Doctoral Dissertation Research: Developmental Adaptation to High-Altitude Hypoxia

高海拔低氧，或高海拔低氧气利用率，是人类进化史上最大的选择压力之一。尽管有这种可怕的环境压力，但数千年来，一些人类群体一直在高海拔地区茁壮成长，并对低氧气供应表现出独特的适应能力。尽管最近的研究已经证明了遗传进化在塑造不同的高原适应能力方面的作用，但关于表观遗传学的作用-或者影响基因表达的影响-关于不同群体如何应对低氧应激，人们知之甚少。这项博士论文研究项目调查了高海拔低氧对人类群体DNA甲基化(dNaM-一种特定的表观遗传效应)模式的影响程度，以及dNaM在适应这种环境中所起的功能作用。在此过程中，该项目通过探索表观遗传变化对高海拔基因表达模式和表型的关键作用，直接为人类进化、变异和适应能力的知识体系做出了贡献。该项目支持STEM在研究和当地社区的重点教育和推广工作，以及对本科生研究助理的培训。该项目使用移民研究设计，分析了三组不同暴露于低氧环境的研究参与者的表观遗传学、转录本和表型数据。三个参与者组之间的差异甲基化分析被用来确定与发育过程中暴露在高海拔低氧环境中相关的差异甲基化位置和区域。同时，使用mRNA测序和分析来确定与高海拔暴露相关的基因表达模式。DNaM水平与1)基因表达和2)适应性表型之间的关联测试确定了与转录和表型变化相关的关键甲基化差异。这一多组学方法为适应发育可塑性在塑造人类对高海拔适应中的作用提供了新的见解。此外，这项研究的结果建立在以前对其他高海拔人群中dNaM模式的研究基础上。通过比较表观遗传变化在不同人群中形成高海拔适应表型的作用，这项研究提供了对高海拔适应表型收敛模式的关键洞察。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

High-altitude hypoxia, or low oxygen availability at high elevations, presents one of the strongest selective pressures in human evolutionary history. Despite this formidable environmental stressor, several human populations have thrived at high altitude for millennia and display unique adaptations to low oxygen availability. Although recent research has documented the role of genetic evolution in shaping different adaptations to high altitude, less is known concerning the role of epigenetics – or influences shaping gene expression – with respect to how different populations respond to the stressor of hypoxia. This doctoral dissertation research project investigates the extent to which high-altitude hypoxia impacts DNA methylation (DNAm – one specific kind of epigenetic effect) patterns in a human population, and the functional role that DNAm contributes to adaptation to this environment. In doing so, this project directly contributes to the body of knowledge on human evolution, variation, and adaptability by exploring the critical role of epigenetic change on high-altitude gene expression patterns and phenotypes. This project supports STEM-focused educational and outreach efforts in research and local communities, and training of undergraduate research assistants.Using a migrant study design, this project analyzes epigenetic, transcriptomic, and phenotypic data from three groups of study participants with differential exposure to hypoxia. Differential methylation analysis between the three participant groups is used to identify differentially methylated positions and regions associated with developmental exposure to high-altitude hypoxia. In tandem, mRNA sequencing and analysis is used to identify gene expression patterns associated with exposure to high altitude. Association testing between DNAm levels and 1) gene expression and 2) adaptive phenotypes identifies key methylation differences associated with transcriptomic and phenotypic changes. This multi-omics approach offers new insight into the role of adaptive developmental plasticity in shaping human adaptation to high altitude. Further, results of this study build on on previous studies of DNAm patterns in other high-altitude populations. By comparing the role of epigenetic changes in shaping high-altitude adaptive phenotypes in different populations, this research provides critical insight into the convergent patterns of high-altitude adaptive phenotypes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.