GENETIC CONTROL OF MEIOTIC CHROMOSOME SEGREGATION

描述(由申请人提供)：减数分裂过程中的错误是我们物种智力低下和妊娠丢失的主要原因。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(S)和年龄影响染色体分离的方式尚不清楚，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着染色体分离。在过去的几年里，我们对涉及减数分裂重组的分子事件的了解大大增加，但我们在很大程度上仍然对控制哺乳动物重组水平和位置的因素一无所知。本申请中概述的研究是基于这样的假设，即重组受到前期事件的影响，这些前期事件涉及姐妹染色单体之间凝聚力的建立、同系物之间联会复合体的形成以及DNA双链断裂的修复。因此，我们提出了三组相互关联的研究，一组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；一组使用突变分析来检查“异常”变异对这些事件的影响；另一组研究前期扰动的下游影响。这种方法，使用在最初的资助期开发的减数分裂“试剂”，将允许我们测试关于凝聚力、DMA序列和联会复合体在建立减数分裂交换中的作用的具体假设。这些研究的综合数据将使我们能够理解哺乳动物中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.