Dissecting the influence of genetic background on aneuploidy tolerance in the model eukaryote Saccharomyces cerevisiae

剖析遗传背景对模型真核生物酿酒酵母非整倍体耐受性的影响

• 批准号: 10667621
• 负责人: AUDREY P GASCH
• 金额: $ 30.57万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667621
• 关键词: Aneuploidy; Architecture; Cells; Chromosome Mapping; Chromosome Segregation; Chromosomes; DNA; Development; Dissection; Down Syndrome; Drug Metabolic Detoxication; Drug resistance; Eukaryota; Evolution; Expression Library; Gene Duplication; Genes; Genetic; Genetic Variation; Genetic study; Genotype; Health; Human; Human Biology; Individual; Infertility; Karyotype; Laboratories; Laboratory Study; Malignant Neoplasms; Mammalian Cell; Maps; Measures; Methods; Modeling; Molecular; Mutation; Organism; Pharmaceutical Preparations; Phenotype; Phylogeny; Physiological; Play; Population Genetics; Production; Proteins; Role; Saccharomyces cerevisiae; Saccharomycetales; Stress; Syndrome; System; Testing; Time; Variant; Yeasts; cancer therapy; comparative genomics; cost; design; developmental disease; drug resistant pathogen; emerging pathogen; fitness; functional genomics; genetic architecture; human pathogen; innovation; insight; non-Native; overexpression; pathogenic fungus; proteostasis; rare variant; tumor; yeast genetics

ABSTRACT Chromosome segregation errors can produce cells with an incorrect number of one or more chromosomes, known as aneuploidy. Aneuploidy is therefore a special class of mutation that can have immediate phenotypic effects. Although aneuploidy is detrimental during mammalian development, it is common in many cancers and a driver in the evolution of drug resistant tumors and fungal pathogens. A major unaddressed question is the degree to which different individuals vary in their ability to tolerate aneuploidy. Understanding how genetic differences influence aneuploidy tolerance has far reaching implications for genetics, human biology, and evolution. But studying this topic mammalian systems is extremely challenging, since it is not possible to systematically manipulate karyotypes in a large number of genetic backgrounds. Here we will address the fundamental question of how genetic variation influences the ability of cells to tolerate chromosome duplications, in the model eukaryote Saccharomyces cerevisiae. Using the power of yeast genetics, we adapted a method to duplicate specific yeast chromosomes in the near absence of selection. We will apply this method to explore the breadth and mechanisms of genetic variation in tolerating chromosome duplications (herein referred to as aneuploidy). Aim 1 will use this approach to duplicate each of the 16 chromosomes in yeast, in dozens of non-laboratory strains across the yeast phylogeny. Results will characterize the range of natural variation in aneuploidy tolerance and will test if this variation occurs sporadically due to rare alleles or persists across many strains within specific lineages. Preliminary results suggest lineage-specific variation in aneuploidy tolerance. Aim 2 will test if variations in aneuploidy sensitivity are due to differences in “generalized” aneuploidy tolerance, in which cells are sensitive regardless of which chromosome is duplicated, versus chromosome-specific sensitivities that are likely driven by the effects of duplicated genes encoded on those chromosomes. We will test how well chromosome-specific sensitivities are explained by an additive gene model that is based on measured fitness costs of the genes’ over-expression, measured here from a gene over-expression library expressed in each strain. Aim 3 will begin to uncover the physiological and genetic mechanisms for variable aneuploidy tolerance. We will first test our hypothesis that genetic variation in aneuploidy tolerance is due to variations in the ability to manage proteostasis stress. We will then use bulk- segregant mapping to study the genetic architecture of that variance and identify casual genes. Yeast is an outstanding model in which to study this fundamental question, since many cellular mechanisms and genetic principles are conserved in other organisms including humans. This project will generate important insights into aneuploidy tolerance that will have broad implications for genetics, human health, and evolution.

摘要

项目成果

Gene-by-environment interactions influence the fitness cost of gene copy-number variation in yeast.

基因与环境的相互作用影响酵母中基因拷贝数变异的适应成本。

• DOI: 10.1101/2023.05.11.540375
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Robinson,DeElegant;Vanacloig-Pedros,Elena;Cai,Ruoyi;Place,Michael;Hose,James;Gasch,AudreyP
• 通讯作者: Gasch,AudreyP