Kimberly T Zhu

ABSTRACT SUBMITTED: High elevation environments impose numerous selective pressures including high-altitude hypoxia, that offer a natural experiment to study human evolutionary change. Human populations residing across the Andean Altiplano and the Tibetan Plateau represent two replications of this natural experiment, and each displays a unique suite of adaptive phenotypes. Both populations show genomic evidence of natural selection, but little is known about developmental adaption. This work utilized high-altitude hypoxia as a unifying environmental pressure to uncover the adaptive basis of population-specific patterns of DNAm and immune response. We analyzed DNA methylation array data for Himalayan Sherpa and Peruvian Quechua participants with differing levels of lifetime exposure to high altitude, finding evidence of developmental adaptation across Himalayan methylomes, and identified a Himalayan-specific methylation pattern across EPAS1 that may blunt HIF2A transcription. In addition, we used DNAm data to estimate circulating proportions of immune cell types and markers of chronic inflammation, revealing population specific immune-response features to high-altitude hypoxia. Ultimately, our results contribute new insights into how adaptive processes can act in unique ways across human populations to underlie a shared human capacity to adapt.