Population dynamics of normal human blood inferred from somatic mutations.
Øbro, Nina Friesgaard
Osborne, Robert J
Stratton, Michael R
Campbell, Peter J
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Lee-Six, H., Øbro, N. F., Shepherd, M., Grossmann, S., Dawson, K., Belmonte, M., Osborne, R. J., et al. (2018). Population dynamics of normal human blood inferred from somatic mutations.. Nature, 561 (7724), 473-478. https://doi.org/10.1038/s41586-018-0497-0
Haematopoietic stem cells drive blood production, but their population size and lifetime dynamics have not been directly quantified in humans. We identified 129,582 spontaneous, genome-wide somatic mutations in 140 single-cell–derived haematopoietic stem and progenitor colonies from a normal 59 year-old man and applied population genetics approaches to reconstruct clonal dynamics. Cell divisions from early embryogenesis were evident in the phylogenetic tree, with all blood deriving from a common ancestor that preceded gastrulation. Stem cell population size grew steadily in early life, reaching a stable plateau by adolescence. We estimate numbers of haematopoietic stem cells actively making white blood cells at any one time to be in the range 50,000-200,000. We observed adult haematopoietic stem cell clones that contribute detectable fractions of granulocytes and B lymphocytes but not T lymphocytes. Harnessing naturally occurring mutations to report an organ’s clonal architecture provides high-resolution reconstruction of somatic cell dynamics in humans.
Blood Cells, Granulocytes, Lymphocytes, Hematopoietic Stem Cells, Clone Cells, Humans, Cell Count, Bayes Theorem, DNA Mutational Analysis, Cell Division, Hematopoiesis, Cell Lineage, Embryonic Development, Mutation, Genome, Human, Time Factors, Middle Aged, Male, Adult Stem Cells
This work was supported by the Leukemia Lymphoma Society and the Wellcome Trust. PJC is a Wellcome Trust Senior Clinical Fellow (WT088340MA). HLS is a recipient of a Wellcome Trust PhD studentship. NFO is the recipient of a Danish Lundbeck Fellowship (2016-17) and MSS is the recipient of a BBSRC CASE Industrial PhD Studentship. Work in the DGK lab 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 ARG Lab 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 EL lab is supported by a Wellcome Trust Sir Henry Dale Fellowship, BBSRC and a European Haematology Association Non-Clinical Advanced Research Fellowship. The DGK, EL and ARG labs 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.
WELLCOME TRUST (107630/Z/15/Z)
MEDICAL RESEARCH COUNCIL (MR/M008975/1)
Medical Research Council (MR/M010392/1)
European Commission Horizon 2020 (H2020) ERC (715371)
External DOI: https://doi.org/10.1038/s41586-018-0497-0
This record's URL: https://www.repository.cam.ac.uk/handle/1810/280650