PT  - JOURNAL ARTICLE
AU  - , 
AU  - Lek, Monkol
AU  - Karczewski, Konrad J
AU  - Minikel, Eric V
AU  - Samocha, Kaitlin E
AU  - Banks, Eric
AU  - Fennell, Timothy
AU  - O’Donnell-Luria, Anne H
AU  - Ware, James S
AU  - Hill, Andrew J
AU  - Cummings, Beryl B
AU  - Tukiainen, Taru
AU  - Birnbaum, Daniel P
AU  - Kosmicki, Jack A
AU  - Duncan, Laramie
AU  - Estrada, Karol
AU  - Zhao, Fengmei
AU  - Zou, James
AU  - Pierce-Hoffman, Emma
AU  - Cooper, David N
AU  - DePristo, Mark
AU  - Do, Ron
AU  - Flannick, Jason
AU  - Fromer, Menachem
AU  - Gauthier, Laura
AU  - Goldstein, Jackie
AU  - Gupta, Namrata
AU  - Howrigan, Daniel
AU  - Kiezun, Adam
AU  - Kurki, Mitja I
AU  - Moonshine, Ami Levy
AU  - Natarajan, Pradeep
AU  - Orozco, Lorena
AU  - Peloso, Gina M
AU  - Poplin, Ryan
AU  - Rivas, Manuel A
AU  - Ruano-Rubio, Valentin
AU  - Ruderfer, Douglas M
AU  - Shakir, Khalid
AU  - Stenson, Peter D
AU  - Stevens, Christine
AU  - Thomas, Brett P
AU  - Tiao, Grace
AU  - Tusie-Luna, Maria T
AU  - Weisburd, Ben
AU  - Won, Hong-Hee
AU  - Yu, Dongmei
AU  - Altshuler, David M
AU  - Ardissino, Diego
AU  - Boehnke, Michael
AU  - Danesh, John
AU  - Elosua, Roberto
AU  - Florez, Jose C
AU  - Gabriel, Stacey B
AU  - Getz, Gad
AU  - Hultman, Christina M
AU  - Kathiresan, Sekar
AU  - Laakso, Markku
AU  - McCarroll, Steven
AU  - McCarthy, Mark I
AU  - McGovern, Dermot
AU  - McPherson, Ruth
AU  - Neale, Benjamin M
AU  - Palotie, Aarno
AU  - Purcell, Shaun M
AU  - Saleheen, Danish
AU  - Scharf, Jeremiah
AU  - Sklar, Pamela
AU  - Sullivan, Patrick F
AU  - Tuomilehto, Jaakko
AU  - Watkins, Hugh C
AU  - Wilson, James G
AU  - Daly, Mark J
AU  - MacArthur, Daniel G
TI  - Analysis of protein-coding genetic variation in 60,706 humans
AID  - 10.1101/030338
DP  - 2015 Jan 01
TA  - bioRxiv
PG  - 030338
4099  - http://biorxiv.org/content/early/2015/10/30/030338.short
4100  - http://biorxiv.org/content/early/2015/10/30/030338.full
AB  - 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) sequence data for 60,706 individuals of diverse ethnicities. The resulting catalogue of human genetic diversity has unprecedented resolution, with an average of one variant every eight bases of coding sequence and the presence of widespread mutational recurrence. The deep catalogue of variation provided by the Exome Aggregation Consortium (ExAC) can be used to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; we identify 3,230 genes with near-complete depletion of truncating variants, 79% of which have no currently established human disease phenotype. Finally, we show 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.