Meiotic Chromosome Inheritance in C. elegans

线虫减数分裂染色体遗传

• 批准号: 10377335
• 负责人: ANNE M VILLENEUVE
• 金额: $ 66.77万
• 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/10377335
• 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; 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.

我们的研究旨在理解信徒的分子和细胞机制 遗传真核染色体。我们的主要重点是阐明有序的事件 减数分裂过程中同源染色体的分离，这是二倍体生殖细胞的关键过程 产生单倍体游戏。这些事件对于性繁殖有机体至关重要，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 和人类的出生缺陷。在减数分裂预言期间，染色体会经历戏剧性和动态性 结构性重组计划，以准备减数分裂分裂。而且，染色体 减数分裂期间的遗传依赖于双链DNA断裂（DSB）的形成和子集修复 这些DSB作为血统跨界（COS）。因为作为发起事件的DSB 减数分裂重组对基因组完整性构成危险，这是减数分裂过程中基因组遗传的成功 需要细胞在COS的有益效应与潜在有害的有益作用之间保持平衡 生成过程的后果。我们研究的主要目标是了解 在减数分裂过程中起作用以实现这种关键平衡的机制。相互关联的目标是了解 如何建立，维护和重塑减数分裂特异性染色体组织以实现 同源染色体的成功分离。我们正在使用线虫来解决这些问题 秀丽隐杆线虫，一种简单的后生动物，特别适合结合强大的细胞学， 单个实验系统中的遗传和基因组方法，其中所研究的事件是 特别可访问。多种研究线正在融合减数分裂propase作为高度 集成生物系统，结合了多个“工程设计功能”，例如正面和 负面反馈，自限制特性，质量控制和故障安全机制共同促进 强大的生物学结果。 MIRA计划下的目标是阐明如何 通过整合高级技术的使用，单独和作为系统的减数分裂计划工作 这使我们能够可视化过程（通过微观成像或计算分析 基于序列的测定）具有秀丽隐杆线虫系统的优势，使实验性扰动 过程。另一个主要的长期目标是了解同源识别的基本基础 对齐的同源染色体之间的界面的性质。我们将审问 在多个不同尺度上的减数分裂：1）在聚集在地点的DNA修复复合物的水平上 减数分裂重组； 2）在促进，调节的减数分裂特异性染色体结构的水平 并回应减数分裂重组事件； 3）在整个染色体的DNA组织级别 规模; 4）在报告染色体状态的信号的核响应水平上。