Ó³»­´«Ã½

Clonal expansions of hematopoietic cells carrying mosaic chromosomal alterations (mCAs) are commonly detectable in elderly individuals. Here we studied 43,617 autosomal mCAs ascertained in 484,081 UK Biobank participants using new, high-resolution computational methods to analyze blood-derived, whole-genome sequencing data. Shorter mCAs (≤1 Mb) clustered at 53 genomic hotspots (46 previously undetected), several of which implicated chromosomal fragile sites as a recurrent source of somatic deletions. Chronic lymphocytic leukemia (CLL)-associated deletions at 13q14 were detectable in 1% of individuals aged 65-70 years, suggesting opportunities for incorporating this mosaic mutation into clinical screening and in genetic association studies of CLL. Rare protein-coding variants in 38 genes associated (P < 1.2 × 10; false recovery rate <0.01) with clonal expansions of copy-neutral loss-of-heterozygosity (CN-LOH) mutations that modified the allelic dosages of these variants, identifying likely targets of clonal selection via CN-LOH-induced allelic substitution. These results show that our blood genomes often accrue mCAs in predictable ways as they evolve with age.