Segregation of error-prone chromosomes in meiosis

描述（由申请人提供）：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，导致大多数自然流产，并经常导致不育。随着母亲年龄的增加，染色体数目不适当的胎儿的发生率增加。同源染色体之间的分离大大增加了它们在减数分裂I时正确分离（彼此分离）的可能性。有人提出，在人类中，许多减数分裂染色体分离错误的发生是因为减数分裂机制的两个连续故障。首先，同源染色体之间的重组失败或不适当地放置使它们“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，但是分离机制的第二个未定义的组件的失败使得细胞无法正确地分配这些容易出错的染色体。第二组分的失败增加被认为是随着女性年龄的增长三体后代发生率增加的原因。第二种失效机制的一个候选者是主轴或主轴检查点功能。对酵母中易错染色体的减数分裂分离的研究揭示了一个与人类情况非常相似的两步失败过程。在酵母中，就像在人类中一样，重组失败使得染色体对在减数分裂中容易出错，并且高度依赖于第二个过程。第二个过程需要保守的纺锤体检查点基因MAD3（与人类的BubR1相关）。本计画的目的是探讨在酵母减数分裂中，错误染色体的分配机制。目的是：1）确定MAD 3如何有助于非交换染色体的分配。2)验证一个假设，即着丝粒配对机制是用来分区错误倾向的非交换染色体在酵母。3)鉴定在非交换染色体对之间观察到的减数分裂着丝粒配对所需的基因。4)验证一个假设，即着丝粒配对在所有染色体的减数分裂特异性行为中起着以前未被认识到的作用。这些研究应该能更好地理解导致人类减数分裂失败的机制问题。

DESCRIPTION (provided by applicant): 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.