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 generate multilineage output, including granulocytes and B lymphocytes. Harnessing naturally occurring mutations to report an organ’s clonal architecture provides high-resolution reconstruction of somatic cell dynamics in humans.
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