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

The gene encoding HIF-2 alpha, 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 O-2) enhanced ventilatory chemosensitivity (assessed as the acute ventilatory response to hypoxia), increased total ventilation and arterial O-2 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-2 alpha inmodulating 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.