藏族人群对高原低氧极端环境遗传适应的多基因互作机制研究

The Tibetan Plateau is the highest mountainous area in the world, an ideal “laboratory” for studying the molecular mechanism of how living organisms adapt to the environmental extreme of high altitude hypoxia. Tibetans, as the indigenous population living in the Tibetan Plateau region have been well-adapted to the high-altitude environment due to longtime natural selection, making them an ideal population for studying adaptation to high-altitude hypoxia in humans. This project aims to dissect the sequence variations and their functions of the 18 candidate genes, selected based on our previous genome-wide analyses in Tibetans, and they are likely involved in hypoxic adaptation. We intend to reveal the strength and timing of natural selection acting on these candidate genes in Tibetans. Combining the approaches of large-sample-size genetic association analysis, gene expression profiling of placenta tissue (an important oxygen-exchange organ), induced hypoxia experiment using endothelial cells and transgenic analysis, we sought to understand “how humans and other organisms have improved their physiological functions through interactions among multiple genes in the genome and developed the ability for high-altitude hypoxia adaptation”. The results of this project will shed light on the molecular mechanism of adaptation to high-altitude hypoxia in humans, and will provide valuable genetic data for drug design in order to prevent and cure the high-altitude related diseases, which is crucial not only for basic research , but also for future medical applications.

青藏高原是地球上海拔最高的高原地区，是研究生物对高原低氧极端环境适应的分子机制的天然实验室。世代生活在青藏高原地区的藏族人群经过长期的自然选择已能很好地适应高原环境，是研究人类对高原低氧适应机制的理想人群。本项目通过对前期全基因组分析筛选的在藏族人群中可能参与低氧适应的18个候选基因的序列多态性和功能的研究，解析这些基因在藏族人群中受自然选择的强度和时间；结合大样本的人群遗传相关性分析、胎盘组织（重要的氧交换器官）表达谱分析和脐带内皮细胞人工低氧诱导实验和转基因实验等，阐明“人类（生物）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。研究结果将有助于了解人类对高原低氧极端环境适应的分子机制，为预防和治疗高原病的药物设计等提供重要的遗传学数据，既有重要的科学意义，也具有重要的医学应用前景。

世代生活在青藏高原地区的藏族人群经过长期的自然选择已能很好地适应高原环境，是研究人类对高原低氧适应机制的理想人群。本项目通过分析低氧适应候选基因的分子进化模式及其与适应表型的遗传相关性找出藏族人群高原低氧适应的关键基因；在此基础上利用表达谱测序和人工低氧诱导功能实验阐明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。经过4年的系统研究，本项目已按计划完成，取得了如下成果：1）通过对近一万份藏族样本遗传背景的分析重构了人类定居高原的史前历史，研究结果显示藏族早在旧石器晚期可能已经定居青藏高原；2）发现低氧基因EGLN1的藏族富集突变，证实该基因是藏族高原低氧适应的关键基因之一；3）发现血红素代谢基因HMOX2参与藏族低氧适应,有利于藏族在高海拔条件下保持相对较低的血红蛋白水平，以避免红细胞过度增殖带来的负效应； 4）首次解析了高原适应关键基因EPAS1基因表达调控模式, 发现藏族富集的EPAS1变异位点下调了EPAS1的表达水平, 从而导致藏族对高原低氧的钝化生理反应。研究结果初步揭示了人类对高原低氧极端环境适应的分子机制，为预防和治疗高原病的药物设计等提供了重要的遗传学数据。