Analysis of protein-coding genetic variation in 60,706 humans
Atzmon, Aarno Palotie, Ripke, Manuel A. Rivas, Hong‐Hee Won, Freimer, Lyon, Rodríguez-Guillén, Barr, Ben Weisburd, Benjamin M. Neale, Pamela Sklar, Dongmei Yu, Fontanillas, Riba, Kaitlin E. Samocha, Kähler, Meigs, Ming T. Tsuang, González-Villalpando, Lehman, Sandor, Mark J. Daly, Hanis, Brett Thomas, Groop, Cox, Mahajan, Bergen, Sladek, King King, Stacey Gabriel, Huerta-Chagoya, Abboud, James S. Ware, Jason Flannick, Kyriakou, Grace Tiao, Chambert, Ruth McPherson, Sekar Kathiresan, Teslovich, Haiman,, Douglas M. Ruderfer, Hopewell, Jeremiah M. Scharf, Patrick F. Sullivan, Gad Getz, Ordóñez-Sánchez, Lorena Orozco, Jiménez-Morale, Frayling, Mercader, James Zou, Michael Boehnke, Samuel A. Rose, Burtt, Christine Stevens, Ami Levy Moonshine, Najmi, Maria T. Tusie-Luna, Stephen J. Glatt, Duggirala, Morris, Valentín Ruano-Rubio, Markku Laakso, Diego Ardissino, Bell,, Mohlke, Marrugat, Rodríguez-Torres, Taru Tukiainen, Mendoza-Caamal, Peter D. Stenson, Tai, Spector,, Daniel G. MacArthur, Goel, Monkol Lek, Danish Saleheen, Anne O’Donnell‐Luria, Moran,, Laramie E. Duncan, Fernandez-Lopez, Mark I. McCarthy, Beryl B. Cummings, Eric Banks, John Danesh, Киров, Budman, Ron Do, Timothy R. Fennell, Namrata Gupta, Ryan Poplin, Mitja Kurki, Bowden,, Abecasis, Soberón, Mark A. DePristo, García-Ortiz
Abstract
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.