TY - JOUR T1 - Analysis of protein-coding genetic variation in 60,706 humans JF - bioRxiv DO - 10.1101/030338 SP - 030338 AU - Exome Aggregation Consortium AU - Monkol Lek AU - Konrad J Karczewski AU - Eric V Minikel AU - Kaitlin E Samocha AU - Eric Banks AU - Timothy Fennell AU - Anne H O’Donnell-Luria AU - James S Ware AU - Andrew J Hill AU - Beryl B Cummings AU - Taru Tukiainen AU - Daniel P Birnbaum AU - Jack A Kosmicki AU - Laramie E Duncan AU - Karol Estrada AU - Fengmei Zhao AU - James Zou AU - Emma Pierce-Hoffman AU - Joanne Berghout AU - David N Cooper AU - Nicole Deflaux AU - Mark DePristo AU - Ron Do AU - Jason Flannick AU - Menachem Fromer AU - Laura Gauthier AU - Jackie Goldstein AU - Namrata Gupta AU - Daniel Howrigan AU - Adam Kiezun AU - Mitja I Kurki AU - Ami Levy Moonshine AU - Pradeep Natarajan AU - Lorena Orozco AU - Gina M Peloso AU - Ryan Poplin AU - Manuel A Rivas AU - Valentin Ruano-Rubio AU - Samuel A Rose AU - Douglas M Ruderfer AU - Khalid Shakir AU - Peter D Stenson AU - Christine Stevens AU - Brett P Thomas AU - Grace Tiao AU - Maria T Tusie-Luna AU - Ben Weisburd AU - Hong-Hee Won AU - Dongmei Yu AU - David M Altshuler AU - Diego Ardissino AU - Michael Boehnke AU - John Danesh AU - Stacey Donnelly AU - Roberto Elosua AU - Jose C Florez AU - Stacey B Gabriel AU - Gad Getz AU - Stephen J Glatt AU - Christina M Hultman AU - Sekar Kathiresan AU - Markku Laakso AU - Steven McCarroll AU - Mark I McCarthy AU - Dermot McGovern AU - Ruth McPherson AU - Benjamin M Neale AU - Aarno Palotie AU - Shaun M Purcell AU - Danish Saleheen AU - Jeremiah M Scharf AU - Pamela Sklar AU - Patrick F Sullivan AU - Jaakko Tuomilehto AU - Ming T Tsuang AU - Hugh C Watkins AU - James G Wilson AU - Mark J Daly AU - Daniel G MacArthur Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/05/10/030338.abstract N2 - 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 generated as part of the Exome Aggregation Consortium (ExAC). The resulting 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 show that this catalogue 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, 72% of which have 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. ER -