Genetic Recombination in C elegans

描述（由申请人提供）：我们的长期目标是了解基因重组如何有助于染色体的忠实遗传。基因重组对于有性生殖的生物体是至关重要的，因为同源染色体的DNA分子之间的交叉重组事件以及由此产生的交叉，是减数分裂I分裂时染色体分离的必要条件。不能形成交叉会导致染色体错误分离和随之而来的非整倍体，这是人类流产和出生缺陷的主要原因之一。大多数生物体每对染色体进行很少的交叉（通常是一对或两条），这表明这个过程必须受到严格的调节，以确保每对染色体在每次减数分裂中至少进行一次交叉。尽管最近在理解减数分裂重组的机制及其发生的结构背景方面取得了重大进展，但控制交叉调节的机制仍然知之甚少。我们建议研究秀丽隐杆线虫的减数分裂交叉控制机制，这是一个简单的后生动物实验系统，在这个实验系统中，研究减数分裂的遗传学、细胞学和分子工具已经建立起来，并且已经证明了染色体范围内的交叉调节。我们将通过研究减数分裂染色体轴或突触复合体（SC）的减少功能或丰度的影响来验证这种交叉控制机制需要减数分裂染色体轴或突触复合体（SC）的结构完整性的假设。我们将使用遗传和功能基因组学方法来识别交叉控制机制的组成部分，并使用我们开发的一系列分析来研究这些组成部分的损伤如何影响减数分裂染色体的组织和形态发生以及减数分裂重组的进展。我们将研究HIM-17蛋白在重组启动和促进交叉和功能性交叉的调控形成中的作用。最后，我们将研究减数分裂重组机制的新组件的作用，我们通过这项工作的过程中确定。

DESCRIPTION (provided by applicant): Our long-term goal is to understand how genetic recombination contributes to the faithful inheritance of chromosomes. Genetic recombination is of central importance to sexually reproducing organisms, since crossover recombination events between the DNA molecules of homologous chromosomes, and the resulting chiasmata, are necessary for proper chromosome segregation at the meiosis I division. Failure to form crossovers leads to chromosome missegregation and consequent aneuploidy, one of the leading causes of miscarriages and birth defects in humans. Most organisms make very few crossovers per chromosome pair (often one or two), indicating that the process must be tightly regulated to ensure that each pair will undergo at least one crossover per meiosis. Despite significant recent advances in understanding the mechanisms of meiotic recombination and the structural context in which it occurs, the mechanisms governing crossover regulation remain poorly understood. We propose to investigate the mechanisms of meiotic crossover control using the nematode C. elegans, a simple metazoan experimental system in which genetic, cytological and molecular tools for investigating meiosis are well established, and in which robust chromosome-wide regulation of crossing over has been demonstrated. We will test the hypothesis that structural integrity of the meiotic chromosome axes or the synaptonemal complex (SC) is required for this crossover control mechanism by investigating the effects of reducing function or abundance of known axis and SC components. We will use genetic and functional genomics approaches to identify components of the crossover control machinery, and use a battery of assays we developed to investigate how impairment of these components affects the organization and morphogenesis of meiotic chromosomes and the progress of meiotic recombination. We will investigate the role of the HIM-17 protein the initiation of recombination and in promoting the regulated formation of crossovers and functional chiasmata. Finally, we will investigate the roles of new components of the meiotic recombination machinery that we identify through the course of this work.