Genetic and Nongenetic Variation in Complex Traits

 描述（由申请人提供）：本研究计划的长期目标是了解复杂性状变异的机制和进化原因。目前的重点是似乎抑制或促进变异的机制。主要的实验方法是对芽殖酵母酿酒酵母的单细胞性状进行大规模分析。一系列的研究表明，隐藏的遗传变异是普遍存在的，这种变异一直被抑制，直到一个扰动揭示了它的表型效应。这一观察结果表明，遗传相互作用（上位性）可能是一个主要的决定因素复杂的性状变异。第二条工作路线与其他人一起提出，一些克隆种群产生异质性是为了对冲环境不确定性。研究计划将遵循这两条工作路线。其中一组项目旨在了解上位性如何促进复杂性状的自然变异。了解复杂性状的变异来源是生物医学研究的一个主要目标，因为这一知识直接影响到个性化医疗的前景，例如预测个体基因型的疾病风险。如果不考虑上位性，上位性可能会混淆这些预测。上位性也很重要，因为它可以限制进化适应遵循特定的路径，使适应更可预测。这种可预测性在治疗具有强烈进化成分的疾病（如微生物感染和癌症）方面可能很有价值。虽然上位性已经使用实验室衍生的突变进行了很好的研究，但在自然界中还没有得到很好的研究，因为大多数实验设计没有足够的能力来检测相互作用的基因座。这项研究计划的一个关键目标是进行研究，以显着增加的力量来检测大量独立表型的相互作用，以获得更丰富的复杂性状差异的根本原因。这些研究将利用最近在开发高通量、基于显微镜的方法来量化许多独立表型方面的进展，他们将创建和使用S。使得上位性的搜索更加有力。另一组项目旨在了解新发现的赌注对冲现象的分子机制，即克隆种群的S。酿酒酵母含有对急性应激敏感的快速生长细胞和耐受急性应激的缓慢生长细胞。这种适应性异质性的分子机制知之甚少，特别是在真核生物中，因此有机会利用强大的遗传，分子和细胞生物学工具在真核生物模型中研究这种系统可能会带来重大进展。将研究控制生长和抗逆性异质性的候选途径。此外，生长率分布的自然变化之间的S。酿酒酵母菌株将被映射，在努力了解生态压力如何塑造赌注对冲机制。这两条线的工作收敛在这里，因为上位性相互作用似乎占主导地位的生长速度方差差异的遗传基础。

 DESCRIPTION (provided by applicant): The long-term goal of this research program is to understand the mechanistic and evolutionary causes of variation in complex traits. The current focus is on mechanisms that appear to either suppress or promote variation. The primary experimental approach is to perform large-scale analyses of single-cell traits of the budding yeast, Saccharomyces cerevisiae. One line of work joins others in showing that cryptic genetic variation, kept suppressed until a perturbation reveals its phenotypic effects, is pervasive. This observation suggests that genetic interactions (epistasis) might be a major determinant of complex-trait variation. A second line of work joins others in suggesting that some clonal populations generate heterogeneity in order to hedge their bets against environmental uncertainty. The research program will follow these two lines of work. One set of projects aims to understand how epistasis contributes to natural variation in complex traits. Understanding the sources of variation in complex traits is a major goal in biomedical research because this knowledge impinges directly on the prospect of personalized medicine, for example the prediction of disease risk from an individual's genotype. If not taken into account, epistasis can confound such predictions. Epistasis is also important because it can constrain evolutionary adaptation to follow particular paths, making adaptation more predictable. This predictability could be valuable in the treatment of diseases that have a strong evolutionary component, such as microbial infections and cancer. Although epistasis has been well studied using lab- derived mutations, it has not been well studied in nature because most experimental designs have insufficient power to detect interacting loci. A key aim of this research program is to perform studies with dramatically increased power to detect interactions, for a large number of independent phenotypes, to gain a far richer view of the underlying causes of differences in complex traits. These studies will leverage recent progress in developing high-throughput, microscopy-based methods of quantifying many independent phenotypes, and they will create and use strains of S. cerevisiae that make searching for epistasis much more powerful. The other set of projects aims to understand the molecular mechanisms underlying a newly discovered bet-hedging phenomenon whereby clonal populations of S. cerevisiae contain fast-growing cells that are sensitive to acute stress and slow-growing cells that are tolerant of acute stress. Molecular mechanisms of this kind of adaptive heterogeneity are poorly understood, especially in eukaryotes, so the opportunity to study such a system in a model eukaryote with powerful genetic, molecular and cell-biological tools could lead to major advances. A candidate pathway for controlling the heterogeneity in growth and stress resistance will be studied. In addition, natural variation in growth-rate distributions between S. cerevisiae strains will be mapped, in an effort to understand how ecological pressures shape bet-hedging mechanisms. The two lines of work converge here because epistatic interactions appear to dominate the genetic basis of differences in growth-rate variance.