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.

项目总结/文摘