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Evolutionary adaptation to extreme environments often requires coordinated changes in multiple intersecting physiological pathways, but how such multi-trait adaptation occurs remains unresolved. Transcription factors, which regulate the expression of many genes and can simultaneously alter multiple phenotypes, may be common targets of selection if the benefits of induced changes outweigh the costs of negative pleiotropic effects. We combined complimentary population genetic analyses and physiological experiments in North American deer mice ( Peromyscus maniculatus ) to examine links between genetic variation in transcription factors that coordinate physiological responses to hypoxia (hypoxia-inducible factors, HIFs) and multiple physiological traits that potentially contribute to high-altitude adaptation. First, we sequenced the exomes of 100 mice sampled from different elevations and discovered that several SNPs in the gene  Epas1 , which encodes the oxygen sensitive subunit of HIF-2α, exhibited extreme allele frequency differences between highland and lowland populations. Broader geographic sampling confirmed that  Epas1  genotype varied predictably with altitude throughout the western US. We then discovered that  Epas1  genotype influences heart rate in hypoxia, and the transcriptomic responses to hypoxia (including HIF targets and genes involved in catecholamine signaling) in the heart and adrenal gland. Finally, we used a demographically-informed selection scan to show that  Epas1  variants have experienced a history of spatially varying selection, suggesting that differences in cardiovascular function and gene regulation contribute to high-altitude adaptation. Our results suggest a mechanism by which  Epas1  may aid long-term survival of high-altitude deer mice and provide general insights into the role that highly pleiotropic transcription factors may play in the process of environmental adaptation.

Physiological and genomic evidence that selection on the transcription factor Epas1 has altered cardiovascular function in high-altitude deer mice