Mechanisms and Phenotypic Consequences of Structural Genomic Variation

直到最近，结构基因组变异才成为人们关注的主要遗传多样性来源 人类，以及整个生物学。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 生物有机体的大规模变化。在过去四年的Mira支持下，我的实验室 采用两种并行和综合的方法来研究这一问题，利用独特的研究 萌芽酵母模型系统中可用的工具。我们的工作卓有成效。我们已经取得了显著的进步 我们研究领域的边界，同时也有助于开发新一代 训练有素、富有创造力的年轻科学家。在下一个资金周期(1)，我们将继续调查 导致染色体断裂的力量，以及负责防止， 勘测和修复这一损坏。为此，我们将使用定制和高度敏感的基于细胞的分析来 测量基因拷贝数变异率(CNV)、杂合性缺失(LOH)和 有丝分裂和减数分裂细胞中的染色体获得和丢失(非整倍体)。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，我们还将继续 通过在当前资金期间开展的工作，在我们开辟的全新调查战线上展开 周而复始。具体地说，我们最近报道了一种新的结构突变形式(系统基因组不稳定， SGI)，通过它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)，我们还将调查与以下相关的表型后果 二倍体酵母菌株的染色体重排具有许多特征 复杂的人类基因组。这些包括高度杂合性，结构染色体 同源基因、基因冗余和CNV之间的多态；同时保留小的和 可管理的酿酒酵母基因组。我坚信，通过开辟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 对结构基因组变异是如何产生的以及它如何影响到 生命，从物种的进化到人类的健康。

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.