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

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. Author summary: Adaptation often requires coordinated evolutionary changes across multiple dynamic systems to maintain physiological function. For example, high-altitude habitats place a premium on tissue-oxygen delivery to cope with limited oxygen availability (hypoxia). Circulatory O₂ transport is regulated dynamically, changing on the order of seconds, and results from several interacting physiological processes. The mechanisms of adaptation in such complex phenotypes are poorly understood. One promising candidate is the gene Epas1, which encodes a transcription factor that regulates physiological responses to hypoxia. We used population genomic analyses and physiological assays to explore the connections between Epas1 genetic variation and physiological function in high-altitude deer mice, which exhibit evolutionary adaptations to hypoxia. We identified a mutation in Epas1 that is associated with variation in cardiovascular function: the predominant variant at high altitude is associated with the maintenance of an elevated heart rate under hypoxia and with differences in the expression of genes that influence heart rate and are regulated by Epas1. Our population genomic analyses demonstrated that Epas1 exhibits a signature of natural selection at high altitude, suggesting that these phenotypic effects influence Darwinian fitness. Our results suggest that adaptation in complex and dynamic traits may be attributable to relatively simple genetic changes. [ABSTRACT FROM AUTHOR]