Geography, Ancestry, Age and Sex Shape Somatic Autosomal Mosaic Chromosomal Alterations in Blood

Clonal hematopoiesis, through the age-associated accumulation of somatic mutations in blood, is strongly associated with hematological malignancies and other chronic diseases. These mutations have largely been characterized in individuals of European ancestry or environments, and consequently, it remains unclear how mutation-recurrence patterns vary across populations of different histories or non-European ancestries. Here, we evaluate how variation in geography, ancestry, genetics and sex shape the prevalence of mosaic chromosomal alterations (mCAs) among 47,369 individuals from the Canadian Partnership for Tomorrows Health, including a founding population cohort in Quebec, and 13,562 individuals from within South, Central, West and East Africa though the H3Africa consortium. We identified autosomal mCA hotspots that were ancestry- and sex-specific, mapped novel ancestry-specific germline variants associated with autosomal mCA prevalence, and estimated heritability rates to quantify the germline genetic contribution to autosomal mCA variance. We also showed how mCAs impact blood transcriptomes, implicating stabilizing selection as a mechanism by which copy number gain mutations are tolerated in healthy blood. Collectively, mapping the landscape of autosomal mCAs in populations of diverse ancestry illustrates similarities but also highlights important ancestry, geographic, and sex-specific differences. O_FIG O_LINKSMALLFIG WIDTH=188 HEIGHT=200 SRC="FIGDIR/small/25338239v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@115f21borg.highwire.dtl.DTLVardef@1c9eaf8org.highwire.dtl.DTLVardef@1615d6borg.highwire.dtl.DTLVardef@13c5908_HPS_FORMAT_FIGEXP M_FIG C_FIG