Characterizing the complex underpinnings of genetic background effects

项目摘要 这项研究计划的长期目标是确定遗传和分子 导致自发突变和诱导突变的机制在不同的环境中表现出不同的效果。 基因不同的个体。这些“背景效应”对人类健康很重要 因为它们会使预测、预防和治疗疾病的工作复杂化， 个性化的基因组数据虽然背景效应是已知的结果，从遗传 突变和常设多态性之间的相互作用，其潜在的遗传 结构和分子机制才刚刚开始被表征。我们最近的工作 表明背景效应通常由多个基因座引起， 不仅与突变相互作用，而且相互作用。这一发现可能具有重要意义 这对绘制疾病遗传基础和其他常见特征的努力具有重要意义。 受突变的影响，因此其普遍性和潜在机制需要更深入的研究。 调查在这里，我们将扩展我们的工作背景影响酵母使用新兴的 高通量表型分析和基因组编辑技术，以及统计学 强大的连锁图谱。我们的工作将解决三个主要问题：（1）什么是 背景效应的普遍性和形式？(2)基因的复杂性和类型 上位性是背景效应的基础（3）基因和遗传的性质是什么？ 造成背景效应的变量？这项工作将产生详细的见解， 背景效应，应该促进努力理解和预测的关系， 基因型和表现型之间的关系。

Project Summary The long-term goal of this research program is to determine the genetic and molecular mechanisms that cause spontaneous and induced mutations to show different effects across genetically distinct individuals. These `background effects' are important to human health because they can complicate efforts to predict, prevent, and treat disease based on personalized genomic data. Although background effects are known to result from genetic interactions between mutations and standing polymorphisms, their underlying genetic architectures and molecular mechanisms have only begun to be characterized. Our recent work in budding yeast suggests that background effects are typically caused by multiple loci that interact not only with a mutation, but also each other. This finding could have important implications for efforts to map the genetic basis of diseases and other traits that are commonly influenced by mutations, and thus its generality and underlying mechanisms require deeper investigation. Here, we will extend our work on background effects in yeast using emerging technologies for high-throughput phenotyping and genome editing, as well as statistically powerful linkage mapping. Our work will address three main questions: (1) What are the prevalence and forms of background effects? (2) What genetic complexities and types of epistasis underlie background effects? And, (3) what are the properties of genes and genetic variants that cause background effects? This work will produce detailed insights into background effects that should advance efforts to understand and predict the relationship between genotype and phenotype in humans and model organisms.