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.

编码缺氧诱导因子-2α（Hypoxia-Inducible Factor 2α，HIF-2α）的基因Epas1，在诸多高海拔类群中均经历过自然选择历程，但目前学界对该基因上突变的功能作用仍知之甚少。本研究以北美鹿鼠（Peromyscus maniculatus）为实验对象，探究了其Epas1基因的高海拔变异在慢性低氧环境下对呼吸调控与颈动脉体生长的影响。我们通过高、低海拔鹿鼠种群杂交构建F2互交繁育群体，以打破遗传位点间的连锁关系，从而可在混合遗传背景下探究Epas1变异的生理学效应。总体而言，慢性低氧（12 kPa氧分压条件下持续4周）可提升通气化学敏感性（以低氧高碳酸血症的急性通气反应作为评估指标），在渐进性异碳酸性低氧状态下提升总通气量与动脉血氧饱和度，并使各基因型个体的红细胞比容与血液血红蛋白含量升高。然而，在携带纯合高海拔Epas1等位基因（Epas1H/H）的小鼠中，慢性低氧对通气化学敏感性的提升效应被显著削弱。在慢性低氧环境下，Epas1L/L小鼠的颈动脉体生长与球细胞增生会被显著诱导，但Epas1H/H小鼠则完全未出现此类变化。与之相反，慢性低氧可提升Epas1H/H小鼠的代谢水平，并缓解低氧环境下的体温下降，但该效应并未出现在Epas1L/L或Epas1H/L小鼠中。基因型对血液学性状无显著影响。本研究结果证实了HIF-2α在慢性低氧环境下调控通气敏感性与颈动脉体生长的重要作用，并表明Epas1基因的遗传变异是高海拔鹿鼠呼吸调控与代谢水平适应性进化改变的关键成因。