GENETIC CONTROL OF MEIOTIC CHROMOSOME SEGREGATION

在我们人类中，减数分裂细胞分裂的错误是智力迟钝和怀孕失败的主要原因。过去十年的研究表明，绝大多数减数分裂错误是母亲的起源，这些错误的发生率与母亲的年龄密切相关。然而，错误的机制以及年龄影响减数分裂染色体分离过程的方式仍然未知。拟议的研究通过关注减数分裂染色体的一个基本特征来解决这个问题，该特征在第一次减数分裂时介导染色体分离;同源染色体之间的相互交换（重组）事件。由于缺乏合适的动物模型，我们对人类高减数分裂错误率的理解受到阻碍。然而，基因靶向技术的出现提供了在特定基因中产生突变的手段。有针对性地破坏DNA错配修复相关基因，导致了第一个重组水平降低的哺乳动物突变体。我们将利用这些突变体以及自然发生的小鼠变异体来了解重组在减数分裂染色体分离中的作用。这些研究将提供有价值的洞察力，正常的女性减数分裂过程的控制，并将使我们能够测试的机制，减数分裂错误的人类女性的假设。

Errors during meiotic cell division are a leading cause of mental retardation and pregnancy failure in our species. Research over the past decade has demonstrated that the vast majority of meiotic errors are maternal in origin and that the incidence of these errors is strongly correlated with maternal age. The mechanism(s) of error, however, and the manner in which age influences the process of meiotic chromosome segregation remain unknown. The proposed research approaches this problem by focusing on an essential feature of meiotic chromosomes that mediates chromosome segregation at the first meiotic division; reciprocal exchange (recombination) events between homologous chromosomes. Our understanding of the high meiotic error rate in our species has been hampered by the lack of a suitable animal model. The advent of gene targeting technology, however, has provided a means of creating mutations in specific gene. Targeted disruption of genes involved in DNA mismatch repair has resulted in the first mammalian mutants that show a reduction in recombination levels. We will utilize these mutants as well as naturally occurring murine variants to understand the role of recombination in meiotic chromosome segregation. These studies will provide valuable insight to the control of the normal female meiotic process and will allow us to test hypotheses about the mechanism of meiotic errors in the human female.