Segregation of error-prone chromosomes in meiosis

描述(申请人提供)：在人类中，减数分裂染色体分离错误会导致基于非整倍体的出生缺陷，如唐氏症、Klinefelter‘s和特纳综合征，导致大多数自然流产，并经常导致不孕不育。随着孕妇年龄的增加，染色体数目不适当的受孕的发生率也会上升。同源染色体之间的重组极大地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是由于减数分裂机制的两次连续故障造成的。首先，同源染色体之间的重组失败或放置不当会使它们“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，但分离机制的第二个未确定的组成部分的故障使细胞无法正确地分割这些容易出错的染色体。随着女性年龄的增长，第二组分的缺陷增加被认为是导致三体后代发生率增加的原因。第二个故障机制的候选之一是主轴或主轴检查点功能。对酵母中容易出错的染色体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，重组失败使染色体对在减数分裂中容易出错，并高度依赖第二个过程。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)。这个项目的目标是检查在酵母减数分裂中用于分割易出错的染色体的机制。目的是：1)确定MAD3对非交换染色体的分割有何作用。2)检验着丝粒配对机制被用来分割酵母中容易出错的非交换染色体的假设。3)确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)验证着丝粒配对在所有染色体的减数分裂特有行为中起着以前未被认识到的作用的假设。这些研究应该有助于更好地理解导致人类月经失败的机械性问题。

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.