Epigenetic regulation underlying phenotypic variation and driving evolutionary trajectories

项目摘要 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 据了解，这是由于遗传和环境因素的结合，但遗传成分是 被认为是系统的主要易处理部分，剩下的大部分表型变异都留在了 无法解释此外，群体遗传学的一个主要问题是，许多遗传变异没有得到解释， 由突变，选择和漂移的进化力量单独，包括可能有害的遗传变异。 这种无法解释的丰富的表型和遗传变异揭示了一个主要的差距，在我们的研究。 了解生命是如何运作的。此外，它对我们理解发展有重大影响， 复杂的疾病，可能会出现随机发展，因为我们有限的了解因素 影响他们。因此，我建议调查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。我提议一套 经验和理论方法，以解决这一差距的两个方面。首先，我会用蛔虫 秀丽隐杆线虫解剖表观遗传变异对表型变异贡献的两个关键 等基因群体中特定环境扰动后的生殖性状。这些实验 将在单蠕虫水平上进行（使用单蠕虫RNA-seq和ATAC-seq），以检验假设 生殖特征的差异是由单个个体的表观遗传状态的差异引起的。 其次，我将扩展群体遗传模型，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， 代这些互补的方法利用了每种系统的优势。与 C.对于线虫来说，产生大量基因相同的个体是直截了当的，而这些个体 不同的数量性状，使其成为一个理想的系统，以了解表观遗传变异的影响， 表型变异与此相反，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在时间尺度上影响遗传变异， 是不可行的实验测试。总的来说，这项工作将朝着长期目标取得重要进展- 长期目标是确定驱动表型和遗传变异的近端和最终机制。

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.