CAREER: Meiotic double strand break repair on sex chromosomes

在减数分裂过程中，DNA双链断裂发生在整个基因组中，必须进行适当的修复，以确保基因组的整体稳定性。这一过程对性染色体(即X和Y)是具有挑战性的，因为可供修复的两条染色体共享的序列有限。清楚地了解双链断裂是如何在这些染色体上分解的是很重要的，因为它可能在维持原本退化的Y染色体上的基本基因功能方面发挥作用。此外，这一过程中的错误被认为与几种疾病有关，包括不孕不育和性反转。这个项目将确定双链断裂是如何在X和Y染色体上定位和修复的。它还将为各级初级科学家提供广泛的研究、教学和指导方面的培训。还将招聘当地中学教师，开发以性染色体生物学为重点的探究式课程。最后，该项目将支持佐治亚大学的一个项目，该项目支持本科生参加一年一度的东南种群、生态和进化遗传学会议。该项目的总体目标是利用三刺鱼的幼年性染色体来(A)了解双链断裂的起始和修复是如何发生的，以及(B)阐明这些过程如何影响Y染色体上基因功能的保存。将采用一系列比较基因组学和功能基因组学、基因编辑和细胞遗传学方法来解决具体目标。目标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中的性染色体特异性变化有关。目标2将确定跨性染色体的双链断裂的优先修复模板。目标3将确定在性染色体上经历非交叉基因转换的基因是否具有必要的功能。该项目的结果将广泛适用于不同物种，因为减数分裂重组在整个生命树上高度保守，并使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启动和修复。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.