Person: Shlyakhter, Ilya
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Shlyakhter
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Ilya
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Shlyakhter, Ilya
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Publication Identifying Recent Adaptations in Large-Scale Genomic Data(Elsevier BV, 2013) Grossman, Shamai; Andersen, Kristian G; Shlyakhter, Ilya; Tabrizi, Shervin; Winnicki, Sarah; Yen, Angela; Park, Daniel J.; Griesemer, Dustin; Karlsson, Elinor K; Wong, Sunny H.; Cabili, Moran; Adegbola, Richard A.; Bamezai, Rameshwar N.K.; Hill, Adrian V.S.; Vannberg, Fredrik O.; Rinn, John; Lander, Eric; Schaffner, Stephen; Sabeti, PardisSummary: Although several hundred regions of the human genome harbor signals of positive natural selection, few of the relevant adaptive traits and variants have been elucidated. Using full-genome sequence variation from the 1000 Genomes (1000G) Project and the composite of multiple signals (CMS) test, we investigated 412 candidate signals and leveraged functional annotation, protein structure modeling, epigenetics, and association studies to identify and extensively annotate candidate causal variants. The resulting catalog provides a tractable list for experimental follow-up; it includes 35 high-scoring nonsynonymous variants, 59 variants associated with expression levels of a nearby coding gene or lincRNA, and numerous variants associated with susceptibility to infectious disease and other phenotypes. We experimentally characterized one candidate nonsynonymous variant in Toll-like receptor 5 (TLR5) and show that it leads to altered NF-κB signaling in response to bacterial flagellin.Publication Natural Selection in a Bangladeshi Population from the Cholera-Endemic Ganges River Delta(American Association for the Advancement of Science (AAAS), 2013) Karlsson, Elinor K; Harris, J. B.; Tabrizi, Shervin; Rahman, A.; Shlyakhter, Ilya; Patterson, N.; O, C.; Schaffner, Stephen; Gupta, S.; Chowdhury, F.; Sheikh, A.; Shin, O. S.; Ellis, C.; Becker, C. E.; Stuart, L. M.; Calderwood, Stephen; Ryan, Edward; Qadri, F.; Sabeti, Pardis; Larocque, ReginaAs an ancient disease with high fatality, cholera has likely exerted strong selective pressure on affected human populations. We performed a genome-wide study of natural selection in a population from the Ganges River Delta, the historic geographic epicenter of cholera. We identified 305 candidate selected regions using the composite of multiple signals (CMS) method. The regions were enriched for potassium channel genes involved in cyclic adenosine monophosphate–mediated chloride secretion and for components of the innate immune system involved in nuclear factor κB (NF-κB) signaling. We demonstrate that a number of these strongly selected genes are associated with cholera susceptibility in two separate cohorts. We further identify repeated examples of selection and association in an NF-κB/inflammasome–dependent pathway that is activated in vitro by Vibrio cholerae. Our findings shed light on the genetic basis of cholera resistance in a population from the Ganges River Delta and present a promising approach for identifying genetic factors influencing susceptibility to infectious diseases.Publication A Map of Human Genome Variation from Population Scale Sequencing(Nature Publishing Group, 2010) Altshuler, David; Lander, Eric; Ambrogio, Lauren; Bloom, Toby; Cibulskis, Kristian; Fennell, Tim J.; Gabriel, Stacey B.; Jaffe, David B.; Shefler, Erica; Sougnez, Carrie L.; Lee, Charles; Mills, Ryan Edward; Shi, Xinghua; Daly, Mark; DePristo, Mark A.; Ball, Aaron D.; Banks, Eric; Browning, Brian L.; Garimella, Kiran V.; Grossman, Sharon; Handsaker, Robert; Hanna, Matt; Hartl, Chris; Kernytsky, Andrew M.; Korn, Joshua M.; Li, Heng; Maguire, Jared R.; McCarroll, Steven; Nemesh, James C.; McKenna, Aaron; Philippakis, Anthony Andrew; Poplin, Ryan E.; Price, Alkes; Rivas, Manuel A.; Sabeti, Pardis; Schaffner, Stephen; Shlyakhter, IlyaThe 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother–father–child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately \(10^{−8}\) per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research.Publication ALLPATHS 2: Small Genomes Assembled Accurately and with High Continuity from Short Paired Reads(BioMed Central, 2009) MacCallum, Iain; Przybylski, Dariusz; Gnerre, Sante; Burton, Joshua; Gnirke, Andreas; Malek, Joel; McKernan, Kevin; Ranade, Swati; Shea, Terrance P; Williams, Louise; Nusbaum, Chad; Jaffe, David B; Shlyakhter, Ilya; Young, SarahWe demonstrate that genome sequences approaching finished quality can be generated from short paired reads. Using 36 base (fragment) and 26 base (jumping) reads from five microbial genomes of varied GC composition and sizes up to 40 Mb, ALLPATHS2 generated assemblies with long, accurate contigs and scaffolds. Velvet and EULER-SR were less accurate. For example, for Escherichia coli, the fraction of 10-kb stretches that were perfect was 99.8% (ALLPATHS2), 68.7% (Velvet), and 42.1% (EULER-SR).Publication Mapping Copy Number Variation by Population Scale Genome Sequencing(Nature Publishing Group, 2011) Mills, Ryan Edward; Handsaker, Robert; Korn, Joshua; Nemesh, James; Shi, Xinghua; Lee, Charles; McCarroll, Steven; Altshuler, David; Gabriel, Stacey B.; Lander, Eric; Ambrogio, Lauren; Bloom, Toby; Cibulskis, Kristian; Fennell, Tim J.; Jaffe, David B.; Shefler, Erica; Sougnez, Carrie L.; Daly, Mark; DePristo, Mark A.; Ball, Aaron D.; Banks, Eric; Browning, Brian L.; Garimella, Kiran V.; Grossman, Sharon; Hanna, Matt; Hartl, Chris; Kernytsky, Andrew M.; Li, Heng; Maguire, Jared R.; McKenna, Aaron; Philippakis, Anthony Andrew; Poplin, Ryan E.; Price, Alkes; Rivas, Manuel A.; Sabeti, Pardis; Schaffner, Stephen; Shlyakhter, Ilya; Wilkinson, JaneGenomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.Publication Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum(Public Library of Science, 2011) Van tyne, Daria; Park, Daniel John; Schaffner, Stephen; Neafsey, Daniel; Angelino, Elaine Lee; Cortese, Joseph F.; Barnes, Kayla G.; Rosen, David M.; Lukens, Amanda; Daniels, Rachel; Milner, Danny; Johnson, Charles A.; Shlyakhter, Ilya; Grossman, Sharon; Becker, Justin S.; Yamins, Daniel Louis Kanef; Karlsson, Elinor K; Ndiaye, Daouda; Sarr, Ousmane; Mboup, Souleymane; Happi, Christian; Furlotte, Nicholas A.; Eskin, Eleazar; Kang, Hyun Min; Hartl, Daniel; Birren, Bruce W.; Wiegand, Roger; Lander, Eric; Wirth, Dyann; Volkman, Sarah; Sabeti, PardisThe Plasmodium falciparum parasite's ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (~1 SNP/kb), and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS), searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome.