Genome-Wide Association for Sensitivity to Chronic Oxidative Stress in <em>Drosophila melanogaster</em>

Reactive oxygen species (ROS) are a common byproduct of mitochondrial energy metabolism, and can also be induced by exogenous sources, including UV light, radiation, and environmental toxins. ROS generation is essential for maintaining homeostasis by triggering cellular signaling pathways and host defense mechanisms. However, an imbalance of ROS induces oxidative stress and cellular death and is associated with human disease, including age-related locomotor impairment. To identify genes affecting sensitivity and resistance to ROS-induced locomotor decline, we assessed locomotion of aged flies of the sequenced, wild-derived lines from the Drosophila melanogaster Genetics Reference Panel on standard medium and following chronic exposure to medium supplemented with 3 mM menadione sodium bisulfite (MSB). We found substantial genetic variation in sensitivity to oxidative stress with respect to locomotor phenotypes. We performed genome-wide association analyses to identify candidate genes associated with variation in sensitivity to ROS-induced decline in locomotor performance, and confirmed the effects for 13 of 16 mutations tested in these candidate genes. Candidate genes associated with variation in sensitivity to MSB-induced oxidative stress form networks of genes involved in neural development, immunity, and signal transduction. Many of these genes have human orthologs, highlighting the utility of genome-wide association in Drosophila for studying complex human disease.活性氧簇（Reactive oxygen species, ROS）是线粒体能量代谢的常见副产物，亦可由外源性因素诱导产生，包括紫外线、辐射与环境毒素。ROS的生成通过触发细胞信号通路与宿主防御机制，对于维持机体稳态至关重要。然而ROS失衡会诱导氧化应激与细胞死亡，且与多种人类疾病相关，包括年龄相关性运动能力受损。为鉴定影响ROS诱导的运动能力衰退敏感性与抗性的基因，我们对黑腹果蝇遗传参考面板（Drosophila melanogaster Genetics Reference Panel）的测序野生衍生品系的衰老果蝇开展了运动能力测定，分别在标准培养基，以及长期暴露于添加3 mM亚硫酸氢钠甲萘醌（menadione sodium bisulfite, MSB）的培养基两种条件下进行检测。我们观察到，针对运动表型的氧化应激敏感性存在显著的遗传变异。我们开展了全基因组关联分析，以筛选与ROS诱导的运动能力衰退敏感性变异相关的候选基因，并验证了16个候选基因测试突变中的13个的效应。与MSB诱导的氧化应激敏感性变异相关的候选基因，共同构成了参与神经发育、免疫应答与信号转导的基因调控网络。其中多数基因存在人类同源基因，这一结果凸显了利用黑腹果蝇开展全基因组关联研究，对复杂人类疾病进行研究的应用价值。