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.

项目总结