CAREER: Meiotic double strand break repair on sex chromosomes

DNA双链断裂在减数分裂期间发生在整个基因组中，必须适当修复以确保整体基因组的稳定性。这一过程在性染色体（即X和Y）上具有挑战性，因为两条染色体共享的可修复序列有限。清楚地了解这些染色体上的双链断裂是如何分解的是很重要的，因为它可能在维持其他退化的Y染色体上的基本基因功能方面发挥作用。此外，这一过程中的错误与几种疾病有关，包括不孕症和性逆转。该项目将确定X和Y染色体上的双链断裂是如何定位和修复的。它还将为各级青年科学家提供研究、教学和指导方面的广泛培训。还将征聘当地中学教师，开发以性染色体生物学为重点的探究式课程。最后，这个项目将使佐治亚大学的一个项目能够支持本科生参加一年一度的东南人口、生态和进化遗传学会议。该项目的总体目标是利用三刺棘鱼的年轻性染色体来(a)了解双链断裂的起始和修复是如何发生的，(b)阐明这些过程如何影响Y染色体上基因功能的保存。一系列比较和功能基因组学、基因编辑和细胞遗传学方法将被用来解决具体的目标。目的1将确定双链断裂是如何定位的，以及断裂是否与染色质特征的性染色体特异性变化有关。目的2将鉴定跨性染色体双链断裂的优先修复模板。目的3将确定性染色体上受非交叉基因转换的基因是否具有基本功能。该项目的结果将广泛适用于物种，因为减数分裂重组在整个生命树中是高度保守的，并且利用相同的蛋白质来调节性染色体和常染色体上的双链断裂起始和修复。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

DNA double strand breaks occur throughout the genome during meiosis and must be properly repaired to ensure overall genome stability. This process is challenging on sex chromosomes (i.e., X and Y) because there is limited sequence shared by the two chromosomes available for repair. A clear understanding of how double strand breaks are resolved on these chromosomes is important, as it may have a role in maintaining essential gene function on an otherwise degenerating Y chromosome. In addition, errors in the process have been linked to several disorders, including sterility and sex reversal. This project will identify how double strand breaks are localized and repaired on X and Y chromosomes. It will also provide extensive training in research, teaching, and mentoring to junior scientists at all levels. Local secondary education teachers will also be recruited to develop inquiry-based curricula focused on sex chromosome biology. Finally, this project will enable a program at University of Georgia that supports undergraduate attendance at the annual Southeastern Population, Ecology, and Evolutionary Genetics Conference.The overall goals of this project are to use the young sex chromosomes of the threespine stickleback fish to (a) understand how double strand break initiation and repair occurs, and (b) clarify how these processes influence the preservation of gene function on the Y chromosome. An array of comparative and functional genomics, gene editing and cytogenetics approaches will be employed to address the specific aims. Aim 1 will determine how double strand breaks are localized and whether breaks are associated with sex-chromosome-specific changes in chromatin features. Aim 2 will identify the preferential repair templates for double strand breaks across sex chromosomes. Aim 3 will determine whether genes subject to non-crossover gene conversion on sex chromosomes have essential functions. The results of this project will be broadly applicable across species, as meiotic recombination is highly conserved across the tree of life and utilizes the same proteins to regulate double strand break initiation and repair on sex chromosomes and autosomes alike.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.