Mechanisms and Phenotypic Consequences of Structural Genomic Variation

结构基因组变异的机制和表型后果

• 批准号: 10631922
• 负责人: Juan Lucas Argueso
• 金额: $ 36.72万
• 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 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631922
• 关键词: Affect; Aneuploidy; Biological Assay; Biological Models; Biology; Cells; Chromosomal Rearrangement; Chromosomes; Complex; Copy Number Polymorphism; Creativeness; Custom; Development; Diploidy; Disease; Evolution; Funding; Gene Dosage; Generations; Genetic Polymorphism; Genetic Variation; Genome; Genomic Instability; Genomics; Haploidy; Health; Heterozygote; Homologous Gene; Human; Human Genome; Investigation; Laboratories; Life; Loss of Heterozygosity; Malignant Neoplasms; Measures; Meiosis; Mentors; Mitotic; Mutagenesis; Organism; Phenotype; Population; Process; Property; Reiterated Genes; Reporting; Research; Risk Factors; Saccharomyces cerevisiae; Saccharomycetales; Scientist; Source; Structure; Surveys; Talents; Time; Training; Work; Yeast Model System; Yeasts; autism spectrum disorder; genomic variation; insight; prevent; repaired; tool

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. Over the last four years of MIRA support, my laboratory has been using two parallel and integrated approaches to study this problem, taking advantage of the unique research tools available in the budding yeast model system. Our work has been fruitful. We have significantly advanced the boundaries of our research field, while also contributing to the development of a new generation of rigorously trained, creative young scientists. In the next funding cycle (1), we will continue to 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, we will use custom and highly sensitive cell-based assays to measure the rate of gene copy number variation (CNV), Loss-of-Heterozygosity (LOH), and whole chromosome gains and losses (aneuploidy), both in mitotic and meiotic cells. We will also deploy advanced genomic analysis tools to characterize the associated structural changes. In addition, we will continue to expand on a brand-new investigation front we opened through work carried out during the current funding cycle. Specifically, we recently reported on a new form of structural mutagenesis (systemic genomic instability, SGI), through which cells can acquire multiple rearrangements simultaneously, and thus radically reconfiguring their genomes. In addition (2), we 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 strongly believe that by opening these new and integrated avenues of investigation, in close partnership with the talented junior colleagues I mentor in my laboratory, we 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.

结构性基因组变异直到最近才成为遗传多样性的主要来源 人类和一般生物学。尽管其重要性至关重要，但我们仍然对 导致基因组结构随着时间而变化的过程以及这些的后果 大规模改变活生物体。在MIRA支持的最后四年中，我的实验室一直是 利用两种平行和集成的方法研究此问题，利用独特的研究 萌芽酵母模型系统中可用的工具。我们的工作富有成果。我们已经大大提高了 我们研究领域的边界，同时也有助于发展新一代 受过严格训练的创意年轻科学家。在下一个资金周期（1）中，我们将继续调查 导致染色体断裂的力以及负责预防， 测量并修复这种损坏。为此，我们将使用自定义和高度敏感的基于细胞的测定 测量基因拷贝数变化（CNV），杂合丧失（LOH）和整个基因拷贝数变化速率（CNV） 在有丝分裂和减数分裂细胞中，染色体的增长和损失（非整倍性）。我们还将部署高级 基因组分析工具以表征相关的结构变化。此外，我们将继续 扩展我们通过当前资助期间通过工作开放的全新调查阵线 循环。具体而言，我们最近报告了一种新的结构诱变形式（全身基因组不稳定性， sgi），细胞可以同时获得多个重排，从而从根本上重新配置 他们的基因组。此外（2），我们还将研究与 二倍体酵母菌菌株中的染色体重排，该菌株具有许多表征的特性 复杂的人类基因组。这些包括高度的杂合性，结构性染色体 同源物，基因冗余和CNV之间的多态性；一直保留小的同时 酿酒酵母的可管理基因组。我坚信，通过开放这些新的和综合的途径 调查，与我在实验室指导的有才华的初级同事密切合作，我们将 对结构性基因组变异的产生及其如何影响的各个方面的结构性变异如何贡献 生命，从物种的进化到人类健康。