HIF-2α基因变异减弱高原鹿小鼠慢性缺氧通气敏感性和颈动脉体生长。

The Journal of Physiology Pub Date : 2022-09-01 Epub Date: 2022-07-31 DOI:10.1113/JP282798
Catherine M Ivy, Jonathan P Velotta, Zachary A Cheviron, Graham R Scott
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引用次数: 4

摘要

编码HIF-2α的基因Epas1在许多高海拔分类群中经历了自然选择的历史,但对该基因突变的功能作用仍知之甚少。我们研究了北美鹿小鼠(Peromyscus maniculatus) Epas1高海拔变异对慢性缺氧条件下呼吸和颈动脉体生长控制的影响。我们在高海拔和低海拔地区的鹿鼠种群之间建立了杂交,以破坏遗传位点之间的联系,以便在混合基因组背景下检测Epas1等位基因(分别为Epas1H和Epas1L)的生理效应。总的来说,慢性缺氧(在12 kPa O2下4周)增强了通气化学敏感性(评估为对缺氧的急性通气反应),在进行性异位缺氧期间增加了总通气量和动脉氧饱和度,并增加了红细胞压积和血红蛋白含量。然而,在高海拔Epas1等位基因(Epas1H/H)纯合的小鼠中,慢性缺氧对通气化学敏感性的影响减弱。Epas1H/H小鼠未观察到Epas1L/L小鼠在慢性缺氧条件下强烈诱导的颈动脉体生长和血管球细胞增生。Epas1基因型还能调节慢性缺氧对机体代谢和体温降低的影响,但对血液学性状无影响。这些发现证实了HIF-2α在慢性缺氧条件下调节通气敏感性和颈动脉体生长中的重要作用,并表明Epas1的遗传变异与高原鹿小鼠呼吸和代谢控制的进化变化有关。许多高海拔原生物种的HIF-2α、Epas1基因编码经历了自然选择,包括高海拔鹿鼠种群。HIF-2α在缺氧条件下调节通气和颈动脉体生长,因此高海拔原住民Epas1的遗传变异可能是呼吸控制进化变化的基础。来自高海拔和低海拔种群对照杂交的鹿鼠被用来研究Epas1基因型对混合基因组背景的影响。在慢性缺氧时,高海拔变异与通气化疗敏感性降低和颈动脉体生长有关,但对血液学没有影响。这些结果有助于我们更好地了解高海拔原住民独特生理表型的遗传基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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 (Epas1H and Epas1L , 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 (Epas1H/H ). Carotid body growth and glomus cell hyperplasia, which was strongly induced in Epas1L/L mice in chronic hypoxia, was not observed in Epas1H/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.

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