Department of Biology, Georgia Southern University, Statesboro, GA 30460, USA.
Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA 30144, USA.
G3 (Bethesda). 2024 Oct 7;14(10). doi: 10.1093/g3journal/jkae188.
Understanding the signaling pathways in which genes participate is essential for discovering the etiology of diseases in humans. The model organism, Drosophila melanogaster, has been crucial in understanding the signaling pathways in humans, given the evolutionary conservation of a significant number of genes between the two species. Genetic screens using Drosophila are a useful way of testing large number of genes to study their function and roles within signaling pathways. We conducted a large-scale genetic screen to identify which human genes cause an alteration in the morphology of the Drosophila eye. The GMR-Gal4 was employed to activate a single UAS-human gene in the eye tissue. In total, we screened 802 UAS-human gene stocks, corresponding to 787 human protein-coding genes, for the ability to influence eye development. We found that overexpression of 64 human genes were capable of disrupting eye development, as determined by phenotypic changes in eye texture, size, shape, bristle morphology, and ommatidia organization. Subsequent analysis revealed that the fly genome encodes proteins that are homologous to a majority of the 64 human genes, raising the possibility that overexpression of these transgenes altered eye development by altering the activity of evolutionarily conserved developmental signaling pathways. Consistent with this hypothesis, a secondary screen demonstrated that overexpression of fly homologs produced phenotypes that mimicked those produced by overexpression of the human gene. Our screening has identified 64 human genes capable of inducing phenotypes in the fly, offering a foundation for ongoing research aimed at understanding functionally conserved pathways across species.
理解基因参与的信号通路对于发现人类疾病的病因至关重要。模式生物果蝇在理解人类信号通路方面发挥了重要作用，因为这两个物种之间有相当数量的基因具有进化保守性。利用果蝇进行遗传筛选是一种测试大量基因的有用方法，可以研究它们在信号通路中的功能和作用。我们进行了大规模的遗传筛选，以确定哪些人类基因会导致果蝇眼睛形态的改变。我们使用 GMR-Gal4 在眼睛组织中激活单个 UAS-人类基因。总共，我们筛选了 802 个 UAS-人类基因品系，对应于 787 个人类蛋白编码基因，以研究它们影响眼睛发育的能力。我们发现，超过 64 个人类基因的过表达能够破坏眼睛发育，这是通过眼睛纹理、大小、形状、刚毛形态和小眼组织的表型变化来确定的。随后的分析表明，果蝇基因组编码的蛋白质与 64 个人类基因中的大多数具有同源性，这表明这些转基因的过表达可能通过改变进化保守的发育信号通路的活性来改变眼睛发育。与这一假设一致的是，二次筛选表明，果蝇同源物的过表达产生的表型类似于人类基因过表达产生的表型。我们的筛选已经确定了 64 个人类基因，这些基因能够在果蝇中诱导表型，为旨在理解跨物种功能保守途径的持续研究提供了基础。
