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GENETIC CONTROL OF MEIOTIC CHROMOSOME SEGREGATION

减数分裂染色体分离的遗传控制

基本信息

批准号：
7932669
负责人：
Patricia Hunt
金额：
$ 8.54万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2010-09-29
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：减数分裂细胞分裂过程中的错误是我们物种智力迟钝和妊娠失败的主要原因。绝大多数的人类减数分裂错误是母亲的起源和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所涉及的分子事件的理解已经大大增加，但我们仍然在很大程度上对哺乳动物中控制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相互作用的影响，这些前期事件涉及姐妹染色单体之间的凝聚力的建立、同源物之间联会复合体的形成以及DNA双链断裂的修复。因此，我们提出了三套相互关联的研究，一个是定义哺乳动物雌性减数分裂前期的关键事件，并评估这些过程中的“正常”遗传变异的影响;一个是使用突变分析来研究这些事件的“异常”变异的影响;一个是研究前期扰动的下游影响。这种方法，使用减数分裂的“试剂”在最初的资助期间开发的，将使我们能够测试特定的假设的凝聚力，DMA序列，和联会复合体的作用，在建立减数分裂交换。这些研究的综合数据将使我们能够理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。