Meiotic Chromosome Inheritance in C. elegans

线虫减数分裂染色体遗传

• 批准号: 9901589
• 负责人: ANNE M VILLENEUVE
• 金额: $ 66.75万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901589
• 关键词: 3-Dimensional; Address; Aneuploidy; Base Sequence; Biological; Biological Assay; Caenorhabditis elegans; Cell Nucleus; Cells; Chromosome Structures; Chromosomes; Computer Analysis; Congenital Abnormality; Cytology; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; Development; Diploidy; Ensure; Equilibrium; Event; Failure; Feedback; Genome; Genomic approach; Germ Cells; Goals; Haploidy; Health; Homologous Gene; Human; Individual; Meiosis; Meiotic Recombination; Molecular; Nature; Nematoda; Organism; Outcome; Preparation; Process; Property; Prophase; Quality Control; Repair Complex; Reporting; Research; Signal Transduction; Site; Spontaneous abortion; Structure; System; Technology; Work; biological systems; engineering design; genetic approach; genome integrity; microscopic imaging; programs; repaired; response; segregation; success; tumor progression

Our research is aimed at understanding the molecular and cellular mechanisms underlying the faithful inheritance eukaryotic chromosomes. Our primary focus is on elucidating the events required for the orderly segregation of homologous chromosomes during meiosis, the crucial process by which diploid germ cells generate haploid gametes. These events are of central importance to sexually reproducing organisms, since failure to execute them correctly leads to chromosomal aneuploidy, one of the leading causes of miscarriages and birth defects in humans. During meiotic prophase, chromosomes undergo a dramatic and dynamic program of structural reorganization in preparation for the meiotic divisions. Moreover, chromosome inheritance during meiosis relies on the formation of double-strand DNA breaks (DSBs) and repair of a subset of these DSBs as inter-homolog crossovers (COs). Because the DSBs that serve as the initiating events of meiotic recombination pose a danger to genome integrity, the success of genome inheritance during meiosis requires cells to maintain a balance between the beneficial effects of COs and the potential harmful consequences of the process by which they are generated. A major goal of our research is to understand the mechanisms that operate during meiosis to achieve this crucial balance. An inter-related goal is to understand how meiosis-specific chromosome organization is established, maintained, and remodeled to bring about successful segregation of homologous chromosomes. We are approaching these issues using the nematode C. elegans, a simple metazoan organism that is especially amenable to combining powerful cytological, genetic and genomic approaches in a single experimental system, and in which the events under study are particularly accessible. Multiple lines of research are converging on a view of meiotic prophase as a highly integrated biological system that incorporates multiple “engineering design features” such as positive and negative feedback, self-limiting properties, quality control and fail-safe mechanisms that together promote a robust biological outcome. Our goal under the MIRA program is to elucidate how the different features of the meiotic program work, both individually and as a system, through integrating the use of advanced technologies that enable us to visualize the process (either through microscopic imaging or computational analysis of sequence-based assays) with advantages of the C. elegans system that enable experimental perturbation of the process. Another major long term goal is to understand the fundamental basis of homolog recognition and the nature of the interface between aligned homologous chromosomes. We will interrogate the process of meiosis at multiple different scales: 1) at the level of the DNA repair complexes that assemble at the sites of meiotic recombination; 2) at the level of the meiosis-specific chromosome structures that promote, regulate and respond to meiotic recombination events; 3) at the level of DNA organization at the whole-chromosome scale; and 4) at the level of nucleus-wide responses to signals that report on the status of the chromosomes.

我们的研究旨在了解忠实的分子和细胞机制 我们的主要重点是阐明有序的事件所需的真核染色体。 减数分裂过程中同源染色体的分离，这是二倍体生殖细胞形成的关键过程 产生单倍体配子。这些事件对于有性生殖生物体至关重要，因为 未能正确执行它们会导致染色体非整倍性，这是流产的主要原因之一 在人类减数分裂前期，染色体经历了戏剧性的动态变化。 为减数分裂做准备的结构重组计划。 减数分裂期间的遗传依赖于双链 DNA 断裂 (DSB) 的形成和子集的修复 这些 DSB 作为同源间交叉 (CO)，因为 DSB 充当起始事件。 减数分裂重组对基因组完整性、减数分裂期间基因组遗传的成功构成危险 需要细胞在CO的有益作用和潜在有害作用之间保持平衡 我们研究的一个主要目标是了解它们产生的过程的后果。 减数分裂过程中实现这一关键平衡的机制是了解一个相互关联的目标。 减数分裂特异性染色体组织是如何建立、维持和重塑的 我们正在利用线虫成功分离同源染色体。 线虫是一种简单的后生动物，特别适合结合强大的细胞学， 在单个实验系统中进行遗传和基因组方法，其中所研究的事件是 多项研究都一致认为减数分裂前期是一个高度易理解的阶段。 集成生物系统，融合了多种“工程设计特征”，例如积极和 负反馈、自限性、质量控制和故障安全机制共同促进了 MIRA 计划的目标是阐明稳健的生物学结果。 通过综合使用先进技术，减数分裂程序可以单独工作，也可以作为一个系统进行工作 使我们能够可视化该过程（通过显微成像或计算分析） 基于序列的测定）具有秀丽隐杆线虫系统的优点，可以进行实验扰动 该过程的另一个主要长期目标是了解同源识别的基本原理和 我们将探究排列的同源染色体之间的界面的性质。 减数分裂在多个不同的尺度上：1）在DNA修复复合物的水平上，这些复合物在减数分裂的位点组装 减数分裂重组；2) 在减数分裂特异性染色体结构水平上促进、调节 并对减数分裂重组事件做出反应；3) 在全染色体的 DNA 组织水平上 规模；4）在细胞核范围内对报告染色体状态的信号的反应。