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The mutational constraint spectrum quantified from variation in 141,456 humans

View ORCID ProfileKonrad J. Karczewski, Laurent C. Francioli, Grace Tiao, Beryl B. Cummings, Jessica Alföldi, Qingbo Wang, Ryan L. Collins, Kristen M. Laricchia, Andrea Ganna, Daniel P. Birnbaum, Laura D. Gauthier, Harrison Brand, Matthew Solomonson, Nicholas A. Watts, Daniel Rhodes, Moriel Singer-Berk, Eleina M. England, Eleanor G. Seaby, Jack A. Kosmicki, Raymond K. Walters, Katherine Tashman, Yossi Farjoun, Eric Banks, Timothy Poterba, Arcturus Wang, Cotton Seed, Nicola Whiffin, Jessica X. Chong, Kaitlin E. Samocha, Emma Pierce-Hoffman, Zachary Zappala, Anne H. O’Donnell-Luria, Eric Vallabh Minikel, Ben Weisburd, Monkol Lek, James S. Ware, Christopher Vittal, Irina M. Armean, Louis Bergelson, Kristian Cibulskis, Kristen M. Connolly, Miguel Covarrubias, Stacey Donnelly, Steven Ferriera, Stacey Gabriel, Jeff Gentry, Namrata Gupta, Thibault Jeandet, Diane Kaplan, Christopher Llanwarne, Ruchi Munshi, Sam Novod, Nikelle Petrillo, David Roazen, Valentin Ruano-Rubio, Andrea Saltzman, Molly Schleicher, Jose Soto, Kathleen Tibbetts, Charlotte Tolonen, Gordon Wade, Michael E. Talkowski, Genome Aggregation Database (gnomAD) Consortium, Benjamin M. Neale, Mark J. Daly, Daniel G. MacArthur
doi: https://doi.org/10.1101/531210
Konrad J. Karczewski
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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  • ORCID record for Konrad J. Karczewski
  • For correspondence: konradk@broadinstitute.org d.macarthur@garvan.org.au
Laurent C. Francioli
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Grace Tiao
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Beryl B. Cummings
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
3Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA
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Jessica Alföldi
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Qingbo Wang
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
4Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA 02115, USA
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Ryan L. Collins
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
4Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA 02115, USA
5Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
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Kristen M. Laricchia
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Andrea Ganna
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
6Institute for Molecular Medicine Finland, Helsinki, Finland
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Daniel P. Birnbaum
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Laura D. Gauthier
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Harrison Brand
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
5Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
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Matthew Solomonson
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Nicholas A. Watts
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2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Daniel Rhodes
8Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London and Barts Health NHS Trust, London, UK
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Moriel Singer-Berk
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Eleina M. England
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2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Eleanor G. Seaby
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2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Jack A. Kosmicki
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
4Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA 02115, USA
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Raymond K. Walters
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Katherine Tashman
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Yossi Farjoun
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Eric Banks
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Timothy Poterba
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Arcturus Wang
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Cotton Seed
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Nicola Whiffin
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
10National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK
11Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London, UK
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Jessica X. Chong
12Department of Pediatrics, University of Washington, Seattle, Washington, 98195, USA
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Kaitlin E. Samocha
13Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
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Emma Pierce-Hoffman
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Zachary Zappala
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
14Vertex Pharmaceuticals Inc. Boston, MA, 02210
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Anne H. O’Donnell-Luria
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
15Division of Genetics and Genomics, Boston Children’s Hospital, Boston, Massachusetts 02115, USA
16Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA
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Eric Vallabh Minikel
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Ben Weisburd
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Monkol Lek
17Department of Genetics, Yale School of Medicine, New Haven, Connecticut
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James S. Ware
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
10National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK
11Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London, UK
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Christopher Vittal
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Irina M. Armean
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Louis Bergelson
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Kristian Cibulskis
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Kristen M. Connolly
18Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Miguel Covarrubias
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Stacey Donnelly
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Steven Ferriera
18Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Stacey Gabriel
18Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Namrata Gupta
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18Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Thibault Jeandet
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Diane Kaplan
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Christopher Llanwarne
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Ruchi Munshi
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Sam Novod
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7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Valentin Ruano-Rubio
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Andrea Saltzman
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Molly Schleicher
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Jose Soto
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Kathleen Tibbetts
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Charlotte Tolonen
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Gordon Wade
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Michael E. Talkowski
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
5Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
19Department of Neurology, Harvard Medical School, Boston, MA, USA
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Benjamin M. Neale
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Mark J. Daly
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
6Institute for Molecular Medicine Finland, Helsinki, Finland
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Daniel G. MacArthur
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
**Centre for Population Genomics, Garvan Institute of Medical Research and Murdoch Children’s Research Institute
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  • For correspondence: konradk@broadinstitute.org d.macarthur@garvan.org.au
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Summary

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes critical for an organism’s function will be depleted for such variants in natural populations, while non-essential genes will tolerate their accumulation. However, predicted loss-of-function (pLoF) variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes1. Here, we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence pLoF variants in this cohort after filtering for sequencing and annotation artifacts. Using an improved human mutation rate model, we classify human protein-coding genes along a spectrum representing tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve gene discovery power for both common and rare diseases.

Footnotes

  • Numerous additions, particularly in the Supplementary Information (including dozens of supplementary figures and tables).

  • https://gnomad.broadinstitute.org/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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The mutational constraint spectrum quantified from variation in 141,456 humans
Konrad J. Karczewski, Laurent C. Francioli, Grace Tiao, Beryl B. Cummings, Jessica Alföldi, Qingbo Wang, Ryan L. Collins, Kristen M. Laricchia, Andrea Ganna, Daniel P. Birnbaum, Laura D. Gauthier, Harrison Brand, Matthew Solomonson, Nicholas A. Watts, Daniel Rhodes, Moriel Singer-Berk, Eleina M. England, Eleanor G. Seaby, Jack A. Kosmicki, Raymond K. Walters, Katherine Tashman, Yossi Farjoun, Eric Banks, Timothy Poterba, Arcturus Wang, Cotton Seed, Nicola Whiffin, Jessica X. Chong, Kaitlin E. Samocha, Emma Pierce-Hoffman, Zachary Zappala, Anne H. O’Donnell-Luria, Eric Vallabh Minikel, Ben Weisburd, Monkol Lek, James S. Ware, Christopher Vittal, Irina M. Armean, Louis Bergelson, Kristian Cibulskis, Kristen M. Connolly, Miguel Covarrubias, Stacey Donnelly, Steven Ferriera, Stacey Gabriel, Jeff Gentry, Namrata Gupta, Thibault Jeandet, Diane Kaplan, Christopher Llanwarne, Ruchi Munshi, Sam Novod, Nikelle Petrillo, David Roazen, Valentin Ruano-Rubio, Andrea Saltzman, Molly Schleicher, Jose Soto, Kathleen Tibbetts, Charlotte Tolonen, Gordon Wade, Michael E. Talkowski, Genome Aggregation Database (gnomAD) Consortium, Benjamin M. Neale, Mark J. Daly, Daniel G. MacArthur
bioRxiv 531210; doi: https://doi.org/10.1101/531210
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The mutational constraint spectrum quantified from variation in 141,456 humans
Konrad J. Karczewski, Laurent C. Francioli, Grace Tiao, Beryl B. Cummings, Jessica Alföldi, Qingbo Wang, Ryan L. Collins, Kristen M. Laricchia, Andrea Ganna, Daniel P. Birnbaum, Laura D. Gauthier, Harrison Brand, Matthew Solomonson, Nicholas A. Watts, Daniel Rhodes, Moriel Singer-Berk, Eleina M. England, Eleanor G. Seaby, Jack A. Kosmicki, Raymond K. Walters, Katherine Tashman, Yossi Farjoun, Eric Banks, Timothy Poterba, Arcturus Wang, Cotton Seed, Nicola Whiffin, Jessica X. Chong, Kaitlin E. Samocha, Emma Pierce-Hoffman, Zachary Zappala, Anne H. O’Donnell-Luria, Eric Vallabh Minikel, Ben Weisburd, Monkol Lek, James S. Ware, Christopher Vittal, Irina M. Armean, Louis Bergelson, Kristian Cibulskis, Kristen M. Connolly, Miguel Covarrubias, Stacey Donnelly, Steven Ferriera, Stacey Gabriel, Jeff Gentry, Namrata Gupta, Thibault Jeandet, Diane Kaplan, Christopher Llanwarne, Ruchi Munshi, Sam Novod, Nikelle Petrillo, David Roazen, Valentin Ruano-Rubio, Andrea Saltzman, Molly Schleicher, Jose Soto, Kathleen Tibbetts, Charlotte Tolonen, Gordon Wade, Michael E. Talkowski, Genome Aggregation Database (gnomAD) Consortium, Benjamin M. Neale, Mark J. Daly, Daniel G. MacArthur
bioRxiv 531210; doi: https://doi.org/10.1101/531210

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