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

Nature
Authors
Monkol Lek
Konrad Karczewski
Eric Minikel
Kaitlin Samocha
Eric Banks
Timothy Fennell
Anne O'Donnell-Luria
James Ware
Andrew Hill
Beryl Cummings
Taru Tukiainen
Daniel Birnbaum
Jack Kosmicki
Laramie Duncan
Karol Estrada
Fengmei Zhao
James Zou
Emma Pierce-Hoffman
Joanne Berghout
David Cooper
Nicole Deflaux
Mark DePristo
Ron Do
Jason Flannick
Menachem Fromer
Laura Gauthier
Jackie Goldstein
Namrata Gupta
Daniel Howrigan
Adam Kiezun
Mitja Kurki
Ami Moonshine
Pradeep Natarajan
Lorena Orozco
Gina Peloso
Ryan Poplin
Manuel Rivas
Valentin Ruano-Rubio
Samuel Rose
Douglas Ruderfer
Khalid Shakir
Peter Stenson
Christine Stevens
Brett Thomas
Grace Tiao
Maria Tusie-Luna
Ben Weisburd
Hong-Hee Won
Dongmei Yu
David Altshuler
Diego Ardissino
Michael Boehnke
John Danesh
Stacey Donnelly
Roberto Elosua
Jose Florez
Stacey Gabriel
Gad Getz
Stephen Glatt
Christina Hultman
Sekar Kathiresan
Markku Laakso
Steven McCarroll
Mark McCarthy
Dermot McGovern
Ruth McPherson
Benjamin Neale
Aarno Palotie
Shaun Purcell
Danish Saleheen
Jeremiah Scharf
Pamela Sklar
Patrick Sullivan
Jaakko Tuomilehto
Ming Tsuang
Hugh Watkins
James Wilson
Mark Daly
Daniel MacArthur
Exome Aggregation Consortium
Keywords
Humans
Phenotype
Genetic Variation
DNA Mutational Analysis
Exome
Proteome
Datasets as Topic
Rare Diseases
Sample Size
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.
Year of Publication
2016
Journal
Nature
Volume
536
Issue
7616
Pages
285-91
Date Published
2016 08 18
ISSN
1476-4687
DOI
10.1038/nature19057
PubMed ID
27535533
PubMed Central ID
PMC5018207
Links
Grant list
MH077139 / MH / NIMH NIH HHS / United States
U01 DK085545 / DK / NIDDK NIH HHS / United States
NIMHRC2MH089905 / PHS HHS / United States
1RC2DK088389 / DK / NIDDK NIH HHS / United States
090532 / Wellcome Trust / United Kingdom
MOP136936 / Canadian Institutes of Health Research / Canada
HHSN268201300049C / PHS HHS / United States
U01 DK085501 / DK / NIDDK NIH HHS / United States
HHSN268201300048C / PHS HHS / United States
2P50MH066392-05A1 / MH / NIMH NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
MH095034 / MH / NIMH NIH HHS / United States
R01HL107816 / HL / NHLBI NIH HHS / United States
MOP82810 / Canadian Institutes of Health Research / Canada
U01DK085526 / DK / NIDDK NIH HHS / United States
G0801418 / Medical Research Council / United Kingdom
HHSN268201300047C / PHS HHS / United States
U01 NS040024 / NS / NINDS NIH HHS / United States
U54HG003067 / HG / NHGRI NIH HHS / United States
R01DK062370 / DK / NIDDK NIH HHS / United States
U41 HG000330 / HG / NHGRI NIH HHS / United States
U01 DK085584 / DK / NIDDK NIH HHS / United States
K02 NS085048 / NS / NINDS NIH HHS / United States
U01 DK085524 / DK / NIDDK NIH HHS / United States
HHSN268201300050C / PHS HHS / United States
G0800509 / Medical Research Council / United Kingdom
5U54HG003067-11 / HG / NHGRI NIH HHS / United States
HHSN268201300046C / PHS HHS / United States
R01DK098032 / DK / NIDDK NIH HHS / United States
RC2DK088389 / DK / NIDDK NIH HHS / United States
090367 / Wellcome Trust / United Kingdom
DK085545 / DK / NIDDK NIH HHS / United States
U01 DK085526 / DK / NIDDK NIH HHS / United States
R01MH085521 / MH / NIMH NIH HHS / United States
MH094421 / MH / NIMH NIH HHS / United States
NS40024-09S1 / NS / NINDS NIH HHS / United States
DK088389 / DK / NIDDK NIH HHS / United States
DK098032 / DK / NIDDK NIH HHS / United States
U01 NS40024-09S1 / NS / NINDS NIH HHS / United States
RC2-DK088389 / DK / NIDDK NIH HHS / United States
U54 DK105566 / DK / NIDDK NIH HHS / United States
5 U54 HG003067-13 / HG / NHGRI NIH HHS / United States
R01HL24799 / HL / NHLBI NIH HHS / United States
098381 / Wellcome Trust / United Kingdom
MOP77682 / Canadian Institutes of Health Research / Canada
R01 GM104371 / GM / NIGMS NIH HHS / United States
RC2F DK088389 / DK / NIDDK NIH HHS / United States
K01HL125751 / HL / NHLBI NIH HHS / United States
F32GM115208 / GM / NIGMS NIH HHS / United States
MH089905 / MH / NIMH NIH HHS / United States
R01MH085560 / MH / NIMH NIH HHS / United States
NS085048 / NS / NINDS NIH HHS / United States
G0601261 / Medical Research Council / United Kingdom
U01-DK085545 / DK / NIDDK NIH HHS / United States

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