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 effects1. 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 syndromes2 and predispose carriers to cancer3,4. 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 tissues5. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos6, 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 signatures7. 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.

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Acknowledgements

We thank M. Zernicka-Goetz at Gurdon Institute, K. J. Dawson at Wellcome Trust Sanger Institute and T. Bleazard at University of Manchester for discussion and assistance with manuscript preparation. This work was supported by the Wellcome Trust (grant reference 077012/Z/05/Z). Y.S.J. is supported by EMBO long-term fellowship (LTF 1203_2012), by KAIST (G04150052), and by a grant of the Korea Health Technology R&D project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (HI16C2387). P.J.C. is a Wellcome Trust Senior Clinical Fellow. The ICGC Breast Cancer Consortium was supported by a grant from the European Union (BASIS) and the Wellcome Trust. For the family study, Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006).

Author information

Affiliations

  1. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK

    • Young Seok Ju
    • , Inigo Martincorena
    • , Moritz Gerstung
    • , Mia Petljak
    • , Ludmil B. Alexandrov
    • , David C. Wedge
    • , Helen R. Davies
    • , Manasa Ramakrishna
    • , Anthony Fullam
    • , Sancha Martin
    • , Christopher Alder
    • , Nikita Patel
    • , Steve Gamble
    • , Sarah O’Meara
    • , Serena Nik-Zainal
    • , Peter J. Campbell
    •  & Michael R. Stratton
  2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea

    • Young Seok Ju
  3. European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton CB10 1SD, UK

    • Moritz Gerstung
  4. Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA

    • Ludmil B. Alexandrov
  5. Genomic Mutation and Genetic Disease, Wellcome Trust Sanger Institute, Hinxton, UK

    • Raheleh Rahbari
    •  & Matthew E. Hurles
  6. Oxford Big Data Institute and Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, Oxford, UK

    • David C. Wedge
  7. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    • Dilip D. Giri
  8. Institute of Clinical Medicine, Campus at Akershus University Hospital, University of Oslo, Lørenskog, Norway

    • Torril Sauer
  9. King’s Health Partners Cancer Biobank, Guy’s Hospital, King’s College London School of Medicine, London, UK

    • Sarah E. Pinder
  10. Department of Pathology, Ninewells Hospital and Medical School, Dundee, UK

    • Colin A. Purdie
  11. BioCare, Strategic Cancer Research Program, Lund, Sweden

    • Åke Borg
  12. CREATE Health, Strategic Centre for Translational Cancer Research, Lund, Sweden

    • Åke Borg
  13. Department of Oncology and Pathology, Lund University Cancer Center, Lund, Sweden

    • Åke Borg
  14. Radboud University Medical Center, Nijmegen, The Netherlands

    • Henk Stunnenberg
  15. Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands

    • Marc van de Vijver
  16. SingHealth Duke-NUS Breast Centre, Division of Surgical Oncology, National Cancer Centre Singapore, Department of General Surgery, Singapore General Hospital, Singapore

    • Benita K. T. Tan
  17. Cancer Research UK (CRUK) Cambridge Institute, University of Cambridge, Cambridge, UK

    • Carlos Caldas
  18. Breast Cancer Now Research Unit, King’s College London, London SE1 9RT, UK

    • Andrew Tutt
  19. Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London SW3 6JB, UK

    • Andrew Tutt
  20. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    • Naoto T. Ueno
  21. Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, USA

    • Laura J. van ’t Veer
  22. Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands

    • John W. M. Martens
  23. Institut Jules Bordet, Brussels, Belgium

    • Christos Sotiriou
  24. Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway

    • Stian Knappskog
  25. Department of Oncology, Haukeland University Hospital, Bergen, Norway

    • Stian Knappskog
  26. Department of Radiation Oncology and Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands

    • Paul N. Span
  27. University of Queensland, School of Medicine, Brisbane, Australia

    • Sunil R. Lakhani
  28. Pathology Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Australia

    • Sunil R. Lakhani
  29. University of Queensland, UQ Centre for Clinical Research, Brisbane, Australia

    • Sunil R. Lakhani
  30. Cancer Research Laboratory, University of Iceland, Reykjavik, Iceland

    • Jórunn Erla Eyfjörd
  31. Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway

    • Anne-Lise Børresen-Dale
  32. The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway

    • Anne-Lise Børresen-Dale
  33. Sibley Pathology Department, Johns Hopkins Medicine, Washington DC 20016, USA

    • Andrea Richardson
  34. Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    • Alastair M. Thompson
  35. Plateforme Gilles Thomas, Synergie Lyon Cancer, Centre Léon Bérard, Lyon Cedex 08, France

    • Alain Viari

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Contributions

M.R.S. designed and directed the project. Y.S.J. performed the overall study with bioinformatics analyses for detection of early embryonic mutations. I.M. and M.G. performed statistical testing to confirm unequal contributions of early cells and early mutation rates. L.B.A. carried out mutational signature analyses. R.R. and M.E.H. designed and directed family studies. D.C.W., H.R.D., M.R. and S.N.-Z. performed cancer genome analyses and provided conceptual advice. M.P., A.F., C.A., N.P., S.G. and S.O. carried out laboratory analyses. S.M. supported clinical data analysis and curation. D.D.G., T.S. and S.E.P. performed pathology review for breast cancer tissues. C.A.P., A.B., H.S., M.v.d.V., B.K.T.T., C.C., A.T., N.T.U., L.J.v.V., J.W.M.M., C.S., S.K., P.N.S., S.R.L., J.E.E., A.-L.B.-D., A.R., A.M.T. and A.V. provided clinical samples and commented on the manuscript. P.J.C. supervised overall analyses. Y.S.J., I.M., M.G., L.B.A. and M.R.S. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michael R. Stratton.

Reviewer Information Nature thanks M. Horowitz, S. Orkin and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains the Supplementary Discussion and additional references.

Excel files

  1. 1.

    Supplementary Table 1

    A list of samples sequenced in this study.

  2. 2.

    Supplementary Table 2

    The list of primers used for targeted amplicon sequencing.

  3. 3.

    Supplementary Table 3

    A list of somatic mutations catalogued in this study.

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DOI

https://doi.org/10.1038/nature21703

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