Doctoral Dissertation Research: Developmental Adaptation to High-Altitude Hypoxia

University Of California-Los Angeles, Los Angeles CA

Investigators

Abstract

High-altitude hypoxia, or low oxygen availability at high elevations, presents one of the strongest selective pressures in human evolutionary history. Despite this formidable environmental stressor, several human populations have thrived at high altitude for millennia and display unique adaptations to low oxygen availability. Although recent research has documented the role of genetic evolution in shaping different adaptations to high altitude, less is known concerning the role of epigenetics – or influences shaping gene expression – with respect to how different populations respond to the stressor of hypoxia. This doctoral dissertation research project investigates the extent to which high-altitude hypoxia impacts DNA methylation (DNAm – one specific kind of epigenetic effect) patterns in a human population, and the functional role that DNAm contributes to adaptation to this environment. In doing so, this project directly contributes to the body of knowledge on human evolution, variation, and adaptability by exploring the critical role of epigenetic change on high-altitude gene expression patterns and phenotypes. This project supports STEM-focused educational and outreach efforts in research and local communities, and training of undergraduate research assistants. Using a migrant study design, this project analyzes epigenetic, transcriptomic, and phenotypic data from three groups of study participants with differential exposure to hypoxia. Differential methylation analysis between the three participant groups is used to identify differentially methylated positions and regions associated with developmental exposure to high-altitude hypoxia. In tandem, mRNA sequencing and analysis is used to identify gene expression patterns associated with exposure to high altitude. Association testing between DNAm levels and 1) gene expression and 2) adaptive phenotypes identifies key methylation differences associated with transcriptomic and phenotypic changes. This multi-omics approach offers new insight into the role of adaptive developmental plasticity in shaping human adaptation to high altitude. Further, results of this study build on on previous studies of DNAm patterns in other high-altitude populations. By comparing the role of epigenetic changes in shaping high-altitude adaptive phenotypes in different populations, this research provides critical insight into the convergent patterns of high-altitude adaptive phenotypes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.