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Analysis ofprotein-codinggenetic variation in60,706 humans Monkol LekKonrad J. KarczewskiEric Vallabh Minikel2016 год

Analysis of protein-coding genetic variation in 60,706 humans
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Аннотация: Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes. Exome sequencing data from 60,706 people of diverse geographic ancestry is presented, providing insight into genetic variation across populations, and illuminating the relationship between DNA variants and human disease. As part of the Exome Aggregation Consortium (ExAC) project, Daniel MacArthur and colleagues report on the generation and analysis of high-quality exome sequencing data from 60,706 individuals of diverse ancestry. This provides the most comprehensive catalogue of human protein-coding genetic variation to date, yielding unprecedented resolution for the analysis of very rare variants across multiple human populations. The catalogue is freely accessible and provides a critical reference panel for the clinical interpretation of genetic variants and the discovery of disease-related genes.
Год издания: 2016
Авторы: Monkol Lek, Konrad J. Karczewski, Eric Vallabh Minikel, Kaitlin E. Samocha, Eric Banks, Timothy R. Fennell, Anne O’Donnell‐Luria, James S. Ware, Andrew Hill, Beryl B. Cummings, Taru Tukiainen, Daniel P. Birnbaum, Jack A. Kosmicki, Laramie E. Duncan, Karol Estrada, Fengmei Zhao, James Zou, Emma Pierce‐Hoffman, Joanne Berghout, D.N. Cooper, Nicole Deflaux, Mark A. DePristo, Ron Do, Jason Flannick, Menachem Fromer, Laura D. Gauthier, Jackie Goldstein, Namrata Gupta, Daniel P. Howrigan, Adam Kieżun, Mitja Kurki, Ami Levy Moonshine, Pradeep Natarajan, Lorena Orozco, Gina M. Peloso, Ryan Poplin, Manuel A. Rivas, Valentín Ruano-Rubio, Samuel A. Rose, Douglas M. Ruderfer, Khalid Shakir, Peter D. Stenson, Christine Stevens, Brett Thomas, Grace Tiao, Maria T. Tusie-Luna, Ben Weisburd, Hong‐Hee Won, Dongmei Yu, David Altshuler, Diego Ardissino, Michael Boehnke, John Danesh, Stacey Donnelly, Roberto Elosúa, José C. Florez, Stacey Gabriel, Gad Getz, Stephen J. Glatt, Christina M. Hultman, Sekar Kathiresan, Markku Laakso, Steven A. McCarroll, Mark I. McCarthy, Dermot McGovern, Ruth McPherson, Benjamin M. Neale, Aarno Palotie, Shaun Purcell, Danish Saleheen, Jeremiah M. Scharf, Pamela Sklar, Patrick F. Sullivan, Jaakko Tuomilehto, Ming T. Tsuang, Hugh Watkins, James G. Wilson, Mark J. Daly, Daniel G. MacArthur
Издательство: Nature Portfolio
Источник: Nature
Ключевые слова: Genomics and Rare Diseases, Genetic Associations and Epidemiology, Genomic variations and chromosomal abnormalities
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