Doctoral Dissertation Research: The genetic basis of epigenetic variation and environmental response in primates

博士论文研究：灵长类表观遗传变异和环境反应的遗传基础

• 批准号: 2216701
• 负责人: James Higham
• 金额: $ 2.51万
• 依托单位: New York University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2216701&HistoricalAwards=false
• 关键词: Doctoral; Dissertation; Research; genetic; basis

Genetic changes which influence the regulation of how and when genes are expressed are a prominent source of heritable differences between individuals. Individuals differ in their degree of epigenetic marks across the genome, which are chemical changes that do not impact the DNA sequence but that alter which genes are turned on or off. This doctoral dissertation research uses a non-human primate population to investigate the genetic differences responsible for epigenetic differences between individuals, and to study how an individual’s social or ecological environment may modify the relationship between genotype and gene regulation. This research aids our understanding of complex genotype-phenotype relationships in primates and identifies the genes where genetic differences may contribute to differential risk or susceptibility following exposure to adversity. This has potential implications for human populations facing similar experiences, including psychosocial stressors and natural disasters. This project trains a female graduate student in STEM and supports high school and undergraduate research mentoring initiatives for individuals from groups that are underrepresented in science.Gene regulatory change is an important mechanism of primate evolution and regulatory differences within populations correlate with fitness-relevant traits. Despite this, the genetic variants responsible for these differences are relatively unknown. This research tests the hypothesis that sequence variation predicts individual differences in a well-known epigenetic mark, DNA methylation, in functional regions of the genome, and that gene-environment interactions (GxE) are prominent contributors to phenotypic differences at the molecular level. The project generates whole genome and methylation data from the same individuals to identify genetic variants associated with methylation differences in the population, and explores the epigenetic changes associated with individual social status and hurricane exposure, to identify context-dependent genetic effects on methylation at environmentally sensitive sites (GxE).The research reveals genes whose expression is sensitive to environmental and genetic changes, and the sources of individual differences in physiological response to the same environmental stressor. Finally, the project comprehensively catalogues the factors that best explain differences in DNA methylation at each site in the genome to determine the relative contribution of genetic, environmental, and GxE effects to gene regulatory variation. Project outcomes shed light on the proximate mechanisms driving transcriptional differences across individuals and environments and generating phenotypic variation on which selection can act.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.

影响基因表达方式和时间的遗传变化是个体间遗传差异的重要来源。个体在基因组中表观遗传标记的程度不同，表观遗传标记是一种化学变化，不会影响DNA序列，但会改变基因的开启或关闭。本博士论文研究利用非人类灵长类动物群体来研究个体之间表观遗传差异的遗传差异，并研究个体的社会或生态环境如何改变基因型与基因调控之间的关系。这项研究有助于我们理解灵长类动物复杂的基因型-表型关系，并确定遗传差异可能导致逆境暴露后不同风险或易感性的基因。这对面临类似经历的人群有潜在的影响，包括社会心理压力和自然灾害。该项目培训一名STEM领域的女研究生，并为来自科学领域代表性不足群体的个人提供高中和本科研究指导计划。基因调控变化是灵长类动物进化的重要机制，种群内的调控差异与适应性相关的性状有关。尽管如此，造成这些差异的基因变异还是相对未知的。该研究验证了以下假设：序列变异预测了基因组功能区域中众所周知的表观遗传标记DNA甲基化的个体差异，以及基因-环境相互作用（GxE）是分子水平上表型差异的重要贡献者。该项目生成来自同一个体的全基因组和甲基化数据，以确定与群体甲基化差异相关的遗传变异，并探索与个体社会地位和飓风暴露相关的表观遗传变化，以确定环境敏感位点（GxE）甲基化的环境依赖遗传效应。该研究揭示了对环境和遗传变化敏感的基因表达，以及对相同环境应激源的生理反应个体差异的来源。最后，该项目全面编目了最能解释基因组中每个位点DNA甲基化差异的因素，以确定遗传、环境和GxE效应对基因调控变异的相对贡献。项目结果揭示了驱动个体和环境之间转录差异的近似机制，并产生了选择可以发挥作用的表型变异。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。