Modeling and Analysis of Meiotic Homolog Pairing

项目摘要 同源染色体配对是孟德尔学派的一个重要生物学现象 遗传，但也发生在减数分裂外的不同背景下，包括DNA修复，横向和X- 染色体失活。但是，尽管许多分子已经被确定为中介同源 识别，同源配对需要染色体在物理上彼此对齐的事实 从聚合物动力学的角度来看，这是一个挑战。单个染色体如何定位并与其各自的 在密集堆积的原子核内部的同系物？细胞骨架马达通过核附着在端粒上 包膜横跨蛋白质，因此拖拽着细胞核中的染色体的末端，但这种运动 看起来是随机定向的，不起到直接将同源基因拉在一起的作用。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，一种被预测为便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 由相邻座位的连续配对驱动的进行性关联。我们的模型预测，积极的力量 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 如核膜附着或减数分裂花束形成。我们建议测试一下这方面的预测 使用活细胞成像和定量图像分析的模型，结合酵母遗传学改变密钥 这一过程的要素包括力产生、核包膜附着、配对位置密度以及 非随机的染色体组织。我们的结果不仅应该影响对减数分裂的理解 同源配对作为一个物理过程，也是一般的染色体运动的物理生物学。

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.