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.
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Whole-genome and targeted sequencing data have been deposited in the European Genome-Phenome Archive (EGA; https://www.ebi.ac.uk/ega/). Whole-genome sequencing data have been deposited with EGA accession number EGAD00001004086 and targeted sequencing data with accession number EGAD00001004087. Substitution calls have been deposited on Mendeley Data (‘Population dynamics of human blood inferred from spontaneous somatic mutations’: https://doi.org/10.17632/yzjw2stk7f.1). Simulated datasets (from the approximate Bayesian computation) are available from the corresponding authors upon reasonable request.
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This work was supported by the Leukemia Lymphoma Society, the WBH Foundation and the Wellcome Trust. P.J.C. is a Wellcome Trust Senior Clinical Fellow (WT088340MA). H.L.-S. is a recipient of a Wellcome Trust PhD studentship. N.F.Ø. is the recipient of a Danish Lundbeck Fellowship (2016-17) and M.S.S. is the recipient of a BBSRC CASE Industrial PhD Studentship. Work in the D.G.K. laboratory is supported by a Bloodwise Bennett Fellowship (15008), a European Research Council Starting Grant (ERC-2016-STG–715371) and a European Hematology Association Non-Clinical Advanced Research Fellowship. Work in the A.R.G. laboratory is supported by the Wellcome Trust, Bloodwise, Cancer Research UK, the Kay Kendall Leukaemia Fund, and the Leukemia and Lymphoma Society of America. Work in E.L. laboratory is supported by a Wellcome Trust Sir Henry Dale Fellowship, BBSRC and a European Haematology Association Non-Clinical Advanced Research Fellowship. The D.G.K., E.L. and A.R.G. laboratories are supported by a core support grant from the Wellcome Trust and Medical Research Council to the Cambridge Stem Cell Institute. We acknowledge further assistance from the National Institute for Health Research Cambridge Biomedical Research Centre and the Cambridge Experimental Cancer Medicine Centre. We thank R. Grenfell and M. Strzelecki in the Flow Cytometry Facility of the Cancer Research UK Cambridge Institute for technical assistance and suggestions; C. Eaves and P. Beer for discussions about the experimental design; P. Goodell for discussions about the results; J. Grinfeld and C. Gonzalez-Arias for drawing peripheral blood; and G. Collord for providing negative control samples for targeted sequencing.
Nature thanks H.-R. Rodewald, L. Shlush and the other anonymous reviewer(s) for their contribution to the peer review of this work.