Investigating Targets of Natural Selection for Hypoxic Adaptation at High Altitudes

Regents Of The University Of Michigan - Ann Arbor, Ann Arbor MI

Investigators

Abstract

Around 11,000 years ago, modern humans adapted to high altitude locations where the oxygen concentration is only 65% of that at sea level. This project seeks to identify the specific genetic changes that have allowed populations to survive at high elevations on the Andean Plateau. Findings from this research will advance our understanding of the ways in which modern human populations have been able to adapt to extreme environments through evolution by natural selection, and will also help to distinguish between natural selection and individual-level developmental adaptability. Improving our understanding of how the human body responds to low oxygen could inform the development of treatments for widespread diseases characterized by low oxygen, such as cancer and heart disease. The project will support student training and mentoring, and results of this study will be shared with the larger research community and integrated into public outreach programs aimed to encourage and financially support participation by underserved public middle school students. Andeans exhibit a unique suite of physiologic adaptations to high altitude including a blunted hypoxic ventilatory response, elevated arterial oxygen saturation, and elevated hemoglobin concentration. Their ability to live in chronic hypoxia provides an unprecedented opportunity to examine the underlying mechanisms of their adaptation. Recent genomic studies have identified the gene EGLN1 as a high priority candidate locus for natural selection among Andean highlanders. However, the functionally important SNP/mutation(s) has not been identified. To address this gap in our knowledge, the investigators will study how genetic changes mechanistically translate into the dramatic Andean phenotype. They will rigorously characterize the strength of natural selection for two candidate functional SNPs using next generation sequencing technologies; link genotype to phenotype through association testing and mRNA expression analysis; and characterize their functional importance using a combination of Crispr technology and chromatin immunoprecipitation assays. By integrating evolutionary and functional approaches to the study of human high altitude adaptation, this research will provide critical insight into the molecular mechanisms governing functional, adaptive change. Additionally, project results will reveal how genetic changes translate into adaptive, fitness-related phenotypes. In so doing, the outcomes of this research will lead to a major change in our understanding of Andean adaptation for which developmental adaptation, as opposed to genetic adaptation, is often considered to be the main adaptive strategy. Furthermore, by contrasting these results to emerging data on the functional consequence of Tibetan EGLN1 genetic changes, this research is uniquely poised to definitively establish convergent evolution between Andeans and Tibetans.