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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.
Exploring large-scale genetic mosaicism and its relationship to hematological malignancies
Genetic variation naturally occurs among the cells of a single individual as a result of somatic mutation. Some somatic mutations proliferate to high frequency within an individual, producing a phenomenon known as clonal mosaicism. Cancer is an extreme example, but mosaicism also exists in cancer-free individuals. We aim to study the distribution of chromosome-scale mosaic aberrations in UK Biobank samples. We then aim to investigate the relationship between these aberrations and diseases of the blood, with a focus on chronic lymphocytic leukemia (CLL). This work will improve our understanding of clonal expansions in the blood, a phenomenon present in many aging individuals that is closely related to leukemia. By investigating mosaicism in a very large prospective cohort, this research may potentially identify signatures of pre-cancerous mosaic events and/or enable earlier diagnoses of leukemia. We will analyze allelic intensity data from genotyped blood samples to identify imbalances in the frequencies of maternally and paternally derived chromosomal segments. Such imbalances indicate large-scale chromosomal aberrations (i.e., losses and gains of long segments of DNA) that have proliferated to significant frequency in the blood. We will then compare incidences of these events to data on blood counts and cancer outcomes. We will analyze the full cohort.