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体用于将其基因组大小减少一半的细胞分裂。在第一次减数分裂期间，同源染色体分离。准确的同源分离是生殖健康的一个关键事件，确定配子是否包含每个染色体的确切一个拷贝。由染色体不平衡的配子产生的合子经常不能正常发育，造成大量的死胎和出生缺陷。在后代存活的情况下，会出现严重的健康问题，包括唐氏综合征或特纳综合征。同源物的分离主要依赖于介导同源物分离到相反细胞两极的交换。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连接在内的几个中间体被加工成交叉。第二，在染色体结构水平上，卷曲螺旋蛋白沿着沿着和在同源物之间延伸，产生稳定并置同源物的联会复合体中心元件。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。我们用的是面包酵母S。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联会复合体的结构。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Pch 2在野生型减数分裂期间重组、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，我们将探讨重组和联会复合体之间的功能关系，通过监测过早Zip1耗尽同源凝聚力和重组的影响。总之，这些方法将澄清联会复合体的作用，从而确定事件，有助于减数分裂染色体的错误分离。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性，即一个或多个染色体的缺陷或过剩。大多数染色体不平衡是由减数分裂时染色体的错误分离引起的。因此，减数分裂错误是人类不育和出生缺陷的主要原因。染色体分离的减数分裂机制的机械理解是必不可少的，使这个问题可以在未来的医疗干预。

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.