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Somatic mutations reveal asymmetric cellular dynamics in the early human embryo

Young Seok Ju 1, 2 Inigo Martincorena 2 Moritz Gerstung 3, 2 Mia Petljak 2 Ludmil B. Alexandrov 4, 2 Raheleh Rahbari 2 David C. Wedge 5, 2 Helen R. Davies 2 Manasa Ramakrishna 2 Anthony Fullam 2 Sancha Martin 2 Christopher Alder 2 Nikita Patel 2 Steve Gamble 2 Sarah O’meara 2 Dilip D. Giri 6, 7 Torril Sauer 8 Sarah E. Pinder 9 Colin A. Purdie 10 Åke Borg 11 Henk Stunnenberg 12 Marc van de Vijver 13 Benita K. T. Tan 14 Carlos Caldas 15 Andrew Tutt 16 Naoto T. Ueno 17 Laura J. van ’t Veer 18 John W. M. Martens 19 Christos Sotiriou 20 Stian Knappskog 21 Paul N. Span 22 Sunil R. Lakhani 23 Jórunn Erla Eyfjörd 24 Anne-Lise Børresen-Dale 25 Andrea Richardson 26 Alastair M. Thompson 27 Alain Viari 28, 29 Matthew E. Hurles 2 Serena Nik-Zainal 2 Peter J. Campbell 2 Michael R. Stratton 2
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.
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Young Seok Ju, Inigo Martincorena, Moritz Gerstung, Mia Petljak, Ludmil B. Alexandrov, et al.. Somatic mutations reveal asymmetric cellular dynamics in the early human embryo. Nature, Nature Publishing Group, 2017, 543 (7647), pp.714 - 718. ⟨10.1038/nature21703⟩. ⟨hal-01525712⟩



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