Analysis of somatic mutations in whole blood from 200,618 individuals identifies pervasive positive selection and novel drivers of clonal hematopoiesis.

Human aging is marked by the emergence of a tapestry of clonal expansions in dividing tissues, particularly evident in blood as clonal hematopoiesis (CH). CH, linked to cancer risk and aging-related phenotypes, often stems from somatic mutations in a set of established genes. However, the majority of clones lack known drivers. Here we infer gene-level positive selection in whole blood exomes from 200,618 individuals in UK Biobank. We identify 17 additional genes, ZBTB33, ZNF318, ZNF234, SPRED2, SH2B3, SRCAP, SIK3, SRSF1, CHEK2, CCDC115, CCL22, BAX, YLPM1, MYD88, MTA2, MAGEC3 and IGLL5, under positive selection at a population level, and validate this selection pattern in 10,837 whole genomes from single-cell-derived hematopoietic colonies. Clones with mutations in these genes grow in frequency and size with age, comparable to classical CH drivers. They correlate with heightened risk of infection, death and hematological malignancy, highlighting the significance of these additional genes in the aging process.