Comprehensive dissection of higher-order genetic interactions

高阶遗传相互作用的全面剖析

• 批准号: 9282754
• 负责人: Ian Michael Ehrenreich
• 金额: $ 27.23万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282754
• 关键词: Agriculture; Architecture; Area; Backcrossings; Biology; Carbon; Chromosome Mapping; Complex; Complex Genetic Trait; DNA biosynthesis; Defect; Dissection; Doxorubicin; Environment; Gene Expression; Gene Expression Profiling; Genetic; Genetic Engineering; Genetic Epistasis; Genome; Genotype; Goals; Growth; Heritability; Human; Individual; Light; Maps; Medicine; Methods; Molecular; Molecular Cloning; Molecular Models; Morphology; Nature; Parents; Pharmaceutical Preparations; Phenotype; Research; Resistance; Saccharomyces cerevisiae; Saccharomycetales; Siblings; Source; Specific qualifier value; Techniques; Temperature; To specify; Variant; Work; Yeast Model System; base; chemotherapy; drug sensitivity; genetic variant; genome sequencing; genome wide association study; improved; inhibitor/antagonist; insight; interest; molecular modeling; offspring; personalized medicine; protein function; public health relevance; screening; trait; whole genome

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.

描述（由申请人提供）：了解复杂性状的遗传基础对于推进医学，进化生物学和农业至关重要。限制这一领域进展的一个核心问题是，遗传变异可以以复杂的方式相互作用，使得它们的影响难以在标准的遗传图谱研究中检测到。特别是，最近的研究表明，“高阶”的遗传相互作用，涉及三个或更多的基因座通常有助于性状变异。对于这些复杂的遗传效应，人们知之甚少，而这些效应却显得B出奇的重要.确定高阶相互作用如何在分子水平上产生并对性状产生影响，可能对解决人类和其他物种的“缺失遗传性”问题至关重要。我们的目标是在这个建议是充分表征的分子基础和多个高阶相互作用的表型效应。我们已经确定了三个性状的酿酒酵母杂交，指定的相互作用位点的集合，每个可以提供独特的见解如何高阶相互作用有助于表型变异。我们将全面剖析离散形态性状（目标1），环境敏感的生长缺陷（目标2），和定量药物敏感性表型（目标3）使用的酵母模型系统的力量。通过完成我们的工作，我们将为高阶相互作用提供一些第一个直接的，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、进化生物学和农业方面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仅确定了一小部分性状的遗传基础。失踪 这些研究中仍然存在的遗传性可以说是个性化医疗和基因组序列信息生物学新时代的主要障碍。涉及三个或更多基因座的高阶遗传相互作用可能是缺失遗传力的重要来源，因为它们在标准遗传作图研究中可能无法检测到。我们是少数研究小组之一，他们发现了令人信服的证据，证明高阶相互作用可以导致重大的、意想不到的表型效应。在这个提议中，我们的目标是了解高阶相互作用的功能机制。我们的工作的完成应该提供重要的见解高阶相互作用的潜在贡献的缺失在人类和其他物种的复杂性状的遗传性。