解析藏族人群精子的遗传背景对青藏高原低氧极端环境中男性生殖能力的影响

Tibetan Plateau represents one of the most extremes of human settlement environment due to its high-altitude hypoxic stress. Currently there are over 5 million indigenous Tibetans residing on the Plateau, and majority of them have acquired superior physiological adaptation to high altitude hypoxic environment. This superior adaptation is both reflected by their adaptive change on the key physiological features of heart and lung as well as the continuous expansion of their population since their ancestors have successfully settled on the Plateau 30,000 years ago, which means that their superior adaptation is realized through reproductive and postnatal adaption to hypoxic environment. Recent findings demonstrated that EPAS1 (HIF2α) and its negative regulator EGLN1 are two key genes involving in the adaptation to high altitude hypoxia in Tibetan, however, their genetic impact on male fertility in high altitude hypoxia environment remains unclear. In this project, we would like to decipher the difference of transcriptome pattern and protein profile of sperms between native Tibetan and migrated Han on the Tibetan Plateau to identify potential key proteins and tsRNA enrichment patterns important for genetic adaption of male fertility on the Tibetan Plateau. In addition, we analyze the frequency distribution pattern of sperms carrying an adaptive mutation in Tibetan man who having heterozygous genotype at EPAS1/EGLN1 loci to clarify whether the number of sperm carrying adaptive mutation at EPAS1/EGLN1 loci is significantly superior than the other type, which showing that the adaptive mutation is under positive selection during spermatogenesis. For the same reason, we analyze the frequency distribution pattern of heterozygous offspring between adaptive heterozygous Tibetan man and non-adaptive homozygous Han woman to clarify whether a sperm carrying an adaptive mutation at EPAS1/EGLN1 loci showing superior fertilizing ability than the other type. The objective of the project is to reveal the impact of genetic background of sperm on male fertility on the Tibetan Plateau. The findings will have important application values in reproductive medical practice on the Tibetan Plateau.

藏族人群已经对青藏高原低氧极端环境产生了最佳的生理适应，主要体现在其关键生理特征的适应性改变和人口的快速增长上，而人口增长的前提是在生殖能力与生长发育方面应有最佳的适应性状。最近的研究结果表明EPAS1及其负调控因子EGLN1基因是藏族生长发育过程中对低氧适应的关键基因，另外，精子中的tsRNA可以将父代的获得性性状隔代遗传给后代。但是藏族男性精子中EPAS1/EGLN1基因的适应性突变对其生殖能力的遗传影响仍然不清楚。本项目通过分析不同基因型的藏族男性精子在转录组与蛋白组水平的遗传差异，以及在藏族群体内具有杂合基因型的男性的成熟精子中适应性突变的频率分布模式，及其与野生纯合基因型的汉族女性的后代中适应性突变个体的频率分布模式，旨在回答“藏族男性精子的遗传背景对其精子生成与受精等男性生殖能力的遗传影响及其作用模式”这一科学问题。研究结果对青藏高原生殖医学具有重要的应用价值。

藏族人群已经对青藏高原低氧极端环境产生了生理适应优势，主要体现在其关键生理特征的适应性改变和人口的快速增长上，而人口增长的前提是在生殖能力与生长发育方面应有适应优势。最近的研究结果表明EPAS1及其负调控因子EGLN1基因是藏族生长发育过程中对低氧适应的关键基因，但是藏族男性精子中EPAS1/EGLN1基因的适应性突变对其生殖能力的遗传影响仍然不清楚。本项目通过分析不同基因型的藏族男性精子在转录组与蛋白组水平的遗传差异，以及在藏族群体内具有杂合基因型的男性的成熟精子中适应性突变的频率分布模式，及其与野生纯合基因型的汉族女性的后代中适应性突变个体的频率分布模式，旨在回答“藏族男性精子的遗传背景对其精子生成与受精等男性生殖能力的遗传影响及其作用模式”这一科学问题。研究结果对青藏高原生殖医学具有重要的应用价值。本课题紧紧围绕“高原低氧环境下藏族人群男性精子的遗传背景对其生殖能力的遗传影响机制”这一核心课题，系统分析了高原低氧环境下世居藏族与移居汉族男性精液的病理生理特征、蛋白质组学特征、男性生精功能的低氧适应特征、高原低氧环境下人体血液中一氧化氮的病理生理特征、藏族人群的标准参考基因组构建、高原适应关键基因EPAS1的染色质可及性全景图谱及其调控网络等研究中取得一批原创性成果，为最终解析藏族人群男性精子的遗传背景对低氧环境下男性生殖能力的遗传影响这一核心课题提供了第一手基础数据。截止课题结题日（2021年2月26日）共发表研究论文6篇，其中中文核心期刊3篇（第一标注）、在《国家科学评论》（National Science Review）（2篇）、Nature Communications（1篇）等影响因子10以上的高水平期刊论文3篇。培养硕士毕业生1人（次旺拉姆，2020）。