Genetic variation in HIF‐2α attenuates ventilatory sensitivity and carotid body growth in chronic hypoxia in high‐altitude deer mice

The gene encoding HIF-2α, Epas1, has experienced a history of natural selection in many high-altitude taxa, but the functional role of mutations in this gene is still poorly understood. We investigated the influence of the high-altitude variant of Epas1 in North American deer mice (Peromyscus maniculatus) on the control of breathing and carotid body growth during chronic hypoxia. We created hybrids between high- and low-altitude populations of deer mice to disrupt linkages between genetic loci so that the physiological effects of Epas1 alleles (Epas1^H and Epas1^L , respectively) could be examined on an admixed genomic background. In general, chronic hypoxia (4 weeks at 12 kPa O₂ ) enhanced ventilatory chemosensitivity (assessed as the acute ventilatory response to hypoxia), increased total ventilation and arterial O₂ saturation during progressive poikilocapnic hypoxia, and increased haematocrit and blood haemoglobin content across genotypes. However, the effects of chronic hypoxia on ventilatory chemosensitivity were attenuated in mice that were homozygous for the high-altitude Epas1 allele (Epas1^H/H ). Carotid body growth and glomus cell hyperplasia, which was strongly induced in Epas1^L/L mice in chronic hypoxia, was not observed in Epas1^H/H mice. Epas1 genotype also modulated the effects of chronic hypoxia on metabolism and body temperature depression in hypoxia, but had no effects on haematological traits. These findings confirm the important role of HIF-2α in modulating ventilatory sensitivity and carotid body growth in chronic hypoxia, and show that genetic variation in Epas1 is responsible for evolved changes in the control of breathing and metabolism in high-altitude deer mice. KEY POINTS: High-altitude natives of many species have experienced natural selection on the gene encoding HIF-2α, Epas1, including high-altitude populations of deer mice. HIF-2α regulates ventilation and carotid body growth in hypoxia, and so the genetic variants in Epas1 in high-altitude natives may underlie evolved changes in control of breathing. Deer mice from controlled crosses between high- and low-altitude populations were used to examine the effects of Epas1 genotype on an admixed genomic background. The high-altitude variant was associated with reduced ventilatory chemosensitivity and carotid body growth in chronic hypoxia, but had no effects on haematology. The results help us better understand the genetic basis for the unique physiological phenotype of high-altitude natives.