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.

我们的研究旨在了解忠实的分子和细胞机制 遗传真核染色体我们的主要重点是阐明有序所需的事件 减数分裂过程中同源染色体的分离，这是二倍体生殖细胞 产生单倍体配子。这些事件对有性生殖的生物至关重要，因为 如果不能正确地执行它们，就会导致染色体非整倍性，这是流产的主要原因之一 和先天缺陷。在减数分裂前期，染色体经历了一个戏剧性的和动态的 为减数分裂做准备的结构重组程序。此外，染色体 减数分裂期间的遗传依赖于双链DNA断裂（DSB）的形成和亚群的修复， 这些DSB作为同源物间交叉（CO）。因为作为启动事件的DSB 减数分裂重组对基因组的完整性、减数分裂期间基因组的成功遗传构成了危险 需要细胞在一氧化碳的有益影响和潜在的有害影响之间保持平衡。 它们产生的过程的后果。我们研究的一个主要目标是了解 在减数分裂期间运作的机制来实现这一关键平衡。一个相互关联的目标是了解 减数分裂特异性染色体组织是如何建立、维持和重塑的， 同源染色体的成功分离。我们正在利用线虫来解决这些问题 C.线虫，一种简单的后生动物，特别适合于将强大的细胞学， 遗传学和基因组学方法在一个单一的实验系统，其中所研究的事件是 特别容易接近。多条研究路线正在汇聚一种观点，认为减数分裂前期是一个高度复杂的过程。 集成生物系统，包括多个“工程设计特征”，如积极的， 负反馈、自我限制特性、质量控制和故障安全机制共同促进了 强大的生物学结果。我们在MIRA计划下的目标是阐明 减数分裂程序工作，无论是个人还是作为一个系统，通过整合使用先进的技术 使我们能够可视化的过程（无论是通过显微成像或计算分析， 基于序列的测定）具有C. elegans系统，使实验扰动的 过程另一个主要的长期目标是了解同源识别的基本基础， 排列的同源染色体之间界面的性质。我们将审问 减数分裂在多个不同的尺度：1）在DNA修复复合物的水平上， 减数分裂重组; 2）在减数分裂特异性染色体结构水平上， 并对减数分裂重组事件作出反应; 3）在整个染色体的DNA组织水平上 规模;和4）在细胞核范围内对报告染色体状态的信号的反应水平。