世居青藏高原的藏族人群是研究人类高原极端环境遗传适应的理想群体。在前期微进化重点项目的支持下，我们通过汉藏群体的全基因组比较和候选基因藏族群体的重测序，发现低氧代谢通路上游两个调控基因EPAS1和EGLN1携带多个在藏族人群中高度富集的序列变异。进一步的分子进化和基因-表型相关性分析证实这两个基因是藏族低氧适应的关键基因。在前期工作的基础上，本集成项目将开展细胞和转基因动物水平的功能验证实验，解析这两个关键基因互作的分子机制及其导致藏族高原低氧生理适应的分子基础；同时，我们将以小鼠为模型检测携带藏族适应突变的转基因小鼠在低氧条件下的繁殖力，计算达尔文适合度并评估高原低氧极端环境的选择压力强度。本集成项目的研究结果将回答“人类是如何通过基因组水平的多基因相互作用来改变其生理机能，进而适应高原低氧极端环境”这一核心科学问题。

Tibetans living at the Qinghai-Tibetan Plateau area is an ideal population for studying genetic adaptation of humans to high altitude extreme environment. Funded by the key project of micro-evolution, we have conducted genome-wide comparison between Han Chinese and Tibetans, and re-sequencing of candidate genes in Tibetan populations. Further molecular evolution and gene-phenotype association analyses demonstrated that EPAS1 and EGLN1 are the two key hypoxic pathway genes containing Tibetan-enriched sequence variants that may contribute to high altitude hypoxic adaptation. In this project, utilizing cellular and transgenic animal models, we aim to dissect the mechanism of molecular interactions between EPAS1 and EGLN1, and to reveal the molecular basis of the adaptive physiological traits of Tibetans. In addition, we will evaluate the reproductive ability of transgenic mice carrying the adaptive mutations of Tibetans by calculating Darwinian fitness and intensity of selective pressure resulting from high altitude hypoxia. The result of this project will shed light on the fundamental question of how humans were adapted to high altitude extreme environments through multi-gene interactions in the genome.