Homolog pairing in meiosis

减数分裂中的同源配对

• 批准号: 10406081
• 负责人: Sean M Burgess
• 金额: $ 46.7万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406081
• 关键词: 3-Dimensional; Address; Aneuploidy; Animal Model; Behavior; Biochemical Pathway; Biology; Cell Nucleus; Cells; Chromosome Pairing; Chromosome Structures; Chromosome abnormality; Chromosomes; Congenital Abnormality; Data Set; Diffuse; Diffusion; Drug Prescriptions; Ensure; Environment; Environmental Pollution; Equilibrium; Event; Exposure to; Female; Food Container; Gametogenesis; Genetic; Genetic Recombination; Germ Cells; Goals; Homologous Gene; Human; Image; Infertility; Lead; Meiosis; Meiotic Prophase I; Modeling; Molecular; Motion; Motor; Movement; Nuclear; Nuclear Envelope; Nuclear Pore Complex; Organism; Outcome; Pathway interactions; Polymers; Positioning Attribute; Pregnancy loss; Process; Prophase; Reproductive Health; Role; Saccharomycetales; Same-sex; Spermatogenesis; Spontaneous abortion; Synapses; Testing; Time; Transact; Waste Products; Work; Yeasts; Zebrafish; base; biophysical properties; epigenetic marker; homologous recombination; insight; lens; male; reproductive; response; telomere; time use

Project Summary/Abstract Chromosome abnormalities due to meiotic errors are a leading cause of birth defects and spontaneous abortions in humans. Our overarching goal is to understand how the organization of chromosomes in the nucleus contributes to the correct pairing, synapsis, and recombination of homologous chromosomes during meiosis I prophase– and how infidelity in these processes lead to chromosomal abnormalities. The basic mechanisms leading to homolog pairing, synapsis and recombination are well conserved. The study of a wide range of organisms has ultimately led to insights into human gamete aneuploidy and infertility. We use two model organisms, budding yeast and zebrafish, each providing a unique lens to address how the 3D configuration of chromosomes is governed to accommodate the changes in the nuclear landscape throughout meiotic prophase. Our work addresses three key questions in the field of chromosome biology: 1) How do chromosomes balance the contributions of diffusive versus active motion, 2) How does movement promote molecular transactions between chromosomes? And 3) how do cells sense and respond to unpaired meiotic chromosomes to ensure reproductive fidelity? 1) To understand how chromosomes move, we will examine the contributions of diffusion, constrained diffusion, and active motor-driven movement on chromosomal loci in yeast by comparing data sets of XYZ coordinates of tagged loci over time using our newly developed imaging pipeline. We will compare these outcomes with newly developed models of chromosome behavior based on simple biophysical properties of polymers. We will test if the nuclear pore complex also contributes to chromosome motion, building on our discovery of a role of the NPC in meiotic chromosome dynamics. 2) To understand how the organization of chromosomes in the much larger vertebrate nucleus contributes to effective homolog pairing we will build on our recent work in zebrafish showing the initial events of pairing and synapsis all take place at the telomere bouquet, suggesting that pairing in the larger nucleus is accommodated by temporally and spatially sequestering pairing factors in time and space. We will test if telomere attachment or positioning at the nuclear membrane is important for pairing, and we will identify the epigenetic markers that define pairing-competent features of chromosomes. 3) To understand how cells respond to unpaired chromosomes and how does this response differ between species, and even between sexes of the same species, we will take advantage of our recent findings that synaptic errors cause arrest in spermatogenesis in zebrafish males. Furthermore, synaptic errors in females are tolerated, thus raising the tantalizing possibility that the surveillance and silencing of asynapsed chromosomes checkpoints does not operate in zebrafish.

项目摘要/摘要 由于减数分裂错误导致的染色体异常是出生缺陷和赞助的主要原因 人类流产。我们的总体目标是了解如何在 核有助于在同源染色体的正确配对，突触和重组。 减数分裂我的预言以及这些过程中的不忠是如何导致染色体异常。基本 导致同源配对，突触和重组的机制是充分保守的。宽阔的研究 一系列生物最终导致了人们对人配子非子宫倍和不育的见解。我们使用两个 模型生物，萌芽的酵母和斑马鱼，每个生物都提供了独特的镜头，以解决3D 染色体的构型均可容纳整个核景观的变化 减数分裂的预言。我们的工作解决了染色体生物学领域的三个关键问题：1）如何 染色体平衡扩散与主动运动的贡献，2）运动如何促进 染色体之间的分子交易？ 3）细胞如何感知和响应未配对的减数分裂 染色体以确保生殖保真度？ 1）了解染色体的移动方式，我们将检查 扩散，约束扩散和主动运动驱动运动对染色体基因座的贡献 通过比较我们新开发的成像，随着时间的流逝，酵母菌的XYZ坐标数据集随时间推移 管道。我们将将这些结果与基于新开发的染色体行为模型进行比较 聚合物的简单生物物理特性。我们将测试核孔复合物是否也有助于 染色体运动，基于我们发现NPC在减数分裂染色体动力学中的作用。 2）到 了解更大的脊椎动物核中染色体的组织如何有助于 有效的同源配对，我们将基于我们最近在斑马鱼的工作，展示配对的最初事件和 突触都在端粒花束上发生 通过临时和空间隔离的配对因子在时空和空间中。我们将测试端粒是否附件 或在核膜上定位对于配对很重要，我们将确定表观遗传标志物 定义染色体的配对特征。 3）了解细胞如何响应不成对的 染色体以及这种反应在物种之间甚至相同的性别之间有何不同 物种，我们将利用我们最近的发现，即突触错误会导致精子发生的逮捕 斑马鱼男性。此外，女性的突触错误被耐受，从而增加了诱人的可能性 斑马鱼的监视和沉默无法在斑马鱼中运行。