The Genetic Mechanisms Underlying Susceptibility to the Effects of Environmental Exposures and Aging

Genetic and environmental factors jointly shape human health and disease. This dissertation examines these factors through studies of telomere biology, environmental carcinogenesis, and genetic effects on biomarkers of environmental chemicals and metabolites. In Chapter 1, we estimate chromosome-specific telomere length (csTL) using long-read whole-genome sequencing data from over 2,500 participants in the NIH All of Us Research Program. By integrating participant-level data, this chapter characterizes variability in csTL attributable to chromosome arms, individuals, participant characteristics, and technical factors. In Chapter 2, we explore the mutational impact of chronic arsenic exposure using whole-exome sequencing data from patient-derived tumors and two cell line models of low-dose arsenite exposure. This work evaluates whether arsenic is associated with a distinct mutational pattern and provides insight into the molecular mechanisms underlying arsenic-related tumorigenesis. Finally, in Chapter 3, we perform genetic association analyses of more than 100 biomarkers of environmental chemicals and metabolites measured in the National Health and Nutrition Examination Survey. This work advances our understanding of the effects of inherited genetics on xenobiotic metabolism and susceptibility to environmental exposures.