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 染色体分离错误会产生一个或多个染色体数目不正确的细胞， 这被称为非整倍体。因此，非整倍体是一种特殊类型的突变，可以直接表现为表型。 效果。虽然非整倍体在哺乳动物发育过程中是有害的，但它在许多癌症中很常见。 也是耐药肿瘤和真菌病原体进化的驱动力。一个尚未解决的主要问题是 不同个体容忍非整倍体能力的不同程度。了解基因是如何 影响非整倍体耐受性的差异对遗传学、人类生物学和 进化论。但研究哺乳动物系统这一主题是极具挑战性的，因为不可能 系统地操纵大量遗传背景中的核型。在这里，我们将讨论 基因变异如何影响细胞耐受染色体的基本问题 复制，在真核生物酿酒酵母的模型中。利用酵母遗传学的力量，我们 采用了一种在几乎没有选择的情况下复制特定酵母染色体的方法。我们会申请 这种方法探索耐受染色体复制的遗传变异的广度和机制 (这里称为非整倍体)。目标1将使用这种方法复制16条染色体中的每一条 酵母，在酵母系统发育的几十个非实验室菌株中。结果将表征以下范围 非整倍体耐受性的自然变异，并将测试这种变异是否由于稀有等位基因或 在特定谱系内的许多菌株中持续存在。初步结果表明，在 非整倍体耐受性。Aim 2将测试非整倍体敏感性的差异是否源于 “广义的”非整倍体耐受性，即无论复制哪条染色体，细胞都很敏感。 与染色体特异性敏感性相比，染色体特异性敏感性可能是由编码的重复基因的影响驱动的 那些染色体。我们将测试一种添加剂对染色体特异性敏感性的解释效果。 基于测量的基因过度表达的适合度成本的基因模型，这里从 各菌株表达的基因过表达文库。目标3将开始揭开生理学和 可变非整倍体耐受性的遗传机制。我们将首先测试我们的假设，即 非整倍体耐受是由于处理蛋白平衡压力的能力不同造成的。然后我们将使用批量- 分离作图，以研究这种变异的遗传结构，并识别偶然基因。酵母是一种 研究这一基本问题的杰出模型，因为许多细胞机制和基因 原则在包括人类在内的其他有机体中是保守的。这个项目将产生重要的见解 这将对遗传学、人类健康和进化产生广泛的影响。

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