Mechanisms and Phenotypic Consequences of Structural Genomic Variation

结构基因组变异只是最近才成为焦点，作为遗传多样性的主要来源， 在人类和生物学中。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，以及这些变化的后果 对生物体的大规模改变。在MIRA的支持下，我的实验室在过去的四年里， 采用两种并行和集成的方法来研究这个问题，利用独特的研究优势， 芽殖酵母模型系统中可用的工具。我们的工作卓有成效。我们已经取得了很大的进步 我们的研究领域的边界，同时也有助于新一代的发展， 受过严格训练有创造力的年轻科学家在下一个融资周期（1），我们将继续调查 导致染色体断裂的力量，以及负责防止， 测量并修复这些损伤为此，我们将使用定制的高灵敏度细胞检测， 测量基因拷贝数变异（CNV）、杂合性丢失（洛）和整体 在有丝分裂和减数分裂细胞中的染色体获得和丢失（非整倍性）。我们还将部署先进的 基因组分析工具来表征相关的结构变化。此外，我们将继续 扩大我们通过在当前资助期间开展的工作开辟的全新调查战线， 周期具体来说，我们最近报道了一种新形式的结构诱变（系统性基因组不稳定性， 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），我们还将研究与下列因素相关的表型后果： 染色体重排在二倍体酵母菌株，共享的许多特性，表征了 复杂的人类基因组这些包括高度的杂合性，结构染色体 同源物、基因冗余和CNVs之间的多态性;同时保留小的和 S.啤酒。我坚信，通过开辟这些新的综合途径， 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 有助于深入了解结构基因组变异是如何产生的，以及它是如何影响基因组的各个方面的。 从物种进化到人类健康。

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.