@article {030338, author = {Exome Aggregation Consortium and Monkol Lek and Konrad J Karczewski and Eric V Minikel and Kaitlin E Samocha and Eric Banks and Timothy Fennell and Anne H O{\textquoteright}Donnell-Luria and James S Ware and Andrew J Hill and Beryl B Cummings and Taru Tukiainen and Daniel P Birnbaum and Jack A Kosmicki and Laramie E Duncan and Karol Estrada and Fengmei Zhao and James Zou and Emma Pierce-Hoffman and Joanne Berghout and David N Cooper and Nicole Deflaux and Mark DePristo and Ron Do and Jason Flannick and Menachem Fromer and Laura Gauthier and Jackie Goldstein and Namrata Gupta and Daniel Howrigan and Adam Kiezun and Mitja I Kurki and Ami Levy Moonshine and Pradeep Natarajan and Lorena Orozco and Gina M Peloso and Ryan Poplin and Manuel A Rivas and Valentin Ruano-Rubio and Samuel A Rose and Douglas M Ruderfer and Khalid Shakir and Peter D Stenson and Christine Stevens and Brett P Thomas and Grace Tiao and Maria T Tusie-Luna and Ben Weisburd and Hong-Hee Won and Dongmei Yu and David M Altshuler and Diego Ardissino and Michael Boehnke and John Danesh and Stacey Donnelly and Roberto Elosua and Jose C Florez and Stacey B Gabriel and Gad Getz and Stephen J Glatt and Christina M Hultman and Sekar Kathiresan and Markku Laakso and Steven McCarroll and Mark I McCarthy and Dermot McGovern and Ruth McPherson and Benjamin M Neale and Aarno Palotie and Shaun M Purcell and Danish Saleheen and Jeremiah M Scharf and Pamela Sklar and Patrick F Sullivan and Jaakko Tuomilehto and Ming T Tsuang and Hugh C Watkins and James G Wilson and Mark J Daly and Daniel G MacArthur}, title = {Analysis of protein-coding genetic variation in 60,706 humans}, elocation-id = {030338}, year = {2016}, doi = {10.1101/030338}, publisher = {Cold Spring Harbor Laboratory}, 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) 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 {\textquotedblleft}knockout{\textquotedblright} variants in protein-coding genes.}, URL = {https://www.biorxiv.org/content/early/2016/05/10/030338}, eprint = {https://www.biorxiv.org/content/early/2016/05/10/030338.full.pdf}, journal = {bioRxiv} }