Comprehensive dissection of higher-order genetic interactions

描述（由申请人提供）：了解复杂性状的遗传基础对推进医学、进化生物学和农业至关重要。限制这一领域进展的一个中心问题是，遗传变异可以以复杂的方式相互作用，使其影响难以在标准的遗传作图研究中检测到。特别是，最近的研究表明，涉及三个或更多基因座的“高阶”遗传相互作用通常有助于性状变异。对于这些复杂的基因效应，我们所知甚少，而它们的重要性却惊人。确定高阶相互作用如何在分子水平上产生并对性状做出贡献，可能对解决人类和其他物种的“缺失遗传性”问题至关重要。我们的目标是充分表征分子基础和多种高阶相互作用的表型效应。我们已经确定了酿酒酵母杂交中的三个性状，这些性状由一系列相互作用位点指定，每个性状都可以为高阶相互作用如何促进表型变异提供独特的见解。我们将利用酵母模型系统的力量全面剖析离散形态特征（Aim 1），环境敏感生长缺陷（Aim 2）和定量药物敏感表型（Aim 3）。通过完成我们的工作，我们将为高阶交互提供一些直接的、机械的见解。相关性：阐明基因型和表型之间的联系对于在医学、进化生物学和农业领域达到新的高度至关重要。然而，对于许多感兴趣的表型，全基因组关联和连锁研究只确定了一小部分性状的遗传基础。失踪的

DESCRIPTION (provided by applicant): Understanding the genetic basis of complex traits is critical for advancing medicine, evolutionary biology, and agriculture. A central problem limiting progress in this area is that genetic variants can interact in complicated ways, making their effects difficult to detect in standard genetic mapping studies. In particular, recent research suggests that 'higher-order' genetic interactions involving three or more loci commonly contribute to trait variation. Little is known about these complex genetic effects that appear to b surprisingly important. Determining how higher-order interactions arise at the molecular level and contribute to traits may prove vital to solving the 'missing heritability' problem in humans and other species. Our goal in this proposal is to fully characterize the molecular bases and phenotypic effects of multiple higher-order interactions. We have identified three traits in Saccharomyces cerevisiae crosses that are specified by sets of interacting loci and can each provide unique insights into how higher-order interactions contribute to phenotypic variation. We will comprehensively dissect a discrete morphological trait (Aim 1), an environmentally sensitive growth defect (Aim 2), and a quantitative drug sensitivity phenotype (Aim 3) using the power of the yeast model system. By completing our work, we will provide some of the first direct, mechanistic insights into higher-order interactions. Relevance: Elucidating the connection between genotype and phenotype is critical to achieving new heights in medicine, evolutionary biology, and agriculture. However, for many phenotypes of interest, genome-wide association and linkage studies have only identified a small fraction of the traits' genetic bases. The missing heritability that remains in these studies is arguably the primary barrier to a new era of personalized medicine and genome sequence-informed biology. Higher-order genetic interactions involving three or more loci could represent a significant source of missing heritability, as they may not be detected in standard genetic mapping studies. We are among a small number of research groups that have found compelling evidence that higher-order interactions can result in major, unexpected phenotypic effects. In this proposal, our goal is to understand the functional mechanisms that underlie higher-order interactions. Completion of our work should provide crucial insights into the potential contribution of higher-order interactions t the missing heritability of complex traits in humans and other species.