Meiotic Chromosome Inheritance in C. elegans

我们的研究旨在了解信徒背后的分子和细胞机制。 真核细胞染色体的遗传。我们的主要焦点是阐明秩序所需的事件 减数分裂中同源染色体的分离，这是二倍体生殖细胞的关键过程 产生单倍体配子。这些事件对有性繁殖生物体至关重要，因为 未能正确地执行它们会导致染色体非整倍体，这是流产的主要原因之一 人类的先天缺陷。在减数分裂前期，染色体经历了戏剧性的和动态的 为减数分裂做准备的结构重组方案。此外，染色体 减数分裂过程中的遗传依赖于双链DNA断裂(DSB)的形成和亚群的修复 这些DSB作为同源间交叉(CoS)。因为作为启动事件的DSB 减数分裂重组对基因组的完整性、减数分裂过程中基因组遗传的成功构成威胁 要求细胞在CoS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 在减数分裂过程中实现这一关键平衡的机制。一个相互关联的目标是理解 减数分裂特有的染色体组织是如何建立、维持和重塑以实现 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 线虫，一种简单的后生动物生物，特别容易结合强大的细胞学， 在单个实验系统中的遗传和基因组方法，其中正在研究的事件是 特别容易接近。许多研究方向都集中在减数分裂前期的观点上，认为这是一种高度 整合了多种“工程设计特征”的综合生物系统，如积极和 负反馈、自我限制特性、质量控制和故障保护机制共同促进 强健的生物学结果。我们在Mira计划下的目标是阐明 减数分裂方案工作，既有单独的，也有作为一个系统的，通过综合使用先进技术 这使我们能够可视化这个过程(通过显微成像或计算分析 基于序列的分析)，具有线虫系统的优点，能够进行实验扰动 这一过程。另一个重要的长期目标是理解同源识别的基本基础和 对齐的同源染色体之间的界面的性质。我们将审问这一过程 多个不同规模的减数分裂：1)在DNA修复复合体水平上，这些DNA修复复合体聚集在 减数分裂重组；2)在减数分裂特有的染色体结构水平上促进、调节 以及对减数分裂重组事件的响应；3)在整个染色体的DNA组织水平上 规模；以及4)在全核范围内对报告染色体状态的信号的反应。

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.