Somatic mutations reveal asymmetric cellular dynamics in the early human embryo.
Identifieur interne : 000364 ( Main/Exploration ); précédent : 000363; suivant : 000365Somatic mutations reveal asymmetric cellular dynamics in the early human embryo.
Auteurs : Young Seok Ju [Royaume-Uni] ; Inigo Martincorena [Royaume-Uni] ; Moritz Gerstung [Royaume-Uni] ; Mia Petljak [Royaume-Uni] ; Ludmil B. Alexandrov [Royaume-Uni] ; Raheleh Rahbari [Royaume-Uni] ; David C. Wedge [Royaume-Uni] ; Helen R. Davies [Royaume-Uni] ; Manasa Ramakrishna [Royaume-Uni] ; Anthony Fullam [Royaume-Uni] ; Sancha Martin [Royaume-Uni] ; Christopher Alder [Royaume-Uni] ; Nikita Patel [Royaume-Uni] ; Steve Gamble [Royaume-Uni] ; Sarah O'Meara [Royaume-Uni] ; Dilip D. Giri [États-Unis] ; Torril Sauer [Norvège] ; Sarah E. Pinder [Royaume-Uni] ; Colin A. Purdie [Royaume-Uni] ; Ke Borg [Suède] ; Henk Stunnenberg [Pays-Bas] ; Marc Van De Vijver [Pays-Bas] ; Benita K T. Tan [Singapour] ; Carlos Caldas [Royaume-Uni] ; Andrew Tutt [Royaume-Uni] ; Naoto T. Ueno [États-Unis] ; Laura J. Van T Veer [États-Unis] ; John W M. Martens [Pays-Bas] ; Christos Sotiriou [Belgique] ; Stian Knappskog [Norvège] ; Paul N. Span [Pays-Bas] ; Sunil R. Lakhani [Australie] ; J Runn Erla Eyfjörd [Islande] ; Anne-Lise B Rresen-Dale [Norvège] ; Andrea Richardson [États-Unis] ; Alastair M. Thompson [États-Unis] ; Alain Viari [France] ; Matthew E. Hurles [Royaume-Uni] ; Serena Nik-Zainal [Royaume-Uni] ; Peter J. Campbell [Royaume-Uni] ; Michael R. Stratton [Royaume-Uni]Source :
- Nature [ 1476-4687 ] ; 2017.
Descripteurs français
- KwdFr :
- Adulte, Cellules sanguines (métabolisme), Développement embryonnaire (génétique), Embryon de mammifère (cytologie), Embryon de mammifère (métabolisme), Génome humain (génétique), Humains, Lignage cellulaire (génétique), Mosaïcisme, Mutagenèse, Mutation, Mutation germinale (génétique), Taux de mutation.
- MESH :
- cytologie : Embryon de mammifère.
- génétique : Développement embryonnaire, Génome humain, Lignage cellulaire, Mutation germinale.
- métabolisme : Cellules sanguines, Embryon de mammifère.
- Adulte, Humains, Mosaïcisme, Mutagenèse, Mutation, Taux de mutation.
English descriptors
- KwdEn :
- MESH :
- cytology : Embryo, Mammalian.
- genetics : Cell Lineage, Embryonic Development, Genome, Human, Germ-Line Mutation.
- metabolism : Blood Cells, Embryo, Mammalian.
- Adult, Humans, Mosaicism, Mutagenesis, Mutation, Mutation Rate.
Abstract
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.
DOI: 10.1038/nature21703
PubMed: 28329761
Affiliations:
- Australie, Belgique, France, Islande, Norvège, Pays-Bas, Royaume-Uni, Singapour, Suède, États-Unis
- Angleterre, Angleterre de l'Est, Californie, District de Columbia, Grand Londres, Gueldre, Hollande-Méridionale, Hollande-Septentrionale, Région de Bruxelles-Capitale, Texas, État de New York, Østlandet
- Amsterdam, Bruxelles, Cambridge, Londres, Nimègue, Oslo, Rotterdam, San Francisco, Washington (district de Columbia)
- Université de Cambridge
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Le document en format XML
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Giri</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Sauer, Torril" sort="Sauer, Torril" uniqKey="Sauer T" first="Torril" last="Sauer">Torril Sauer</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Clinical Medicine, Campus at Akershus University Hospital, University of Oslo, Lørenskog, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Institute of Clinical Medicine, Campus at Akershus University Hospital, University of Oslo, Lørenskog</wicri:regionArea><wicri:noRegion>Lørenskog</wicri:noRegion></affiliation></author><author><name sortKey="Pinder, Sarah E" sort="Pinder, Sarah E" uniqKey="Pinder S" first="Sarah E" last="Pinder">Sarah E. Pinder</name><affiliation wicri:level="3"><nlm:affiliation>King's Health Partners Cancer Biobank, Guy's Hospital, King's College London School of Medicine, London, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>King's Health Partners Cancer Biobank, Guy's Hospital, King's College London School of Medicine, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Purdie, Colin A" sort="Purdie, Colin A" uniqKey="Purdie C" first="Colin A" last="Purdie">Colin A. Purdie</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology, Ninewells Hospital and Medical School, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pathology, Ninewells Hospital and Medical School, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></affiliation></author><author><name sortKey="Borg, Ke" sort="Borg, Ke" uniqKey="Borg " first=" Ke" last="Borg"> Ke Borg</name><affiliation wicri:level="1"><nlm:affiliation>BioCare, Strategic Cancer Research Program, Lund, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>BioCare, Strategic Cancer Research Program, Lund</wicri:regionArea><wicri:noRegion>Lund</wicri:noRegion></affiliation></author><author><name sortKey="Stunnenberg, Henk" sort="Stunnenberg, Henk" uniqKey="Stunnenberg H" first="Henk" last="Stunnenberg">Henk Stunnenberg</name><affiliation wicri:level="3"><nlm:affiliation>Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Radboud University Medical Center, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Van De Vijver, Marc" sort="Van De Vijver, Marc" uniqKey="Van De Vijver M" first="Marc" last="Van De Vijver">Marc Van De Vijver</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pathology, Academic Medical Center, Amsterdam</wicri:regionArea><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region></placeName></affiliation></author><author><name sortKey="Tan, Benita K T" sort="Tan, Benita K T" uniqKey="Tan B" first="Benita K T" last="Tan">Benita K T. Tan</name><affiliation wicri:level="1"><nlm:affiliation>SingHealth Duke-NUS Breast Centre, Division of Surgical Oncology, National Cancer Centre Singapore, Department of General Surgery, Singapore General Hospital, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>SingHealth Duke-NUS Breast Centre, Division of Surgical Oncology, National Cancer Centre Singapore, Department of General Surgery, Singapore General Hospital</wicri:regionArea><wicri:noRegion>Singapore General Hospital</wicri:noRegion></affiliation></author><author><name sortKey="Caldas, Carlos" sort="Caldas, Carlos" uniqKey="Caldas C" first="Carlos" last="Caldas">Carlos Caldas</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK (CRUK) Cambridge Institute, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK (CRUK) Cambridge Institute, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Tutt, Andrew" sort="Tutt, Andrew" uniqKey="Tutt A" first="Andrew" last="Tutt">Andrew Tutt</name><affiliation wicri:level="1"><nlm:affiliation>Breast Cancer Now Research Unit, King's College London, London SE1 9RT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Breast Cancer Now Research Unit, King's College London, London SE1 9RT</wicri:regionArea><wicri:noRegion>London SE1 9RT</wicri:noRegion></affiliation></author><author><name sortKey="Ueno, Naoto T" sort="Ueno, Naoto T" uniqKey="Ueno N" first="Naoto T" last="Ueno">Naoto T. Ueno</name><affiliation wicri:level="2"><nlm:affiliation>Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas</wicri:regionArea><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Van T Veer, Laura J" sort="Van T Veer, Laura J" uniqKey="Van T Veer L" first="Laura J" last="Van T Veer">Laura J. Van T Veer</name><affiliation wicri:level="3"><nlm:affiliation>Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco</wicri:regionArea><placeName><settlement type="city">San Francisco</settlement><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Martens, John W M" sort="Martens, John W M" uniqKey="Martens J" first="John W M" last="Martens">John W M. Martens</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam</wicri:regionArea><placeName><settlement type="city">Rotterdam</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Sotiriou, Christos" sort="Sotiriou, Christos" uniqKey="Sotiriou C" first="Christos" last="Sotiriou">Christos Sotiriou</name><affiliation wicri:level="3"><nlm:affiliation>Institut Jules Bordet, Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Institut Jules Bordet, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName></affiliation></author><author><name sortKey="Knappskog, Stian" sort="Knappskog, Stian" uniqKey="Knappskog S" first="Stian" last="Knappskog">Stian Knappskog</name><affiliation wicri:level="1"><nlm:affiliation>Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Section of Oncology, Department of Clinical Science, University of Bergen, Bergen</wicri:regionArea><wicri:noRegion>Bergen</wicri:noRegion></affiliation></author><author><name sortKey="Span, Paul N" sort="Span, Paul N" uniqKey="Span P" first="Paul N" last="Span">Paul N. Span</name><affiliation wicri:level="3"><nlm:affiliation>Department of Radiation Oncology and Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Radiation Oncology and Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Lakhani, Sunil R" sort="Lakhani, Sunil R" uniqKey="Lakhani S" first="Sunil R" last="Lakhani">Sunil R. Lakhani</name><affiliation wicri:level="1"><nlm:affiliation>University of Queensland, School of Medicine, Brisbane, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>University of Queensland, School of Medicine, Brisbane</wicri:regionArea><wicri:noRegion>Brisbane</wicri:noRegion></affiliation></author><author><name sortKey="Eyfjord, J Runn Erla" sort="Eyfjord, J Runn Erla" uniqKey="Eyfjord J" first="J Runn Erla" last="Eyfjörd">J Runn Erla Eyfjörd</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Research Laboratory, University of Iceland, Reykjavik, Iceland.</nlm:affiliation><country xml:lang="fr">Islande</country><wicri:regionArea>Cancer Research Laboratory, University of Iceland, Reykjavik</wicri:regionArea><wicri:noRegion>Reykjavik</wicri:noRegion></affiliation></author><author><name sortKey="B Rresen Dale, Anne Lise" sort="B Rresen Dale, Anne Lise" uniqKey="B Rresen Dale A" first="Anne-Lise" last="B Rresen-Dale">Anne-Lise B Rresen-Dale</name><affiliation wicri:level="1"><nlm:affiliation>Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, 0310 Oslo</wicri:regionArea><placeName><settlement type="city">Oslo</settlement><region nuts="2">Østlandet</region></placeName></affiliation></author><author><name sortKey="Richardson, Andrea" sort="Richardson, Andrea" uniqKey="Richardson A" first="Andrea" last="Richardson">Andrea Richardson</name><affiliation wicri:level="1"><nlm:affiliation>Sibley Pathology Department, Johns Hopkins Medicine, Washington DC 20016, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Sibley Pathology Department, Johns Hopkins Medicine, Washington DC 20016</wicri:regionArea><placeName><settlement type="city">Washington (district de Columbia)</settlement><region type="state">District de Columbia</region></placeName></affiliation></author><author><name sortKey="Thompson, Alastair M" sort="Thompson, Alastair M" uniqKey="Thompson A" first="Alastair M" last="Thompson">Alastair M. Thompson</name><affiliation wicri:level="2"><nlm:affiliation>Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas</wicri:regionArea><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Viari, Alain" sort="Viari, Alain" uniqKey="Viari A" first="Alain" last="Viari">Alain Viari</name><affiliation wicri:level="1"><nlm:affiliation>Plateforme Gilles Thomas, Synergie Lyon Cancer, Centre Léon Bérard, Lyon Cedex 08, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Plateforme Gilles Thomas, Synergie Lyon Cancer, Centre Léon Bérard, Lyon Cedex 08</wicri:regionArea><wicri:noRegion>Lyon Cedex 08</wicri:noRegion><wicri:noRegion>Lyon Cedex 08</wicri:noRegion></affiliation></author><author><name sortKey="Hurles, Matthew E" sort="Hurles, Matthew E" uniqKey="Hurles M" first="Matthew E" last="Hurles">Matthew E. Hurles</name><affiliation wicri:level="1"><nlm:affiliation>Genomic Mutation and Genetic Disease, Wellcome Trust Sanger Institute, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Genomic Mutation and Genetic Disease, Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author><author><name sortKey="Nik Zainal, Serena" sort="Nik Zainal, Serena" uniqKey="Nik Zainal S" first="Serena" last="Nik-Zainal">Serena Nik-Zainal</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Campbell, Peter J" sort="Campbell, Peter J" uniqKey="Campbell P" first="Peter J" last="Campbell">Peter J. Campbell</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R" last="Stratton">Michael R. Stratton</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:28329761</idno><idno type="pmid">28329761</idno><idno type="doi">10.1038/nature21703</idno><idno type="wicri:Area/PubMed/Corpus">000F19</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000F19</idno><idno type="wicri:Area/PubMed/Curation">000F16</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000F16</idno><idno type="wicri:Area/PubMed/Checkpoint">000F16</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000F16</idno><idno type="wicri:Area/Ncbi/Merge">004510</idno><idno type="wicri:Area/Ncbi/Curation">004510</idno><idno type="wicri:Area/Ncbi/Checkpoint">004510</idno><idno type="wicri:Area/Main/Merge">000359</idno><idno type="wicri:Area/Main/Curation">000364</idno><idno type="wicri:Area/Main/Exploration">000364</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Somatic mutations reveal asymmetric cellular dynamics in the early human embryo.</title><author><name sortKey="Ju, Young Seok" sort="Ju, Young Seok" uniqKey="Ju Y" first="Young Seok" last="Ju">Young Seok Ju</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Martincorena, Inigo" sort="Martincorena, Inigo" uniqKey="Martincorena I" first="Inigo" last="Martincorena">Inigo Martincorena</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Gerstung, Moritz" sort="Gerstung, Moritz" uniqKey="Gerstung M" first="Moritz" last="Gerstung">Moritz Gerstung</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Petljak, Mia" sort="Petljak, Mia" uniqKey="Petljak M" first="Mia" last="Petljak">Mia Petljak</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Alexandrov, Ludmil B" sort="Alexandrov, Ludmil B" uniqKey="Alexandrov L" first="Ludmil B" last="Alexandrov">Ludmil B. Alexandrov</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Rahbari, Raheleh" sort="Rahbari, Raheleh" uniqKey="Rahbari R" first="Raheleh" last="Rahbari">Raheleh Rahbari</name><affiliation wicri:level="1"><nlm:affiliation>Genomic Mutation and Genetic Disease, Wellcome Trust Sanger Institute, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Genomic Mutation and Genetic Disease, Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author><author><name sortKey="Wedge, David C" sort="Wedge, David C" uniqKey="Wedge D" first="David C" last="Wedge">David C. Wedge</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Davies, Helen R" sort="Davies, Helen R" uniqKey="Davies H" first="Helen R" last="Davies">Helen R. Davies</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Ramakrishna, Manasa" sort="Ramakrishna, Manasa" uniqKey="Ramakrishna M" first="Manasa" last="Ramakrishna">Manasa Ramakrishna</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Fullam, Anthony" sort="Fullam, Anthony" uniqKey="Fullam A" first="Anthony" last="Fullam">Anthony Fullam</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Martin, Sancha" sort="Martin, Sancha" uniqKey="Martin S" first="Sancha" last="Martin">Sancha Martin</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Alder, Christopher" sort="Alder, Christopher" uniqKey="Alder C" first="Christopher" last="Alder">Christopher Alder</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Patel, Nikita" sort="Patel, Nikita" uniqKey="Patel N" first="Nikita" last="Patel">Nikita Patel</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Gamble, Steve" sort="Gamble, Steve" uniqKey="Gamble S" first="Steve" last="Gamble">Steve Gamble</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="O Meara, Sarah" sort="O Meara, Sarah" uniqKey="O Meara S" first="Sarah" last="O'Meara">Sarah O'Meara</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Giri, Dilip D" sort="Giri, Dilip D" uniqKey="Giri D" first="Dilip D" last="Giri">Dilip D. Giri</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Sauer, Torril" sort="Sauer, Torril" uniqKey="Sauer T" first="Torril" last="Sauer">Torril Sauer</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Clinical Medicine, Campus at Akershus University Hospital, University of Oslo, Lørenskog, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Institute of Clinical Medicine, Campus at Akershus University Hospital, University of Oslo, Lørenskog</wicri:regionArea><wicri:noRegion>Lørenskog</wicri:noRegion></affiliation></author><author><name sortKey="Pinder, Sarah E" sort="Pinder, Sarah E" uniqKey="Pinder S" first="Sarah E" last="Pinder">Sarah E. Pinder</name><affiliation wicri:level="3"><nlm:affiliation>King's Health Partners Cancer Biobank, Guy's Hospital, King's College London School of Medicine, London, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>King's Health Partners Cancer Biobank, Guy's Hospital, King's College London School of Medicine, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Purdie, Colin A" sort="Purdie, Colin A" uniqKey="Purdie C" first="Colin A" last="Purdie">Colin A. Purdie</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology, Ninewells Hospital and Medical School, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pathology, Ninewells Hospital and Medical School, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></affiliation></author><author><name sortKey="Borg, Ke" sort="Borg, Ke" uniqKey="Borg " first=" Ke" last="Borg"> Ke Borg</name><affiliation wicri:level="1"><nlm:affiliation>BioCare, Strategic Cancer Research Program, Lund, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>BioCare, Strategic Cancer Research Program, Lund</wicri:regionArea><wicri:noRegion>Lund</wicri:noRegion></affiliation></author><author><name sortKey="Stunnenberg, Henk" sort="Stunnenberg, Henk" uniqKey="Stunnenberg H" first="Henk" last="Stunnenberg">Henk Stunnenberg</name><affiliation wicri:level="3"><nlm:affiliation>Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Radboud University Medical Center, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Van De Vijver, Marc" sort="Van De Vijver, Marc" uniqKey="Van De Vijver M" first="Marc" last="Van De Vijver">Marc Van De Vijver</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pathology, Academic Medical Center, Amsterdam</wicri:regionArea><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region></placeName></affiliation></author><author><name sortKey="Tan, Benita K T" sort="Tan, Benita K T" uniqKey="Tan B" first="Benita K T" last="Tan">Benita K T. Tan</name><affiliation wicri:level="1"><nlm:affiliation>SingHealth Duke-NUS Breast Centre, Division of Surgical Oncology, National Cancer Centre Singapore, Department of General Surgery, Singapore General Hospital, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>SingHealth Duke-NUS Breast Centre, Division of Surgical Oncology, National Cancer Centre Singapore, Department of General Surgery, Singapore General Hospital</wicri:regionArea><wicri:noRegion>Singapore General Hospital</wicri:noRegion></affiliation></author><author><name sortKey="Caldas, Carlos" sort="Caldas, Carlos" uniqKey="Caldas C" first="Carlos" last="Caldas">Carlos Caldas</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK (CRUK) Cambridge Institute, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK (CRUK) Cambridge Institute, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Tutt, Andrew" sort="Tutt, Andrew" uniqKey="Tutt A" first="Andrew" last="Tutt">Andrew Tutt</name><affiliation wicri:level="1"><nlm:affiliation>Breast Cancer Now Research Unit, King's College London, London SE1 9RT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Breast Cancer Now Research Unit, King's College London, London SE1 9RT</wicri:regionArea><wicri:noRegion>London SE1 9RT</wicri:noRegion></affiliation></author><author><name sortKey="Ueno, Naoto T" sort="Ueno, Naoto T" uniqKey="Ueno N" first="Naoto T" last="Ueno">Naoto T. Ueno</name><affiliation wicri:level="2"><nlm:affiliation>Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas</wicri:regionArea><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Van T Veer, Laura J" sort="Van T Veer, Laura J" uniqKey="Van T Veer L" first="Laura J" last="Van T Veer">Laura J. Van T Veer</name><affiliation wicri:level="3"><nlm:affiliation>Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco</wicri:regionArea><placeName><settlement type="city">San Francisco</settlement><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Martens, John W M" sort="Martens, John W M" uniqKey="Martens J" first="John W M" last="Martens">John W M. Martens</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam</wicri:regionArea><placeName><settlement type="city">Rotterdam</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Sotiriou, Christos" sort="Sotiriou, Christos" uniqKey="Sotiriou C" first="Christos" last="Sotiriou">Christos Sotiriou</name><affiliation wicri:level="3"><nlm:affiliation>Institut Jules Bordet, Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Institut Jules Bordet, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName></affiliation></author><author><name sortKey="Knappskog, Stian" sort="Knappskog, Stian" uniqKey="Knappskog S" first="Stian" last="Knappskog">Stian Knappskog</name><affiliation wicri:level="1"><nlm:affiliation>Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Section of Oncology, Department of Clinical Science, University of Bergen, Bergen</wicri:regionArea><wicri:noRegion>Bergen</wicri:noRegion></affiliation></author><author><name sortKey="Span, Paul N" sort="Span, Paul N" uniqKey="Span P" first="Paul N" last="Span">Paul N. Span</name><affiliation wicri:level="3"><nlm:affiliation>Department of Radiation Oncology and Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Radiation Oncology and Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Lakhani, Sunil R" sort="Lakhani, Sunil R" uniqKey="Lakhani S" first="Sunil R" last="Lakhani">Sunil R. Lakhani</name><affiliation wicri:level="1"><nlm:affiliation>University of Queensland, School of Medicine, Brisbane, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>University of Queensland, School of Medicine, Brisbane</wicri:regionArea><wicri:noRegion>Brisbane</wicri:noRegion></affiliation></author><author><name sortKey="Eyfjord, J Runn Erla" sort="Eyfjord, J Runn Erla" uniqKey="Eyfjord J" first="J Runn Erla" last="Eyfjörd">J Runn Erla Eyfjörd</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Research Laboratory, University of Iceland, Reykjavik, Iceland.</nlm:affiliation><country xml:lang="fr">Islande</country><wicri:regionArea>Cancer Research Laboratory, University of Iceland, Reykjavik</wicri:regionArea><wicri:noRegion>Reykjavik</wicri:noRegion></affiliation></author><author><name sortKey="B Rresen Dale, Anne Lise" sort="B Rresen Dale, Anne Lise" uniqKey="B Rresen Dale A" first="Anne-Lise" last="B Rresen-Dale">Anne-Lise B Rresen-Dale</name><affiliation wicri:level="1"><nlm:affiliation>Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, 0310 Oslo</wicri:regionArea><placeName><settlement type="city">Oslo</settlement><region nuts="2">Østlandet</region></placeName></affiliation></author><author><name sortKey="Richardson, Andrea" sort="Richardson, Andrea" uniqKey="Richardson A" first="Andrea" last="Richardson">Andrea Richardson</name><affiliation wicri:level="1"><nlm:affiliation>Sibley Pathology Department, Johns Hopkins Medicine, Washington DC 20016, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Sibley Pathology Department, Johns Hopkins Medicine, Washington DC 20016</wicri:regionArea><placeName><settlement type="city">Washington (district de Columbia)</settlement><region type="state">District de Columbia</region></placeName></affiliation></author><author><name sortKey="Thompson, Alastair M" sort="Thompson, Alastair M" uniqKey="Thompson A" first="Alastair M" last="Thompson">Alastair M. Thompson</name><affiliation wicri:level="2"><nlm:affiliation>Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas</wicri:regionArea><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Viari, Alain" sort="Viari, Alain" uniqKey="Viari A" first="Alain" last="Viari">Alain Viari</name><affiliation wicri:level="1"><nlm:affiliation>Plateforme Gilles Thomas, Synergie Lyon Cancer, Centre Léon Bérard, Lyon Cedex 08, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Plateforme Gilles Thomas, Synergie Lyon Cancer, Centre Léon Bérard, Lyon Cedex 08</wicri:regionArea><wicri:noRegion>Lyon Cedex 08</wicri:noRegion><wicri:noRegion>Lyon Cedex 08</wicri:noRegion></affiliation></author><author><name sortKey="Hurles, Matthew E" sort="Hurles, Matthew E" uniqKey="Hurles M" first="Matthew E" last="Hurles">Matthew E. Hurles</name><affiliation wicri:level="1"><nlm:affiliation>Genomic Mutation and Genetic Disease, Wellcome Trust Sanger Institute, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Genomic Mutation and Genetic Disease, Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author><author><name sortKey="Nik Zainal, Serena" sort="Nik Zainal, Serena" uniqKey="Nik Zainal S" first="Serena" last="Nik-Zainal">Serena Nik-Zainal</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Campbell, Peter J" sort="Campbell, Peter J" uniqKey="Campbell P" first="Peter J" last="Campbell">Peter J. Campbell</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R" last="Stratton">Michael R. Stratton</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author></analytic><series><title level="j">Nature</title><idno type="eISSN">1476-4687</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>Blood Cells (metabolism)</term><term>Cell Lineage (genetics)</term><term>Embryo, Mammalian (cytology)</term><term>Embryo, Mammalian (metabolism)</term><term>Embryonic Development (genetics)</term><term>Genome, Human (genetics)</term><term>Germ-Line Mutation (genetics)</term><term>Humans</term><term>Mosaicism</term><term>Mutagenesis</term><term>Mutation</term><term>Mutation Rate</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adulte</term><term>Cellules sanguines (métabolisme)</term><term>Développement embryonnaire (génétique)</term><term>Embryon de mammifère (cytologie)</term><term>Embryon de mammifère (métabolisme)</term><term>Génome humain (génétique)</term><term>Humains</term><term>Lignage cellulaire (génétique)</term><term>Mosaïcisme</term><term>Mutagenèse</term><term>Mutation</term><term>Mutation germinale (génétique)</term><term>Taux de mutation</term></keywords><keywords scheme="MESH" qualifier="cytologie" xml:lang="fr"><term>Embryon de mammifère</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Embryo, Mammalian</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Cell Lineage</term><term>Embryonic Development</term><term>Genome, Human</term><term>Germ-Line Mutation</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Développement embryonnaire</term><term>Génome humain</term><term>Lignage cellulaire</term><term>Mutation germinale</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Blood Cells</term><term>Embryo, Mammalian</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cellules sanguines</term><term>Embryon de mammifère</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Humans</term><term>Mosaicism</term><term>Mutagenesis</term><term>Mutation</term><term>Mutation Rate</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adulte</term><term>Humains</term><term>Mosaïcisme</term><term>Mutagenèse</term><term>Mutation</term><term>Taux de mutation</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Australie</li><li>Belgique</li><li>France</li><li>Islande</li><li>Norvège</li><li>Pays-Bas</li><li>Royaume-Uni</li><li>Singapour</li><li>Suède</li><li>États-Unis</li></country><region><li>Angleterre</li><li>Angleterre de l'Est</li><li>Californie</li><li>District de Columbia</li><li>Grand Londres</li><li>Gueldre</li><li>Hollande-Méridionale</li><li>Hollande-Septentrionale</li><li>Région de Bruxelles-Capitale</li><li>Texas</li><li>État de New York</li><li>Østlandet</li></region><settlement><li>Amsterdam</li><li>Bruxelles</li><li>Cambridge</li><li>Londres</li><li>Nimègue</li><li>Oslo</li><li>Rotterdam</li><li>San Francisco</li><li>Washington (district de Columbia)</li></settlement><orgName><li>Université de Cambridge</li></orgName></list><tree><country name="Royaume-Uni"><noRegion><name sortKey="Ju, Young Seok" sort="Ju, Young Seok" uniqKey="Ju Y" first="Young Seok" last="Ju">Young Seok Ju</name></noRegion><name sortKey="Alder, Christopher" sort="Alder, Christopher" uniqKey="Alder C" first="Christopher" last="Alder">Christopher Alder</name><name sortKey="Alexandrov, Ludmil B" sort="Alexandrov, Ludmil B" uniqKey="Alexandrov L" first="Ludmil B" last="Alexandrov">Ludmil B. Alexandrov</name><name sortKey="Caldas, Carlos" sort="Caldas, Carlos" uniqKey="Caldas C" first="Carlos" last="Caldas">Carlos Caldas</name><name sortKey="Campbell, Peter J" sort="Campbell, Peter J" uniqKey="Campbell P" first="Peter J" last="Campbell">Peter J. Campbell</name><name sortKey="Davies, Helen R" sort="Davies, Helen R" uniqKey="Davies H" first="Helen R" last="Davies">Helen R. Davies</name><name sortKey="Fullam, Anthony" sort="Fullam, Anthony" uniqKey="Fullam A" first="Anthony" last="Fullam">Anthony Fullam</name><name sortKey="Gamble, Steve" sort="Gamble, Steve" uniqKey="Gamble S" first="Steve" last="Gamble">Steve Gamble</name><name sortKey="Gerstung, Moritz" sort="Gerstung, Moritz" uniqKey="Gerstung M" first="Moritz" last="Gerstung">Moritz Gerstung</name><name sortKey="Hurles, Matthew E" sort="Hurles, Matthew E" uniqKey="Hurles M" first="Matthew E" last="Hurles">Matthew E. 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Martens</name><name sortKey="Span, Paul N" sort="Span, Paul N" uniqKey="Span P" first="Paul N" last="Span">Paul N. Span</name><name sortKey="Van De Vijver, Marc" sort="Van De Vijver, Marc" uniqKey="Van De Vijver M" first="Marc" last="Van De Vijver">Marc Van De Vijver</name></country><country name="Singapour"><noRegion><name sortKey="Tan, Benita K T" sort="Tan, Benita K T" uniqKey="Tan B" first="Benita K T" last="Tan">Benita K T. Tan</name></noRegion></country><country name="Belgique"><region name="Région de Bruxelles-Capitale"><name sortKey="Sotiriou, Christos" sort="Sotiriou, Christos" uniqKey="Sotiriou C" first="Christos" last="Sotiriou">Christos Sotiriou</name></region></country><country name="Australie"><noRegion><name sortKey="Lakhani, Sunil R" sort="Lakhani, Sunil R" uniqKey="Lakhani S" first="Sunil R" last="Lakhani">Sunil R. Lakhani</name></noRegion></country><country name="Islande"><noRegion><name sortKey="Eyfjord, J Runn Erla" sort="Eyfjord, J Runn Erla" uniqKey="Eyfjord J" first="J Runn Erla" last="Eyfjörd">J Runn Erla Eyfjörd</name></noRegion></country><country name="France"><noRegion><name sortKey="Viari, Alain" sort="Viari, Alain" uniqKey="Viari A" first="Alain" last="Viari">Alain Viari</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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