Mechanisms and phenotypic consequences of structural geonomic variation

结构地理变异的机制和表型后果

• 批准号: 9142862
• 负责人: Juan Lucas Argueso
• 金额: $ 34.86万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-11 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9142862
• 关键词: Address; Affect; Biological Assay; Biological Models; Biology; Cells; Chromosomal Rearrangement; Chromosomes; Collection; Complex; Copy Number Polymorphism; Custom; DNA; Diploid Cells; Diploidy; Disease; Evolution; Gene Dosage; Genetic Polymorphism; Genetic Variation; Genome; Genomics; Haploidy; Health; Heterozygote; Homologous Gene; Human; Human Genome; Investigation; Life; Measures; Organism; Population; Process; Property; Reiterated Genes; Research; Saccharomyces cerevisiae; Saccharomycetales; Sampling; Series; Source; Structure; Structure-Activity Relationship; Surveys; System; Testing; Time; Variant; Yeast Model System; Yeasts; functional genomics; genetic variant; genomic variation; innovation; insight; mutant; prevent; repaired; stem; structural genomics; tool; whole genome

Structural genomic variation has only recently come into focus as a major source of genetic diversity in humans, and in biology in general. Despite its critical importance, we still have a very limited understanding of the processes that cause the structure of genomes to change over time, and of the consequences of these large-scale changes to living organisms. I propose to use two parallel and integrated approaches to study this problem, taking advantage of the unique research tools available in the budding yeast model system. (1) I will investigate the forces that cause chromosomes to break, and the cellular mechanisms that are responsible for preventing, surveying, and repairing this damage. To do so, I will use a custom and highly sensitive assay to measure the rate of gene copy number variation (CNV), and genomic analysis tools to characterize the associated structural changes. The CNV assay has two uniquely innovative features that will allow the study of problems that have never been properly addressed by conventional experimental systems. First, the assay uses diploid cells, making the results much more germane to the processes that occur in humans; and Second, this assay can detect chromosomal rearrangements stemming from DNA breaks anywhere in the genome, allowing a more comprehensive sampling of genomic variants. (2) I will also investigate the phenotypic consequences associated with chromosomal rearrangements in a diploid yeast strain that shares many of the properties that characterize the complex human genome. These include a high degree of heterozygosity, structural chromosomal polymorphisms between homologs, gene redundancy, and CNVs; all the while retaining the small (and manageable) genome of S. cerevisiae. I will use this strain to conduct a systematic functional genomics study of structural variation. This strain (JAY270) will be manipulated to generate targeted chromosomal rearrangements in all chromosomes. This collection of chromosomal mutants will then be taken through a series of phenotypic tests to establish structure-function relationships for the entire genome. I strongly believe that by opening these new and integrated avenues of investigation, my studies will contribute much needed insight into how structural genomic variation arises and how it affects all aspects of life, from the evolution of species to human health.

结构基因组变异最近才作为遗传多样性的主要来源而受到关注。 人类，以及一般生物学。尽管它至关重要，但我们对它的了解仍然非常有限 导致基因组结构随时间变化的过程以及这些过程的后果 生物体发生大规模变化。我建议使用两种并行和集成的方法来研究这个问题 问题，利用芽殖酵母模型系统中可用的独特研究工具。 (1) 我会 研究导致染色体断裂的力以及导致染色体断裂的细胞机制 预防、调查和修复这种损害。为此，我将使用定制的高灵敏度测定法来 测量基因拷贝数变异 (CNV) 的比率，并使用基因组分析工具来表征 相关的结构变化。 CNV 检测具有两个独特的创新功能，可用于研究 传统实验系统从未正确解决过的问题。一、化验 使用二倍体细胞，使结果与人类发生的过程更加密切相关；其次， 该检测可以检测基因组中任何位置的 DNA 断裂引起的染色体重排， 允许对基因组变异进行更全面的采样。 (2)我还将研究表型 与二倍体酵母菌株中染色体重排相关的后果，该菌株具有许多共同点 表征复杂人类基因组的特性。这些包括高度的杂合性， 同源物、基因冗余和 CNV 之间的结构染色体多态性；一直以来 保留酿酒酵母的小（且易于管理）基因组。我将利用这个菌株进行系统的 结构变异的功能基因组学研究。该菌株（JAY270）将被操纵以产生目标 所有染色体中的染色体重排。然后将收集该染色体突变体的集合 通过一系列表型测试来建立整个基因组的结构-功能关系。我 坚信通过开辟这些新的综合调查途径，我的研究将做出贡献 迫切需要了解结构基因组变异如何产生以及它如何影响生活的各个方面，从 物种进化对人类健康的影响。