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Title: 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 asymmetricallymore » to adult blood at an approximately 2:1 ratio. As a result, this study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.« less
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  1. Wellcome Trust Sanger Institute, Hinxton (United Kingdom); Korea Advanced Institute of Science and Technology, Daejeon (Republic of Korea)
  2. Wellcome Trust Sanger Institute, Hinxton (United Kingdom)
  3. Wellcome Trust Sanger Institute, Hinxton (United Kingdom); European Bioinformatics Institute, Hinxton (United Kingdom)
  4. Wellcome Trust Sanger Institute, Hinxton (United Kingdom); Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  5. Wellcome Trust Sanger Institute, Hinxton (United Kingdom); Wellcome Trust Centre for Human Genetics, Oxford (United Kingdom)
  6. Memorial Sloan-Kettering Cancer Center, New York, NY (United States)
  7. Univ. of Oslo, Lorenskog (Norway)
  8. King's College London School of Medicine, London (United Kindgom)
  9. Ninewells Hospital and Medicine School, Dundee (United Kingdom)
  10. BioCare, Lund (Sweden); CREATE Health, Lund (Sweden); Lund Univ., Lund (Sweden)
  11. Radboud Univ. Medical Center, Nijmegen (The Netherlands)
  12. Academic Medical Center, Amsterdam (The Netherlands)
  13. Singapore General Hospital (Singapore)
  14. Univ. of Cambridge, Cambridge (United Kingdom)
  15. King's College London, London (United Kingdom); Institute of Cancer Research, London (United Kingdom)
  16. The Univ. of Texas MD Anderson Cancer Center, Houston, TX (United States)
  17. Univ. of California, San Francisco, CA (United States)
  18. Erasmus Univ. Medical Center, Rotterdam (Netherlands)
  19. Institut Jules Bordet, Brussels (Belgium)
  20. Univ. of Bergen, Bergen (Norway); Haukeland Univ. Hospital, Bergen (Norway)
  21. Radboud Univ. Medical Center, Nijmegen (Netherlands)
  22. Univ. of Queensland, Brisbane (Australia); Royal Brisbane and Women's Hospital, Brisbane (Australia)
  23. Univ. of Iceland, Reykjavik (Iceland)
  24. Oslo Univ. Hospital, The Norwegian Radium Hospital, Oslo (Norway); Univ. of Oslo, Oslo (Norway)
  25. Johns Hopkins Medicine, Washington, D.C. (United States)
  26. Centre Leon Berard, Lyon Cedex (France)
Publication Date:
Report Number(s):
Journal ID: ISSN 0028-0836
Grant/Contract Number:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 543; Journal Issue: 7647; Journal ID: ISSN 0028-0836
Nature Publishing Group
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE Laboratory Directed Research and Development (LDRD) Program
Country of Publication:
United States
OSTI Identifier: