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The Dynamic Genome: Studying the Interplay between Local Strand-Passage and Reconnection

动态基因组：研究局部链通道和重新连接之间的相互作用

基本信息

批准号：
1716987
负责人：
Mariel Vazquez
金额：
$ 29万
依托单位：
University of California-Davis
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1716987&HistoricalAwards=false
关键词：
Dynamic Genome Studying Interplay between

项目摘要

Reconnection processes appear in a variety of settings at widely different scales, from microscopic DNA recombination to large-scale reconnection of vortices in fluid turbulence and magnetic reconnection of solar coronal loops. Experimental data show striking similarities between the pathways of topology simplification in newly replicated circular DNA plasmids by recombination and those in interlinked fluid vortices thus pointing to a universal process of unlinking by local reconnection. A drive toward topological simplification is ubiquitous in nature and this work will develop a mathematical understanding of the laws underlying it. Enzymes such as topoisomerases and recombinases are DNA-binding proteins able simplify the topology of circular DNA. They act by local crossing changes and local reconnection. The main objective of this project is to characterize the topological mechanism of DNA topology simplification using knot theory, low-dimensional topology and computer simulations. In pursuit of this research objective, the central hypothesis is that under normal conditions topoisomerases and recombinases follow optimal topological pathways of DNA unknotting and unlinking. The principal investigator will test this hypothesis through two specific aims. (1) Use techniques from low-dimensional topology, to find possible topological pathways of DNA unknotting and unlinking by type II topoisomerases and by recombinases. (2) Conduct computer simulations of DNA topology simplification by signed crossing changes and by local reconnection and explore connections to genome architecture. The PI and her group will be involved in a variety of dissemination and outreach activities, and are committed to increasing diversity in the Mathematical Sciences. The research will produce rigorous mathematical models for DNA unknotting and unlinking by local reconnection and signed crossing change, which will contribute to our understanding of the unknotting and unlinking mechanisms by topoisomerases and by recombinases. The enzymatic action can be modeled as local crossing changes, and as coherent or non-coherent band surgery, respectively. Assuming a chiral enzymatic action, this project will study signed crossing changes and characterize knots that can be unknotted with a single type of crossing change. Different minimal multi-step reconnection pathways will be identified between given pairs of knots or links. The research will extend results related to the nugatory crossing conjecture and analogous open questions in knot theory, which concerns the characterization of crossing changes and non-coherent band surgeries, which preserve the topological knot type. The proposed project will develop a computer model (a multiple Markov chain Monte Carlo algorithm) where DNA recombination at inversely repeated sites is modeled as non-coherent band surgery. The principal investigator will compute minimal recombination pathways and assess the efficiency of this form of topology simplification under different geometric and topological filters. Via simulations, the research will determine the transition probability networks for each method and choice of parameters for the models developed for signed crossing change and recombination of DNA. This will provide a ranking of the nodes and identify topology types with high-connectivity. An important focus is placed on the interplay of strand-passage and reconnection events.

重新连接过程出现在各种不同尺度的环境中，从微观DNA重组到流体湍流中的大规模涡旋重连和太阳日冕环的磁重连。实验数据表明，在新复制的环状DNA质粒的重组和互连的流体涡旋，从而指向一个普遍的过程中，局部重连的拓扑结构简化的途径之间的惊人的相似之处。拓扑简化的动力在自然界中无处不在，这项工作将发展其背后的规律的数学理解。拓扑异构酶和重组酶等酶是DNA结合蛋白，能够简化环状DNA的拓扑结构。它们通过局部交叉变化和局部重新连接来起作用。本研究的主要目的是利用纽结理论、低维拓扑学和计算机模拟来描述DNA拓扑简化的拓扑机制。为了实现这一研究目标，中心假设是在正常条件下拓扑异构酶和重组酶遵循DNA解结和解链的最佳拓扑途径。主要研究者将通过两个具体目标来检验这一假设。 (1)使用低维拓扑学技术，通过II型拓扑异构酶和重组酶寻找DNA解结和解链的可能拓扑途径。(2)通过符号交叉变化和局部重连进行DNA拓扑简化的计算机模拟，并探索与基因组结构的连接。PI和她的团队将参与各种传播和推广活动，并致力于增加数学科学的多样性。该研究将产生严格的数学模型，DNA解结和解链的局部重连接和符号交叉的变化，这将有助于我们了解解结和解链机制的拓扑异构酶和重组酶。酶的作用可以被建模为局部交叉变化，并作为相干或非相干带手术，分别。假设一个手性酶的行动，这个项目将研究签署交叉变化和特点的结，可以解开一个单一类型的交叉变化。不同的最小多步重联途径将被确定之间的给定对结或链接。该研究将扩展与nugulatory交叉猜想和纽结理论中类似的开放问题相关的结果，这些问题涉及交叉变化和非相干带手术的表征，这些手术保留了拓扑纽结类型。拟议的项目将开发一个计算机模型（多马尔可夫链蒙特卡罗算法），其中反向重复位点的DNA重组被建模为非相干带手术。主要研究者将计算最小的重组途径，并评估不同几何和拓扑过滤器下这种形式的拓扑简化的效率。通过模拟，研究将确定每种方法的转移概率网络以及为DNA的符号交叉变化和重组开发的模型的参数选择。这将提供节点的排名并识别具有高连接性的拓扑类型。一个重要的焦点是放在相互作用的链通道和重连事件。