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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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).
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Genetics in Medicine (2018)