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

Sanna Gudmundsson^{1

2

3}, Konrad J Karczewski^{4

5}, Laurent C Francioli^{1

2}, Grace Tiao^{1

2}, Beryl B Cummings^{1

2

6}, Jessica Alföldi^{1

2}, Qingbo Wang^{1

2

7}, Ryan L Collins^{1

7

8}, Kristen M Laricchia^{1

2}, Andrea Ganna^{1

2

9}, Daniel P Birnbaum^{1

2}, Laura D Gauthier¹⁰, Harrison Brand^{1

8}, Matthew Solomonson^{1

2}, Nicholas A Watts^{1

2}, Daniel Rhodes¹¹, Moriel Singer-Berk^{1

2}, Eleina M England^{1

2}, Eleanor G Seaby^{1

2}, Jack A Kosmicki^{1

2

7}, Raymond K Walters^{1

2

12}, Katherine Tashman^{1

2

12}, Yossi Farjoun¹⁰, Eric Banks¹⁰, Timothy Poterba^{1

2

12}, Arcturus Wang^{1

2

12}, Cotton Seed^{1

2

12}, Nicola Whiffin^{1

2

13

14}, Jessica X Chong¹⁵, Kaitlin E Samocha¹⁶, Emma Pierce-Hoffman^{1

2}, Zachary Zappala^{1

2

17}, Anne H O'Donnell-Luria^{1

2

3

18}, Eric Vallabh Minikel¹, Ben Weisburd¹⁰, Monkol Lek¹⁹, James S Ware^{1

13

14}, Christopher Vittal^{2

12}, Irina M Armean^{1

2}, Louis Bergelson¹⁰, Kristian Cibulskis¹⁰, Kristen M Connolly²⁰, Miguel Covarrubias¹⁰, Stacey Donnelly¹, Steven Ferriera²⁰, Stacey Gabriel²⁰, Jeff Gentry¹⁰, Namrata Gupta^{1

20}, Thibault Jeandet¹⁰, Diane Kaplan¹⁰, Christopher Llanwarne¹⁰, Ruchi Munshi¹⁰, Sam Novod¹⁰, Nikelle Petrillo¹⁰, David Roazen¹⁰, Valentin Ruano-Rubio¹⁰, Andrea Saltzman¹, Molly Schleicher¹, Jose Soto¹⁰, Kathleen Tibbetts¹⁰, Charlotte Tolonen¹⁰, Gordon Wade¹⁰, Michael E Talkowski^{1

8

21}; Genome Aggregation Database Consortium; Benjamin M Neale^{1

2

12}, Mark J Daly^{1

2

9

12}, Daniel G MacArthur^{22

23

24

25}

Collaborators, Affiliations

Collaborators

Genome Aggregation Database Consortium:
Carlos A Aguilar Salinas, Tariq Ahmad, Christine M Albert, Diego Ardissino, Gil Atzmon, John Barnard, Laurent Beaugerie, Emelia J Benjamin, Michael Boehnke, Lori L Bonnycastle, Erwin P Bottinger, Donald W Bowden, Matthew J Bown, John C Chambers, Juliana C Chan, Daniel Chasman, Judy Cho, Mina K Chung, Bruce Cohen, Adolfo Correa, Dana Dabelea, Mark J Daly, Dawood Darbar, Ravindranath Duggirala, Josée Dupuis, Patrick T Ellinor, Roberto Elosua, Jeanette Erdmann, Tõnu Esko, Martti Färkkilä, Jose Florez, Andre Franke, Gad Getz, Benjamin Glaser, Stephen J Glatt, David Goldstein, Clicerio Gonzalez, Leif Groop, Christopher Haiman, Craig Hanis, Matthew Harms, Mikko Hiltunen, Matti M Holi, Christina M Hultman, Mikko Kallela, Jaakko Kaprio, Sekar Kathiresan, Bong-Jo Kim, Young Jin Kim, George Kirov, Jaspal Kooner, Seppo Koskinen, Harlan M Krumholz, Subra Kugathasan, Soo Heon Kwak, Markku Laakso, Terho Lehtimäki, Ruth J F Loos, Steven A Lubitz, Ronald C W Ma, Daniel G MacArthur, Jaume Marrugat, Kari M Mattila, Steven McCarroll, Mark I McCarthy, Dermot McGovern, Ruth McPherson, James B Meigs, Olle Melander, Andres Metspalu, Benjamin M Neale, Peter M Nilsson, Michael C O'Donovan, Dost Ongur, Lorena Orozco, Michael J Owen, Colin N A Palmer, Aarno Palotie, Kyong Soo Park, Carlos Pato, Ann E Pulver, Nazneen Rahman, Anne M Remes, John D Rioux, Samuli Ripatti, Dan M Roden, Danish Saleheen, Veikko Salomaa, Nilesh J Samani, Jeremiah Scharf, Heribert Schunkert, Moore B Shoemaker, Pamela Sklar, Hilkka Soininen, Harry Sokol, Tim Spector, Patrick F Sullivan, Jaana Suvisaari, E Shyong Tai, Yik Ying Teo, Tuomi Tiinamaija, Ming Tsuang, Dan Turner, Teresa Tusie-Luna, Erkki Vartiainen, Marquis P Vawter, James S Ware, Hugh Watkins, Rinse K Weersma, Maija Wessman, James G Wilson, Ramnik J Xavier

Affiliations

¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
³ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. konradk@broadinstitute.org.
⁵ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. konradk@broadinstitute.org.
⁶ Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.
⁷ Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA.
⁸ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁹ Institute for Molecular Medicine Finland, Helsinki, Finland.
¹⁰ Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹¹ Centre 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.
¹² Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹³ National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK.
¹⁴ Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London, UK.
¹⁵ Department of Pediatrics, University of Washington, Seattle, WA, USA.
¹⁶ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
¹⁷ Vertex Pharmaceuticals Inc, Boston, MA, USA.
¹⁸ Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
¹⁹ Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
²⁰ Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²¹ Department of Neurology, Harvard Medical School, Boston, MA, USA.
²² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. d.macarthur@garvan.org.au.
²³ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. d.macarthur@garvan.org.au.
²⁴ Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, New South Wales, Australia. d.macarthur@garvan.org.au.
²⁵ Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia. d.macarthur@garvan.org.au.

PMID: 34373650
PMCID: PMC8410591
DOI: 10.1038/s41586-021-03758-y

Published Erratum

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

Sanna Gudmundsson et al. Nature. 2021 Sep.

. 2021 Sep;597(7874):E3-E4.

doi: 10.1038/s41586-021-03758-y.

Authors

Collaborators

Genome Aggregation Database Consortium:
Carlos A Aguilar Salinas, Tariq Ahmad, Christine M Albert, Diego Ardissino, Gil Atzmon, John Barnard, Laurent Beaugerie, Emelia J Benjamin, Michael Boehnke, Lori L Bonnycastle, Erwin P Bottinger, Donald W Bowden, Matthew J Bown, John C Chambers, Juliana C Chan, Daniel Chasman, Judy Cho, Mina K Chung, Bruce Cohen, Adolfo Correa, Dana Dabelea, Mark J Daly, Dawood Darbar, Ravindranath Duggirala, Josée Dupuis, Patrick T Ellinor, Roberto Elosua, Jeanette Erdmann, Tõnu Esko, Martti Färkkilä, Jose Florez, Andre Franke, Gad Getz, Benjamin Glaser, Stephen J Glatt, David Goldstein, Clicerio Gonzalez, Leif Groop, Christopher Haiman, Craig Hanis, Matthew Harms, Mikko Hiltunen, Matti M Holi, Christina M Hultman, Mikko Kallela, Jaakko Kaprio, Sekar Kathiresan, Bong-Jo Kim, Young Jin Kim, George Kirov, Jaspal Kooner, Seppo Koskinen, Harlan M Krumholz, Subra Kugathasan, Soo Heon Kwak, Markku Laakso, Terho Lehtimäki, Ruth J F Loos, Steven A Lubitz, Ronald C W Ma, Daniel G MacArthur, Jaume Marrugat, Kari M Mattila, Steven McCarroll, Mark I McCarthy, Dermot McGovern, Ruth McPherson, James B Meigs, Olle Melander, Andres Metspalu, Benjamin M Neale, Peter M Nilsson, Michael C O'Donovan, Dost Ongur, Lorena Orozco, Michael J Owen, Colin N A Palmer, Aarno Palotie, Kyong Soo Park, Carlos Pato, Ann E Pulver, Nazneen Rahman, Anne M Remes, John D Rioux, Samuli Ripatti, Dan M Roden, Danish Saleheen, Veikko Salomaa, Nilesh J Samani, Jeremiah Scharf, Heribert Schunkert, Moore B Shoemaker, Pamela Sklar, Hilkka Soininen, Harry Sokol, Tim Spector, Patrick F Sullivan, Jaana Suvisaari, E Shyong Tai, Yik Ying Teo, Tuomi Tiinamaija, Ming Tsuang, Dan Turner, Teresa Tusie-Luna, Erkki Vartiainen, Marquis P Vawter, James S Ware, Hugh Watkins, Rinse K Weersma, Maija Wessman, James G Wilson, Ramnik J Xavier

Affiliations

¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
³ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. konradk@broadinstitute.org.
⁵ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. konradk@broadinstitute.org.
⁶ Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.
⁷ Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA.
⁸ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁹ Institute for Molecular Medicine Finland, Helsinki, Finland.
¹⁰ Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹¹ Centre 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.
¹² Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹³ National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK.
¹⁴ Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London, UK.
¹⁵ Department of Pediatrics, University of Washington, Seattle, WA, USA.
¹⁶ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
¹⁷ Vertex Pharmaceuticals Inc, Boston, MA, USA.
¹⁸ Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
¹⁹ Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
²⁰ Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²¹ Department of Neurology, Harvard Medical School, Boston, MA, USA.
²² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. d.macarthur@garvan.org.au.
²³ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. d.macarthur@garvan.org.au.
²⁴ Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, New South Wales, Australia. d.macarthur@garvan.org.au.
²⁵ Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia. d.macarthur@garvan.org.au.

PMID: 34373650
PMCID: PMC8410591
DOI: 10.1038/s41586-021-03758-y

No abstract available

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Figures

**Fig. 1. Assessment of pLoF variants in LoF-tolerant genes associated with autosomal recessive and X-linked phenotypes in OMIM.**
a, Autosomal recessive and X-linked (AR) OMIM phenotypes: likely to be found (blue), likely to be depleted (yellow) or not expected (red) to be found in gnomAD, for the 158 phenotypes associated with LoF-tolerant genes in gnomAD and a set of 100 randomly selected AR and X-linked OMIM traits. ***P = 3.0 × 10⁻⁵, Fisher’s exact test. b, Extended literature review of the 46 out of 158 OMIM phenotypes not expected to be found in gnomAD. c, Extended variant curation of 32 pLoF variants in 30 LoF-tolerant genes beyond criteria presented in our original Article revealed pLoF with suggested evasion of pLoF (purple), and pLoF with no conclusive (pink) or no evidence (grey) contradicting pLoF in these genes. NMD, nonsense-mediated decay. Further details are provided in Supplementary Table 1.

See this image and copyright information in PMC

Erratum for

The mutational constraint spectrum quantified from variation in 141,456 humans.
Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, Collins RL, Laricchia KM, Ganna A, Birnbaum DP, Gauthier LD, Brand H, Solomonson M, Watts NA, Rhodes D, Singer-Berk M, England EM, Seaby EG, Kosmicki JA, Walters RK, Tashman K, Farjoun Y, Banks E, Poterba T, Wang A, Seed C, Whiffin N, Chong JX, Samocha KE, Pierce-Hoffman E, Zappala Z, O'Donnell-Luria AH, Minikel EV, Weisburd B, Lek M, Ware JS, Vittal C, Armean IM, Bergelson L, Cibulskis K, Connolly KM, Covarrubias M, Donnelly S, Ferriera S, Gabriel S, Gentry J, Gupta N, Jeandet T, Kaplan D, Llanwarne C, Munshi R, Novod S, Petrillo N, Roazen D, Ruano-Rubio V, Saltzman A, Schleicher M, Soto J, Tibbetts K, Tolonen C, Wade G, Talkowski ME; Genome Aggregation Database Consortium; Neale BM, Daly MJ, MacArthur DG. Karczewski KJ, et al. Nature. 2020 May;581(7809):434-443. doi: 10.1038/s41586-020-2308-7. Epub 2020 May 27. Nature. 2020. PMID: 32461654 Free PMC article.

References

1. Hamosh A, Scott AF, Amberger JS, Bocchini CA, McKusick VA. Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res. 2005;33:D514–D517. doi: 10.1093/nar/gki033. - DOI - PMC - PubMed
1. Abou Tayoun AN, et al. Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. Hum. Mutat. 2018;39:1517–1524. doi: 10.1002/humu.23626. - DOI - PMC - PubMed
1. MacArthur DG, Tyler-Smith C. Loss-of-function variants in the genomes of healthy humans. Hum. Mol. Genet. 2010;19:R125–R130. doi: 10.1093/hmg/ddq365. - DOI - PMC - PubMed
1. MacArthur DG, et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science. 2012;335:823–828. doi: 10.1126/science.1215040. - DOI - PMC - PubMed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Figures

Erratum for

References

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