How genomic shock triggers transposition during hybrid dysgenesis

杂种发育不全过程中基因组休克如何触发转座

• 批准号: 2025197
• 负责人: Justin Blumenstiel
• 金额: $ 82.14万
• 依托单位: University of Kansas Center for Research Inc
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2025197&HistoricalAwards=false
• 关键词: How; genomic; shock; triggers; transposition

This project seeks to determine how genome instability is triggered by transposable elements. Transposable elements (TEs) are selfish DNA elements that proliferate through genomes and cause mutation. More than sixty years ago, the geneticist Barbara McClintock demonstrated that DNA damage can lead to TE activation but how this happens is poorly understood. Moreover, since TEs themselves cause DNA damage, the activation of some TEs can trigger the activation of others. This is known as co-mobilization. By combining genetic manipulation with new methods of genome sequencing, this project will determine how the DNA damage caused by TEs triggers co-mobilization. The outcomes will provide new insight into how genome integrity is maintained across generations. This project will engage diverse undergraduate student researchers, providing training in genetic modification and genome analysis. Furthermore, it involves development and dissemination of teaching tools to the broader community, including video tutorials and software modules for genetic simulations.To determine how TE mobilization triggers the movement of other TEs, hybrid dysgenesis in Drosophila virilis will be used as a model. Hybrid dysgenesis is a syndrome of sterility caused by rampant transposition when paternally inherited TEs become mis-regulated in the germline. Long-read sequencing will be performed to directly measure transposition and co-mobilization across generations. This approach will be combined with strain-specific CRISPR to identify genetic factors that shape the profile of co-mobilization. There are two primary models for how co-mobilization may occur. One model proposes that TE activation is caused by disrupted genome defense. An alternate model is that TEs are directly activated by elements of the host DNA damage response. These two hypotheses will be tested using reporter analysis. Finally, the same methods will also be used to characterize co-mobilization in other model systems, in order to determine the generality of TE co-mobilization across species.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该项目旨在确定基因组不稳定性是如何由转座因子触发的。转座因子（te）是自私的DNA因子，它们在基因组中增殖并引起突变。60多年前，遗传学家芭芭拉·麦克林托克（Barbara McClintock）证明，DNA损伤会导致TE激活，但人们对这一过程的机制知之甚少。此外，由于te本身会导致DNA损伤，一些te的激活可以触发其他te的激活。这就是所谓的联合动员。通过将基因操作与基因组测序的新方法相结合，该项目将确定TEs引起的DNA损伤如何触发共同动员。这些结果将为研究基因组的完整性是如何跨代维持提供新的见解。该项目将吸引不同的本科生研究人员，提供基因改造和基因组分析方面的培训。此外，它还涉及开发和向更广泛的社区传播教学工具，包括视频教程和遗传模拟软件模块。为了确定TE的动员如何触发其他TE的运动，将以果蝇的杂交发育不良为模型。杂种发育不良是一种不育综合征，当父系遗传的te在种系中被错误调节时，由猖獗的转位引起。长读测序将被执行，以直接测量跨代的转位和共同动员。这种方法将与菌株特异性CRISPR相结合，以确定塑造共同动员概况的遗传因素。关于联合动员如何发生，主要有两种模式。一种模型提出TE激活是由基因组防御被破坏引起的。另一种模型是te被宿主DNA损伤反应的元素直接激活。这两个假设将使用报告分析进行检验。最后，同样的方法也将用于表征其他模型系统中的共动员，以确定跨物种TE共动员的普遍性。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。