Modeling and Analysis of Meiotic Homolog Pairing

项目摘要 同源染色体配对是孟德尔遗传学的一个重要生物学现象， 遗传，但也发生在减数分裂以外的不同情况下，包括DNA修复，transvection和X- 染色体失活但是，虽然许多分子已被确定为介导同源 识别，同源配对需要染色体彼此物理对齐的事实构成了 从聚合物动力学的角度来看是一个挑战。单个染色体如何定位并与它们的 在密集的细胞核内部的同源物？细胞骨架马达通过细胞核附着在端粒上 包膜蛋白质，从而通过它们的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，并不能直接将同源物拉在一起。我们假设 这些随机的作用力增加了染色体的移动性，使染色体经历 反常超扩散，一种预测有助于搜索和捕获的运动。我们已经开发出一种 预测超扩散和拉链的减数分裂染色体配对的布朗动力学模拟， 由相邻基因座的连续配对驱动的进行性联合。我们的模型预测， 即使与非随机染色体定位效应相比， 如核膜附着或减数分裂花束形成。我们建议测试这一预测 模型使用活细胞成像和定量图像分析，结合酵母遗传学改变关键 该过程的要素包括力的产生、核膜附着、配对位点密度，以及 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， 同源配对作为一种物理过程，也是染色体运动的一般物理生物学。

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.