EPAS1或HIF2α及其负调控因子EGLN1可能在藏族人群对高原低氧环境的长期适应中起着关键作用，但其在低氧通路中的生物学功能及其调控机制还不清楚。我们的研究结果发现EGLN1基因上极度保守的非同义突变位点D4E和C127S在藏族人群中的频率要极显著地高于包括汉族在内的其它人群，且与藏族人群中的低血红蛋白浓度呈正相关，提示这两个突变位点可能是藏族人群对高原低氧长期适应的潜在功能位点，但是这两个位点是如何调控EGLN1基因功能的分子机制还不清楚。为了验证这两个关键功能位点的调控机制，本项目重点选择藏族新生儿脐静脉内皮细胞和Cas9定点突变小鼠的人工低氧诱导实验，并结合高原藏族人群与平原汉族人群的离体胎盘组织的表达谱分析，旨在阐明藏族人群中EGLN1基因的D4E和C127S等潜在功能位点对高原低氧环境响应的分子调控机制。研究结果对最终揭示人类对高原低氧环境适应的分子机制具有重要的科学意义。

Previous studies suggested that the EPAS1 (also known as HIF2α) and its negative regulator EGLN1 are two potential key genes that playing key roles in genetic adaptation to high-altitude hypoxia in Tibetan populations on the Tibetan Plateau, but genetic mechanism that how these genes response to the hypoxia through regulating the physiological functions of key organs remains unclear. Our recent analysis identified D4E (rs186996510) and C127S (rs12097901), two nonsynonymous mutations that having surprisingly high frequency in Tibetan populations than other populations including Han Chinese. These two mutations also showed a significant positive correlation with lower hemoglobin concentration in Tibetan populations, implying that they may have important effects on the adaptation to high altitude hypoxia in Tibetans. However, the genetic mechanism that how these two potential key mutations regulate the function of EGLN1 is unknown so far. This project aims to dissect the functional effects of D4E and C127S by using endothelial cells obtained from Tibetan newborns and CRISPR/Cas9 site-directed mutation mouse model as well as gene expression profiles of the placenta tissues in Tibetan populations, we sought to reveal how Tibetans have improved their physiological functions through the EGLN1 gene and developed the ability of genetic adaptation to high-altitude hypoxic environment. The findings of this project will provide new clues for the delineating the molecular mechanism of genetic adaptation to high-altitude hypoxia in Tibetan populations on the Tibetan Plateau.