflava strains. We revealed two distinct phylogroups and two different kinds of variability in phenotypic traits and genomic content. The strains exhibited phase variation in phenotypes including pathogenicity and soft rot on potato. We showed that the presence of two configurations of the Type III Secretion System [single (S-PAI) and tripartite (T-PAI) pathogenicity islands] are not correlated with pathogenicity or with the capacity to induce soft rot in contrast to previous reports. The presence/absence of the avrE effector gene was the only trait we found to be correlated with pathogenicity of P.viridiflava. Other Type III secretion effector genes were not correlated with pathogenicity. A genomic region resembling an exchangeable effector locus (EEL) was found in S-PAI strains, and a probable recombination between the two PAIs is described. The ensemble of the variability observed in these phylogroups of P.syringae likely contributes to their adaptability to alternating opportunities for pathogenicity or saprophytic survival. © 2014 Society for Applied Microbiology and John Wiley & Sons Ltd.

London S.J.,Epidemiology Branch and Laboratory of Respiratory Biology | London S.J.,U.S. National Institutes of Health | Gao W.,Boston University | Hancock D.B.,Epidemiology Branch and Laboratory of Respiratory Biology | And 16 more authors.
Circulation: Cardiovascular Genetics | Year: 2014

Background-The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome-wide association studies (GWASs) have identified numerous loci associated with FEV1 and FEV1/FVC, but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWASs may explain the significant associations between FEV1/FVC and 2 genes: ADAM19 and HTR4. Methods and Results-We sequenced ADAM19 and its promoter region along with the ̃21-kb portion of HTR4 harboring GWAS single-nucleotide polymorphisms for pulmonary function and analyzed associations with FEV1/FVC among 3983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Meta-Analysis of common variants in each region identified statistically significant associations (316 tests; P<1.58×10-4) with FEV1/FVC for 14 ADAM19 single-nucleotide polymorphisms and 24 HTR4 singlenucleotide polymorphisms. After conditioning on the sentinel GWASs hit in each gene (ADAM19 rs1422795, minor allele frequency=0.33 and HTR4 rs11168048, minor allele frequency=0.40], 1 single-nucleotide polymorphism remained statistically significant (ADAM19 rs13155908, minor allele frequency=0.12; P=1.56×10-4). Analysis of rare variants (minor allele frequency <1%) using sequence kernel association test did not identify associations with either region. Conclusions-Sequencing identified 1 common variant associated with FEV1/FVC independent of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not seem to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4. © 2014 American Heart Association, Inc.

PubMed | University of North Carolina at Chapel Hill and Carolina Center for Genome science
Type: Journal Article | Journal: Acta neuropsychiatrica | Year: 2016

In bulimia nervosa (BN), borderline personality disorder (BPD) and major depression (MDD) are frequently comorbid conditions. Executive function has been found to be impaired in BPD and MDD, but the impact of comorbidity on neuropsychological function has rarely been investigated.To investigate neuropsychological function in BN with a focus on comorbid BPD and MDD.One hundred forty-four medication-free female patients entering a study of psychological treatments for BN performed a brief battery of neuropsychological tests. Comorbid MDD and BPD were systematically identified using standard interviews. Neuropsychological test results were compared.Forty-one subjects had comorbid BPD and 35 had comorbid MDD, while 15 had both. There was no effect of comorbid MDD, but there was a significant effect of BPD and a significant interaction between the diagnosis of MDD and BPD on executive tasks (trail making and Stroop). Thus, compared with subjects without BPD, subjects with BPD performed significantly worse on tests of executive function, while the group with both comorbidities performed even worse.There appears to be an additive effect of BPD and MDD resulting in impaired executive neuropsychological function. Future studies on either disorder and on BN should examine and account for the effect of comorbidity.

Baltrus D.A.,University of Arizona | Nishimura M.T.,University of North Carolina at Chapel Hill | Dougherty K.M.,University of Arizona | Biswas S.,University of North Carolina at Chapel Hill | And 7 more authors.
Molecular Plant-Microbe Interactions | Year: 2012

Biotrophic phytopathogens are typically limited to their adapted host range. In recent decades, investigations have teased apart the general molecular basis of intraspecific variation for innate immunity of plants, typically involving receptor proteins that enable perception of pathogen-associated molecular patterns or avirulence elicitors from the pathogen as triggers for defense induction. However, general consensus concerning evolutionary and molecular factors that alter host range across closely related phytopathogen isolates has been more elusive. Here, through genome comparisons and genetic manipulations, we investigate the underlying mechanisms that structure host range across closely related strains of Pseudomonas syringae isolated from different legume hosts. Although type III secretionindependent virulence factors are conserved across these three strains, we find that the presence of two genes encoding type III effectors (hopC1 and hopM1) and the absence of another (avrB2) potentially contribute to host range differences between pathovars glycinea and phaseolicola. These findings reinforce the idea that a complex genetic basis underlies host range evolution in plant pathogens. This complexity is present even in host-microbe interactions featuring relatively little divergence among both hosts and their adapted pathogens. © 2012 The American Phytopathological Society.

Egelhofer T.A.,University of California at Santa Cruz | Minoda A.,University of California at Berkeley | Minoda A.,Lawrence Berkeley National Laboratory | Klugman S.,Ludwig Institute for Cancer Research | And 41 more authors.
Nature Structural and Molecular Biology | Year: 2011

We have tested the specificity and utility of more than 200 antibodies raised against 57 different histone modifications in Drosophila melanogaster, Caenorhabditis elegans and human cells. Although most antibodies performed well, more than 25% failed specificity tests by dot blot or western blot. Among specific antibodies, more than 20% failed in chromatin immunoprecipitation experiments. We advise rigorous testing of histone-modification antibodies before use, and we provide a website for posting new test results ( © 2011 Nature America, Inc. All rights reserved.

Manning A.J.,University of Washington | Rogers S.L.,University of North Carolina at Chapel Hill | Rogers S.L.,Lineberger Comprehensive Cancer Center | Rogers S.L.,Carolina Center for Genome science
Developmental Biology | Year: 2014

Epithelia form the building blocks of many tissue and organ types. Epithelial cells often form a contiguous 2-dimensional sheet that is held together by strong adhesions. The mechanical properties conferred by these adhesions allow the cells to undergo dramatic three-dimensional morphogenetic movements while maintaining cell-cell contacts during embryogenesis and post-embryonic development. The Drosophila Folded gastrulation pathway triggers epithelial cell shape changes that drive gastrulation and tissue folding and is one of the most extensively studied examples of epithelial morphogenesis. This pathway has yielded key insights into the signaling mechanisms and cellular machinery involved in epithelial remodeling. In this review, we discuss principles of morphogenesis and signaling that have been discovered through genetic and cell biological examination of this pathway. We also consider various regulatory mechanisms and the system[U+05F3]s relevance to mammalian development. We propose future directions that will continue to broaden our knowledge of morphogenesis across taxa. © 2014 The Authors.

Monda K.L.,Carolina Center for Genome science | North K.E.,Carolina Center for Genome science | Hunt S.C.,University of North Carolina at Chapel Hill | Rao D.C.,University of Utah | And 2 more authors.
Endocrine, Metabolic and Immune Disorders - Drug Targets | Year: 2010

In this review, we discuss the genetic architecture of obesity and the metabolic syndrome, highlighting recent advances in identifying genetic variants and loci responsible for a portion of the variation in components of the metabolic syndrome, namely, adiposity traits, serum HDL and triglycerides, blood pressure, and glycemic traits. We focus particularly on recent progress from large-scale genome-wide association studies (GWAS), by detailing their successes and how lessons learned can pave the way for future discovery. Results from recent GWAS coalesce with earlier work suggesting numerous interconnections between obesity and the metabolic syndrome, developed through several potentially pleiotropic effects. We detail recent work by way of a case study on the cadherin 13 gene and its relation with adiponectin in the HyperGEN and the Framingham Heart Studies, and its association with obesity and the metabolic syndrome. We provide also a gene network analysis of recent variants related to obesity and metabolic syndrome discovered through genome-wide association studies, and 4 gene networks based on searching the NCBI database. © 2010 Bentham Science Publishers Ltd.

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