Somatic mutations reveal asymmetric cellular dynamics in the early human embryo.
Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.|Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Young Seok
YS
Ju
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Inigo
I
Martincorena
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.|European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton CB10 1SD, UK.
Moritz
M
Gerstung
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Mia
M
Petljak
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.|Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.
Ludmil B
LB
Alexandrov
Genomic Mutation and Genetic Disease, Wellcome Trust Sanger Institute, Hinxton, UK.
Raheleh
R
Rahbari
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.|Oxford Big Data Institute and Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, Oxford, UK.
David C
DC
Wedge
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Helen R
HR
Davies
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Manasa
M
Ramakrishna
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Anthony
A
Fullam
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Sancha
S
Martin
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Christopher
C
Alder
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Nikita
N
Patel
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Steve
S
Gamble
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Sarah
S
O'Meara
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Dilip D
DD
Giri
Institute of Clinical Medicine, Campus at Akershus University Hospital, University of Oslo, Lørenskog, Norway.
Torril
T
Sauer
King's Health Partners Cancer Biobank, Guy's Hospital, King's College London School of Medicine, London, UK.
Sarah E
SE
Pinder
Department of Pathology, Ninewells Hospital and Medical School, Dundee, UK.
Colin A
CA
Purdie
BioCare, Strategic Cancer Research Program, Lund, Sweden.|CREATE Health, Strategic Centre for Translational Cancer Research, Lund, Sweden.|Department of Oncology and Pathology, Lund University Cancer Center, Lund, Sweden.
Åke
Å
Borg
Radboud University Medical Center, Nijmegen, The Netherlands.
Henk
H
Stunnenberg
Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
Marc
M
van de Vijver
SingHealth Duke-NUS Breast Centre, Division of Surgical Oncology, National Cancer Centre Singapore, Department of General Surgery, Singapore General Hospital, Singapore.
Benita K T
BK
Tan
Cancer Research UK (CRUK) Cambridge Institute, University of Cambridge, Cambridge, UK.
Carlos
C
Caldas
Breast Cancer Now Research Unit, King's College London, London SE1 9RT, UK.|Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London SW3 6JB, UK.
Andrew
A
Tutt
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Naoto T
NT
Ueno
Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, USA.
Laura J
LJ
van 't Veer
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands.
John W M
JW
Martens
Institut Jules Bordet, Brussels, Belgium.
Christos
C
Sotiriou
Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Oncology, Haukeland University Hospital, Bergen, Norway.
Stian
S
Knappskog
Department of Radiation Oncology and Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
Paul N
PN
Span
University of Queensland, School of Medicine, Brisbane, Australia.|Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia.|University of Queensland, UQ Centre for Clinical Research, Brisbane, Australia.
Sunil R
SR
Lakhani
Cancer Research Laboratory, University of Iceland, Reykjavik, Iceland.
Jórunn Erla
JE
Eyfjörd
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway.|The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Anne-Lise
AL
Børresen-Dale
Sibley Pathology Department, Johns Hopkins Medicine, Washington DC 20016, USA.
Andrea
A
Richardson
Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Alastair M
AM
Thompson
Plateforme Gilles Thomas, Synergie Lyon Cancer, Centre Léon Bérard, Lyon Cedex 08, France.
Alain
A
Viari
Genomic Mutation and Genetic Disease, Wellcome Trust Sanger Institute, Hinxton, UK.
Matthew E
ME
Hurles
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Serena
S
Nik-Zainal
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Peter J
PJ
Campbell
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Michael R
MR
Stratton
D000328:Adult; D001773:Blood Cells / Q000378:metabolism; D019070:Cell Lineage / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology* / Q000378:metabolism*; D047108:Embryonic Development / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D009030:Mosaicism; D016296:Mutagenesis; D009154:Mutation; D059645:Mutation Rate