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。遗传重组对有性生殖生物体至关重要，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对于减数分裂I分裂时的适当染色体分离是必要的。未能形成交叉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。大多数生物在每对染色体上很少发生交换（通常是一个或两个），这表明这个过程必须受到严格的调控，以确保每对染色体在每次减数分裂中至少发生一次交换。尽管最近在了解减数分裂重组的机制和发生重组的结构背景方面取得了重大进展，但对控制交叉调节的机制仍然知之甚少。我们打算利用线虫C. elegans，一个简单的后生动物实验系统，其中研究减数分裂的遗传学，细胞学和分子工具已经很好地建立起来，并且已经证明了强大的染色体范围内的交换调节。我们将测试的假设，减数分裂染色体轴或联会复合体（SC）的结构完整性是需要这种交叉控制机制，通过调查已知的轴和SC组件的功能或丰度降低的影响。我们将使用遗传和功能基因组学的方法来确定组件的交叉控制机制，并使用一组我们开发的检测来研究这些组件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蛋白在启动重组和促进交叉和功能性交叉形成中的作用。最后，我们将调查的减数分裂重组机制，我们通过这项工作的过程中确定的新组件的作用。

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.