Genetic and Nongenetic Variation in Complex Traits

复杂性状的遗传和非遗传变异

• 批准号: 10552384
• 负责人: Mark L Siegal
• 金额: $ 49.69万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552384
• 关键词: Biological Models; Biomedical Research; Cell Shape; Cell Size; Cells; Clinical; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease; Genes; Genetic; Genetic Epistasis; Genotype; Goals; Growth; Health; Heterogeneity; Human; Individual; Infection; Knowledge; Malignant Neoplasms; Measurement; Mediating; Methods; Microbe; Microscopy; Molecular; Mutation; Pathway interactions; Pharmaceutical Preparations; Phosphotransferases; Population; Predisposition; Process; Research; Role; Saccharomyces cerevisiae; Saccharomycetales; Source; Uncertainty; Variant; Virus; Work; acute stress; chemical genetics; disorder risk; experimental study; genetic manipulation; microbial; neoplastic cell; non-genetic; pathogen; pathogenic microbe; personalized medicine; pressure; programs; response; single cell analysis; stress tolerance; trait; tumor

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.

项目概要/摘要 该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 芽殖酵母（酿酒酵母）的特征，并遵循两条主要工作路线。一条线工作目标 了解基因之间的相互作用（上位性）如何导致自然性状变异。理解 复杂性状变异的来源是生物医学研究的一个主要目标，因为这些知识 直接影响个性化医疗的前景，例如预测疾病风险 个体的基因型。如果不考虑在内，上位性可能会混淆此类预测。上位性也是 很重要，因为它可以限制进化适应遵循特定的路径，使适应更加有效 可预测的。这种可预测性对于治疗具有很强进化性的疾病可能很有价值 成分，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，以及在某些病毒或微生物在强大压力下进化的情况下，其在 人们对确定自然群体特征如何变化知之甚少。该研究计划的主要目标 进行实验，检测相互作用的能力显着增强，并扩大范围 研究的特征包括细胞形状和大小，这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，他们将创建并使用酿酒酵母菌株，从而使寻找 上位性更加强大。另一项工作旨在了解允许 克隆细胞群产生异质性，这可能有利于面对环境 不确定。这种异质性体现在病原微生物和肿瘤细胞对药物的反应中，并且 因此具有重大的临床意义，但人们对异质性是如何调节的知之甚少 以及如何改变它。最近的工作表明，酿酒酵母克隆群体包含快速生长的 易受急性应激影响的细胞和能够耐受急性应激的生长缓慢的细胞 差异是由保守 Ras/环 AMP/蛋白激酶 A 通路的可变活性介导的。这 该激酶在调节生长速率和应激耐受性中的作用将使用化学遗传技术进行探讨 操纵。目标是更好地理解该模型中自适应异质性的机制基础 系统，并最终推进对持久性病原体和癌症的治疗。