Homologous Chromosome Pairing in Meiosis

项目摘要/摘要 减数分裂错误引起的染色体异常是导致出生缺陷和自发性的主要原因 人类的堕胎。这项工作的长期目标是阐明减数分裂配对和 为了了解这些机制如何帮助确保染色体传输的保真度 代代相传。虽然减数分裂事件在物种之间保存得很好，但它们的执行 适应核体积和基因组大小的几个数量级的变化。我们的目标 阐述了染色体的3D构型是离散的、动态的，并在 在整个课程中适应不断变化的核结构/功能要求的空间和时间 减数分裂前期。这一建议建立在我们最近的发现基础上，酵母的125个氨基酸区域 核孔蛋白Nup2是减数分裂中染色体正确分离所必需的，与它在 运输。我们将确定这个减数分裂自治区(MAR)如何发挥这一作用 各种遗传和基于结构的方法。我们还引入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的减数分裂染色体动力学。我们到目前为止的发现 提示斑马鱼可能是研究人类男性减数分裂的良好模型。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。我们将决定 同源配对、DNA双链断裂形成和突触形成的时空程序 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 我们为芽殖酵母建立了成像管道，以测量同源基因和同源基因之间的相互作用动力学 两种性别斑马鱼的异位染色体。我们的结果将引导我们理解如何 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.