Person:

McCarroll, Steven

Clonally expanded blood cells with somatic mutations (clonal hematopoiesis, CH) are commonly acquired with age and increase risk of later blood cancer. To identify genes and mutations that give selective advantage to mutant clones, we identified among 482,789 UK Biobank participants some 19,632 autosomal mosaic chromosomal alterations (mCAs), including deletions, duplications, and copy number-neutral loss of heterozygosity (CNN-LOH). Analysis of these acquired mutations, along with inherited genetic variation, revealed 52 inherited, rare, large-effect coding or splice variants (in seven genes) that greatly (odds ratios of 11 to 758) increased vulnerability to CH with specific acquired CNN-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 attrition; another two (MPL, SH2B3) encode proteins that regulate stem cell self-renewal. In addition to these monogenic inherited forms of CH, we found a common and surprisingly polygenic form: CNN-LOH mutations across the genome tended to cause chromosomal segments with alleles that promote hematopoietic cell proliferation to replace their homologous (allelic) counter-parts, increasing polygenic drive for blood-cell proliferation traits. This dynamic reveals a challenge for lifelong cytopoiesis in any genetically diverse species: individuals inherit unequal proliferative genetic potentials on paternally and maternally derived chromosomepairs, and readily-acquired mutations that replace chromosomal segments with their homologous counterparts give selective advantage to mutant cells.

The burden of mosaic chromosomal alterations in blood-derived DNA, a type of clonal hematopoiesis, is associated with an increased risk for diverse types of infections, including sepsis and pneumonia. Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 x 10(-7)), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 x 10(-28)), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 x 10(-15)), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 x 10(-9)) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 x 10(-4)). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.