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.

高海拔处的高海拔低氧或低氧气可用性是人类进化史上最强的选择压力之一。尽管这种巨大的环境压力源，但数千年来，几个人口在高海拔地区蓬勃发展，并显示出对低氧气可用性的独特适应性。尽管最近的研究已经记录了遗传进化在塑造高海拔不同适应性的作用中，但对于表观遗传学的作用（或影​​响基因表达）的作用却鲜为人知，这是对不同种群对缺氧压力的反应方式的作用。该博士学位论文研究项目研究了人口中高空缺氧影响DNA甲基化（DNAM - 一种特定的表观遗传效应）模式的程度，以及DNAM有助于适应这种环境的功能作用。在这样做的过程中，该项目直接通过探索表观遗传变化对高海高基因表达模式和表型的关键作用而直接有助于有关人类进化，变异和适应性的知识体系。该项目支持研究和当地社区中以STEM为重点的教育和推广工作，并培训本科研究助理。使用移民研究设计，该项目分析了来自三组研究参与者的表观遗传学，转录组和表型数据，患有低氧较低的研究参与者。三个参与组之间的差异甲基化分析用于识别与高空缺氧相关的不同甲基化位置和区域。在串联中，mRNA测序和分析用于鉴定与暴露于高海拔的基因表达模式。 DNAM水平与1）基因表达和2）自适应表型识别与转录组和表型变化相关的关键甲基化差异。这种多媒体方法为适应性发育可塑性在塑造人类适应高海拔地区的作用提供了新的见解。此外，这项研究的结果是基于对其他高海拔种群中DNAN模式的先前研究。通过比较表观遗传变化在塑造不同人群中高空自适应表型中的作用，这项研究提供了对高空自适应表型的收敛模式的批判性见解。该奖项反映了NSF的法定任务，并通过基金会的知识优点和广泛的影响来通过评估来诚实地通过评估来诚实地进行评估。