UC San Diego

Genomic studies of high-altitude populations exposed to chronic low oxygen (hypoxia) have identified signals of selection linked to adaptive phenotypes. However, substantial variation both across and within populations suggests that human adaptation to hypoxia arises through multiple, distinct physiological and evolutionary pathways. Many Tibetans living at altitude exhibit lower hemoglobin and heightened ventilatory responses, whereas Andeans more commonly exhibit a higher average hemoglobin concentration and blunted ventilatory responses. Variation in hypoxia responses is shaped by factors such as the duration of high-altitude exposure (e.g., generations, years, days, hours), ancestry, and other biological factors and environmental influences. This dissertation examines human adaptation to altitude using a multi-omics framework designed to capture the heterogeneity of adaptive mechanisms. Chapter 1 examines convergent and divergent genomic signals of selection in Tibetan and Andean highland populations. Chapter 2 characterizes the transcriptomic landscape of individuals with chronic maladaptive excessive erythrocytosis undergoing isovolumic hemodilution. Chapter 3 investigates epigenetic remodeling during short-term acclimatization in unacclimatized lowland individuals across four days at altitude. Together, these studies identify previously unrecognized genotype-phenotype relationships and advance understanding of hypoxia biology with broad implications for human health, particularly cardiometabolic, pulmonary, and sleep physiology.