Genetic Determinants of Genomic Plasticity and Chromosome Evolution

基因组可塑性和染色体进化的遗传决定因素

• 批准号: 7318499
• 负责人: FORREST A. SPENCER
• 金额: $ 30.42万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-10 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7318499
• 关键词: Address; Affect; Aneuploidy; Binding Proteins; Biological Assay; Biological Models; Cell physiology; Cells; Centromere; Chromatin; Chromosome Breakage; Chromosome Structures; Chromosomes; Class; Color; Congenital Abnormality; Constitutional; DNA Repair; DNA Sequence; DNA Sequence Rearrangement; Data; Diagnosis; Diploidy; Disease; Disease Progression; Down Syndrome; Enhancers; Environment; Eukaryota; Eukaryotic Cell; Event; Evolution; Exhibits; Financial compensation; Fungal Genome; Future; Gene Deletion; Gene Mutation; Genes; Genetic Determinism; Genetic Nondisjunction; Genome; Genomic Instability; Genomics; Genotype; Goals; Growth; Haploid Cells; Haploidy; Homologous Gene; Human; Individual; Individuality; Investigation; Kinetochores; Laboratories; Maintenance; Malignant Neoplasms; Microtubules; Mitosis; Modification; Molecular; Monitor; Nucleotide Biosynthesis; Numbers; Online Mendelian Inheritance In Man; Organism; Outcome; Pathway interactions; Phenotype; Ploidies; Polycystic Kidney Diseases; Population; Predisposition; Property; Protein Binding; Proteins; Purine Nucleotides; Range; Research; Research Personnel; Role; Saccharomycetales; Structure; Syndrome; Testing; Therapeutic; Tissues; Variant; Work; Yeast Model System; Yeasts; base; cancer cell; cell type; chromosome loss; disease phenotype; functional group; human disease; insertion/deletion mutation; insight; mutant; pressure; prevent; programs; research study; response; segregation; tool

DESCRIPTION (provided by applicant): Genome change is the result of functional interactions between proteins that maintain genome structure and the chromosomal structures present. An understanding of the mechanisms underlying these functional interactions is fundamental to understanding evolution, population variation, and somatic individuality. In previous work, we found that the chromosomal features correlating with specific gene deletion vulnerabilities include the presence or absence of a homologous chromosome, genome ploidy, and centromere environment. The proposed aims will convert these correlations to molecular mechanisms amenable to study in the yeast model, with relevance to future work in humans and other organisms. Our data suggest that specific genes acting in DNA repair and chromatin modification are particularly important in the absence of a homolog. In AIM 1, we propose to define the homolog interaction pathway(s). This may be especially important in outbred populations like our own, where chromosome structural variation includes frequent insertion/deletion difference between homologs. These structural variants may serve as enhancers of rearrangement in mutant cells. In our preliminary data, mutants that exhibit strong instability phenotypes only in diploid (but not haploid) cells may identify genes with importance proportional to chromosome number. In AIM 2, we will address this hypothesis. This pathway may reveal functions that are overwhelmed in cancer cells of high chromosome number. This may contribute to ongoing instability observed in such cells. Finally, centromere vulnerabilities tolerated well in wild-type cells are revealed in mutants. Yeast centromeres are divergent in DNA sequence, within the kinetochore-protein-binding regions and in surrounding chromatin context. It is likely that different viable mutants, which decrease segregation fidelity, affect centromeres differentially. In AIM 3, we will determine whether this is observed. Centromere evolution requires coordinate change in DNA sequence and binding proteins. In AIMS, we will also define the tolerated range of functional divergence through investigation of natural centromere fidelity as well as the genomic response to stringent challenge. In humans, distinct chromosome nondisjunction signatures that reveal specific dysfunctional pathways could enhance diagnosis and treatment of disease.

描述（由申请人提供）：基因组变化是维持基因组结构的蛋白质与现有染色体结构之间功能相互作用的结果。了解这些功能相互作用背后的机制是理解进化、种群变异和体细胞个体的基础。在之前的工作中，我们发现与特定基因缺失漏洞相关的染色体特征包括同源染色体的存在或不存在、基因组倍性和着丝粒环境。拟议的目标是将这些相关性转化为适合在酵母模型中研究的分子机制，并与人类和其他生物体的未来工作相关。 我们的数据表明，在缺乏同源物的情况下，作用于 DNA 修复和染色质修饰的特定基因尤其重要。在 AIM 1 中，我们建议定义同源相互作用途径。这对于像我们这样的远交种群来说可能尤其重要，其中染色体结构变异包括同源物之间频繁的插入/删除差异。这些结构变体可以充当突变细胞中重排的增强剂。 在我们的初步数据中，仅在二倍体（而非单倍体）细胞中表现出强烈不稳定表型的突变体可能会识别出重要性与染色体数量成正比的基因。在 AIM 2 中，我们将解决这个假设。该途径可能揭示高染色体数目癌细胞中被压倒的功能。这可能导致此类细胞中观察到的持续不稳定。 最后，在野生型细胞中耐受良好的着丝粒脆弱性在突变体中也得到了揭示。酵母着丝粒在着丝粒蛋白结合区域和周围染色质环境中的 DNA 序列是不同的。不同的存活突变体可能会降低分离保真度，对着丝粒的影响不同。在 AIM 3 中，我们将确定是否观察到这种情况。着丝粒进化需要 DNA 序列和结合蛋白的协调变化。在 AIMS 中，我们还将通过研究自然着丝粒保真度以及基因组对严格挑战的反应来定义功能分歧的耐受范围。在人类中，揭示特定功能障碍途径的独特染色体不分离特征可以增强疾病的诊断和治疗。