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 are still poorly understood. We investigated the influence of the high-altitude variant of Epas1 in North American deer mice (Peromyscus maniculatus) on control of breathing and carotid body growth during chronic hypoxia. We created hybrids between high- and low-altitude populations of deer mice (F2 intercross breeding design) to disrupt linkages between genetic loci so physiological effects of Epas1 variants 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 hypoxic-hypercapnia), increased total ventilation and arterial O2 saturation during progressive poikilocapnic hypoxia, and increased haematocrit and blood haemoglobin content across genotypes. However, effects of chronic hypoxia on ventilatory chemosensitivity were attenuated in mice that were homozygous for the high-altitude Epas1 allele (Epas1H/H). Carotid body growth and glomus cell hyperplasia, which was strongly induced in Epas1L/L mice in chronic hypoxia, was completely absent in Epas1H/H mice. In contrast, chronic hypoxia increased metabolism and attenuated body temperature depression in hypoxia in Epas1H/H mice, but not in Epas1L/L or Epas1H/L mice. Genotype 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.