Somatic mutations acquired in healthy tissues as we age are major determinants of cancer risk. Whether variants confer a fitness advantage or rise to detectable frequencies by chance remains largely unknown. Blood sequencing data from ~50,000 individuals reveal how mutation, genetic drift, and fitness shape the genetic diversity of healthy blood (clonal hematopoiesis). We show that positive selection, not drift, is the major force shaping clonal hematopoiesis, provide bounds on the number of hematopoietic stem cells, and quantify the fitness advantages of key pathogenic variants, at single-nucleotide resolution, as well as the distribution of fitness effects (fitness landscape) within commonly mutated driver genes. These data are consistent with clonal hematopoiesis being driven by a continuing risk of mutations and clonal expansions that become increasingly detectable with age.

Somatic mutations acquired in healthy tissues as we age are major determinants of cancer risk. Whether variants confer a fitness advantage or rise to detectable frequencies by chance, however, remains largely unknown. Here, by combining blood sequencing data from ∼50,000 individuals, we reveal how mutation, genetic drift and fitness differences combine to shape the genetic diversity of healthy blood ('clonal haematopoiesis'). By analysing the spectrum of variant allele frequencies we quantify fitness advantages for key pathogenic variants and genes and provide bounds on the number of haematopoietic stem cells. Positive selection, not drift, is the major force shaping clonal haematopoiesis. The remarkably wide variation in variant allele frequencies observed across individuals is driven by chance differences in the timing of mutation acquisition combined with differences in the cell-intrinsic fitness effect of variants. Contrary to the widely held view that clonal haematopoiesis is driven by ageing-related alterations in the stem cell niche, the data are consistent with the age dependence being driven simply by continuing risk of mutations and subsequent clonal expansions that lead to increased detectability at older ages. clonal haematopoiesis | haematopoietic stem cells | evolution | population genetics | DNMT3A | TET2 | spliceosome | TP53 | acute myeloid leukaemia Correspondence: cw672@cam.ac.uk & jrb75@cam.ac.uk ResultsThe VAF distribution from ∼50,000 individuals. We analysed VAF measurements for somatic variants in the blood from ∼50,000 blood-cancer-free individuals from nine publicly available blood sequencing datasets 7-15 (Supplementary Information 1). VAF measurements in bone marrow and peripheral blood show good concordance 30 and so Watson | bioRχiv |