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: 7630623
• 负责人: FORREST A. SPENCER
• 金额: $ 30.89万
• 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/7630623
• 关键词: Address; Affect; Aneuploidy; Binding Proteins; Biological Assay; Biological Models; Cell physiology; Cells; Centromere; Chromatin; Chromosome Breakage; Chromosome Structures; Chromosomes; Color; Congenital Abnormality; Constitutional; DNA Repair; DNA Sequence; DNA Sequence Rearrangement; Data; Diagnosis; Diploidy; Disease; Disease Progression; Down Syndrome; Enhancers; Environment; Eukaryota; 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; Molecular; Monitor; Nucleotide Biosynthesis; Online Mendelian Inheritance In Man; Organism; Outcome; Pathway interactions; Phenotype; Ploidies; Polycystic Kidney Diseases; Population; Predisposition; Property; Protein Binding; Proteins; Purine Nucleotides; Research; Research Personnel; Role; Saccharomycetales; Structure; Syndrome; Testing; Therapeutic; Tissues; Variant; Work; Yeast Model System; Yeasts; base; cancer cell; cell type; chromatin modification; 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存在的染色体结构之间的功能相互作用的结果。理解这些功能相互作用的机制是理解进化、种群变异和体细胞个体性的基础。在以前的工作中，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。提出的目标将这些相关性转化为适合在酵母模型中研究的分子机制，与人类和其他生物体的未来工作相关。 我们的数据表明，在DNA修复和染色质修饰中起作用的特定基因在没有同源物的情况下特别重要。在AIM 1中，我们建议定义同源相互作用途径。这可能是特别重要的远交种群像我们自己的，其中染色体结构变异包括频繁的插入/删除同源物之间的差异。这些结构变异体可作为突变细胞中重排的增强子。 在我们的初步数据中，仅在二倍体（而不是单倍体）细胞中表现出强烈不稳定表型的突变体可能识别出与染色体数目成比例的重要基因。在AIM 2中，我们将讨论这个假设。这种途径可能揭示了在高染色体数目的癌细胞中被淹没的功能。这可能有助于在这些细胞中观察到的持续不稳定性。 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被揭示。酵母着丝粒在DNA序列中是不同的，在着丝粒蛋白结合区域内和周围的染色质环境中。不同的能存活的突变体可能会降低分离保真度，从而对着丝粒产生不同的影响。在AIM 3中，我们将确定是否观察到这一点。着丝粒的进化需要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。