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Search Results: 1 - 10 of 9709 matches for " Dongliang Ge equal contributor "
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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.
Genome-Wide mRNA Expression Correlates of Viral Control in CD4+ T-Cells from HIV-1-Infected Individuals
Margalida Rotger equal contributor,Kristen K. Dang equal contributor,Jacques Fellay equal contributor,Erin L. Heinzen,Sheng Feng,Patrick Descombes,Kevin V. Shianna,Dongliang Ge,Huldrych F. Günthard,David B. Goldstein ,Amalio Telenti ,The Swiss HIV Cohort Study and the Center for HIV/AIDS Vaccine Immunology
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000781
Abstract: There is great interindividual variability in HIV-1 viral setpoint after seroconversion, some of which is known to be due to genetic differences among infected individuals. Here, our focus is on determining, genome-wide, the contribution of variable gene expression to viral control, and to relate it to genomic DNA polymorphism. RNA was extracted from purified CD4+ T-cells from 137 HIV-1 seroconverters, 16 elite controllers, and 3 healthy blood donors. Expression levels of more than 48,000 mRNA transcripts were assessed by the Human-6 v3 Expression BeadChips (Illumina). Genome-wide SNP data was generated from genomic DNA using the HumanHap550 Genotyping BeadChip (Illumina). We observed two distinct profiles with 260 genes differentially expressed depending on HIV-1 viral load. There was significant upregulation of expression of interferon stimulated genes with increasing viral load, including genes of the intrinsic antiretroviral defense. Upon successful antiretroviral treatment, the transcriptome profile of previously viremic individuals reverted to a pattern comparable to that of elite controllers and of uninfected individuals. Genome-wide evaluation of cis-acting SNPs identified genetic variants modulating expression of 190 genes. Those were compared to the genes whose expression was found associated with viral load: expression of one interferon stimulated gene, OAS1, was found to be regulated by a SNP (rs3177979, p = 4.9E-12); however, we could not detect an independent association of the SNP with viral setpoint. Thus, this study represents an attempt to integrate genome-wide SNP signals with genome-wide expression profiles in the search for biological correlates of HIV-1 control. It underscores the paradox of the association between increasing levels of viral load and greater expression of antiviral defense pathways. It also shows that elite controllers do not have a fully distinctive mRNA expression pattern in CD4+ T cells. Overall, changes in global RNA expression reflect responses to viral replication rather than a mechanism that might explain viral control.
The Characterization of Twenty Sequenced Human Genomes
Kimberly Pelak equal contributor,Kevin V. Shianna equal contributor,Dongliang Ge equal contributor,Jessica M. Maia,Mingfu Zhu,Jason P. Smith,Elizabeth T. Cirulli,Jacques Fellay,Samuel P. Dickson,Curtis E. Gumbs,Erin L. Heinzen,Anna C. Need,Elizabeth K. Ruzzo,Abanish Singh,C. Ryan Campbell,Linda K. Hong,Katharina A. Lornsen,Alexander M. McKenzie,Nara L. M. Sobreira,Julie E. Hoover-Fong,Joshua D. Milner,Ruth Ottman,Barton F. Haynes,James J. Goedert,David B. Goldstein
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1001111
Abstract: We present the analysis of twenty human genomes to evaluate the prospects for identifying rare functional variants that contribute to a phenotype of interest. We sequenced at high coverage ten “case” genomes from individuals with severe hemophilia A and ten “control” genomes. We summarize the number of genetic variants emerging from a study of this magnitude, and provide a proof of concept for the identification of rare and highly-penetrant functional variants by confirming that the cause of hemophilia A is easily recognizable in this data set. We also show that the number of novel single nucleotide variants (SNVs) discovered per genome seems to stabilize at about 144,000 new variants per genome, after the first 15 individuals have been sequenced. Finally, we find that, on average, each genome carries 165 homozygous protein-truncating or stop loss variants in genes representing a diverse set of pathways.
Copy Number Variation of KIR Genes Influences HIV-1 Control
Kimberly Pelak equal contributor,Anna C. Need equal contributor,Jacques Fellay equal contributor,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 ,on behalf of NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI)
PLOS Biology , 2011, 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.
A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia
Anna C. Need equal contributor,Dongliang Ge equal contributor,Michael E. Weale equal contributor,Jessica Maia,Sheng Feng,Erin L. Heinzen,Kevin V. Shianna,Woohyun Yoon,Dalia Kasperavi?iūt?,Massimo Gennarelli,Warren J. Strittmatter,Cristian Bonvicini,Giuseppe Rossi,Karu Jayathilake,Philip A. Cola,Joseph P. McEvoy,Richard S. E. Keefe,Elizabeth M. C. Fisher,Pamela L. St. Jean,Ina Giegling,Annette M. Hartmann,Hans-Jürgen M?ller,Andreas Ruppert,Gillian Fraser,Caroline Crombie,Lefkos T. Middleton,David St. Clair,Allen D. Roses,Pierandrea Muglia,Clyde Francks,Dan Rujescu,Herbert Y. Meltzer,David B. Goldstein
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000373
Abstract: We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater “load” of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.
Common Genetic Variation and the Control of HIV-1 in Humans
Jacques Fellay equal contributor,Dongliang Ge equal contributor,Kevin V. Shianna,Sara Colombo,Bruno Ledergerber,Elizabeth T. Cirulli,Thomas J. Urban,Kunlin Zhang,Curtis E. Gumbs,Jason P. Smith,Antonella Castagna,Alessandro Cozzi-Lepri,Andrea De Luca,Philippa Easterbrook,Huldrych F. Günthard,Simon Mallal,Cristina Mussini,Judith Dalmau,Javier Martinez-Picado,José M. Miro,Niels Obel,Steven M. Wolinsky,Jeremy J. Martinson,Roger Detels,Joseph B. Margolick,Lisa P. Jacobson,Patrick Descombes,Stylianos E. Antonarakis,Jacques S. Beckmann,Stephen J. O'Brien,Norman L. Letvin,Andrew J. McMichael,Barton F. Haynes,Mary Carrington,Sheng Feng,Amalio Telenti ,David B. Goldstein ,NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI)
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000791
Abstract: To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.
Tor1/Sch9-Regulated Carbon Source Substitution Is as Effective as Calorie Restriction in Life Span Extension
Min Wei equal contributor,Paola Fabrizio equal contributor,Federica Madia,Jia Hu,Huanying Ge,Lei M. Li,Valter D. Longo
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000467
Abstract: The effect of calorie restriction (CR) on life span extension, demonstrated in organisms ranging from yeast to mice, may involve the down-regulation of pathways, including Tor, Akt, and Ras. Here, we present data suggesting that yeast Tor1 and Sch9 (a homolog of the mammalian kinases Akt and S6K) is a central component of a network that controls a common set of genes implicated in a metabolic switch from the TCA cycle and respiration to glycolysis and glycerol biosynthesis. During chronological survival, mutants lacking SCH9 depleted extracellular ethanol and reduced stored lipids, but synthesized and released glycerol. Deletion of the glycerol biosynthesis genes GPD1, GPD2, or RHR2, among the most up-regulated in long-lived sch9Δ, tor1Δ, and ras2Δ mutants, was sufficient to reverse chronological life span extension in sch9Δ mutants, suggesting that glycerol production, in addition to the regulation of stress resistance systems, optimizes life span extension. Glycerol, unlike glucose or ethanol, did not adversely affect the life span extension induced by calorie restriction or starvation, suggesting that carbon source substitution may represent an alternative to calorie restriction as a strategy to delay aging.
The Maternal-Effect Gene cellular island Encodes Aurora B Kinase and Is Essential for Furrow Formation in the Early Zebrafish Embryo
Taijiro Yabe,Xiaoyan Ge equal contributor,Robin Lindeman equal contributor,Sreelaja Nair,Greg Runke,Mary C. Mullins,Francisco Pelegri
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000518
Abstract: Females homozygous for a mutation in cellular island (cei) produce embryos with defects in cytokinesis during early development. Analysis of the cytoskeletal events associated with furrow formation reveal that these defects include a general delay in furrow initiation as well as a complete failure to form furrow-associated structures in distal regions of the blastodisc. A linkage mapping-based candidate gene approach, including transgenic rescue, shows that cei encodes the zebrafish Aurora B kinase homologue. Genetic complementation analysis between the cei mutation and aurB zygotic lethal mutations corroborate gene assignment and reveal a complex nature of the maternal-effect cei allele, which appears to preferentially affect a function important for cytokinesis in the early blastomeres. Surprisingly, in cei mutant embryos a short yet otherwise normal furrow forms in the center of the blastodisc. Furrow formation is absent throughout the width of the blastodisc in cei mutant embryos additionally mutant for futile cycle, which lack a spindle apparatus, showing that the residual furrow signal present in cei mutants is derived from the mitotic spindle. Our analysis suggests that partially redundant signals derived from the spindle and astral apparatus mediate furrow formation in medial and distal regions of the early embryonic blastomeres, respectively, possibly as a spatial specialization to achieve furrow formation in these large cells. In addition, our data also suggest a role for Cei/AurB function in the reorganization of the furrow-associated microtubules in both early cleavage- and somite-stage embryos. In accordance with the requirement for cei/aurB in furrow induction in the early cleavage embryo, germ plasm recruitment to the forming furrow is also affected in embryos lacking normal cei/aurB function.
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