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Population dynamics of normal human blood inferred from somatic mutations.

Accepted version
Peer-reviewed

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Authors

Lee-Six, Henry 
Øbro, Nina Friesgaard 
Shepherd, Mairi S 
Grossmann, Sebastian 
Dawson, Kevin 

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.

Description

Keywords

Adult Stem Cells, Bayes Theorem, Blood Cells, Cell Count, Cell Division, Cell Lineage, Clone Cells, DNA Mutational Analysis, Embryonic Development, Genome, Human, Granulocytes, Hematopoiesis, Hematopoietic Stem Cells, Humans, Lymphocytes, Male, Middle Aged, Mutation, Time Factors

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

561

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (107630/Z/15/Z)
Medical Research Council (MC_PC_12009)
Medical Research Council (MR/M008975/1)
Medical Research Council (MR/M010392/1)
Medical Research Council (MR/R009708/1)
European Research Council (715371)
Bloodwise (15008)
Medical Research Council (MR/S036113/1)
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.