Genetic interactions and the evolution of complex traits in yeast

酵母中的遗传相互作用和复杂性状的进化

• 批准号: 10622677
• 负责人: Gregory I Lang
• 金额: $ 40.89万
• 依托单位: LEHIGH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622677
• 关键词: Address; Antibiotic Resistance; Biological Assay; Biology; Complex; Cytoplasm; Environment; Evolution; Future; Gene Pool; Generations; Genes; Genetic; Genetic Variation; Genome; Genotype; Health; Human; Immune Evasion; Immune system; Knowledge; Laboratories; Life; Malignant Neoplasms; Methods; Mutation; Nuclear; Pathway interactions; Pharmacotherapy; Phenotype; Planet Earth; Population; Process; System; Techniques; Testing; Time; Variant; Work; Yeasts; experimental study; functional genomics; gene environment interaction; human pathogen; insight; pathogen; pathogenic virus; pressure; purge; theories; tool; trait

PROJECT SUMMARY/ABSTRACT Adaptive evolution is a fundamental process in biology. At its simplest random mutation produces phenotypic variation on which selection acts, enriching for favorable phenotypes and purging the less- favorable ones. This process has produced the diversity of life on Earth. Yet at the same time, adaptive evolution is responsible for some of the most vexing problems in human health, from the growing problem of antibiotic resistance to real-time evolution of viral pathogens to cancers that resist drug treatments and evade the immune system. Despite this, we lack a basic mechanistic understanding of how genomes respond to selection. One major unknown is how adaptive evolution “chooses” one particular path from among a vast number of possible ones. Another major unknown is how genetic variation produces new phenotypes on which selection acts. Experimental Evolution provides a way forward to address both of these significant gaps in our knowledge. With advances in high-throughput biology we can evolve hundreds of initially identical populations in parallel for thousands of generations, with exquisite control over experimental parameters. This versatile technique makes it possible to test evolutionary theory through experiments that are impossible to perform in natural populations. At the same time, experimental evolution is powerful tool for functional genomics. By identifying the genes and pathways that respond to selective pressures, and how these mutations interact to alter phenotype, laboratory evolution experiments identify previously unknown cellular connections. In the past five years my laboratory has advanced a mechanistic understanding of adaptive evolution. Future work will determine how genetic changes give rise to complex phenotypes. We will perform evolution experiments following perturbation of the genetic background and in shifting environments. In addition to advancing our understanding of adaptive evolution, we expect, based on our prior work, to identify previously unknown nuclear-nuclear, nuclear-cytoplasmic, and gene- environment interactions. Finally, we will develop a fast and reliable method for performing multiple rounds of pooled gene editing in yeast, and we will use this method to systematically assay genetic interactions that have been missed by other methods. By connecting genotype to phenotype in an evolutionary context, our work will provide a mechanistic understanding of how complex traits evolve. This work will advance our understanding of adaptive evolution and the genetic basis of complex traits in less tractable systems, including humans and human pathogens.

项目概要/摘要 适应性进化是生物学的一个基本过程。最简单的随机突变产生 选择作用的表型变异，富集有利的表型并清除较少的表型 有利的。这个过程产生了地球上生命的多样性。但与此同时，适应性 进化是人类健康中一些最棘手的问题的原因，这些问题日益严重 抗生素耐药性、病毒病原体实时进化到抗药物治疗的癌症，以及 逃避免疫系统。尽管如此，我们对基因组如何运作缺乏基本的机制理解。 响应选择。一个主要的未知数是适应性进化如何“选择”一条特定的路径 在众多可能的情况中。另一个主要的未知数是遗传变异如何产生新的 选择作用的表型。实验进化提供了解决这两个问题的方法 我们知识中的这些重大差距。随着高通量生物学的进步，我们可以进化出数百种 最初相同的种群并行数千代，对 实验参数。这种多功能技术使得通过以下方式测试进化论成为可能： 在自然群体中不可能进行的实验。与此同时，实验进化 是功能基因组学的强大工具。通过识别响应选择性的基因和途径 压力，以及这些突变如何相互作用以改变表型，实验室进化实验确定 以前未知的蜂窝连接。在过去的五年里，我的实验室已经推进了机械化 对适应性进化的理解。未来的工作将确定基因变化如何产生复杂的 表型。我们将在遗传背景扰动后进行进化实验 在不断变化的环境中。除了增进我们对适应性进化的理解之外，我们期望， 基于我们之前的工作，识别以前未知的核-核、核-细胞质和基因- 环境相互作用。最后，我们将开发一种快速可靠的方法来执行多轮 酵母中的汇集基因编辑，我们将使用这种方法系统地分析遗传相互作用 是其他方法所遗漏的。通过在进化背景下将基因型与表型联系起来， 我们的工作将为复杂性状的演变提供机械性的理解。这项工作将推进 我们对适应性进化的理解以及难以处理的系统中复杂特征的遗传基础， 包括人类和人类病原体。