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; 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.

项目摘要/摘要 自适应进化是生物学的基本过程。以最简单的随机突变产生 选择性作用的表型变化，丰富有利的表型，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。但同时，自适应 进化是由于日益严重的问题而造成人类健康中一些最烦人的问题 病毒病原体对抗药性治疗和 逃避免疫系统。尽管如此，我们对基因组的基本机械理解缺乏基本的理解 回应选择。一个主要未知的是自适应演变如何从 在许多可能的可能中。另一个主要未知的是遗传变异如何产生新的 选择的表型。实验进化为解决两个 我们知识上的这些显着差距。随着高通量生物学的进步，我们可以发展数百种 最初并行的数千代人的人口，对 实验参数。这种多功能技术使得可以通过 在自然种群中无法执行的实验。同时，实验进化 是功能基因组学的强大工具。通过识别对选择性响应的基因和途径 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 以前未知的细胞连接。在过去的五年中，我的实验室提高了机械性 了解适应性进化。未来的工作将决定遗传变化如何引起复杂 表型。在遗传背景和 在转移环境中。除了促进我们对适应性进化的理解外，我们还希望 基于我们的先前工作，以确定以前未知的核核，核质质和基因 环境互动。最后，我们将开发一种快速可靠的方法来执行多个回合 酵母中的汇集基因编辑，我们将使用此方法系统地测定遗传相互作用 其他方法遗漏了。通过将基因型与进化环境中的表型联系起来， 我们的工作将提供对复杂性状发展的机械理解。这项工作将进步 我们对适应性进化和复杂性状的遗传基础的理解 包括人类和人类病原体。