Segregation of error-prone chromosomes in meiosis

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、克莱菲尔特氏症和特纳氏综合症是大多数自然流产的原因，而且经常是 对不孕不育负有责任。染色体数目不适当的受孕率上升 随着产妇年龄的增加。同源染色体之间的重组大大增加了 它们在第一次减数分裂时适当分离(彼此分开)的概率。 人类许多减数分裂染色体分离错误的发生是因为两个连续的失败 减数分裂机制。首先，同源染色体之间的重组失败或放置不当 这使得它们“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，隔离机制的第二个未定义组件的故障导致单元无法划分 这些容易出错的染色体是正确的。第二个组件的故障增加被认为是 导致三体后代的发生率随着女性年龄的增长而增加。一位候选人竞选第二位候选人 故障机制是主轴或主轴检查点工作正常。易错株系减数分裂分离的研究 酵母中的染色体显示了一个两步失败的过程，与人类有很强的相似性 情况。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个过程。第二个过程需要保存的主轴 检查点基因MAD3(与人类的BubR1相关)。这个项目的目标是研究 酵母菌减数分裂中易出错染色体的分割机制。目标是：1)确定如何 MAD3有助于非交换染色体的分裂。2)检验假设 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。3) 鉴定在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 成对的。4)检验着丝粒配对在中介过程中发挥以前未被认识到的作用的假设 减数分裂--所有染色体特有的行为。这些研究应该有助于更好地理解 导致人类经期失败的机械性问题。

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.