Functional analysis of the synaptonemal complex

描述(申请人提供)：减数分裂是所有有性繁殖有机体用来将其基因组大小减少一半的细胞分裂。在第一次减数分裂过程中，同源染色体被分离。准确的同源分离是决定配子是否包含每条染色体的一个拷贝的生殖健康的关键事件。由染色体不平衡配子产生的受精卵往往不能正常发育，导致大量死胎和出生缺陷。在后代可以存活的情况下，会出现严重的健康问题，包括唐氏综合症或特纳综合征。同源基因的分离很大程度上依赖于介导同源基因向相反细胞两极分离的交叉。两条重要的、在空间和时间上协调的路径有助于形成交叉。首先，在DNA水平上，双链断裂被诱导，并通过包括双Holliday连接在内的几个中间体被处理成交叉。第二，在染色体结构水平上，螺旋卷曲蛋白沿着同源物和在同源物之间聚合，产生联会复合体中心元件，稳定地并列在同源物之间。我们的长期目标是了解联会复合体和减数分裂重组之间的功能相互作用。我们正在使用面包师的酵母S.cerevisiae作为模型来理解这个问题。作为我们的第一个目标，我们将确定联会复合体的结构是如何控制的。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在重组、染色体结构和野生型减数分裂过程中的细胞周期进展中的功能。当减数分裂有缺陷时，Pch2也起到检查点的作用。作为我们的第二个目标，我们将通过监测ZIP1过早缺失对同源凝聚力和重组的影响来探索重组和突触复合体之间的功能关系。总之，这些方法将阐明联会复合体的作用，从而识别导致减数分裂染色体错误分离的事件。公共卫生相关性：高达30%的临床确认的人类妊娠表现出非整倍体，即一个或几个染色体的缺失或过剩。大多数染色体不平衡是由减数分裂过程中的染色体错误分离引起的。因此，减数分裂错误是人类不孕不育和出生缺陷的主要原因。从机制上理解染色体分离的减数分裂机制对于使这一问题成为未来医学干预的基础是至关重要的。

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.