Analysis of protein-coding genetic variation in 60,706 humans

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Lek , M , Karczewski , K J , Minikel , E V , Samocha , K E , Banks , E , Fennell , T , O'Donnell-Luria , A H , Ware , J S , Hill , A J , Cummings , B B , Tukiainen , T , Birnbaum , D P , Kosmicki , J A , Duncan , L E , Estrada , K , Zhao , F , Zou , J , Pierce-Hollman , E , Berghout , J , Cooper , D N , Deflaux , N , DePristo , M , Do , R , Flannick , J , Fromer , M , Gauthier , L , Goldstein , J , Gupta , N , Howrigan , D , Kiezun , A , Kurki , M I , Moonshine , A L , Natarajan , P , Orozeo , L , Peloso , G M , Poplin , R , Rivas , M A , Ruano-Rubio , V , Rose , S A , Ruderfer , D M , Shakir , K , Stenson , P D , Stevens , C , Thomas , B P , Tiao , G , Tusie-Luna , M T , Weisburd , B , Palotie , A , Tuomilehto , J , Daly , M J & Exome Aggregation Consortium 2016 , ' Analysis of protein-coding genetic variation in 60,706 humans ' , Nature , vol. 536 , no. 7616 , pp. 285-+ . https://doi.org/10.1038/nature19057

Title: Analysis of protein-coding genetic variation in 60,706 humans
Author: Lek, Monkol; Karczewski, Konrad J.; Minikel, Eric V.; Samocha, Kaitlin E.; Banks, Eric; Fennell, Timothy; O'Donnell-Luria, Anne H.; Ware, James S.; Hill, Andrew J.; Cummings, Beryl B.; Tukiainen, Taru; Birnbaum, Daniel P.; Kosmicki, Jack A.; Duncan, Laramie E.; Estrada, Karol; Zhao, Fengmei; Zou, James; Pierce-Hollman, Emma; Berghout, Joanne; Cooper, David N.; Deflaux, Nicole; DePristo, Mark; Do, Ron; Flannick, Jason; Fromer, Menachem; Gauthier, Laura; Goldstein, Jackie; Gupta, Namrata; Howrigan, Daniel; Kiezun, Adam; Kurki, Mitja I.; Moonshine, Ami Levy; Natarajan, Pradeep; Orozeo, Lorena; Peloso, Gina M.; Poplin, Ryan; Rivas, Manuel A.; Ruano-Rubio, Valentin; Rose, Samuel A.; Ruderfer, Douglas M.; Shakir, Khalid; Stenson, Peter D.; Stevens, Christine; Thomas, Brett P.; Tiao, Grace; Tusie-Luna, Maria T.; Weisburd, Ben; Palotie, Aarno; Tuomilehto, Jaakko; Daly, Mark J.; Exome Aggregation Consortium
Contributor organization: Institute for Molecular Medicine Finland
Aarno Palotie / Principal Investigator
Jaakko Tuomilehto Research Group
Department of Public Health
Clinicum
Genomics of Neurological and Neuropsychiatric Disorders
Date: 2016-08-18
Language: eng
Number of pages: 13
Belongs to series: Nature
ISSN: 0028-0836
DOI: https://doi.org/10.1038/nature19057
URI: http://hdl.handle.net/10138/167702
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.
Subject: HUMAN-POPULATION HISTORY
HUMAN-DISEASE
SEQUENCE VARIANTS
MUTATION
GUIDELINES
EVOLUTION
DISCOVERY
FRAMEWORK
NETWORKS
3111 Biomedicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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