Tibetan populations have lived at high-elevation since the late Pleistocene, adapting to an oxygen concentration that is just 60% what is available at sea-level. Understanding the consequences of such local adaptations is a major goal in human genetics research. However, although decades of research have provided a strong foundation of evidence concerning Tibetan phenotypes and genetic signatures of adaptation, disentangling the functional and molecular impact of these selection signals remains a challenge. In the dissertation work presented here, I comprehensively examine functional and molecular impacts of Tibetan genetic adaptation using an interdisciplinary approach. First, I dissect the regulatory architecture of EPAS1 - the gene which carries the strongest signatures of selection in the Tibetan genome – and assess the contribution of variation at this locus to adaptive phenotypes. I uncover evidence of striking pleiotropic activity in regulatory elements impacted by Tibetan variation, implicating adaptive pleiotropy in Tibetan adaptation. Next, I describe the generation of a panel of induced pluripotent stem cells (iPSCs) from Tibetan and Han Chinese populations. These cells offer an unprecedented opportunity to explore gene networks shaped by local adaptation in cell types of interest in a controlled and well-balanced experiment. Finally, I discuss my initial differentiation of this iPSC panel into vascular endothelium, and detail the challenges and possible solutions to managing inter-individual variation in population panels such as ours. Taken together, the work described here provides both novel insights into the role of pleiotropy in Tibetan adaptation to hypoxia, and new tools to further investigate cell-type specific gene expression networks and phenotypes which result from Tibetan genetic variation.




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