Meiotic Chromosome Inheritance in Caenorhabditis

秀丽隐杆线虫减数分裂染色体遗传

• 批准号: 10623710
• 负责人: ANNE M VILLENEUVE
• 金额: $ 80.8万
• 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 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623710
• 关键词: Aneuploidy; Area; Biochemical; Caenorhabditis; Caenorhabditis elegans; Cells; Chromosome Pairing; Chromosome Structures; Chromosomes; Congenital Abnormality; Cytology; DNA Double Strand Break; DNA Repair; Development; Diploidy; Distant; Ensure; Equilibrium; Event; Failure; Genetic; Genetic Crossing Over; Genome; Genomics; Germ Cells; Goals; Haploidy; Health; Homologous Gene; Human; Hybrids; Investigation; Meiosis; Meiotic Recombination; Modeling; Molecular; Nematoda; Organism; Positioning Attribute; Preparation; Process; Property; Prophase; Research; Spontaneous abortion; System; Work; genome integrity; novel strategies; programs; repaired; segregation; spatial relationship; success; tumor progression

Program Summary 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 Caenorhabditis nematodes, simple metazoan organisms that are especially amenable to an integrated application of powerful cytological, genetic, genomic, and biochemical approaches, and in which the events under study are particularly accessible. Our goal under the MIRA program is to pursue a systems-level understanding of meiosis, based on the recognition that multiple distinct aspects of the meiotic program are intimately interconnected, and that robustness of the system is an emergent property of this interconnectedness. Our approach will build on recent technical advances and new discoveries in the well-established C. elegans experimental system, in combination with opportunities afforded by a newly-introduced Caenorhabditis interspecies hybrid model, to interrogate the meiotic program at multiple levels. Planned areas of investigation will include: Elucidating mechanisms that ensure reliable formation of CO- based connections for all chromosome pairs; Exploring how different events and developmental transitions in the meiotic program are temporally and spatially coordinated; Investigating the functional organization of meiosis-specific chromosome structures that promote and regulate meiotic recombination and enable chromosomes to sense and respond to events occurring at distant positions; Pursuing a new approach aimed at understanding the fundamental basis of homolog recognition.

节目概要 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程序 为减数分裂做准备的结构重组。此外，染色体遗传期间， 减数分裂依赖于双链DNA断裂（DSB）的形成和这些DSB的一个子集的修复， 同源物间交叉（CO）。因为作为减数分裂重组起始事件的DSB 对基因组完整性构成危险，减数分裂期间基因组遗传的成功需要细胞维持 在二氧化碳的有益影响和该过程的潜在有害后果之间取得平衡， 它们是生成的。我们研究的一个主要目标是了解减数分裂过程中的运作机制 来实现这一关键的平衡。一个相互关联的目标是了解减数分裂特异性染色体 建立、维护和改造组织，以实现同源物的成功分离 染色体我们正在利用小杆线虫来解决这些问题， 特别适合于强大的细胞学、遗传学、基因组学和 生物化学方法，并且其中所研究的事件特别容易获得。我们的目标是 MIRA计划是追求一个系统层面的了解减数分裂，基于认识到，多个 减数分裂程序的不同方面是密切相关的，系统的鲁棒性是一个重要的因素。 这种内在联系的自然属性。我们的方法将建立在最近的技术进步和新的 发现在完善的C. elegans实验系统，结合提供的机会 通过一个新引进的小杆线虫种间杂交模型，在多个染色体上询问减数分裂程序， 程度.计划的调查领域将包括：阐明机制，确保可靠的形成CO- 基于所有染色体对的连接;探索不同的事件和发育转变如何在 减数分裂程序在时间和空间上是协调的;研究减数分裂的功能组织 减数分裂特异性染色体结构，促进和调节减数分裂重组， 染色体对发生在远处的事件的感知和反应;追求一种新的方法， 理解同源识别的基本基础。