Investigating Targets of Natural Selection for Hypoxic Adaptation at High Altitudes

大约11000年前，现代人类适应了高海拔地区，那里的氧气浓度只有海平面的65%。该项目旨在确定使种群能够在安第斯高原高海拔地区生存的特定基因变化。这项研究的发现将促进我们对现代人类群体通过自然选择进化适应极端环境的方式的理解，也将有助于区分自然选择和个体水平的发展适应性。提高我们对人体对低氧反应的理解，可以为以低氧为特征的广泛疾病（如癌症和心脏病）的治疗提供信息。该项目将支持学生培训和指导，研究结果将与更大的研究界共享，并纳入旨在鼓励和资助服务不足的公立中学生参与的公共推广计划。安第斯人对高海拔表现出一套独特的生理适应，包括迟钝的缺氧通气反应、动脉血氧饱和度升高和血红蛋白浓度升高。它们在慢性缺氧环境下生存的能力为研究它们适应的潜在机制提供了前所未有的机会。最近的基因组研究已经确定EGLN1基因是安第斯高地人自然选择的优先候选基因座。然而，功能上重要的SNP/突变尚未被确定。为了解决我们知识上的这一差距，研究人员将研究遗传变化如何机械地转化为戏剧性的安第斯表型。他们将使用下一代测序技术严格表征两个候选功能snp的自然选择强度；通过关联检测和mRNA表达分析将基因型与表型联系起来；并结合Crispr技术和染色质免疫沉淀测定来表征它们的功能重要性。通过整合进化和功能方法来研究人类的高海拔适应，本研究将为控制功能和适应性变化的分子机制提供关键的见解。此外，项目结果将揭示遗传变化如何转化为适应性、健康相关的表型。在这样做的过程中，这项研究的结果将导致我们对安第斯适应的理解发生重大变化，在这种适应中，发育适应，而不是遗传适应，通常被认为是主要的适应策略。

Around 11,000 years ago, modern humans adapted to high altitude locations where the oxygen concentration is only 65% of that at sea level. This project seeks to identify the specific genetic changes that have allowed populations to survive at high elevations on the Andean Plateau. Findings from this research will advance our understanding of the ways in which modern human populations have been able to adapt to extreme environments through evolution by natural selection, and will also help to distinguish between natural selection and individual-level developmental adaptability. Improving our understanding of how the human body responds to low oxygen could inform the development of treatments for widespread diseases characterized by low oxygen, such as cancer and heart disease. The project will support student training and mentoring, and results of this study will be shared with the larger research community and integrated into public outreach programs aimed to encourage and financially support participation by underserved public middle school students. Andeans exhibit a unique suite of physiologic adaptations to high altitude including a blunted hypoxic ventilatory response, elevated arterial oxygen saturation, and elevated hemoglobin concentration. Their ability to live in chronic hypoxia provides an unprecedented opportunity to examine the underlying mechanisms of their adaptation. Recent genomic studies have identified the gene EGLN1 as a high priority candidate locus for natural selection among Andean highlanders. However, the functionally important SNP/mutation(s) has not been identified. To address this gap in our knowledge, the investigators will study how genetic changes mechanistically translate into the dramatic Andean phenotype. They will rigorously characterize the strength of natural selection for two candidate functional SNPs using next generation sequencing technologies; link genotype to phenotype through association testing and mRNA expression analysis; and characterize their functional importance using a combination of Crispr technology and chromatin immunoprecipitation assays. By integrating evolutionary and functional approaches to the study of human high altitude adaptation, this research will provide critical insight into the molecular mechanisms governing functional, adaptive change. Additionally, project results will reveal how genetic changes translate into adaptive, fitness-related phenotypes. In so doing, the outcomes of this research will lead to a major change in our understanding of Andean adaptation for which developmental adaptation, as opposed to genetic adaptation, is often considered to be the main adaptive strategy. Furthermore, by contrasting these results to emerging data on the functional consequence of Tibetan EGLN1 genetic changes, this research is uniquely poised to definitively establish convergent evolution between Andeans and Tibetans.