Project Summary With age, dividing cells acquire DNA mutations. A small number of these somatic mutations confer a selective advantage leading to a clonal proliferation of cells harboring the somatic mutation. In blood, this process is termed ‘clonal hematopoiesis’. These mutations include both point mutations in cancer driver genes (eg. clonal hematopoiesis of indeterminate potential ‘CHIP’) and megabase-scale deletions, duplications and copy-neutral loss-of-heterozygosity (eg, mosaic chromosomal alterations, ‘mCAs’). CHIP and mCAs have each been detected in ~5% of individuals over 60. While both predict shorter lifespans, CHIP leads to a myeloid biased stem cell differentiation while mCAs lead to a lymphoid biased stem cell differentiation. As a result, CHIP and mCAs have distinct disease associations with infection, cardiovascular disease, cancer and other diseases of aging. Although CHIP has been an area of significant research activity, multiple gaps persist in our knowledge of mCAs and their impacts on aging and population health. mCA clones that expand to make up a larger proportion of the blood predict worse health consequences. However, we do not know why some mCA clones but not others expand, what factors predict the rate of clonal expansion and how rate of expansion associates with disease outcomes. Overall, we hypothesize that mCAs with higher rates of clonal expansion confer a greater impact on health and that the propensity to expand has genetic and environmental underpinnings that are mediated through gene expression. A barrier to addressing this gap is a paucity of large well-annotated collections of longitudinally-sampled blood. Fortuitously, our team has two recent accomplishments that enable us to address this gap: 1) a survey of mCAs in 67,000 whole genomes and 2) development of a novel computational method to estimate the rate of mCA expansion from single timepoints. In Aim 1, we will measure the rate of mCA expansion by leveraging unique serial blood samples (collected up to 19 years apart) from 729 individuals with mCAs from three deeply phenotyped cohorts. In Aim 2, we will refine our method for clonal expansion rate estimation and apply this method at population scale to estimate mCA clonal expansion rates in 1.3 million individuals from several diverse cohorts. We will identify genetic and environmental factors predisposing to clonal expansion and establish the relationship between mCA clonal expansion and disease. In Aim 3, we will analyze bulk and single-cell RNA-sequencing to ascertain the cell type specific biological impact of mCAs and identify pathways leading to clonal expansion. Our multidisciplinary team with deep expertise in computational genomics, statistics, hematology and human epidemiology is uniquely poised for success in this effort. Successful execution of our aims will inform risk models to stratify individuals with mCAs for personalized prevention, such as interventions or enhanced screening, and iden...