Modeling and Analysis of Meiotic Homolog Pairing

减数分裂同源配对的建模和分析

• 批准号: 9291479
• 负责人: JENNIFER C FUNG
• 金额: $ 35.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-08 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9291479
• 关键词: Achievement; Affect; Biological; Biological Phenomena; Biological Process; Biology; Cell Nucleus; Cells; Centromere; Cereals; Chromatin; Chromosome Pairing; Chromosome Positioning; Chromosome Segregation; Chromosome Structures; Chromosomes; Computer Simulation; Coupling; Crowding; DNA Repair; DNA Sequence; Development; Developmental Disabilities; Diagnostic tests; Diffusion; Elements; Ensure; Environment; Event; Generations; Genetic; Homologous Gene; Human; Image Analysis; Individual; Infertility; Kinetics; Label; Lead; Location; Measurement; Measures; Mediating; Medical; Meiosis; Mental Retardation; Methods; Mitotic; Modeling; Molecular; Motion; Motor; Movement; Nuclear Envelope; Operative Surgical Procedures; Play; Polymers; Positioning Attribute; Process; Property; Proteins; Research; Rest; Role; Saccharomycetales; Sequence Homology; Site; Study models; Tail; Testing; Work; X Inactivation; Yeasts; base; defined contribution; density; experimental study; homologous recombination; infertility treatment; live cell imaging; neglect; physical process; predictive modeling; quantitative imaging; simulation; telomere; yeast genetics

Project Summary Pairing of homologous chromosomes is a key biological phenomenon that underlies Mendelian inheritance but also occurs outside of meiosis in diverse contexts including DNA repair, transvection, and X- chromosome inactivation. But while many of the molecules have been identified that mediate homolog recognition, the fact that homolog pairing requires the chromosomes to physically align with each other poses a challenge from a polymer dynamics perspective. How can individual chromosomes locate and pair with their homologs in the densely packed interior of a nucleus? Cytoskeletal motors attach to telomeres via nuclear envelope spanning proteins, thus dragging chromosomes around in the nucleus by their ends, but this motion appears to be randomly directed, and does not serve to pull homologs directly together. We hypothesize that these random active forces serve to increase chromosome mobility, causing chromosomes to undergo anomalous superdiffusion, a type of motion predicted to facilitate search and capture. We have developed a Brownian dynamics simulation of meiotic chromosome pairing that predicts super-diffusion and zippering, a processive association driven by successive pairing of neighboring loci. Our model predicts that active forces can have a large effect on pairing rates even in comparison with non-random chromosome positioning effects such as nuclear envelope attachment or meiotic bouquet formation. We propose to test the predictions of this model using live cell imaging and quantitative image analysis, combined with yeast genetics to alter key elements of the process including force generation, nuclear envelope attachment, pairing site density, and nonrandom chromosome organization. Our results should impact not only the understanding of meiotic homolog pairing as a physical process, but also the physical biology of chromosome motion in general.

项目摘要 同源染色体的配对是Mendelian的基础的关键生物学现象 遗传性但也出现在减数分裂以外的不同情况下，包括DNA修复，转向和X- 染色体灭活。但是，尽管已经确定了许多分子介导同源物 认识，同源配对需要染色体彼此物理对齐这一事实 从聚合物动力学的角度来看，这是一个挑战。单个染色体如何找到并与它们的染色体配对 核的密集包装内部的同源物？细胞骨架电动机通过核与端粒相连 包膜跨越蛋白质，从而将细胞核中的染色体拖到末端，但是这种运动 似乎是随机定向的，并且不用于将同源物直接拉在一起。我们假设这一点 这些随机活性力有助于增加染色体的迁移率，导致染色体发生 异常的超扩散是一种预测的一种运动，可促进搜索和捕获。我们已经开发了 Brownian动力学模拟减数分裂染色体配对，预测超扩散和拉链，一个 连续的相邻基因座配对驱动的过程关联。我们的模型预测主动力 即使与非随机染色体定位效果相比，即使对配对速率也有很大的影响 例如核包膜附着或减数分裂花束的形成。我们建议测试这一点的预测 使用活细胞成像和定量图像分析的模型，与酵母遗传学结合使用键 该过程的要素，包括力产生，核包膜附着，配对位点密度和 非随机染色体组织。我们的结果不仅会影响对减数分裂的理解 同源物配对是一种物理过程，也是染色体运动的物理生物学。