Doctoral Dissertation Research: Epigenomics of Andean High-Altitude Adaptation

在高海拔地区，大多数人表现为血氧水平下降，血压飙升，心率和呼吸频率增加。然而，长期居住在高海拔的种群具有独特的生理适应能力，使它们能够在这个极端的生态环境中生存和繁殖。这个项目将研究表观遗传学的变化，特别是DNA甲基化的变化，以了解在高海拔出生和长大对人类生物学的影响。多年来，生物人类学家一直试图了解允许在高海拔地区生存的可遗传遗传变异，这一项目对于从遗传焦点转移到表观遗传焦点具有重要意义。与个体遗传或不遗传的高海拔基因变体不同，DNA甲基化可以在个体的一生中发生变化，因为它在早期发育过程中经历了重新编程，因此容易受到环境的影响。项目发现将有助于我们理解早期发育如何影响极端环境的适应性表型。识别缺氧(低氧)反应途径的表观遗传学变化也可能为未来关于缺氧在癌症病因、心脏缺血和中风中的作用的研究提供信息。该项目还将支持本科生和研究生在实验室研究方法方面的培训。全基因组和基因特异性DNA甲基化签名将在安第斯山脉的一个高海拔种群-秘鲁克丘亚人中进行测量。研究参与者(n=601)被招募来代表不同的高原发育暴露，包括：1)在低海拔出生和长大(n=150)，2)在高海拔出生并在青春期移居低海拔(n=150)，3)在高海拔出生和长大(n=301)。这个项目建立在研究人员坚实的研究基础上，以了解在同一人群中有助于高海拔适应的基因变化。该项目可以评估遗传学和表观遗传学如何相互作用来创造安第斯山脉海拔适应的表型。了解这种相互作用对于专门研究高海拔适应和更广泛地研究人类生物适应具有重要意义。

At high altitudes, most people show a decrease in blood oxygen levels, a spike in blood pressure, and increased heart and breathing rates. However, long-term resident populations at high altitudes have unique physiological adaptations that allow them to survive and reproduce in this extreme niche. This project will examine epigenetic changes, specifically changes in DNA methylation, to understand how being born and raised at high altitude affects human biology. For many years biological anthropologists have sought to understand the heritable genetic variants that allow survival at high altitudes, and this project is significant in moving from a genetic to an epigenetic focus. Unlike high altitude gene variants that an individual either inherits or not, DNA methylation can change during an individual's lifetime because it undergoes reprogramming during early development and is therefore susceptible to the effects of the environment. Project findings will contribute to our understanding of how early development influences adaptive phenotypes to extreme environments. Identification of epigenetic changes in the hypoxia (low-oxygen) response pathway may also inform future research on the role of hypoxia in cancer etiology, cardiac ischemia, and stroke. The project will also support undergraduate and graduate training in laboratory research methods. Whole-genome and gene-specific DNA methylation signatures will be measured in one high altitude population from the Andes - the Peruvian Quechua. Study participants (n= 601) have been recruited to represent different high-altitude developmental exposures including: 1) born and raised at low altitude (n=150), 2) born at high altitude and moved to low altitude during adolescence (n = 150), 3) born and raised at high altitude (n=301). This project builds on the investigators' strong foundation of research to understand the genetic changes that contribute to high-altitude adaptation in this same population. This project allows the assessment of how genetics and epigenetics interact to create the Andean altitude-adaptive phenotype. Understanding this interaction has implications for the study of high-altitude adaptation specifically and human biological adaptation more generally.