Characterising the loss-of-function impact of 5' untranslated region variants in 15,708 individuals.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
27 05 2020
27 05 2020
Historique:
received:
06
03
2019
accepted:
23
05
2019
entrez:
29
5
2020
pubmed:
29
5
2020
medline:
25
8
2020
Statut:
epublish
Résumé
Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection. This selection signal is significantly stronger for variants arising upstream of genes intolerant to loss-of-function variants. Furthermore, variants creating uORFs that overlap the coding sequence show signals of selection equivalent to coding missense variants. Finally, we identify specific genes where modification of uORFs likely represents an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in neurofibromatosis. Our results highlight uORF-perturbing variants as an under-recognised functional class that contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data in studying non-coding variant classes.
Identifiants
pubmed: 32461616
doi: 10.1038/s41467-019-10717-9
pii: 10.1038/s41467-019-10717-9
pmc: PMC7253449
doi:
Substances chimiques
5' Untranslated Regions
0
Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2523Subventions
Organisme : British Heart Foundation
ID : RG/18/10/33842
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1102/20
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 107469/Z/15/Z
Pays : United Kingdom
Organisme : NIMH NIH HHS
ID : R01 MH085548
Pays : United States
Organisme : Department of Health
ID : IS-BRC-1215-20007
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U120085815
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : U54 DK105566
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM104371
Pays : United States
Organisme : Department of Health
ID : HICF-R6-373
Pays : United Kingdom
Organisme : British Heart Foundation
ID : CS/14/2/30841
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : P30 DK020572
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Investigateurs
Irina M Armean
(IM)
Eric Banks
(E)
Louis Bergelson
(L)
Kristian Cibulskis
(K)
Ryan L Collins
(RL)
Kristen M Connolly
(KM)
Miguel Covarrubias
(M)
Beryl Cummings
(B)
Mark J Daly
(MJ)
Stacey Donnelly
(S)
Yossi Farjoun
(Y)
Steven Ferriera
(S)
Stacey Gabriel
(S)
Laura D Gauthier
(LD)
Jeff Gentry
(J)
Namrata Gupta
(N)
Thibault Jeandet
(T)
Diane Kaplan
(D)
Kristen M Laricchia
(KM)
Christopher Llanwarne
(C)
Eric V Minikel
(EV)
Ruchi Munshi
(R)
Benjamin M Neale
(BM)
Sam Novod
(S)
Nikelle Petrillo
(N)
Timothy Poterba
(T)
David Roazen
(D)
Valentin Ruano-Rubio
(V)
Andrea Saltzman
(A)
Kaitlin E Samocha
(KE)
Molly Schleicher
(M)
Cotton Seed
(C)
Matthew Solomonson
(M)
Jose Soto
(J)
Grace Tiao
(G)
Kathleen Tibbetts
(K)
Charlotte Tolonen
(C)
Christopher Vittal
(C)
Gordon Wade
(G)
Arcturus Wang
(A)
Qingbo Wang
(Q)
Nicholas A Watts
(NA)
Ben Weisburd
(B)
Carlos A Aguilar Salinas
(CA)
Tariq Ahmad
(T)
Christine M Albert
(CM)
Diego Ardissino
(D)
Gil Atzmon
(G)
John Barnard
(J)
Laurent Beaugerie
(L)
Emelia J Benjamin
(EJ)
Michael Boehnke
(M)
Lori L Bonnycastle
(LL)
Erwin P Bottinger
(EP)
Donald W Bowden
(DW)
Matthew J Bown
(MJ)
John C Chambers
(JC)
Juliana C Chan
(JC)
Daniel Chasman
(D)
Judy Cho
(J)
Mina K Chung
(MK)
Bruce Cohen
(B)
Adolfo Correa
(A)
Dana Dabelea
(D)
Mark J Daly
(MJ)
Dawood Darbar
(D)
Ravindranath Duggirala
(R)
Josée Dupuis
(J)
Patrick T Ellinor
(PT)
Roberto Elosua
(R)
Jeanette Erdmann
(J)
Tõnu Esko
(T)
Martti Färkkilä
(M)
Jose Florez
(J)
Andre Franke
(A)
Gad Getz
(G)
Benjamin Glaser
(B)
Stephen J Glatt
(SJ)
David Goldstein
(D)
Clicerio Gonzalez
(C)
Leif Groop
(L)
Christopher Haiman
(C)
Craig Hanis
(C)
Matthew Harms
(M)
Mikko Hiltunen
(M)
Matti M Holi
(MM)
Christina M Hultman
(CM)
Mikko Kallela
(M)
Jaakko Kaprio
(J)
Sekar Kathiresan
(S)
Bong-Jo Kim
(BJ)
Young Jin Kim
(YJ)
George Kirov
(G)
Jaspal Kooner
(J)
Seppo Koskinen
(S)
Harlan M Krumholz
(HM)
Subra Kugathasan
(S)
Soo Heon Kwak
(SH)
Markku Laakso
(M)
Terho Lehtimäki
(T)
Ruth J F Loos
(RJF)
Steven A Lubitz
(SA)
Ronald C W Ma
(RCW)
Jaume Marrugat
(J)
Kari M Mattila
(KM)
Steven McCarroll
(S)
Mark I McCarthy
(MI)
Dermot McGovern
(D)
Ruth McPherson
(R)
James B Meigs
(JB)
Olle Melander
(O)
Andres Metspalu
(A)
Benjamin M Neale
(BM)
Peter M Nilsson
(PM)
Michael C O'Donovan
(MC)
Dost Ongur
(D)
Lorena Orozco
(L)
Michael J Owen
(MJ)
Colin N A Palmer
(CNA)
Aarno Palotie
(A)
Kyong Soo Park
(KS)
Carlos Pato
(C)
Ann E Pulver
(AE)
Nazneen Rahman
(N)
Anne M Remes
(AM)
John D Rioux
(JD)
Samuli Ripatti
(S)
Dan M Roden
(DM)
Danish Saleheen
(D)
Veikko Salomaa
(V)
Nilesh J Samani
(NJ)
Jeremiah Scharf
(J)
Heribert Schunkert
(H)
Moore B Shoemaker
(MB)
Pamela Sklar
(P)
Hilkka Soininen
(H)
Harry Sokol
(H)
Tim Spector
(T)
Patrick F Sullivan
(PF)
Jaana Suvisaari
(J)
E Shyong Tai
(ES)
Yik Ying Teo
(YY)
Tuomi Tiinamaija
(T)
Ming Tsuang
(M)
Dan Turner
(D)
Teresa Tusie-Luna
(T)
Erkki Vartiainen
(E)
Hugh Watkins
(H)
Rinse K Weersma
(RK)
Maija Wessman
(M)
James G Wilson
(JG)
Ramnik J Xavier
(RJ)
Marquis P Vawter
(MP)
Commentaires et corrections
Type : CommentIn
Type : ErratumIn
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