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Title: Somatic mutations reveal asymmetric cellular dynamics in the early human embryo

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 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

Authors:
 [1];  [2];  [3];  [2]; ORCiD logo [4];  [2];  [5];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [6];  [7];  [8];  [9];  [10] more »;  [11];  [12];  [13];  [14];  [15];  [16];  [17];  [18];  [19];  [20];  [21];  [22];  [23];  [24];  [25];  [16];  [26];  [2];  [2];  [2];  [2] « less
  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:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE Laboratory Directed Research and Development (LDRD) Program
OSTI Identifier:
1356130
Report Number(s):
LA-UR-16-20126
Journal ID: ISSN 0028-0836
Grant/Contract Number:
AC52-06NA25396
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 543; Journal Issue: 7647; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Biological Science

Citation Formats

Ju, Young Seok, Martincorena, Inigo, Gerstung, Moritz, Petljak, Mia, Alexandrov, Ludmil B., Rahbari, Raheleh, Wedge, David C., Davies, Helen R., Ramakrishna, Manasa, Fullam, Anthony, Martin, Sancha, Alder, Christopher, Patel, Nikita, Gamble, Steve, O’Meara, Sarah, Giri, Dilip D., Sauer, Torril, Pinder, Sarah E., Purdie, Colin A., Borg, Åke, Stunnenberg, Henk, van de Vijver, Marc, Tan, Benita K. T., Caldas, Carlos, Tutt, Andrew, Ueno, Naoto T., van ’t Veer, Laura J., Martens, John W. M., Sotiriou, Christos, Knappskog, Stian, Span, Paul N., Lakhani, Sunil R., Eyfjörd, Jórunn Erla, Børresen-Dale, Anne-Lise, Richardson, Andrea, Thompson, Alastair M., Viari, Alain, Hurles, Matthew E., Nik-Zainal, Serena, Campbell, Peter J., and Stratton, Michael R. Somatic mutations reveal asymmetric cellular dynamics in the early human embryo. United States: N. p., 2017. Web. doi:10.1038/nature21703.
Ju, Young Seok, Martincorena, Inigo, Gerstung, Moritz, Petljak, Mia, Alexandrov, Ludmil B., Rahbari, Raheleh, Wedge, David C., Davies, Helen R., Ramakrishna, Manasa, Fullam, Anthony, Martin, Sancha, Alder, Christopher, Patel, Nikita, Gamble, Steve, O’Meara, Sarah, Giri, Dilip D., Sauer, Torril, Pinder, Sarah E., Purdie, Colin A., Borg, Åke, Stunnenberg, Henk, van de Vijver, Marc, Tan, Benita K. T., Caldas, Carlos, Tutt, Andrew, Ueno, Naoto T., van ’t Veer, Laura J., Martens, John W. M., Sotiriou, Christos, Knappskog, Stian, Span, Paul N., Lakhani, Sunil R., Eyfjörd, Jórunn Erla, Børresen-Dale, Anne-Lise, Richardson, Andrea, Thompson, Alastair M., Viari, Alain, Hurles, Matthew E., Nik-Zainal, Serena, Campbell, Peter J., & Stratton, Michael R. Somatic mutations reveal asymmetric cellular dynamics in the early human embryo. United States. doi:10.1038/nature21703.
Ju, Young Seok, Martincorena, Inigo, Gerstung, Moritz, Petljak, Mia, Alexandrov, Ludmil B., Rahbari, Raheleh, Wedge, David C., Davies, Helen R., Ramakrishna, Manasa, Fullam, Anthony, Martin, Sancha, Alder, Christopher, Patel, Nikita, Gamble, Steve, O’Meara, Sarah, Giri, Dilip D., Sauer, Torril, Pinder, Sarah E., Purdie, Colin A., Borg, Åke, Stunnenberg, Henk, van de Vijver, Marc, Tan, Benita K. T., Caldas, Carlos, Tutt, Andrew, Ueno, Naoto T., van ’t Veer, Laura J., Martens, John W. M., Sotiriou, Christos, Knappskog, Stian, Span, Paul N., Lakhani, Sunil R., Eyfjörd, Jórunn Erla, Børresen-Dale, Anne-Lise, Richardson, Andrea, Thompson, Alastair M., Viari, Alain, Hurles, Matthew E., Nik-Zainal, Serena, Campbell, Peter J., and Stratton, Michael R. Wed . "Somatic mutations reveal asymmetric cellular dynamics in the early human embryo". United States. doi:10.1038/nature21703. https://www.osti.gov/servlets/purl/1356130.
@article{osti_1356130,
title = {Somatic mutations reveal asymmetric cellular dynamics in the early human embryo},
author = {Ju, Young Seok and Martincorena, Inigo and Gerstung, Moritz and Petljak, Mia and Alexandrov, Ludmil B. and Rahbari, Raheleh and Wedge, David C. and Davies, Helen R. and Ramakrishna, Manasa and Fullam, Anthony and Martin, Sancha and Alder, Christopher and Patel, Nikita and Gamble, Steve and O’Meara, Sarah and Giri, Dilip D. and Sauer, Torril and Pinder, Sarah E. and Purdie, Colin A. and Borg, Åke and Stunnenberg, Henk and van de Vijver, Marc and Tan, Benita K. T. and Caldas, Carlos and Tutt, Andrew and Ueno, Naoto T. and van ’t Veer, Laura J. and Martens, John W. M. and Sotiriou, Christos and Knappskog, Stian and Span, Paul N. and Lakhani, Sunil R. and Eyfjörd, Jórunn Erla and Børresen-Dale, Anne-Lise and Richardson, Andrea and Thompson, Alastair M. and Viari, Alain and Hurles, Matthew E. and Nik-Zainal, Serena and Campbell, Peter J. and Stratton, Michael R.},
abstractNote = {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. 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.},
doi = {10.1038/nature21703},
journal = {Nature (London)},
number = 7647,
volume = 543,
place = {United States},
year = {Wed Mar 22 00:00:00 EDT 2017},
month = {Wed Mar 22 00:00:00 EDT 2017}
}

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  • Five cosmid clones, isolated by procedures to screen genomic libraries for homologous variants of the human prohibitin gene (PHB), were analyzed to determine their genomic structures. Four of these (PHBP1-4) were found to be processed pseudogenes, each located on a different chromosome from their counter-parts on chromosome 17q21. The DNA sequence of one clone (PHBP1, on chromosome 6q25) shared a 91.3% identity at the nucleotide level with the cDNA of functional prohibitin. A large number of human tumors of the breast, ovary, liver, and lung were examined for somatic mutations in the PHB gene. Although mutations were observed in amore » few sporadic breast cancers, none were identified in any of the other cancers. 15 refs., 2 figs., 1 tab.« less
  • The technology underlying genetic toxicology has undergone enormous change during the last 25 years. Technology has permitted studies of somatic mutations in humans to achieve scientific respectability. However, the author is concerned that in the zeal to develop assays for detecting mutations in humans, it was assumed that they would be useful in public health. Now that assumption must be tested so the question is no longer can we measure mutations? but why? The author discusses the challenge for in vivo somatic mutations, at least those measured by most genetic toxicologists, viz. mutations in reporter genes. These genes are irrelevantmore » in themselves but ideal for assessing the mutation process itself. How well do surrogate mutations in surrogate tissue mimic disease gene mutations in target tissues? 28 refs.« less
  • The glycophorin A (GPA) assay was developed to quantify somatic mutations in humans by measuring the frequency of peripheral erythrocytes with mutant phenotypes that are presumed to be progeny of mutated erythroid precursor cells. This assay has been used to identify GPA variant cells in unexposed individuals at a frequency of {approximately}10 per million erythrocytes, and to demonstrate significant increases in variant frequency after mutagenic exposures. Characterization of the mutations responsible for these variant cells requires that the assay be modified to allow flow analysis and sorting of variant erythroid precursor cells that contain nucleic acids. Cord blood samples containmore » low levels of both reticulocytes and nucleated erythrocytes. We have developed enrichment methods using centrifugation that yield samples containing up to 30% nucleated erythrocytes, and immunomagnetic separation methods that yield samples containing up to 90% reticulocytes. Enrichment methods for these two cell types are also being developed for adult bone marrow samples. We have confirmed that enrichment and labeling with a nucleic acid-specific dye are compatible with GPA analysis of erythrocytes, reticulocytes, and nucleated erythrocytes. Enriched samples have been successfully used for flow cytometric detection of GPA variant reticulocytes in cord blood. PCR-based analysis methods are being developed for molecular characterization of sorted variant cells at the mRNA level.« less
  • We have used the APRT locus located at 16q24.3 to study the nature of loss of heterozygosity (LOH) in human T lymphocytes in vivo. T lymphocytes were isolated from blood from APRT (+/{minus}) obligated heterozygotes with known germline mutations. The cells were immediatley placed in culture medium containing 100 {mu}M 2,6-diaminopurine (DAP) to select for drug-resistant clones ({minus}/{minus}) already present. These clones were first examined using polymorphic CA microsatellite repeat markers D16S303 and D16S305 that are distal and proximal to APRT, respectively. The retention of heterozygosity of these markers is suggestive of minor changes in the APRT gene, the exactmore » nature of which were determined by DNA sequencing. Nineteen out of 70 DAP-resistant clones from one heterozygote showed APRT sequence changes. The loss of heterozygosity of markers D16S303 and D16S305 in the remaining clones suggests LOH involving multilocus chromosomal events. These clones were then sequentially typed using additional CA repeat markers proximal and distal to APRT. The extent of LOH in these clones was found to vary from <5 cM to almost the entire 16q arm. Preliminary results suggest that there are multiple sites along the chromosome from which LOH proceeds distally in these clones. Cytogenetic analysis of 10 clones suggested mitotic recombination in 9 and deletion in one. Studies are in progress to further characterize the molecular mechanisms of LOH.« less
  • To assess the potential effect of maternal environments on human embryonic/fecal somatic mutation, we measured the frequencies of hypoxanthine-guanine phosphoribosyltransferase (HPRT, hprt gene), mutant T lymphocytes (M{sub f}) and glycophorin A (GPA) variant erythrocytes (V{sub f}) of both allele-loss ({phi}/N) and allele-loss-and duplication (N/N) phenotypes in umbilical cord blood. The mean hprt M{sub F} were significantly lower than those previously reported for adult populations. In addition, the hprt M{sub f} was significantly higher than that of a published study of newborn cord blood samples from a geographically distant population (0.64 {+-} 0.41 x 10{sup -6}, N = 45, P <more » 0.01; t test, P < 0.01, Mann-Whitney U test). An examination of the demographic data from these two populations led to the sampling of 10 additional newborns specifically matched to the published study for maternal socioeconomic status. The hprt M{sub f} (0.70 {+-} 0.49 x 10{sup -6}) of this selected population was consistent with the published report and significantly lower than that of our initial population (P < 0.03, t test; P < 0.01, Mann-Whitney U test). These results indicate that there is an environmental effect related to maternal socioeconomic status of the frequency of embryonic/fetal somatic mutations. Molecular analyses of hprt mutants from this cohort with elevated M{sub f} revealed a significant decrease in the relative contribution of gross structural mutations to the overall M{sub f} (25 of 38, 66% vs. 34 of 41, 83%, P = 0.024, {chi}{sup 2} test), suggesting that the higher M{sub f} resulted from an elevated level of {open_quotes}point{close_quotes} mutations. No individual maternal demographic or environmental factor was identified as contributing more significantly than any other factor to the observed variability in hprt M{sub f} or GPA V{sub f}. 43 refs., 4 tabs.« less