Analysis of protein-coding genetic variation in 60,706 humans.
Document Type
Article
Publication Date
8-18-2016
Keywords
DNA Mutational Analysis, Datasets as Topic, Exome, Genetic Variation, Humans, Phenotype, Proteome, Rare Diseases, Sample Size
JAX Source
Nature 2016 Aug 18; 536(7616):285-91
Volume
536
Issue
7616
First Page
285
Last Page
291
ISSN
1476-4687
PMID
27535533
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. Nature 2016 Aug 18; 536(7616):285-91.
Recommended Citation
Lek M,
Karczewski K,
Minikel E,
Samocha K,
Banks E,
Fennell T,
O'Donnell-Luria A,
Ware J,
Hill A,
Cummings B,
Tukiainen T,
Birnbaum D,
Kosmicki J,
Duncan L,
Estrada K,
Zhao F,
Zou J,
Pierce-Hoffman E,
Berghout J,
Cooper D,
Deflaux N,
DePristo M,
Do R,
Flannick J,
Fromer M,
Gauthier L,
Goldstein J,
Gupta N,
Howrigan D,
Kiezun A,
Kurki M,
Moonshine A,
Natarajan P,
Orozco L,
Peloso G,
Poplin R,
Rivas M,
Ruano-Rubio V,
Rose S,
Ruderfer D,
Shakir K,
Stenson P,
Stevens C,
Thomas B,
Tiao G,
Tusie-Luna M,
Weisburd B,
Won H,
Yu D,
Altshuler D,
Ardissino D,
Boehnke M,
Danesh J,
Donnelly S,
Elosua R,
Florez J,
Gabriel S,
Getz G,
Glatt S,
Hultman C,
Kathiresan S,
Laakso M,
McCarroll S,
McCarthy M,
McGovern D,
McPherson R,
Neale B,
Palotie A,
Purcell S,
Saleheen D,
Scharf J,
Sklar P,
Sullivan P,
Tuomilehto J,
Tsuang M,
Watkins H,
Wilson J,
Daly M,
MacArthur D.
Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016 Aug 18; 536(7616):285-91