The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing.
Autism Spectrum Disorder
/ pathology
Cell Division
/ genetics
Chromatin
/ genetics
Embryonic Development
/ genetics
Epigenesis, Genetic
Exons
Female
Gene Regulatory Networks
/ genetics
Genetic Predisposition to Disease
Genome, Human
/ genetics
Germ-Line Mutation
/ genetics
High-Throughput Nucleotide Sequencing
Humans
Polymorphism, Single Nucleotide
Prefrontal Cortex
/ pathology
Pregnancy
Whole Genome Sequencing
Journal
Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
10
01
2020
accepted:
21
11
2020
pubmed:
13
1
2021
medline:
20
3
2021
entrez:
12
1
2021
Statut:
ppublish
Résumé
We characterize the landscape of somatic mutations-mutations occurring after fertilization-in the human brain using ultra-deep (~250×) whole-genome sequencing of prefrontal cortex from 59 donors with autism spectrum disorder (ASD) and 15 control donors. We observe a mean of 26 somatic single-nucleotide variants per brain present in ≥4% of cells, with enrichment of mutations in coding and putative regulatory regions. Our analysis reveals that the first cell division after fertilization produces ~3.4 mutations, followed by 2-3 mutations in subsequent generations. This suggests that a typical individual possesses ~80 somatic single-nucleotide variants present in ≥2% of cells-comparable to the number of de novo germline mutations per generation-with about half of individuals having at least one potentially function-altering somatic mutation somewhere in the cortex. ASD brains show an excess of somatic mutations in neural enhancer sequences compared with controls, suggesting that mosaic enhancer mutations may contribute to ASD risk.
Identifiants
pubmed: 33432195
doi: 10.1038/s41593-020-00765-6
pii: 10.1038/s41593-020-00765-6
pmc: PMC7983596
mid: NIHMS1648954
doi:
Substances chimiques
Chromatin
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
176-185Subventions
Organisme : NINDS NIH HHS
ID : R01 NS032457
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH106883
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
ID : P50MH106933
Organisme : NIMH NIH HHS
ID : U01 MH106876
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : T32GM007753
Organisme : NICHD NIH HHS
ID : U54 HD090255
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH106874
Pays : United States
Organisme : NIMH NIH HHS
ID : P50 MH106933
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)
ID : T32HG002295
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
ID : R01NS032457
Organisme : NIMH NIH HHS
ID : U01 MH106892
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH108898
Pays : United States
Organisme : NIMH NIH HHS
ID : F31 MH124393
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH106884
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD103538
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG000040
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG002295
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007753
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH106891
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH106882
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH106893
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
ID : U01MH106883
Organisme : NIGMS NIH HHS
ID : T32 GM007544
Pays : United States
Investigateurs
Christopher A Walsh
(CA)
Javier Ganz
(J)
Mollie B Woodworth
(MB)
Pengpeng Li
(P)
Rachel E Rodin
(RE)
Robert S Hill
(RS)
Sara Bizzotto
(S)
Zinan Zhou
(Z)
Eunjung A Lee
(EA)
Alison R Barton
(AR)
Alissa M D'Gama
(AM)
Alon Galor
(A)
Craig L Bohrson
(CL)
Daniel Kwon
(D)
Doga C Gulhan
(DC)
Elaine T Lim
(ET)
Isidro Ciriano Cortes
(IC)
Lovelace J Luquette
(LJ)
Maxwell A Sherman
(MA)
Michael E Coulter
(ME)
Michael A Lodato
(MA)
Peter J Park
(PJ)
Rebeca B Monroy
(RB)
Sonia N Kim
(SN)
Yanmei Dou
(Y)
Andrew Chess
(A)
Attila Gulyás-Kovács
(A)
Chaggai Rosenbluh
(C)
Schahram Akbarian
(S)
None Ben Langmead
Jeremy Thorpe
(J)
Jonathan Pevsner
(J)
Soonweng Cho
(S)
Andrew E Jaffe
(AE)
Apua Paquola
(A)
Daniel R Weinberger
(DR)
Jennifer A Erwin
(JA)
Jooheon H Shin
(JH)
Richard E Straub
(RE)
Rujuta Narurkar
(R)
Alexej S Abyzov
(AS)
Taejeong Bae
(T)
Anjene Addington
(A)
David Panchision
(D)
Doug Meinecke
(D)
Geetha Senthil
(G)
Lora Bingaman
(L)
Tara Dutka
(T)
Thomas Lehner
(T)
Laura Saucedo-Cuevas
(L)
Tara Conniff
(T)
Kenneth Daily
(K)
Mette Peters
(M)
Fred H Gage
(FH)
Meiyan Wang
(M)
Patrick J Reed
(PJ)
Sara B Linker
(SB)
Alex E Urban
(AE)
Bo Zhou
(B)
Xiaowei Zhu
(X)
Aitor Serres
(A)
David Juan
(D)
Inna Povolotskaya
(I)
Irene Lobón
(I)
Manuel Solis-Moruno
(M)
Raquel García-Pérez
(R)
Tomas Marquès-Bonet
(T)
Gary W Mathern
(GW)
Jing Gu
(J)
Joseph G Gleeson
(JG)
Laurel L Ball
(LL)
Renee D George
(RD)
Tiziano Pramparo
(T)
Diane A Flasch
(DA)
Trenton J Frisbie
(TJ)
Jeffrey M Kidd
(JM)
John B Moldovan
(JB)
John V Moran
(JV)
Kenneth Y Kwan
(KY)
Ryan E Mills
(RE)
Sarah B Emery
(SB)
Weichen Zhou
(W)
Yifan Wang
(Y)
Aakrosh Ratan
(A)
Michael J McConnell
(MJ)
Flora M Vaccarino
(FM)
Gianfilippo Coppola
(G)
Jessica B Lennington
(JB)
Liana Fasching
(L)
Nenad Sestan
(N)
Sirisha Pochareddy
(S)
Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Type : ErratumIn
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