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Journal Articles Nature Year : 2020

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

Konrad Karczewski , Laurent Francioli , Grace Tiao , Beryl Cummings , Jessica Alföldi , Qingbo Wang , Ryan Collins , Kristen Laricchia , Andrea Ganna , Daniel Birnbaum , Laura Gauthier , Harrison Brand , Matthew Solomonson , Nicholas Watts , Daniel Rhodes , Moriel Singer-Berk , Eleina England , Eleanor Seaby , Jack Kosmicki , Raymond Walters , Katherine Tashman , Yossi Farjoun , Eric Banks , Timothy Poterba , Arcturus Wang , Cotton Seed , Nicola Whiffin , Jessica Chong , Kaitlin Samocha , Emma Pierce-Hoffman , Zachary Zappala , Anne O’donnell-Luria , Eric Vallabh Minikel , Ben Weisburd , Monkol Lek , James Ware , Christopher Vittal , Irina Armean , Louis Bergelson , Kristian Cibulskis , Kristen 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 Talkowski , Carlos Aguilar Salinas , Tariq Ahmad , Christine Albert , Diego Ardissino , Gil Atzmon , John Barnard , Laurent Beaugerie , Emelia Benjamin , Michael Boehnke , Lori Bonnycastle , Erwin Bottinger , Donald Bowden , Matthew Bown , John Chambers , Juliana Chan , Daniel Chasman , Judy Cho , Mina Chung , Bruce Cohen , Adolfo Correa , Dana Dabelea , Mark Daly , Dawood Darbar , Ravindranath Duggirala , Josée Dupuis , Patrick Ellinor , Roberto Elosua , Jeanette Erdmann , Tõnu Esko , Martti Färkkilä , Jose Florez , Andre Franke , Gad Getz , Benjamin Glaser , Stephen Glatt , David Goldstein , Clicerio Gonzalez , Leif Groop , Christopher Haiman , Craig Hanis , Matthew Harms , Mikko Hiltunen , Matti Holi , Christina Hultman , Mikko Kallela , Jaakko Kaprio , Sekar Kathiresan , Bong-Jo Kim , Young Jin Kim , George Kirov , Jaspal Kooner , Seppo Koskinen , Harlan Krumholz , Subra Kugathasan , Soo Heon Kwak , Markku Laakso , Terho Lehtimäki , Ruth Loos , Steven Lubitz , Ronald Ma , Daniel Macarthur , Jaume Marrugat , Kari Mattila , Steven Mccarroll , Mark Mccarthy , Dermot Mcgovern , Ruth Mcpherson , James Meigs , Olle Melander , Andres Metspalu , Benjamin Neale , Peter Nilsson , Michael O’donovan , Dost Ongur , Lorena Orozco , Michael Owen , Colin Palmer , Aarno Palotie , Kyong Soo Park , Carlos Pato , Ann Pulver , Nazneen Rahman , Anne Remes , John Rioux , Samuli Ripatti , Dan Roden , Danish Saleheen , Veikko Salomaa , Nilesh Samani , Jeremiah Scharf , Heribert Schunkert , Moore Shoemaker , Pamela Sklar , Hilkka Soininen , Harry Sokol (1) , Tim Spector , Patrick Sullivan , Jaana Suvisaari , E. Shyong Tai , Yik Ying Teo , Tuomi Tiinamaija , Ming Tsuang , Dan Turner , Teresa Tusie-Luna , Erkki Vartiainen , Marquis Vawter , James Ware , Hugh Watkins , Rinse Weersma , Maija Wessman , James Wilson , Ramnik Xavier , Benjamin Neale , Mark Daly , Daniel Macarthur
Konrad Karczewski
Laurent Francioli
Grace Tiao
  • Function : Author
Beryl Cummings
  • Function : Author
Jessica Alföldi
Qingbo Wang
Ryan Collins
Kristen Laricchia
  • Function : Author
Andrea Ganna
  • Function : Author
Daniel Birnbaum
  • Function : Author
Laura Gauthier
  • Function : Author
Harrison Brand
  • Function : Author
Matthew Solomonson
  • Function : Author
Nicholas Watts
  • Function : Author
Daniel Rhodes
  • Function : Author
Moriel Singer-Berk
  • Function : Author
Eleina England
  • Function : Author
Eleanor Seaby
  • Function : Author
Jack Kosmicki
  • Function : Author
Raymond Walters
Katherine Tashman
  • Function : Author
Yossi Farjoun
Eric Banks
  • Function : Author
Timothy Poterba
  • Function : Author
Arcturus Wang
  • Function : Author
Cotton Seed
  • Function : Author
Nicola Whiffin
  • Function : Author
Jessica Chong
  • Function : Author
Kaitlin Samocha
Emma Pierce-Hoffman
  • Function : Author
Zachary Zappala
  • Function : Author
Anne O’donnell-Luria
Eric Vallabh Minikel
  • Function : Author
Ben Weisburd
  • Function : Author
Monkol Lek
  • Function : Author
James Ware
Christopher Vittal
  • Function : Author
Irina Armean
Louis Bergelson
  • Function : Author
Kristian Cibulskis
  • Function : Author
Kristen Connolly
  • Function : Author
Miguel Covarrubias
  • Function : Author
Stacey Donnelly
  • Function : Author
Steven Ferriera
  • Function : Author
Stacey Gabriel
  • Function : Author
Jeff Gentry
  • Function : Author
Namrata Gupta
  • Function : Author
Thibault Jeandet
  • Function : Author
Diane Kaplan
  • Function : Author
Christopher Llanwarne
  • Function : Author
Ruchi Munshi
  • Function : Author
Sam Novod
  • Function : Author
Nikelle Petrillo
  • Function : Author
David Roazen
  • Function : Author
Valentin Ruano-Rubio
  • Function : Author
Andrea Saltzman
  • Function : Author
Molly Schleicher
  • Function : Author
Jose Soto
  • Function : Author
Kathleen Tibbetts
  • Function : Author
Charlotte Tolonen
  • Function : Author
Gordon Wade
  • Function : Author
Michael Talkowski
Carlos Aguilar Salinas
  • Function : Author
Tariq Ahmad
  • Function : Author
Christine Albert
  • Function : Author
Diego Ardissino
  • Function : Author
Gil Atzmon
  • Function : Author
John Barnard
  • Function : Author
Laurent Beaugerie
  • Function : Author
Emelia Benjamin
  • Function : Author
Michael Boehnke
  • Function : Author
Lori Bonnycastle
  • Function : Author
Erwin Bottinger
  • Function : Author
Donald Bowden
  • Function : Author
Matthew Bown
  • Function : Author
John Chambers
  • Function : Author
Juliana Chan
  • Function : Author
Daniel Chasman
  • Function : Author
Judy Cho
  • Function : Author
Mina Chung
  • Function : Author
Bruce Cohen
  • Function : Author
Adolfo Correa
  • Function : Author
Dana Dabelea
  • Function : Author
Mark Daly
  • Function : Author
Dawood Darbar
  • Function : Author
Ravindranath Duggirala
  • Function : Author
Josée Dupuis
  • Function : Author
Patrick Ellinor
  • Function : Author
Roberto Elosua
  • Function : Author
Jeanette Erdmann
  • Function : Author
Tõnu Esko
  • Function : Author
Martti Färkkilä
  • Function : Author
Jose Florez
  • Function : Author
Andre Franke
  • Function : Author
Gad Getz
  • Function : Author
Benjamin Glaser
  • Function : Author
Stephen Glatt
  • Function : Author
David Goldstein
  • Function : Author
Clicerio Gonzalez
  • Function : Author
Leif Groop
  • Function : Author
Christopher Haiman
  • Function : Author
Craig Hanis
  • Function : Author
Matthew Harms
  • Function : Author
Mikko Hiltunen
  • Function : Author
Matti Holi
  • Function : Author
Christina Hultman
  • Function : Author
Mikko Kallela
  • Function : Author
Jaakko Kaprio
  • Function : Author
Sekar Kathiresan
  • Function : Author
Bong-Jo Kim
  • Function : Author
Young Jin Kim
  • Function : Author
George Kirov
  • Function : Author
Jaspal Kooner
  • Function : Author
Seppo Koskinen
  • Function : Author
Harlan Krumholz
  • Function : Author
Subra Kugathasan
  • Function : Author
Soo Heon Kwak
  • Function : Author
Markku Laakso
  • Function : Author
Terho Lehtimäki
  • Function : Author
Ruth Loos
  • Function : Author
Steven Lubitz
  • Function : Author
Ronald Ma
  • Function : Author
Daniel Macarthur
  • Function : Author
Jaume Marrugat
  • Function : Author
Kari Mattila
  • Function : Author
Steven Mccarroll
  • Function : Author
Mark Mccarthy
  • Function : Author
Dermot Mcgovern
  • Function : Author
Ruth Mcpherson
  • Function : Author
James Meigs
  • Function : Author
Olle Melander
  • Function : Author
Andres Metspalu
  • Function : Author
Benjamin Neale
  • Function : Author
Peter Nilsson
  • Function : Author
Michael O’donovan
  • Function : Author
Dost Ongur
  • Function : Author
Lorena Orozco
  • Function : Author
Michael Owen
  • Function : Author
Colin Palmer
  • Function : Author
Aarno Palotie
  • Function : Author
Kyong Soo Park
  • Function : Author
Carlos Pato
  • Function : Author
Ann Pulver
  • Function : Author
Nazneen Rahman
  • Function : Author
Anne Remes
  • Function : Author
John Rioux
  • Function : Author
Samuli Ripatti
  • Function : Author
Dan Roden
  • Function : Author
Danish Saleheen
  • Function : Author
Veikko Salomaa
  • Function : Author
Nilesh Samani
  • Function : Author
Jeremiah Scharf
  • Function : Author
Heribert Schunkert
  • Function : Author
Moore Shoemaker
  • Function : Author
Pamela Sklar
  • Function : Author
Hilkka Soininen
  • Function : Author
Tim Spector
  • Function : Author
Patrick Sullivan
  • Function : Author
Jaana Suvisaari
  • Function : Author
E. Shyong Tai
  • Function : Author
Yik Ying Teo
  • Function : Author
Tuomi Tiinamaija
  • Function : Author
Ming Tsuang
  • Function : Author
Dan Turner
  • Function : Author
Teresa Tusie-Luna
  • Function : Author
Erkki Vartiainen
  • Function : Author
Marquis Vawter
  • Function : Author
James Ware
  • Function : Author
Hugh Watkins
  • Function : Author
Rinse Weersma
  • Function : Author
Maija Wessman
  • Function : Author
James Wilson
  • Function : Author
Ramnik Xavier
  • Function : Author
Benjamin Neale
Mark Daly
  • Function : Author
Daniel Macarthur

Abstract

Abstract Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function 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 sizes 1 . 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 predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.

Dates and versions

hal-04007166 , version 1 (27-02-2023)

Identifiers

Cite

Konrad Karczewski, Laurent Francioli, Grace Tiao, Beryl Cummings, Jessica Alföldi, et al.. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature, 2020, 581 (7809), pp.434-443. ⟨10.1038/s41586-020-2308-7⟩. ⟨hal-04007166⟩
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