High‐altitude Adaptation and Hypoxia Signaling in Deer Mice

The hypoxic and cold environment at high altitudes requires that endothermic animals sustain high rates of O 2 consumption for both locomotion and thermogenesis while facing a diminished O 2 supply. Recent evidence suggests that genes in the hypoxia inducible factor (HIF) pathway have been targeted by natural selection and have contributed to evolutionary adaptation to high altitudes in several species. Here, we examine the role of hypoxia signaling in high‐altitude adaptation in deer mice ( Peromyscus maniculatus ). Maximal O 2 consumption (VO 2 max) in hypoxia is augmented in high‐altitude populations, underpinned by increases in pulmonary O 2 extraction, arterial O 2 saturation, cardiac output, and tissue O 2 extraction compared to low‐altitude populations. Highlanders also maintain higher heart rates during deep hypoxia at rest. Associated with the population differences in physiology is extreme allele frequency variation in a non‐synonymous single nucleotide polymorphism in Epas1 , the gene encoding HIF‐2α. Transcriptome scans indicate that these differences in Epas1 allele frequency stem from a history of spatially varying selection between high and low altitudes. RNA‐Seq measurements of gene expression in the left ventricle show that transcriptomic variation in HIF target genes is correlated to VO 2 max. Furthermore, comparisons of the hypoxia response between mice with different Epas1 genotypes (captured from an admixed population on the summit Mount Evans CO) show that the high‐altitude Epas1 allele is associated with higher heart rates in deep hypoxia, but that it has no association with variation in breathing or blood haemoglobin content. Our results therefore suggest that changes in hypoxia signaling contribute to high‐altitude adaptation in deer mice. Support or Funding Information Supported by NSERC of Canada and the USA National Science Foundation