Population dynamics of normal human blood inferred from somatic mutations

Abstract

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.