The evolutionary dynamics and fitness landscape of clonal hematopoiesis

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 change remains largely unknown. Blood
sequencing data from ∼50,000 individuals reveals 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.