Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes - Sorbonne Université Access content directly
Journal Articles Nature Communications Year : 2020

Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes

Qingbo Wang , Emma Pierce-Hoffman , Beryl Cummings , Jessica Alföldi , Laurent Francioli , Laura Gauthier , Andrew Hill , Anne O’donnell-Luria , Irina Armean , Eric Banks , Louis Bergelson , Kristian Cibulskis , Ryan Collins , Kristen Connolly , Miguel Covarrubias , Mark Daly , Stacey Donnelly , Yossi Farjoun , Steven Ferriera , Stacey Gabriel , Jeff Gentry , Namrata Gupta , Thibault Jeandet , Diane Kaplan , Kristen Laricchia , Christopher Llanwarne , Eric Minikel , Ruchi Munshi , Benjamin Neale , Sam Novod , Nikelle Petrillo , Timothy Poterba , David Roazen , Valentin Ruano-Rubio , Andrea Saltzman , Kaitlin Samocha , Molly Schleicher , Cotton Seed , Matthew Solomonson , Jose Soto , Grace Tiao , Kathleen Tibbetts , Charlotte Tolonen , Christopher Vittal , Gordon Wade , Arcturus Wang , James Ware , Nicholas Watts , Ben Weisburd , Nicola Whiffin , 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 , 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 , Jaume Marrugat , Kari Mattila , Steven Mccarroll , Mark Mccarthy , Dermot Mcgovern , Ruth Mcpherson , James Meigs , Olle Melander , Andres Metspalu , 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 , Hugh Watkins , Rinse Weersma , Maija Wessman , James Wilson , Ramnik Xavier , Marquis Vawter , Konrad Karczewski , Daniel Macarthur
Qingbo Wang
Emma Pierce-Hoffman
  • Function : Author
Beryl Cummings
  • Function : Author
Jessica Alföldi
Laurent Francioli
Laura Gauthier
  • Function : Author
Andrew Hill
  • Function : Author
Anne O’donnell-Luria
Irina Armean
  • Function : Author
Eric Banks
  • Function : Author
Louis Bergelson
  • Function : Author
Kristian Cibulskis
  • Function : Author
Ryan Collins
  • Function : Author
Kristen Connolly
  • Function : Author
Miguel Covarrubias
  • Function : Author
Mark Daly
  • Function : Author
Stacey Donnelly
  • Function : Author
Yossi Farjoun
  • 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
Kristen Laricchia
  • Function : Author
Christopher Llanwarne
  • Function : Author
Eric Minikel
  • Function : Author
Ruchi Munshi
  • Function : Author
Benjamin Neale
  • Function : Author
Sam Novod
  • Function : Author
Nikelle Petrillo
  • Function : Author
Timothy Poterba
  • Function : Author
David Roazen
  • Function : Author
Valentin Ruano-Rubio
  • Function : Author
Andrea Saltzman
  • Function : Author
Kaitlin Samocha
  • Function : Author
Molly Schleicher
  • Function : Author
Cotton Seed
  • Function : Author
Matthew Solomonson
  • Function : Author
Jose Soto
  • Function : Author
Grace Tiao
  • Function : Author
Kathleen Tibbetts
  • Function : Author
Charlotte Tolonen
  • Function : Author
Christopher Vittal
  • Function : Author
Gordon Wade
  • Function : Author
Arcturus Wang
  • Function : Author
James Ware
  • Function : Author
Nicholas Watts
  • Function : Author
Ben Weisburd
  • Function : Author
Nicola Whiffin
  • Function : Author
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
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
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
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
Hugh Watkins
  • Function : Author
Rinse Weersma
  • Function : Author
Maija Wessman
  • Function : Author
James Wilson
  • Function : Author
Ramnik Xavier
  • Function : Author
Marquis Vawter
  • Function : Author
Konrad Karczewski
Daniel Macarthur

Abstract

Abstract Multi-nucleotide variants (MNVs), defined as two or more nearby variants existing on the same haplotype in an individual, are a clinically and biologically important class of genetic variation. However, existing tools typically do not accurately classify MNVs, and understanding of their mutational origins remains limited. Here, we systematically survey MNVs in 125,748 whole exomes and 15,708 whole genomes from the Genome Aggregation Database (gnomAD). We identify 1,792,248 MNVs across the genome with constituent variants falling within 2 bp distance of one another, including 18,756 variants with a novel combined effect on protein sequence. Finally, we estimate the relative impact of known mutational mechanisms - CpG deamination, replication error by polymerase zeta, and polymerase slippage at repeat junctions - on the generation of MNVs. Our results demonstrate the value of haplotype-aware variant annotation, and refine our understanding of genome-wide mutational mechanisms of MNVs.

Dates and versions

hal-04007413 , version 1 (28-02-2023)

Identifiers

Cite

Qingbo Wang, Emma Pierce-Hoffman, Beryl Cummings, Jessica Alföldi, Laurent Francioli, et al.. Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes. Nature Communications, 2020, 11 (1), pp.2539. ⟨10.1038/s41467-019-12438-5⟩. ⟨hal-04007413⟩
15 View
0 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More