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Abstract
Clonal expansion of blood cells harboring somatic mutations ( clonal hematopoiesis ) is a common age-acquired condition that greatly increases risk of future blood cancer. However, most individuals with such mutations do not go on to develop blood cancer, and the mechanisms that shape most clonal expansions in healthy individuals are not understood. We detected clonal hematopoiesis involving mosaic alterations of chromosomes 1-22 in ~4% of UK Biobank participants and identified several genetic loci at which rare inherited variants strongly influence the development of clones in which nearby genomic segments are altered by somatic mutation. We also detected mosaic loss of the Y chromosome in ~20% of male participants and identified 156 genetic determinants of Y loss. We further observed that several specific alterations strongly associated with future blood cancer. Our results revealed multiple paths toward clonal expansions with a wide range of effects on human health.