Monogenic and polygenic inheritance become instruments for clonal selection

Clonally expanded blood cells with somatic mutations (clonal hematopoiesis, CH) are commonly acquired with age and increase risk of blood cancer1–9. The blood clones identified to date contain diverse large-scale mosaic chromosomal alterations (mCAs: deletions, duplications, and copy-neutral loss of heterozygosity [CN-LOH]) on all chromosomes1,2,5,6,9, but the sources of selective advantage that drive expansion of most clones remain unknown. To identify genes, mutations and biological processes that give selective advantage to mutant clones, we analyzed genotyping data from the blood-derived DNA of 482,789 UK Biobank participants10, identifying 19,632 autosomal mCAs which we analyzed for relationships to inherited genetic variation. Fifty-two inherited, rare, large-effect coding or splice variants in seven genes associated with greatly increased (odds ratios 11 to 758) vulnerability to CH with specific acquired CN-LOH mutations. Acquired mutations systematically replaced the inherited risk alleles (at MPL) or duplicated them to the homologous chromosome (at FH, NBN, MRE11, ATM, SH2B3, and TM2D3). Three of the seven genes (MRE11, NBN, and ATM) encode components of the MRN-ATM pathway, which limits cell division after DNA damage and telomere attrition11−13; another two (MPL, SH2B3) encode proteins that regulate stem cell self-renewal14–16. In addition to these monogenic inherited forms of CH, we found a common and surprisingly polygenic form: CN-LOH mutations across the genome tended to cause chromosomal segments with alleles that promote hematopoietic cell expansions to replace their homologous (allelic) counterparts, increasing polygenic drive for blood-cell proliferation traits. Readily-acquired mutations that replace chromosomal segments with their homologous counterparts appear to interact with pervasive inherited variation to create a challenge for lifelong cytopoiesis.