Mechanisms of meiotic and mitotic recombination

摘要 重组既是避免基因组不稳定的一种手段，也是产生基因组不稳定的过程。 在减数分裂过程中，dna双链断裂被修复成对精确度 同源染色体的分离；这一过程中的缺陷导致不育或非整倍体，主要 妊娠丢失和三体的原因。相反，在有丝分裂增殖的细胞中，双链断裂是一种 危险级别的DNA损伤。在这种情况下，修复断裂是在不进行交叉的情况下完成的； 有丝分裂细胞的交叉形成可导致染色体重排和肿瘤的发生。 我实验室的研究重点是促进减数分裂细胞和非减数分裂细胞交叉的机制。 有丝分裂细胞修复的交叉结果。我们为理解这些问题做出了重要贡献 20年来，我培养了许多活跃在研究和研究领域的科学家 与研究相关的职业。这项提议勾勒出了继续和新的方向，将推动 前场前锋。其中包括调查如何修复较大的缺口(对于设计CAS9很重要 片段整合实验和基于Cas9的基因驱动系统)以及减数分裂杂交是如何进行的 有花纹的(对于将染色体适当地分离成配子很重要)。我们使用的组合是 遗传学，主要以果蝇为模式生物，基因组学，生物化学，细胞生物学，进化 生物学和数学建模。

ABSTRACT Recombination is both a means to avoid genome instability and to process that generates genome instability. In meiosis, DNA double-strand breaks are repaired into crossovers that are essential for accurate segregation of homologous chromosomes; defects in this process result in sterility or aneuploidy, the major cause of pregnancy loss and trisomy. Conversely, in mitotically proliferating cells double-strand breaks are a dangerous class of DNA damage. Repair of breaks in this context is done without making crossovers; formation of crossovers in mitotic cells can lead to chromosome rearrangements and tumorigenesis. Research in my laboratory focuses on mechanisms that promote crossovers in meiotic cells and non- crossover outcomes of repair in mitotic cells. We have made important contributions to understand these problems for 20 years, during which time I have trained numerous scientists who are active in research and research-related careers. This proposal sketches out both continued and new directions that will drive the field forward. These include investigations of how large gaps are repaired (important for designing Cas9 fragment integration experiments and Cas9-based gene drive systems) and how meiotic crossovers are patterned (important for proper segregation of chromosomes into gametes). We use a combination of genetics, primarily using Drosophila as a model organism, genomics, biochemistry, cell biology, evolutionary biology, and mathematical modeling.