A PROGRAM OF RESEARCH IN POPULATION CYTOGENETICS

描述（申请人提供）：染色体异常在人类中发生的频率惊人，估计10-30%的受精卵含有结构或数量异常。在不同类型的染色体异常中，非整倍体是迄今为止最常见的，在临床上也是最重要的--它是已知的导致流产的主要原因，在那些存活到足月的受孕中，它是导致发育障碍的主要遗传原因。大多数非整倍体是由母体减数分裂错误引起的，但是，尽管它们在临床上很重要，我们对人类女性减数分裂过程中的染色体动力学知之甚少，并且仍然不知道为什么这个过程如此容易出错。在这些研究中，我们描述了一系列的细胞学和分子生物学方法来研究正常和异常的人类女性减数分裂。具体来说，我们将进行第一次系统的分析前期I在人类女性，检查同源染色体配对，突触和重组的方式。这将使我们能够评估这些过程中的异常水平，并询问已知不倾向于分离的人类染色体（例如，16和21）是“注定”，因为错误的配对，突触或重组。这些对胎儿卵母细胞的研究将与三体胎儿的分子分析相结合，三体胎儿的亲本和减数分裂阶段是已知的，这使我们能够确定胎儿卵母细胞中的错误是否确实转化为非整倍体概念。 累积起来，这些研究代表了首次对人类女性的前期I进行系统分析，并首次尝试将产前染色体行为与多年后减数分裂I恢复时发生的分离事件联系起来。最终，我们的目标是确定导致减数分裂不分离增加的因素，并询问我们是否可以干预以降低这些异常的频率。

DESCRIPTION (provided by applicant): Chromosome abnormalities occur with astonishing frequency in humans, with an estimated 10-30% of all fertilized eggs containing structural or numerical abnormalities. Of the different classes of chromosome abnormality, aneuploidy is by far the most common and, clinically, the most important - it is the leading known cause of pregnancy loss and, among those conceptions which survive to term, the leading genetic cause of developmental disabilities. Most aneuploidy results from maternal meiotic errors but, despite their clinical importance, we know very little about chromosome dynamics during human female meiosis, and remain ignorant of the reasons why the process is so error-prone. In the proposed studies, we describe a series of cytological and molecular approaches to study normal and abnormal human female meiosis. Specifically, we will conduct the first systematic analysis of prophase I in the human female, examining the way in which homologous chromosomes pair, synapse and recombine. This will allow us to assess the level of abnormalities in these processes, and to ask whether human chromosomes that are known to be nondisjunction-prone (e.g., 16 and 21) are "predestined" to mal-segregate because of errors in pairing, synapsis or recombination. These studies of fetal oocytes will be partnered with molecular analyses of trisomic fetuses in which the parental and meiotic stage of origin is known, allowing us to determine whether errors in the fetal oocyte are indeed translated into aneuploid conceptions. Cumulatively, these studies represent the first systematic analysis of prophase I in the human female, and the first attempt to link prenatal chromosome behavior with segregation events occurring years later at the time of resumption of meiosis I. Ultimately, our goal is to identify factors responsible for increasing meiotic nondisjunction, and to ask whether we can intervene to decrease the frequency of these abnormalities.