Abstract
BackgroundAerobic organisms are susceptible to damage by reactive oxygen species. Oxidative stress resistance is a quantitative trait with population variation attributable to the interplay between genetic and environmental factors. Drosophila melanogaster provides an ideal system to study the genetics of variation for resistance to oxidative stress.Methods and FindingsWe used 167 wild-derived inbred lines of the Drosophila Genetic Reference Panel for a genome-wide association study of acute oxidative stress resistance to two oxidizing agents, paraquat and menadione sodium bisulfite. We found significant genetic variation for both stressors. Single nucleotide polymorphisms (SNPs) associated with variation in oxidative stress resistance were often sex-specific and agent-dependent, with a small subset common for both sexes or treatments. Associated SNPs had moderately large effects, with an inverse relationship between effect size and allele frequency. Linear models with up to 12 SNPs explained 67–79% and 56–66% of the phenotypic variance for resistance to paraquat and menadione sodium bisulfite, respectively. Many genes implicated were novel with no known role in oxidative stress resistance. Bioinformatics analyses revealed a cellular network comprising DNA metabolism and neuronal development, consistent with targets of oxidative stress-inducing agents. We confirmed associations of seven candidate genes associated with natural variation in oxidative stress resistance through mutational analysis.ConclusionsWe identified novel candidate genes associated with variation in resistance to oxidative stress that have context-dependent effects. These results form the basis for future translational studies to identify oxidative stress susceptibility/resistance genes that are evolutionary conserved and might play a role in human disease.
Highlights
Oxidative stress, or the overabundance of reactive oxygen species (ROS) as an unavoidable consequence of aerobic respiration, has been implicated in aging [1,2], neurodegenerative and cardiovascular disease [3,4] and the disruption of cell signaling processes that control cell growth and death [5]
We found extensive phenotypic and genetic variation for survival time on both paraquat and menadione sodium bisulfite (MSB) (Figure 1A–B; Table 1), similar to the broad variation observed for other traits in this population [28,30]
Conclusions and future directions We have shown that the genetic architecture of oxidative stress susceptibility in Drosophila is complex, sexually dimorphic and dependent on the oxidative stress inducing agent
Summary
The overabundance of reactive oxygen species (ROS) as an unavoidable consequence of aerobic respiration, has been implicated in aging [1,2], neurodegenerative and cardiovascular disease [3,4] and the disruption of cell signaling processes that control cell growth and death [5]. Genetic variants associated with susceptibility to oxidative stress in human populations have largely been identified indirectly, as many alleles associated with increased risk for common diseases and aging are in genes in oxidative stress response pathways [4]. Biochemical studies have implicated Superoxide dismutase (Sod) [15,16] and Catalase (Cat) [17,18] as fundamental mediators for the removal of ROS Overexpression of both Sod and Cat transgenes results in enhanced oxidative stress resistance and longevity in specific Drosophila genetic backgrounds [19,20,21]. Genome-wide expression has been assayed on lines that have undergone multigenerational selection for increased resistance to hyperoxia This resulted in the identification of several candidate genes involved in survival under hyperoxia, including Diptericin, Tropomyosin, and Attacin [23]. Drosophila melanogaster provides an ideal system to study the genetics of variation for resistance to oxidative stress
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