Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523.
Cell and Molecular Biology Graduate Program, Colorado State University, Fort Collins, CO 80523.
Proc Natl Acad Sci U S A. 2020 Nov 10;117(45):28221-28231. doi: 10.1073/pnas.2010303117. Epub 2020 Oct 26.
Conventional models of genome evolution are centered around the principle that mutations form independently of each other and build up slowly over time. We characterized the occurrence of bursts of genome-wide loss-of-heterozygosity (LOH) in , providing support for an additional nonindependent and faster mode of mutation accumulation. We initially characterized a yeast clone isolated for carrying an LOH event at a specific chromosome site, and surprisingly found that it also carried multiple unselected rearrangements elsewhere in its genome. Whole-genome analysis of over 100 additional clones selected for carrying primary LOH tracts revealed that they too contained unselected structural alterations more often than control clones obtained without any selection. We also measured the rates of coincident LOH at two different chromosomes and found that double LOH formed at rates 14- to 150-fold higher than expected if the two underlying single LOH events occurred independently of each other. These results were consistent across different strain backgrounds and in mutants incapable of entering meiosis. Our results indicate that a subset of mitotic cells within a population can experience discrete episodes of systemic genomic instability, when the entire genome becomes vulnerable and multiple chromosomal alterations can form over a narrow time window. They are reminiscent of early reports from the classic yeast genetics literature, as well as recent studies in humans, both in cancer and genomic disorder contexts. The experimental model we describe provides a system to further dissect the fundamental biological processes responsible for punctuated bursts of structural genomic variation.
传统的基因组进化模型以这样一个原则为中心，即突变是相互独立形成的，并随着时间的推移缓慢积累。我们描述了 在 中发生的全基因组杂合性丢失 (LOH) 爆发的情况，这为突变积累的另一种非独立且更快的模式提供了支持。我们最初对一个在特定染色体位点携带 LOH 事件的酵母克隆进行了特征描述，令人惊讶的是，我们还发现它在基因组的其他地方携带了多个未选择的重排。对 100 多个携带原发性 LOH 区的额外克隆进行的全基因组分析表明，与未经过任何选择而获得的对照克隆相比，它们携带未选择的结构改变的频率更高。我们还测量了两个不同染色体上同时发生的 LOH 率，发现如果两个潜在的单 LOH 事件相互独立发生，双 LOH 的形成率比预期高出 14 到 150 倍。这些结果在不同的菌株背景下和不能进入减数分裂的突变体中都是一致的。我们的研究结果表明，在群体中的一部分有丝分裂细胞中，当整个基因组变得脆弱，多个染色体改变可以在一个狭窄的时间窗口内形成时，它们可以经历系统基因组不稳定性的离散事件。这些结果让人想起经典酵母遗传学文献中的早期报道，以及最近在癌症和基因组紊乱背景下的人类研究。我们描述的实验模型提供了一个系统，可以进一步剖析导致结构基因组变异突发的基本生物学过程。
