Analysis of protein-coding genetic variation in 60,706 humans.
Authors
Lek, Monkol
Karczewski, Konrad J
Minikel, Eric V
Samocha, Kaitlin E
Banks, Eric
Fennell, Timothy
O'Donnell-Luria, Anne H
Ware, James S
Hill, Andrew J
Cummings, Beryl B
Tukiainen, Taru
Birnbaum, Daniel P
Kosmicki, Jack A
Duncan, Laramie E
Estrada, Karol
Zhao, Fengmei
Zou, James
Pierce-Hoffman, Emma
Berghout, Joanne
Cooper, David N
Deflaux, Nicole
DePristo, Mark
Do, Ron
Flannick, Jason
Fromer, Menachem
Gauthier, Laura
Goldstein, Jackie
Gupta, Namrata
Howrigan, Daniel
Kiezun, Adam
Kurki, Mitja I
Moonshine, Ami Levy
Natarajan, Pradeep
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
Altshuler, David M
Ardissino, Diego
Boehnke, Michael
Donnelly, Stacey
Elosua, Roberto
Florez, Jose C
Gabriel, Stacey B
Getz, Gad
Glatt, Stephen J
Hultman, Christina M
Kathiresan, Sekar
Laakso, Markku
McCarroll, Steven
McCarthy, Mark I
McGovern, Dermot
McPherson, Ruth
Neale, Benjamin M
Palotie, Aarno
Purcell, Shaun M
Saleheen, Danish
Scharf, Jeremiah M
Sklar, Pamela
Sullivan, Patrick F
Tuomilehto, Jaakko
Tsuang, Ming T
Watkins, Hugh C
Wilson, James G
Daly, Mark J
MacArthur, Daniel G
Exome Aggregation Consortium
Publication Date
2016-08-18Journal Title
Nature
ISSN
0028-0836
Publisher
Springer Science and Business Media LLC
Volume
536
Issue
7616
Pages
285-291
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print
Metadata
Show full item recordCitation
Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., et al. (2016). Analysis of protein-coding genetic variation in 60,706 humans.. Nature, 536 (7616), 285-291. https://doi.org/10.1038/nature19057
Abstract
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.
Keywords
Exome Aggregation Consortium, Humans, Rare Diseases, Proteome, Sample Size, DNA Mutational Analysis, Phenotype, Genetic Variation, Exome, Datasets as Topic
Sponsorship
Medical Research Council (MR/P02811X/1)
European Commission and European Federation of Pharmaceutical Industries and Associations (EFPIA) FP7 Innovative Medicines Initiative (IMI) (116074)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC)
British Heart Foundation (CH/12/2/29428)
Medical Research Council (MR/P013880/1)
Ume� University (unknown)
NHS Blood and Transplant (NHSBT) (WP12-01)
European Commission (279143)
NHS Blood and Transplant (NHSBT) (11-01-GEN)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)
British Heart Foundation (None)
Medical Research Council (MR/L003120/1)
European Commission (279233)
European Research Council (268834)
MRC (MR/J015709/1)
MRC (MR/J006602/1)
MRC (MR/J006599/1)
Medical Research Council (MR/M012816/1)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
British Heart Foundation (RG/16/4/32218)
Cambridge University Hospitals NHS Foundation Trust (CUH) (3819-1617-25)
Department of Health (via National Institute for Health Research (NIHR)) (NIHR BTRU-2014-10024)
Cambridge University Hospitals NHS Foundation Trust (CUH) (3819-1516-29)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Identifiers
External DOI: https://doi.org/10.1038/nature19057
This record's URL: https://www.repository.cam.ac.uk/handle/1810/270516
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