Match!

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

Published on Aug 1, 2016in Nature43.07
· DOI :10.1038/nature19057
Monkol Lek35
Estimated H-index: 35
(Broad Institute),
Konrad J. Karczewski35
Estimated H-index: 35
(Broad Institute)
+ 76 AuthorsDaniel G. MacArthur57
Estimated H-index: 57
(Broad Institute)
View in Source
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.
Figures & Tables
  • References (39)
  • Citations (4484)
References39
Newest
#1Douglas M. RuderferH-Index: 49
#2Tymor HamamsyH-Index: 5
Last.Shaun PurcellH-Index: 102
view all 10 authors...
88 CitationsSource
#1Vagheesh M. Narasimhan (Wellcome Trust Sanger Institute)H-Index: 12
#2Karen A. Hunt (QMUL: Queen Mary University of London)H-Index: 23
Last.David A. van Heel (QMUL: Queen Mary University of London)H-Index: 56
view all 36 authors...
140 CitationsSource
#1Eric Minikel (MIT: Massachusetts Institute of Technology)H-Index: 12
#2Sonia M. Vallabh (MIT: Massachusetts Institute of Technology)H-Index: 4
Last.Daniel G. MacArthur (MIT: Massachusetts Institute of Technology)H-Index: 57
view all 63 authors...
163 CitationsSource
#1Danesh Saleheen (UPenn: University of Pennsylvania)H-Index: 1
#2Pradeep Natarajan (Harvard University)H-Index: 24
Last.Sekar Kathiresan (Harvard University)H-Index: 106
view all 40 authors...
14 CitationsSource
#1Yuval Itan (Rockefeller University)H-Index: 30
#2Lei Shang (Rockefeller University)H-Index: 8
Last.Jean-Laurent CasanovaH-Index: 121
view all 26 authors...
100 CitationsSource
#1Frederick E. Dewey (Cardiovascular Institute of the South)H-Index: 29
#2Megan E. Grove (Cardiovascular Institute of the South)H-Index: 10
Last.Euan A. AshleyH-Index: 58
view all 18 authors...
21 CitationsSource
#1Adam Auton (Yeshiva University)H-Index: 36
#2Gonçalo R. Abecasis (UM: University of Michigan)H-Index: 144
Last.Jeffery A. Schloss (NIH: National Institutes of Health)H-Index: 9
view all 477 authors...
4,576 CitationsSource
#1Jessica X. Chong (UW: University of Washington)H-Index: 19
#2Kati J. Buckingham (UW: University of Washington)H-Index: 15
Last.Michael J. Bamshad (UW: University of Washington)H-Index: 75
view all 42 authors...
297 CitationsSource
#1Axel FreischmidtH-Index: 11
#2Thomas WielandH-Index: 29
Last.Jochen H. WeishauptH-Index: 27
view all 40 authors...
313 CitationsSource
#2Hannes HelgasonH-Index: 23
Last.Kari StefanssonH-Index: 168
view all 48 authors...
354 CitationsSource
Cited By4484
Newest
#1Yalda Baradaran-Heravi (University of Antwerp)H-Index: 2
#2C. Van Broeckhoven (University of Antwerp)H-Index: 113
Last.Julie van der Zee (University of Antwerp)H-Index: 35
view all 3 authors...
Source
#1Dana M. Bis-Brewer (UM: University of Miami)H-Index: 2
#2Sarah Fazal (UM: University of Miami)
Last.Stephan L Zuchner (UM: University of Miami)H-Index: 48
view all 3 authors...
Source
Source
#1Milind C. Mahajan (Mount Sinai Hospital)H-Index: 1
#2Andrew S. McLellan (Mount Sinai Hospital)H-Index: 1
1 CitationsSource
#1Matthew K. Breitenstein (UPenn: University of Pennsylvania)H-Index: 5
#2Erin L. Crowgey (Wilmington University)
Source
#1Shengfeng Wang (PKU: Peking University)H-Index: 4
#2Jason J. Pitt (U of C: University of Chicago)H-Index: 10
Last.Olufunmilayo I. Olopade (U of C: University of Chicago)H-Index: 81
view all 22 authors...
Source
#1Taku Miyagawa (UTokyo: University of Tokyo)H-Index: 20
#2Akiko HidaH-Index: 19
Last.Makoto HondaH-Index: 19
view all 13 authors...
Source
#1Pauline E. Schneeberger (UHH: University of Hamburg)
#2Tatjana Bierhals (UHH: University of Hamburg)H-Index: 6
Last.Kerstin Kutsche (UHH: University of Hamburg)H-Index: 32
view all 5 authors...
Source
#1Christinna V. Jørgensen (UCPH: University of Copenhagen)H-Index: 2
#2Sylvia J. Gasparini (USYD: University of Sydney)H-Index: 4
Last.Hans Bräuner-Osborne (UCPH: University of Copenhagen)H-Index: 43
view all 6 authors...
Source
#1Ran Zhu (Peking Union Medical College Hospital)
#2Huanwen Wu (Peking Union Medical College Hospital)H-Index: 7
Last.Zhen Huo (Peking Union Medical College Hospital)H-Index: 6
view all 5 authors...
Source
View next paperMutationTaster2: mutation prediction for the deep-sequencing age