Segregation of error-prone chromosomes in meiosis

在人类中，减数分裂染色体分离错误导致基于非整倍性的出生缺陷，如 唐氏综合征、克氏综合征和特纳综合征是大多数自然流产的原因， 导致不孕不育染色体数目不合适的胚胎发生率上升 随着母亲年龄的增长。同源染色体之间的分离大大增加了 在减数分裂I中，它们将正确分离（彼此分离）的概率。有人提出，在 人类许多减数分裂染色体分离错误的发生是由于两个连续的失败， 减数分裂机制首先，同源染色体之间的重组失败或位置不当 使他们“容易出错”。这些容易出错的染色体可能在大多数减数分裂中正确分离， 但分离机制的第二个未定义的组件的故障使细胞无法分离， 这些容易出错的染色体。第二部分的故障增加被认为是 导致随着女性年龄的增长，三体后代的发生率增加。第二个候选人 故障机制是主轴或主轴检查点功能。易错染色体减数分裂分离的研究 酵母中的染色体揭示了一个两步失败的过程，与人类非常相似。 形势在酵母中，就像在人类中一样，重组失败使染色体对在减数分裂中容易出错 ，并且高度依赖于第二过程。这第二个过程需要保守的纺锤体 检查点基因，MAD3（与人类中的BubR1相关）。本项目的目标是检查 在酵母减数分裂中用于划分易出错染色体的机制。目标是：1）确定如何 MAD3有助于非交换染色体的分配。2)测试假设， 着丝粒配对机制被用于在酵母中划分易错的非交换染色体。第三章 确定非交换染色体之间观察到的减数分裂着丝粒配对所需的基因 对. 4)测试假设，即着丝粒配对在介导 所有染色体的减数分裂特异性行为。这些研究应有助于更好地了解 导致人类减数分裂失败的机械问题。

In humans, meiotic chromosome segregation errors result in aneuploidy-based birth defects such as Down's, Klinefelter's, and Turner's Syndromes, cause most spontaneous abortions, and are frequently responsible for infertility. The incidence of conceptuses with inappropriate numbers of chromosomes rises with increased maternal age. Recombination between homologous chromosomes greatly increases the probability that they will segregate properly (away from each other) at meiosis I. It has been proposed that in humans many meiotic chromosome segregation errors occur because of two sequential failures of the meiotic machinery. First, failed or inappropriately placed recombination between homologous chromosomes makes them "error-prone". These error-prone chromosomes probably segregate correctly in most meioses, but failures of a second, undefined, component of the segregation machinery renders cells unable to partition these error-prone chromosomes properly. Increased failures in the second component are thought to be responsible for the increased incidence of trisomic progeny as woman age. One candidate for the second failed mechanism is spindle, or spindle checkpoint, function. Studies of meiotic segregation of error-prone chromosomes in yeast have revealed a two-step failure process with strong similarities to the human situation. In yeast, as in humans, failures in recombination render chromosome pairs error-prone in meiosis , and highly dependent on a second process. This second process requires the conserved spindle checkpoint gene, MAD3 (related to BubR1 in humans). The goal of this project is to examine the mechanisms used to partition error-prone chromosomes in yeast meiosis. The aims are: 1) Determine how MAD3 contributes to the partitioning of non-exchange chromosomes. 2) Test the hypothesis that a centromere-pairing mechanism is used to partition error-prone non-exchange chromosomes in yeast. 3) Identify the genes required for the meiotic centromere pairing observed between non-exchange chromosome pairs. 4) Test the hypothesis that centromere pairing plays a previously unrecognized role in mediating meiosis-specific behavior of all chromosomes. These studies should lead to a better understanding of the mechanistic problems that lead to failed meioses in humans.