Structure and dynamics of meiotic chromosomes

减数分裂过程中的染色体分离将一条染色体(母本或父本)置于 每一个配子。遗传物质的准确分离需要亲本染色体与 并通过形成杂交来交换遗传信息。交叉编队 要求染色体经历一系列精心策划的形态转换。未能取得成功 交叉会导致减数分裂染色体分离错误，从而导致不孕和先天性 先天缺陷。这里提出的研究将使用线虫和发芽酵母来解决这一机制 通过使用实验方法来研究染色体相互作用和分离 这些模型系统的独特功能，包括对活体动物的染色体动态的直接成像。 允许染色体形成、调节和响应交叉的分子机制很差。 明白了。这一建议探讨了减数分裂染色体组织和动力学的三个方面。第一 该项目将探索联会复合体(SC)--一种组装在 同源染色体并调节交叉的分布-在整个染色体范围内实现 监管。这项工作建立在最近的理解之上，即SC尽管在以下情况下出现有序 电子显微镜下可见液体状的相分离隔室。一种新的诱变和 基因筛选策略将分离扰乱细胞液体性质的功能分离突变 SC，并以这种方式将特定功能分配给SC组件。此外，对染色体知之甚少-- 广泛的SC动态将首次使用长期实时成像直接可视化。机械师 对这些动力学的理解将解释减数分裂程序如何对核型异常做出反应， 以及SC如何监管和回应跨界。 第二个项目的重点是重组染色体，以转换交叉-一个局部的 DNA链的交换-进入将亲本染色体连接在一起的连接 减数分裂，并促进它们正确地分离成配子。一种新颖的方式，只标记其中一个 两条亲本染色体及其在减数分裂过程中的形态可视化将依赖于 线虫性腺中染色体的组织和超分辨显微镜。 第三个项目致力于将减数分裂染色体组织成固定的染色质环。 在它们的底部到一个蛋白质轴。这种保守的染色体组织是减数分裂所必需的。 计划，但调节其组装和动力学的机制仍然是个谜。一种新的技术来 获得发芽酵母中染色体构象和动力学的高分辨率描述将采取 一项新兴技术对超长DNA分子进行测序的优势。这项技术可能是 广泛应用于其他细胞过程中的染色体组织探测。

Chromosome segregation during meiosis places one chromosome, either the maternal or paternal copy, in each gamete. Accurate segregation of genetic material requires that the parental chromosomes interact with one another and exchange genetic information through the formation of crossovers. Crossover formation requires that chromosomes undergo an orchestrated series of morphological transformations. Failure to make crossovers leads to errors in meiotic chromosome segregation, and consequently to infertility and congenital birth defects. The research proposed here will use nematodes and budding yeast to address the mechanisms of chromosome interaction and segregation by employing experimental approaches that take advantage of the unique features of these model systems, including direct imaging of chromosome dynamics in living animals. The molecular mechanisms that allow chromosomes to form, regulate, and respond to crossovers are poorly understood. This proposal probes three aspects of meiotic chromosome organization and dynamics. The first project will explore how the Synaptonemal Complex (SC)—a conserved structure that assembles between homologous chromosomes and regulates the distribution of crossovers—implements chromosome-wide regulation. This work builds on the recent understanding that the SC, despite its ordered appearance when visualized by electron microscopy, is a liquid-like phase-separated compartment. A novel mutagenesis and genetic screening strategy will isolate separation-of-function mutations that perturb the liquid properties of the SC, and in that way assign specific functions to SC components. In addition, poorly understood chromosome- wide SC dynamics will be directly visualized for the first time using long-term live-imaging. A mechanistic understanding of these dynamics will explain how the meiotic program responds to karyotype abnormalities, and how the SC regulates, and responds to, crossovers. The second project focuses on the reorganization of the chromosomes that transforms crossovers—a local exchange of DNA strands—into the connections that hold the parental chromosomes together during the meiotic divisions, and promotes their correct segregation into gametes. A novel way to label only one of the two parental chromosomes and to visualize its morphology throughout meiosis will rely on the advantageous organization of chromosomes in the C. elegans gonad and on super-resolution microscopy. The third project addresses the organization of meiotic chromosomes as loops of chromatin that are anchored at their base to a proteinaceous axis. This conserved chromosome organization is integral to the meiotic program, but the mechanisms regulating its assembly and dynamics remain enigmatic. A novel technique to obtain a high-resolution description of chromosome conformation and dynamics in budding yeast will take advantage of an emerging technology to sequence very long molecules of DNA. This technique could be widely applied to probe chromosome organization in other cellular processes.