Gray O A, Witonsky D B, Di Rienzo A
Department of Human Genetics, University of Chicago, Chicago, IL.
bioRxiv. 2025 Jun 8:2025.06.04.657917. doi: 10.1101/2025.06.04.657917.
Tibetan adaptation to high-altitude hypoxia remains a classic example of Darwinian selection in humans. To identify adaptive traits that might have evolved in Tibetans in response to long-term exposure to hypoxia, we previously established a library of induced pluripotent stem cells (iPSCs), derived from Tibetan and Han Chinese individuals, as a robust model system for the exploration of condition-specific molecular and cellular responses. We used this system to characterize and compare the transcriptome of iPSC-derived endothelial cells and found that angiogenesis, energy metabolism and immune pathways differ between the cell lines from these two populations. Here, we harness the same experimental system to characterize and compare the transcriptome of iPSC-derived cardiomyocytes in Tibetan and Han Chinese in hypoxia. We find that several pathways, such as the hypoxia, myogenesis and glycolysis pathways, are significantly enriched for differentially expressed genes across populations. These pathways are candidate targets of natural selection due to exposure to the high-altitude hypoxic environment and point to adaptive cardiac traits such as sustained cardiac function in hypoxia. A better understanding of these adaptations may offer insights into novel therapeutic strategies for hypoxia-related cardiovascular conditions, such as pulmonary hypertension and ischemic heart disease.
藏族人对高原缺氧的适应仍然是人类达尔文ian选择的一个经典例子。为了确定藏族人可能因长期暴露于缺氧环境而进化出的适应性特征，我们之前建立了一个诱导多能干细胞（iPSC）文库，该文库来源于藏族和汉族个体，作为探索特定条件下分子和细胞反应的强大模型系统。我们使用这个系统来表征和比较iPSC衍生的内皮细胞的转录组，发现这两个人群的细胞系在血管生成、能量代谢和免疫途径方面存在差异。在这里，我们利用相同的实验系统来表征和比较藏族和汉族iPSC衍生的心肌细胞在缺氧条件下的转录组。我们发现，缺氧、肌生成和糖酵解等几种途径在不同人群中差异表达基因显著富集。由于暴露于高海拔缺氧环境，这些途径是自然选择的候选靶点，并指向适应性心脏特征，如在缺氧条件下维持心脏功能。更好地理解这些适应性可能为缺氧相关心血管疾病，如肺动脉高压和缺血性心脏病，提供新的治疗策略见解。
