Doctoral Dissertation Research: Developmental Adaptation to High-Altitude Hypoxia

博士论文研究：高原缺氧的发育适应

• 批准号: 2316944
• 负责人: Abigail Bigham
• 金额: $ 3.9万
• 依托单位: University of California-Los Angeles
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2316944&HistoricalAwards=false
• 关键词: Doctoral; Dissertation; Research; Developmental; Adaptation

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.

在人类进化史上，高海拔缺氧或高海拔地区的低氧可用性表现出最强的选择压力之一。尽管有这种可怕的环境压力，一些人类种群在高海拔地区繁衍了数千年，并表现出对低氧可用性的独特适应。尽管最近的研究已经记录了遗传进化在形成不同的高海拔适应性方面的作用，但关于表观遗传学的作用（或影响形成基因表达的因素）在不同种群对缺氧应激源的反应方面的作用知之甚少。本博士论文研究项目调查了高海拔缺氧对人类群体DNA甲基化（DNAm -一种特殊的表观遗传效应）模式的影响程度，以及DNAm在适应这种环境中的功能作用。因此，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、变异和适应性的知识体系做出贡献。该项目支持在研究和当地社区开展以stem为重点的教育和推广工作，并培训本科生研究助理。采用迁移研究设计，本项目分析了三组不同缺氧暴露程度的研究参与者的表观遗传学、转录组学和表型数据。三个参与者组之间的差异甲基化分析用于确定与发育暴露于高海拔缺氧相关的差异甲基化位置和区域。同时，mRNA测序和分析用于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组和表型变化相关的关键甲基化差异。这种多组学方法为适应性发育可塑性在塑造人类对高海拔的适应中所起的作用提供了新的见解。此外，这项研究的结果建立在先前对其他高海拔人群dna模式的研究基础上。通过比较表观遗传变化在不同种群高海拔适应表型形成中的作用，本研究为高海拔适应表型的趋同模式提供了重要的见解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。