Genetic and Nongenetic Variation in Complex Traits

项目摘要/摘要 这项研究计划的长期目标是了解 复杂性状的变异。主要的实验方法是对单细胞进行大规模分析 酿酒酵母的特性，并遵循两个主要的工作。一条工作目标是 了解基因之间的相互作用(上位性)如何影响自然性状变异。理解 复杂性状变异的来源是生物医学研究的主要目标，因为这一知识 直接影响个性化医疗的前景，例如，从 个体的基因型别。如果不考虑上位性，上位性可能会混淆这样的预测。上位主义也是 重要的是，它可以约束进化适应遵循特定的路径，使适应更 这是可预见的。这种可预测性在治疗具有很强进化性的疾病中可能是有价值的。 例如微生物感染和癌症。尽管上位性已经通过实验室得到了很好的研究- 衍生突变，以及在某些情况下的病毒或微生物在强大的进化压力下，其在 确定自然种群中的特征是如何变化的还知之甚少。本研究计划的主要目标 是以极大的能力进行实验，以检测相互作用并扩大范围 研究包括细胞形状和大小的特征，这些特征在许多疾病过程中都很重要。这些 研究将利用高通量、基于显微镜的方法的最新进展来量化许多 独立的细胞特征，他们将创造和使用酿酒酵母菌株，使搜索 上位主义要强大得多。另一项工作旨在了解分子机制，使 克隆细胞群体产生的异质性在面对环境时可能是有益的 不确定性。这种异质性体现在致病微生物和肿瘤细胞对药物的反应中，以及 因此具有重大的临床意义，但对于异质性是如何调节的却知之甚少。 以及如何才能改变它。最近的研究表明，酿酒酵母的克隆种群包含快速增长的 对急性应激敏感的细胞和耐受急性应激的生长缓慢的细胞，以及这些 差异是由保守的RAS/cAMP/蛋白激酶A途径的不同活性所调节的。这个 该激酶在调节生长速度和压力耐受性方面的作用将通过化学遗传学来探讨。 操纵。目标是更好地理解该模型中适应性异质性的机制基础 系统，并最终推进对持久性病原体和癌症的治疗。

PROJECT SUMMARY/ABSTRACT The long-term goal of this research program is to understand the mechanistic and evolutionary causes of variation in complex traits. The primary experimental approach is to perform large-scale analyses of single-cell traits of the budding yeast, Saccharomyces cerevisiae, and follows two major lines of work. One line of work aims to understand how interaction between genes (epistasis) contributes to natural trait variation. 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, as well as in some cases of viruses or microbes under strong pressures to evolve, its role in determining how traits vary in natural populations is poorly understood. Key goals of this research program are to perform experiments with dramatically increased power to detect interactions, and to expand the range of traits that are studied to include cell shape and size, which are important in many disease processes. These studies will leverage recent progress in using high-throughput, microscopy-based methods to quantify many independent cellular features, and they will create and use strains of S. cerevisiae that make searching for epistasis much more powerful. The other line of work aims to understand molecular mechanisms that allow clonal cell populations to generate heterogeneity that might be beneficial in the face of environmental uncertainty. Such heterogeneity is seen in the responses of pathogenic microbes and tumor cells to drugs, and therefore has major clinical implications, yet there is very little known about how heterogeneity is regulated and how it can be altered. Recent work has shown that clonal populations of S. cerevisiae contain fast-growing cells that are susceptible to acute stress and slow-growing cells that are tolerant of acute stress, and that these differences are mediated by variable activity of the conserved Ras/cyclic AMP/protein kinase A pathway. The role of this kinase in tuning growth rates and stress tolerances will be probed using chemical-genetic manipulation. The goal is to better understand the mechanistic basis of adaptive heterogeneity in this model system, and ultimately to advance treatment of persistent pathogens and cancers.