GENETIC CONTROL OF MEIOTIC CHROMOSOME SEGREGATION

描述（由申请人提供）：减数分裂细胞分裂过程中的错误是人类智力迟钝和怀孕失败的主要原因。绝大多数人类减数分裂错误源于母体，错误率受到年龄的强烈影响。虽然错误的机制和年龄影响染色体分离的方式仍然未知，但最近的研究表明，减数分裂重组事件的数量和位置深刻地影响染色体分离。在过去的几年里，我们对减数分裂重组中涉及的分子事件的理解有了显著的提高，然而，我们仍然在很大程度上对控制哺乳动物重组水平和位置的因素一无所知。本应用程序中概述的研究基于以下假设，即重组受到涉及姐妹染色单体之间内聚的建立、同源物之间突触复合物的形成以及DNA双链断裂修复的前期事件的相互作用的影响。因此，我们提出了三组相互关联的研究，一是定义哺乳动物雌性减数分裂前期的关键事件，并评估“正常”遗传变异对这些过程的影响；一种是利用突变分析来检验“异常”变异对这些事件的影响；一个是研究前期扰动的下游效应。这种方法，使用减数分裂“试剂”在初始资助期间开发，将使我们能够测试关于内聚，DMA序列和突触复合体在减数分裂交换建立中的作用的特定假设。这些研究的综合数据将使我们了解哺乳动物重组的控制以及前期事件如何影响减数分裂染色体分离。

DESCRIPTION (provided by applicant): Errors during meiotic cell division are a leading cause of mental retardation and pregnancy loss in our species. The vast majority of human meiotic errors are maternal in origin and the rate of errors is strongly influenced by age. While the mechanism(s) of error and the way in which age influences chromosome segregation remain unknown, recent studies have demonstrated that the number and placement of meiotic recombination events profoundly influences chromosome segregation. In the past several years our understanding of the molecular events involved in meiotic recombination has increased dramatically, yet we remain largely ignorant of the factors that control recombination levels and placement in mammals. The studies outlined in this application are predicated on the assumption that recombination is influenced by the interplay of prophase events involved in the establishment of cohesion between sister chromatids, the formation of the synaptonemal complex between homologs, and the repair of DNA double stand breaks. Accordingly, we propose three sets of interrelated studies, one to define the key events in prophase of mammalian female meiosis and to assess the impact of "normal"genetic variation on these processes; one using mutational analysis to examine the effect of "abnormal" variation on these events; and one to examine the downstream effects of perturbations in prophase. This approach, using the meiotic "reagents" developed during the initial funding period, will allow us to test specific hypotheses about the role of cohesion, DMA sequence, and the synaptonemal complex in the establishment of meiotic exchanges. The combined data from these studies will allow us to understand the control of recombination In mammals and how the events of prophase influence meiotic chromosome segregation.