Modeling and Analysis of Meiotic Homolog Pairing

减数分裂同源配对的建模和分析

• 批准号: 9174051
• 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/9174051
• 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; Genetic Models; Homologous Gene; Human; Image Analysis; Individual; Infertility; Kinetics; Label; Lead; Life; 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; Tail; Testing; Work; X Inactivation; Yeasts; base; defined contribution; density; homologous recombination; infertility treatment; interest; live cell imaging; neglect; physical process; quantitative imaging; research study; 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.

项目概要 同源染色体配对是孟德尔定律的关键生物学现象 遗传，但也发生在减数分裂之外的不同环境中，包括 DNA 修复、横传和 X- 染色体失活。但是，尽管许多分子已被鉴定为介导同源物 识别，同源配对需要染色体在物理上彼此对齐这一事实 从聚合物动力学的角度来看，这是一个挑战。个体染色体如何定位并与其配对 细胞核内部密集的同系物？细胞骨架马达通过核附着在端粒上 包膜跨越蛋白质，从而通过其末端在细胞核中拖动染色体，但是这种运动 似乎是随机定向的，并且不能将同源物直接拉到一起。我们假设 这些随机的作用力有助于增加染色体的移动性，导致染色体经历 异常超扩散，一种预计有助于搜索和捕获的运动。我们开发了一个 减数分裂染色体配对的布朗动力学模拟可预测超扩散和拉链， 由相邻基因座的连续配对驱动的进行性关联。我们的模型预测主力 即使与非随机染色体定位效应相比，也会对配对率产生很大影响 例如核膜附着或减数分裂花束形成。我们建议测试这一预测 使用活细胞成像和定量图像分析的模型，结合酵母遗传学来改变关键 该过程的要素包括力的产生、核膜附着、配对位点密度和 非随机染色体组织。我们的结果不仅应该影响减数分裂的理解 同源配对作为一个物理过程，也是染色体运动的物理生物学的总称。