Homologous Chromosome Pairing in Meiosis

项目总结/摘要 由于减数分裂错误导致的染色体异常是出生缺陷和自发性染色体异常的主要原因。 人类的堕胎这项工作的长期目标是阐明减数分裂配对的机制， 为了了解这些机制如何帮助确保染色体从一个人传递的保真度， 下一代。虽然减数分裂的事件在物种间保存得很好，但它们的执行 容纳了几个数量级变化的核体积和基因组大小。我们的目标 解决了染色体的3D配置是离散的，动态的，并在 空间和时间，以适应整个过程中不断变化的核结构/功能要求 减数分裂前期这一建议建立在我们最近发现的基础上，即酵母的125个氨基酸区域 核孔蛋白Nup2是减数分裂中正确的染色体分离所必需的，与其在细胞分裂中的作用无关。 运输我们将确定这个减数分裂自治区（MAR）是如何发挥作用的， 各种基于遗传和结构的方法。我们还介绍了斑马鱼作为一种新的遗传模型 研究卵子发生和精子发生过程中减数分裂染色体动态。我们目前的发现 表明斑马鱼可能是人类雄性减数分裂极好模型。成年斑马鱼产生配子 在整个生命过程中，后代数以百计，胚胎在体外发育。我们将确定 同源物配对、DNA双链断裂形成和突触形成时空程序， 与其他物种的典型减数分裂程序有关。最后，我们将应用三维活细胞 我们为芽殖酵母创建了成像管道，以测量同源和 两种性别斑马鱼的异位染色体位点。我们的研究结果将帮助我们理解 环境危害增加了基于染色体的出生缺陷和遗传性疾病的发生。

Project Summary/Abstract Chromosome abnormalities due to meiotic errors are a leading cause of birth defects and spontaneous abortions in humans. The long-term objective of this work is to elucidate the mechanisms of meiotic pairing and to understand how these mechanisms help to ensure the fidelity of chromosome transmission from one generation to the next. While the events of meiosis are well conserved across species, their execution accommodates nuclear volumes and genome sizes that vary by several orders of magnitude. Our aims address the hypothesis that the 3D configurations of chromosomes are discrete, dynamic, and governed in space and time to accommodate the changing nuclear structure/function requirements throughout the course of meiotic prophase. This proposal builds on our recent discovery that a 125 amino acid region of the yeast nucleoporin Nup2 is required for proper chromosome segregation in meiosis, independent of its role in transport. We will determine how this meiotic autonomous region (MAR) functions in carrying out this role using a variety of genetic and structure-based approaches. We also introduce zebrafish as a new genetic model organism to study meiotic chromosome dynamics during oogenesis and spermatogenesis. Our finding so far suggest that zebrafish may an excellent model for human male meiosis. Adult zebrafish produce gametes throughout life, progeny number in the hundreds and embryos develop outside the body. We will determine the spatial and temporal program of homolog pairing, DNA double-strand break formation and synapsis as it relates to the canonical meiosis program in other species. Finally, we will apply a three-dimensional live-cell imaging pipeline we created for budding yeast to measure interaction kinetics between homologous and ectopic chromosomal loci in the two zebrafish sexes. Our results will lead to an understanding of how environmental hazards increase the occurrence of chromosome-based birth defects and inherited disease.