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: 7847720
• 负责人: FORREST A. SPENCER
• 金额: $ 30.57万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847720
• 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(申请人提供)：基因组变化是维持基因组结构的蛋白质和现有的染色体结构之间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的基础。在以前的工作中，我们发现与特定基因缺失易感性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。拟议的目标将把这些相关性转化为分子机制，适合在酵母模型中进行研究，这与未来在人类和其他生物体中的工作有关。 我们的数据表明，在缺乏同源基因的情况下，作用于DNA修复和染色质修饰的特定基因特别重要。在目标1中，我们建议定义同源相互作用途径(S)。这在像我们这样的异种繁殖群体中可能特别重要，因为染色体结构变异包括同源基因之间频繁的插入/缺失差异。这些结构变异可以作为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(而不是单倍体)细胞中表现出强烈不稳定表型的突变可能识别与染色体数量成正比的重要基因。在目标2中，我们将解决这一假设。这一途径可能揭示了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持续的不稳定。 最后，在野生型细胞中可以很好地容忍着丝粒的脆弱性在突变体中被揭示出来。酵母着丝粒在DNA序列、动粒蛋白结合区和周围染色质环境中是不同的。不同的活性突变体可能会降低分离的保真度，对着丝粒的影响是不同的。在目标3中，我们将确定是否观察到了这一点。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的保真度和基因组对严格挑战的反应来定义功能差异的容忍范围。在人类中，揭示特定功能障碍途径的独特的染色体不分离信号可以增强疾病的诊断和治疗。