Epigenetic regulation underlying phenotypic variation and driving evolutionary trajectories

表型变异和驱动进化轨迹的表观遗传调控

• 批准号: 10604435
• 负责人: Amy Katherine Webster
• 金额: $ 6.91万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604435
• 关键词: ATAC-seq; Address; Adult; Affect; Alleles; Automobile Driving; Back; Biological Assay; Caenorhabditis elegans; Chromatin; Complex; DNA Sequence Alteration; Development; Diploidy; Disease; Engineering; Environmental Risk Factor; Epigenetic Process; Etiology; Exhibits; Gene Expression; Generations; Genes; Genetic; Genetic Models; Genetic Transcription; Genetic Variation; Genotype; Goals; Heritability; Human; Individual; Individual Differences; Left; Life; Life Experience; Maintenance; Maps; Maternal Age; Measures; Mediating; Modeling; Molecular; Mutation; Nature; Nematoda; Organism; Outcome; Output; Phenotype; Planet Earth; Play; Population; Population Genetics; Probability; Regulation; Resolution; Role; Shapes; System; Temperature; Testing; Theoretical model; Time; Traction; Twin Studies; Variant; Work; dynamic system; egg; emerging adult; epigenetic regulation; epigenetic variation; epigenomics; experience; experimental study; fitness; gene expression variation; gene network; genetic variant; insight; non-genetic; reproductive; trait; transcriptome sequencing

PROJECT SUMMARY In nature, we observe an abundance of both phenotypic and genetic variation. Phenotypic variation is understood to be due to a combination of genetic and environmental factors, but the genetic component is considered the primary tractable part of the system, and much of the remaining phenotypic variation is left unexplained. In addition, a major problem in population genetics is that much genetic variation in not explained by evolutionary forces of mutation, selection, and drift alone, including genetic variants that may be deleterious. This unexplained abundance of both phenotypic and genetic variation reveals a major gap in our understanding of how life works. Further, it has major implications for our understanding of the development of complex diseases, which may appear to develop randomly because of our limited understanding of factors influencing them. I therefore propose investigating differences in epigenetic regulation (‘epigenetic variation’) as a unifying causal factor to account for unexplained phenotypic and genetic variation. I propose a set of empirical and theoretical approaches to address both facets of this gap. First, I will use the roundworm Caenorhabditis elegans to dissect the contribution of epigenetic variation to phenotypic variation in two key reproductive traits following specific environmental perturbations in isogenic populations. These experiments will be performed at the single-worm level (using single-worm RNA-seq and ATAC-seq) to test the hypothesis that differences in reproductive traits are caused by differences in the epigenetic state of single individuals. Second, I will extend population-genetic models to incorporate epigenetic variation to test the hypothesis that epigenetic variation is a major contributor to the maintenance of genetic variation in populations over many generations. These complementary approaches take advantage of the strengths of each type of system. With C. elegans, it is straight-forward to generate large populations of genetically identical individuals, and these differ for quantitative traits, making it an ideal system to understand the influence of epigenetic variation on phenotypic variation. Using theoretical models, in contrast, facilitates the incorporation of genetic and epigenetic variation simultaneously to ask how epigenetic variants affect genetic variation over timescales that are not feasible to test experimentally. Collectively, this work will make important progress toward the long- term goal of identifying proximate and ultimate mechanisms driving phenotypic and genetic variation.

项目总结 在自然界中，我们观察到大量的表型和遗传变异。表型变异是 被理解为是由于遗传和环境因素的组合，但遗传成分是 被认为是系统的主要易处理部分，留下了大部分剩余的表型变异 无法解释。此外，种群遗传学中的一个主要问题是，许多遗传变异没有得到解释 通过突变、选择和漂移的进化力量，包括可能有害的遗传变异。 这种无法解释的表型和遗传变异的丰富揭示了我们的 理解生活是如何运作的。此外，它还对我们理解 复杂的疾病，可能因为我们对因素的有限理解而随机发展 影响着他们。因此，我建议研究表观遗传调控的差异(‘表观遗传变异’) 作为一个统一的因果因素来解释无法解释的表型和遗传变异。我提出了一套 解决这一差距的两个方面的经验和理论方法。首先，我会用蛔虫 秀丽线虫剖析表观遗传变异对表型变异的贡献 在等基因群体中，特定环境扰动后的生殖特征。这些实验 将在单虫级别执行(使用单虫RNA-seq和atac-seq)来检验假设 生殖特征的差异是由单个个体表观遗传状态的差异引起的。 其次，我将扩展种群遗传模型，将表观遗传变异纳入其中，以检验以下假设 表观遗传变异是维持种群遗传变异的主要因素 几代人。这些互补的方法利用了每种类型系统的优势。使用 线虫，很容易产生大量基因相同的个体，而这些 数量性状不同，使其成为了解表观遗传变异对 表型变异。相比之下，使用理论模型有助于将遗传和 表观遗传变异同时询问表观遗传变异如何影响时间尺度上的遗传变异 在实验上测试是不可行的。总体而言，这项工作将朝着长远的方向取得重要进展- 术语目标是确定驱动表型和遗传变异的近端和终极机制。