Genomic and physiological mechanisms of hypoxia adaptation in high-altitude mice

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PROJECT SUMMARY High-altitude animals have evolved the ability to survive and function under conditions of oxygen deprivation (hypoxia) that mimic disease states in humans. Identifying evolved mechanisms of hypoxia adaptation in mammals that are long-term high-altitude natives can therefore yield discoveries of biomedical relevance while also providing general insights into the evolution of complex traits. A number of wild rodent species inhabit far more extreme altitudes than Tibetan and Andean humans and also represent far more tractable subjects for experimental approaches that involve genetic crosses and invasive physiological manipulations. This project integrates genomics and experimental physiology to dissect the mechanistic basis of adaptive enhancements of whole-animal performance in hypoxia in extreme high-altitude rodents. The experiments compare high- and low- altitude populations of two species: the deer mouse (Peromyscus maniculatus), which has the broadest altitudinal range of any North American mammal (sea level to 4350 m), and the Andean leaf-eared mouse (Phyllotis vaccarum), an extremophile species that holds the record as the world’s highest dwelling mammal and that also has the broadest altitudinal range (sea level to >6700 m [>22,000’]). To test hypotheses about adaptive regulatory responses to hypoxia, we will use a common-garden experimental design to integrate measures of whole-animal physiological performance (aerobic exercise capacity in hypoxia) and various subordinate traits (respiratory, cardiovascular, and metabolic) with tissue-specific transcriptomic and metabolomic profiles. Experiments will involve highly invasive manipulations (e.g., surgical instrumentation of arterial and venous catheters to measure blood gases during exercise trials and terminal sampling of vital organs) that are not feasible in human subjects. In both species, mechanistic experiments will be complemented by population genomic experiments to generate hypotheses about the specific genes and pathways that may have contributed to hypoxia adaptation. Such hypotheses will then be tested using follow-up experiments to measure phenotypic effects of changes in gene function and/or gene expression, as illustrated by our ongoing work on deer mice. The specific aims of the research are (1) to elucidate the mechanistic basis of adaptive enhancements of aerobic performance capacity in hypoxia; (2) to determine how regulatory changes in gene expression translate into changes in phenotype at different hierarchical levels of biological organization; and (3) to identify and experimentally test new candidate genes and pathways for hypoxia adaptation. The integration of population genomics, functional genomics, and experimental physiology will advance the field by elucidating the mechanistic basis of adaptive evolutionary change in complex performance traits.