Functional analysis of the synaptonemal complex

描述（由申请人提供）：减数分裂是所有有性生殖生物使用的细胞分裂，使其基因组大小减少一半。在第一次减数分裂中，同源染色体被分离。准确的同源分离是生殖健康的关键事件，决定配子是否只包含每条染色体的一个拷贝。染色体不平衡的配子产生的受精卵经常不能正常发育，导致大量的死产和出生缺陷。在后代能够存活的情况下，会出现严重的健康问题，包括唐氏综合症或特纳综合症。同源分离主要依赖于交叉，交叉介导同源分离到相反的细胞极点。两个突出的，空间和时间协调的途径有助于交叉形成。首先，在DNA水平上，双链断裂被诱导，并通过包括双霍利迪结在内的几个中间体被加工成交叉。其次，在染色体结构水平上，螺旋状蛋白沿着同源物和在同源物之间聚合，产生突触复合中心元件，稳定地将同源物并列。我们的长期目标是了解突触复合体和减数分裂重组之间的功能相互作用。我们使用面包酵母酿酒酵母作为模型来理解这个问题。作为我们的第一个目标，我们将确定如何控制突触复合体的结构。染色体结构的细胞学分析以及重组的物理和遗传分析将用于确定Pch2在野生型减数分裂中重组、染色体结构和细胞周期进程中的功能。当减数分裂有缺陷时，Pch2也起检查点的作用。作为我们的第二个目标，我们将通过监测Zip1过早耗尽对同源内聚和重组的影响来探索重组与突触复合体之间的功能关系。总之，这些方法将阐明突触复合体的作用，从而确定导致减数分裂染色体错分离的事件。公共卫生相关性：高达30%的临床确认的人类妊娠表现为非整倍体，即一条或多条染色体的缺失或过剩。大多数染色体失衡是由于减数分裂过程中染色体分离错误造成的。因此，减数分裂错误是人类不育和出生缺陷的主要原因。对染色体分离的减数分裂机制的机制理解是必要的，使这一问题可用于未来的医学干预。

DESCRIPTION (provided by applicant): Meiosis is the cell division used by all sexually reproducing organisms to reduce their genome size by half. During the first meiotic division, homologous chromosomes are separated. Accurate homolog segregation is a key event for reproductive health determining whether gametes contain exactly one copy of every chromosome. Zygotes arising from chromosomally imbalanced gametes frequently fail to develop normally, accounting for large numbers of still births and birth defects. In cases where offspring are viable, severe health problems occur including Down or Turner syndromes. Homolog segregation critically depends on crossovers which mediate the separation of homologs to opposite cell poles. Two prominent, spatially and temporally coordinated pathways contribute to crossover formation. First, on the DNA level, double strand breaks are induced and get processed into crossovers via several intermediates including the double Holliday junction. Second, on the chromosome structure level, coiled-coil proteins polymerize along and between homologs, giving rise to the synaptonemal complex central element which stably juxtaposes homologs. Our long term goal is to understand the functional interplay between the synaptonemal complex and meiotic recombination. We are using the baker's yeast S. cerevisiae as a model to understand this problem. As our first aim, we will determine how the structure of the synaptonemal complex is controlled. Cytological analysis of chromosome structure as well as physical and genetic analysis of recombination will be used to determine functions of Pch2 in recombination, chromosome architecture and cell cycle progression during wild-type meiosis. Pch2 also functions as a checkpoint when meiosis is defective. As our second aim, we will explore the functional relationship between recombination and the synaptonemal complex by monitoring effects of premature Zip1 depletion on homolog cohesion and recombination. Together, these approaches will clarify the role of the synaptonemal complex, thereby identifying events that contribute to meiotic chromosome missegregation. PUBLIC HEALTH RELEVANCE: Up to 30% of clinically recognized human pregnancies exhibit aneuploidies, i.e. a deficit or surplus of one or several chromosomes. Most chromosomal imbalances result from chromosome missegregation during meiosis. Meiotic mistakes thus are the leading cause of infertility and birth defects in humans. A mechanistic understanding of meiotic mechanisms of chromosome segregation is essential to make this problem accessible to future medical intervention.