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Search Results: 1 - 10 of 136632 matches for " Kevin V. Shianna "
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Host Genetics and HIV-1: The Final Phase?
Jacques Fellay ,Kevin V. Shianna,Amalio Telenti,David B. Goldstein
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1001033
Abstract: This is a crucial transition time for human genetics in general, and for HIV host genetics in particular. After years of equivocal results from candidate gene analyses, several genome-wide association studies have been published that looked at plasma viral load or disease progression. Results from other studies that used various large-scale approaches (siRNA screens, transcriptome or proteome analysis, comparative genomics) have also shed new light on retroviral pathogenesis. However, most of the inter-individual variability in response to HIV-1 infection remains to be explained: genome resequencing and systems biology approaches are now required to progress toward a better understanding of the complex interactions between HIV-1 and its human host.
High-Throughput Isolation and Mapping of C. elegans Mutants Susceptible to Pathogen Infection
Laura E. Fuhrman, Kevin V. Shianna, Alejandro Aballay
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002882
Abstract: We present a novel strategy that uses high-throughput methods of isolating and mapping C. elegans mutants susceptible to pathogen infection. We show that C. elegans mutants that exhibit an enhanced pathogen accumulation (epa) phenotype can be rapidly identified and isolated using a sorting system that allows automation of the analysis, sorting, and dispensing of C. elegans by measuring fluorescent bacteria inside the animals. Furthermore, we validate the use of Amplifluor? as a new single nucleotide polymorphism (SNP) mapping technique in C. elegans. We show that a set of 9 SNPs allows the linkage of C. elegans mutants to a 5–8 megabase sub-chromosomal region.
Exome sequencing: the expert view
Leslie G Biesecker, Kevin V Shianna, Jim C Mullikin
Genome Biology , 2011, DOI: 10.1186/gb-2011-12-9-128
Abstract: Exomes are ideal to help us understand high-penetrance allelic variation and its relationship to phenotype. Because exomes focus on exons, which include coding regions of genes, and because most high-penetrance (Mendelian or nearly so) variation is mediated by non-synonymous, frameshifting and canonical splice variation, exomes are ideal for studying the relationship of such variation to health and disease.Sequencing using any approach is still in its early days, but it is clear that exome sequencing will often lead to the identification of the causative variant for Mendelian diseases. This should not be surprising given that we know that most mutations causing Mendelian disease are exonic. That said, there are clear limitations even for Mendelian disease. Structural variations (SVs), which are also important for Mendelian disease, are not easily detected using an exome approach. How well exome sequencing may do for complex traits is an entirely open question since we do not know what kinds of mutations are important there, but it is possible they are more often regulatory than for Mendelian disease.Cost is a huge factor - every day we ask ourselves the question, 'Would we rather have six samples analyzed by whole exome sequencing (WES) or one by whole genome sequencing (WGS)?' Our current, fully loaded price for a WGS is six times that of a WES assay - a ratio that has changed surprisingly little in the past 2 years. Which study one should use depends on the biomedical question that is being asked. If it is primarily a genotype-phenotype question, and the putative variant is high penetrance, then it is crucial to increase our statistical power by increasing our N, so exomes provide a big advantage here. If the question is different, it could be that a smaller number of WGS interrogations would be more effective. WES and WGS are tools - one has to select the optimal tool considering the biomedical question and the available resources.The lower cost of exome sequenci
Nucleolar Proteins Suppress Caenorhabditis elegans Innate Immunity by Inhibiting p53/CEP-1
Laura E. Fuhrman,Ajay Kumar Goel,Jason Smith,Kevin V. Shianna,Alejandro Aballay
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000657
Abstract: The tumor suppressor p53 has been implicated in multiple functions that play key roles in health and disease, including ribosome biogenesis, control of aging, and cell cycle regulation. A genetic screen for negative regulators of innate immunity in Caenorhabditis elegans led to the identification of a mutation in NOL-6, a nucleolar RNA-associated protein (NRAP), which is involved in ribosome biogenesis and conserved across eukaryotic organisms. Mutation or silencing of NOL-6 and other nucleolar proteins results in an enhanced resistance to bacterial infections. A full-genome microarray analysis on animals with altered immune function due to mutation in nol-6 shows increased transcriptional levels of genes regulated by a p53 homologue, CEP-1. Further studies indicate that the activation of innate immunity by inhibition of nucleolar proteins requires p53/CEP-1 and its transcriptional target SYM-1. Since nucleoli and p53/CEP-1 are conserved, our results reveal an ancient immune mechanism by which the nucleolus may regulate immune responses against bacterial pathogens.
Tissue-Specific Genetic Control of Splicing: Implications for the Study of Complex Traits
Erin L. Heinzen,Dongliang Ge,Kenneth D. Cronin,Jessica M. Maia,Kevin V. Shianna,Willow N. Gabriel,Kathleen A. Welsh-Bohmer,Christine M. Hulette,Thomas N. Denny,David B. Goldstein
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000001
Abstract: Numerous genome-wide screens for polymorphisms that influence gene expression have provided key insights into the genetic control of transcription. Despite this work, the relevance of specific polymorphisms to in vivo expression and splicing remains unclear. We carried out the first genome-wide screen, to our knowledge, for SNPs that associate with alternative splicing and gene expression in human primary cells, evaluating 93 autopsy-collected cortical brain tissue samples with no defined neuropsychiatric condition and 80 peripheral blood mononucleated cell samples collected from living healthy donors. We identified 23 high confidence associations with total expression and 80 with alternative splicing as reflected by expression levels of specific exons. Fewer than 50% of the implicated SNPs however show effects in both tissue types, reflecting strong evidence for distinct genetic control of splicing and expression in the two tissue types. The data generated here also suggest the possibility that splicing effects may be responsible for up to 13 out of 84 reported genome-wide significant associations with human traits. These results emphasize the importance of establishing a database of polymorphisms affecting splicing and expression in primary tissue types and suggest that splicing effects may be of more phenotypic significance than overall gene expression changes.
Screening the human exome: a comparison of whole genome and whole transcriptome sequencing
Elizabeth T Cirulli, Abanish Singh, Kevin V Shianna, Dongliang Ge, Jason P Smith, Jessica M Maia, Erin L Heinzen, James J Goedert, David B Goldstein, the Center for HIV/AIDS Vaccine Immunology (CHAVI)
Genome Biology , 2010, DOI: 10.1186/gb-2010-11-5-r57
Abstract: Here we provide a systematic exploration of how well RNA-Seq can identify human coding variants by comparing variants identified through high coverage whole-genome sequencing to those identified by high coverage RNA-Seq in the same individual. This comparison allowed us to directly evaluate the sensitivity and specificity of RNA-Seq in identifying coding variants, and to evaluate how key parameters such as the degree of coverage and the expression levels of genes interact to influence performance. We find that although only 40% of exonic variants identified by whole genome sequencing were captured using RNA-Seq; this number rose to 81% when concentrating on genes known to be well-expressed in the source tissue. We also find that a high false positive rate can be problematic when working with RNA-Seq data, especially at higher levels of coverage.We conclude that as long as a tissue relevant to the trait under study is available and suitable quality control screens are implemented, RNA-Seq is a fast and inexpensive alternative approach for finding coding variants in genes with sufficiently high expression levels.The study of common human diseases is rapidly moving away from an exclusive focus on common variants using genome-wide association studies and toward sequencing approaches that represent most variants, including those that are rare in the general population.Although rapidly falling, the per base costs of next generation sequencing platforms still preclude the generation of large sample sizes of entirely sequenced genomes at high coverage. In addition to this economic constraint, it is widely appreciated that the very large number of variants identified in such studies will make it difficult to use association evidence alone to identify causal sites. For these reasons, there has been considerable interest in focusing attention on coding variants as a first step at complete representation of human variation. Part of the motivation for this approach stems from th
Tissue-Specific Genetic Control of Splicing: Implications for the Study of Complex Traits
Erin L Heinzen equal contributor,Dongliang Ge equal contributor,Kenneth D Cronin,Jessica M Maia,Kevin V Shianna,Willow N Gabriel,Kathleen A Welsh-Bohmer,Christine M Hulette,Thomas N Denny,David B Goldstein
PLOS Biology , 2008, DOI: 10.1371/journal.pbio.1000001
Abstract: Numerous genome-wide screens for polymorphisms that influence gene expression have provided key insights into the genetic control of transcription. Despite this work, the relevance of specific polymorphisms to in vivo expression and splicing remains unclear. We carried out the first genome-wide screen, to our knowledge, for SNPs that associate with alternative splicing and gene expression in human primary cells, evaluating 93 autopsy-collected cortical brain tissue samples with no defined neuropsychiatric condition and 80 peripheral blood mononucleated cell samples collected from living healthy donors. We identified 23 high confidence associations with total expression and 80 with alternative splicing as reflected by expression levels of specific exons. Fewer than 50% of the implicated SNPs however show effects in both tissue types, reflecting strong evidence for distinct genetic control of splicing and expression in the two tissue types. The data generated here also suggest the possibility that splicing effects may be responsible for up to 13 out of 84 reported genome-wide significant associations with human traits. These results emphasize the importance of establishing a database of polymorphisms affecting splicing and expression in primary tissue types and suggest that splicing effects may be of more phenotypic significance than overall gene expression changes.
Whole-Genome Sequencing of a Single Proband Together with Linkage Analysis Identifies a Mendelian Disease Gene
Nara L. M. Sobreira equal contributor,Elizabeth T. Cirulli equal contributor,Dimitrios Avramopoulos equal contributor,Elizabeth Wohler,Gretchen L. Oswald,Eric L. Stevens,Dongliang Ge,Kevin V. Shianna,Jason P. Smith,Jessica M. Maia,Curtis E. Gumbs,Jonathan Pevsner,George Thomas,David Valle ?,Julie E. Hoover-Fong ?,David B. Goldstein ?
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1000991
Abstract: Although more than 2,400 genes have been shown to contain variants that cause Mendelian disease, there are still several thousand such diseases yet to be molecularly defined. The ability of new whole-genome sequencing technologies to rapidly indentify most of the genetic variants in any given genome opens an exciting opportunity to identify these disease genes. Here we sequenced the whole genome of a single patient with the dominant Mendelian disease, metachondromatosis (OMIM 156250), and used partial linkage data from her small family to focus our search for the responsible variant. In the proband, we identified an 11 bp deletion in exon four of PTPN11, which alters frame, results in premature translation termination, and co-segregates with the phenotype. In a second metachondromatosis family, we confirmed our result by identifying a nonsense mutation in exon 4 of PTPN11 that also co-segregates with the phenotype. Sequencing PTPN11 exon 4 in 469 controls showed no such protein truncating variants, supporting the pathogenicity of these two mutations. This combination of a new technology and a classical genetic approach provides a powerful strategy to discover the genes responsible for unexplained Mendelian disorders.
A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci
Sreekumar G. Pillai ,Dongliang Ge equal contributor,Guohua Zhu equal contributor,Xiangyang Kong equal contributor,Kevin V. Shianna,Anna C. Need,Sheng Feng,Craig P. Hersh,Per Bakke,Amund Gulsvik,Andreas Ruppert,Karin C. L?drup Carlsen,Allen Roses,Wayne Anderson,ICGN Investigators,Stephen I. Rennard,David A. Lomas,Edwin K. Silverman,David B. Goldstein
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000421
Abstract: There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of α1-antitrypsin, which is present in 1–2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48×10?10, (rs8034191) and 5.74×10?10 (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer.
Copy Number Variation of KIR Genes Influences HIV-1 Control
Kimberly Pelak,Anna C. Need,Jacques Fellay,Kevin V. Shianna,Sheng Feng,Thomas J. Urban,Dongliang Ge,Andrea De Luca,Javier Martinez-Picado,Steven M. Wolinsky,Jeremy J. Martinson,Beth D. Jamieson,Jay H. Bream,Maureen P. Martin,Persephone Borrow,Norman L. Letvin,Andrew J. McMichael,Barton F. Haynes,Amalio Telenti,Mary Carrington,David B. Goldstein,Galit Alter
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1001208
Abstract: A genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control as measured by plasma viral load at set point in individuals of European ancestry. This CNV encompasses the KIR3DL1-KIR3DS1 locus, encoding receptors that interact with specific HLA-Bw4 molecules to regulate the activation of lymphocyte subsets including natural killer (NK) cells. We quantified the number of copies of KIR3DS1 and KIR3DL1 in a large HIV-1 positive cohort, and showed that an increase in KIR3DS1 count associates with a lower viral set point if its putative ligand is present (p = 0.00028), as does an increase in KIR3DL1 count in the presence of KIR3DS1 and appropriate ligands for both receptors (p = 0.0015). We further provide functional data that demonstrate that NK cells from individuals with multiple copies of KIR3DL1, in the presence of KIR3DS1 and the appropriate ligands, inhibit HIV-1 replication more robustly, and associated with a significant expansion in the frequency of KIR3DS1+, but not KIR3DL1+, NK cells in their peripheral blood. Our results suggest that the relative amounts of these activating and inhibitory KIR play a role in regulating the peripheral expansion of highly antiviral KIR3DS1+ NK cells, which may determine differences in HIV-1 control following infection.
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