Analysis of protein-coding genetic variation in 60,706 humans

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Author
Banks, Eric
Fennell, Timothy
O'Donnell-Luria, Anne H
Ware, James S
Hill, Andrew J
Tukiainen, Taru
Birnbaum, Daniel P
Duncan, Laramie E
Estrada, Karol
Zhao, Fengmei
Zou, James
Pierce-Hoffman, Emma
Berghout, Joanne
Cooper, David N
Deflaux, Nicole
DePristo, Mark
Do, Ron
Fromer, Menachem
Gauthier, Laura
Goldstein, Jackie
Gupta, Namrata
Kiezun, Adam
Moonshine, Ami Levy
Orozco, Lorena
Peloso, Gina M
Poplin, Ryan
Rivas, Manuel A
Ruano-Rubio, Valentin
Rose, Samuel A
Ruderfer, Douglas M
Shakir, Khalid
Stenson, Peter D
Stevens, Christine
Thomas, Brett P
Tiao, Grace
Tusie-Luna, Maria T
Weisburd, Ben
Won, Hong-Hee
Yu, Dongmei
Ardissino, Diego
Boehnke, Michael
Danesh, John
Donnelly, Stacey
Elosua, Roberto
Gabriel, Stacey B
Glatt, Stephen J
Hultman, Christina M
Kathiresan, Sekar
Laakso, Markku
McCarthy, Mark I
McGovern, Dermot
McPherson, Ruth
Purcell, Shaun M
Saleheen, Danish
Sklar, Pamela
Sullivan, Patrick F
Tuomilehto, Jaakko
Tsuang, Ming T
Watkins, Hugh C
Wilson, James G
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https://doi.org/10.1038/nature19057Metadata
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Lek, M., K. J. Karczewski, E. V. Minikel, K. E. Samocha, E. Banks, T. Fennell, A. H. O'Donnell-Luria, et al. 2016. “Analysis of protein-coding genetic variation in 60,706 humans.” Nature 536 (7616): 285-291. doi:10.1038/nature19057. http://dx.doi.org/10.1038/nature19057.Abstract
Summary Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. We describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities 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 truncating variants with 72% 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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018207/pdf/Terms of Use
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