Genetic and Nongenetic Variation in Complex Traits

项目总结/摘要 这项研究计划的长期目标是了解的机械和进化的原因， 复杂性状的变异。主要的实验方法是进行大规模的单细胞分析， 性状的芽殖酵母，酿酒酵母，并遵循两个主要的工作路线。一行工作目标 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 复杂性状的变异来源是生物医学研究的主要目标，因为这种知识 直接影响到个性化医疗的前景，例如， 个体的基因型。如果不考虑上位性，上位性可能会混淆这些预测。上位性也是 重要的是，它可以限制进化适应遵循特定的路径，使适应更加复杂。 可预测的。这种可预测性在治疗具有强烈进化性的疾病方面可能是有价值的。 例如微生物感染和癌症。虽然上位性已经很好地研究了使用实验室- 衍生的突变，以及在某些情况下，病毒或微生物在强大的压力下进化，它的作用， 确定性状在自然群体中如何变化的理解很少。本研究计划的主要目标 是进行实验，大大提高检测相互作用的能力，并扩大范围， 研究的特征包括细胞的形状和大小，这在许多疾病过程中很重要。这些 研究将利用最近的进展，使用高通量，显微镜为基础的方法来量化许多 独立的细胞特征，他们将创造和使用S.酿酒厂，使寻找 上位性更强大。另一项工作旨在了解分子机制， 克隆细胞群体产生异质性，这可能是有益的，在面对环境 不确定性这种异质性见于病原微生物和肿瘤细胞对药物的反应， 因此具有重要的临床意义，但对异质性如何调节知之甚少 以及如何改变它。最近的研究表明，S。酿酒酵母含有快速生长的 对急性应激敏感的细胞和对急性应激耐受的生长缓慢的细胞，这些细胞 这些差异是由保守的Ras/环AMP/蛋白激酶A途径的可变活性介导的。的 该激酶在调节生长速率和胁迫耐受性中的作用将使用化学遗传学方法来探索。 操纵我们的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.