Variations in HIF-1α Contributed to High Altitude Hypoxia Adaptation via Affected Oxygen Metabolism in Tibetan Sheep

SIMPLE SUMMARY: Hypoxia-inducible factors (HIFs) play an important role in the adaptation of animals to high-altitude hypoxia. In high-altitude indigenous species, variation in the hypoxia-inducible factor-1 alpha (HIF-1α) gene has been reported in Tibetans, yaks and Tibetan horses, but has not been investigated in Tibetan sheep, and is not known if it might affect high-altitude hypoxia adaptation in these sheep. In this study, Kompetitive Allele-Specific PCR (KASP) was used for genotyping of ovine HIF-1α and investigated the effect of variation in HIF-1α on the high-altitude hypoxia adaptation of Tibetan sheep. The results suggest that ovine HIF-1α variants may promote the ability of oxygen utilization in Tibetan sheep and it may serve as a genetic marker for improving high-altitude hypoxia adaptability. ABSTRACT: The Tibetan sheep is an indigenous species of the Tibetan plateau and has been well adapted to high-altitude hypoxia. In comparison to lowland sheep breeds, the blood gas indicators have changed and the HIFs signaling pathway is activated in Tibetan sheep. These phenotypic and genetic alterations in Tibetan sheep are thought to be an important basis for adaptation to high-altitude hypoxia and variation in genes encoding the subunits that make up HIFs, such as HIF-1α can affect blood gas indicators. In this study, exons 9, 10, 12 of the HIF-1α gene were sequenced to find variations and 3 SNPs were detected, and these 3 SNPs were genotyped by KASP in 341 Hu sheep and 391 Tibetan sheep. In addition, 197 Hu sheep, 160 Tibetan sheep and 12 Gansu alpine merino sheep were used for blood gas indicators analysis. The results showed significant differences between the blood gas indicators of high-altitude breeds (Tibetan sheep and Gansu alpine merino sheep) and low-altitude breeds (Hu sheep), implying that the differences in blood gas indicators are mainly caused by differences in altitude. The haplotype combinations H2H3 and H1H3 were more frequent in the Tibetan sheep population, H2H3 increases O(2) carrying capacity by increasing hematocrit and hemoglobin concentrations; H1H3 makes O(2) dissociate more readily from oxyhemoglobin by decreasing partial pressure of oxygen and oxygen saturation. These results suggest that variants at the HIF-1α promote the ability of oxygen utilization in Tibetan sheep, which may underpin the survival and reproduction of Tibetan sheep on the Tibetan plateau.