Fitness, Fate, and Function of Clonal Hematopoiesis

Abstract

Clonal hematopoiesis (CH), an age-associated phenomenon where somatically mutated hematopoietic stem cells produce a large fraction of peripheral blood cells, has emerged as a central mechanism of human aging and a cause of hematologic malignancy, cardiovascular disease, and all-cause mortality. Despite rapid growth in our understanding of CH biology, critical gaps remain in its accurate measurement, dynamic characterization, and clinical translation. This dissertation addresses these gaps through an integrated framework spanning genetic epidemiology, longitudinal cohort analysis, population-scale somatic genomics, epigenetic biomarker development, and single-cell computational biology. We first demonstrate that sequencing depth systematically biases detection of clonal hematopoiesis of indeterminate potential (CHIP), with shallow whole-genome and whole-exome sequencing underestimating its true clinical associations. We then leverage a 16-year longitudinal cohort of nearly 7,000 women to establish clonal expansion rate as a potent predictor of leukemia and all-cause mortality, identifying germline and inflammatory factors as key regulators of clonal dynamics. Expanding the scope of somatic mosaicism in the blood beyond point mutations, we present the largest characterization of mosaic chromosomal alterations (mCAs) in over one million individuals, delineating their genetic architecture and heterogeneous disease consequences. Shifting toward a mutation-specific paradigm, we introduce peripheral blood DNA methylation-based activity scores that quantify enzymatic impairment of TET2 and DNMT3A, demonstrating their superiority over current risk prediction models as biomarkers for disease risk stratification. Finally, we develop a closed-loop in silico perturbation framework using single-cell foundation models to systematically prioritize therapeutic targets in hereditary blood cancer syndromes that predispose to early-onset CHIP. Collectively, this work advances the measurement, mechanistic understanding, and therapeutic targeting of clonal hematopoiesis, laying the groundwork for its integration into personalized medicine frameworks that may ultimately reduce the burden of aging-associated disease.