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Population dynamics of normal human blood inferred from somatic mutations

Author

Listed:
  • Henry Lee-Six

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Nina Friesgaard Øbro

    (University of Cambridge)

  • Mairi S. Shepherd

    (University of Cambridge)

  • Sebastian Grossmann

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Kevin Dawson

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Miriam Belmonte

    (University of Cambridge)

  • Robert J. Osborne

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Brian J. P. Huntly

    (University of Cambridge)

  • Inigo Martincorena

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Elizabeth Anderson

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Laura O’Neill

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Michael R. Stratton

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Elisa Laurenti

    (University of Cambridge)

  • Anthony R. Green

    (University of Cambridge)

  • David G. Kent

    (University of Cambridge)

  • Peter J. Campbell

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

Abstract

Haematopoietic stem cells drive blood production, but their population size and lifetime dynamics have not been quantified directly in humans. Here we identified 129,582 spontaneous, genome-wide somatic mutations in 140 single-cell-derived haematopoietic stem and progenitor colonies from a healthy 59-year-old man and applied population-genetics approaches to reconstruct clonal dynamics. Cell divisions from early embryogenesis were evident in the phylogenetic tree; all blood cells were derived from a common ancestor that preceded gastrulation. The size of the stem cell population grew steadily in early life, reaching a stable plateau by adolescence. We estimate the numbers of haematopoietic stem cells that are actively making white blood cells at any one time to be in the range of 50,000–200,000. We observed adult haematopoietic stem cell clones that generate multilineage outputs, including granulocytes and B lymphocytes. Harnessing naturally occurring mutations to report the clonal architecture of an organ enables the high-resolution reconstruction of somatic cell dynamics in humans.

Suggested Citation

  • Henry Lee-Six & Nina Friesgaard Øbro & Mairi S. Shepherd & Sebastian Grossmann & Kevin Dawson & Miriam Belmonte & Robert J. Osborne & Brian J. P. Huntly & Inigo Martincorena & Elizabeth Anderson & Lau, 2018. "Population dynamics of normal human blood inferred from somatic mutations," Nature, Nature, vol. 561(7724), pages 473-478, September.
    • Handle: RePEc:nat:nature:v:561:y:2018:i:7724:d:10.1038_s41586-018-0497-0
    DOI: 10.1038/s41586-018-0497-0
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    Citations

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    Cited by:

    1. Kitty Sherwood & Joseph C. Ward & Ignacio Soriano & Lynn Martin & Archie Campbell & Raheleh Rahbari & Ioannis Kafetzopoulos & Duncan Sproul & Andrew Green & Julian R. Sampson & Alan Donaldson & Kai-Re, 2023. "Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Szu-Hsien Sam Wu & Somi Kim & Heetak Lee & Ji-Hyun Lee & So-Yeon Park & Réka Bakonyi & Isaree Teriyapirom & Natalia Hallay & Sandra Pilat-Carotta & Hans-Christian Theussl & Jihoon Kim & Joo-Hyeon Lee , 2024. "Red2Flpe-SCON: a versatile, multicolor strategy for generating mosaic conditional knockout mice," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    3. Márton Demeter & Imre Derényi & Gergely J. Szöllősi, 2022. "Trade-off between reducing mutational accumulation and increasing commitment to differentiation determines tissue organization," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    4. Heather E. Machado & Nina F. Øbro & Nicholas Williams & Shengjiang Tan & Ahmed Z. Boukerrou & Megan Davies & Miriam Belmonte & Emily Mitchell & E. Joanna Baxter & Nicole Mende & Anna Clay & Philip Anc, 2023. "Convergent somatic evolution commences in utero in a germline ribosomopathy," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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