Epigenetic regulation underlying phenotypic variation and driving evolutionary trajectories

项目概要 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 被认为是遗传和环境因素共同作用的结果，但遗传成分是 被认为是系统的主要易处理部分，并且留下了许多剩余的表型变异 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无法解释。 仅通过突变、选择和漂变的进化力量，包括可能有害的遗传变异。 这种无法解释的大量表型和遗传变异揭示了我们在 了解生活如何运作。此外，它对我们理解计算机科学的发展也具有重大意义。 复杂的疾病，由于我们对因素的了解有限，这些疾病可能看起来是随机发展的 影响他们。因此，我建议研究表观遗传调控的差异（“表观遗传变异”） 作为解释无法解释的表型和遗传变异的统一因果因素。我建议一套 解决这一差距的两个方面的经验和理论方法。首先，我将使用蛔虫 秀丽隐杆线虫剖析表观遗传变异在两个关键方面对表型变异的贡献 同基因群体中特定环境扰动后的生殖特征。这些实验 将在单蠕虫水平上进行（使用单蠕虫 RNA-seq 和 ATAC-seq）来检验假设 生殖性状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： 表观遗传变异是许多群体中维持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。与 线虫，产生大量基因相同的个体是很简单的，而且这些 数量性状不同，使其成为了解表观遗传变异影响的理想系统 表型变异。相反，使用理论模型有助于将遗传和 同时研究表观遗传变异，以了解表观遗传变异如何影响时间尺度上的遗传变异 无法通过实验进行测试。总的来说，这项工作将在长期目标方面取得重要进展 确定驱动表型和遗传变异的直接和最终机制的长期目标。

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.