Kimberly T Zhu

High-altitude hypoxia, or low oxygen availability at high elevations, presents one of the strongest selective pressures in human evolutionary history. Several human populations have resided at high altitudes for millennia and display unique phenotypic adaptations to hypoxia. Genomic evolution has contributed towards these adaptive phenotypes, but less is known concerning the role of developmental exposure in shaping epigenomic and phenotypic changes. Among Andeans, developmental exposure to high-altitude hypoxia shapes DNA methylation (DNAm) at key oxygen sensing genes. However, the role of developmentally-induced epigenetic changes in shaping high-altitude adaptations is not understood for Himalayan populations. This research investigates how developmental exposure to high-altitude hypoxia affects DNAm among Nepali Sherpa and considers the functional consequences of these epigenetic differences. Using a migrant study design, we will analyze epigenetic, transcriptomic, and phenotypic data from three groups of Sherpa study participants with differential exposure to hypoxia in order to identify differences in DNAm. We then will test for associations between DNAm levels and 1). gene expression and 2). adaptive phenotypes. By investigating how developmental exposure to hypoxia impacts DNAm underlying transcriptional changes and adaptive phenotypes in Nepali Sherpa, this work will produce novel insight into the role of developmental exposure in shaping human adaptation.