title: Genome-wide association analysis of oxidative stress resistance in Drosophila melanogaster.
abstract: BACKGROUND
  Aerobic 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Department of Genetics, North Carolina State University, Raleigh, North Carolina, United States of America. allisonwebergenetics@gmail.com
authors.forename: Allison L
authors.initials: AL
authors.lastname: Weber
authors.forename: George F
authors.initials: GF
authors.lastname: Khan
authors.forename: Michael M
authors.initials: MM
authors.lastname: Magwire
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Tabor
authors.forename: Trudy F C
authors.initials: TF
authors.lastname: Mackay
authors.forename: Robert R H
authors.initials: RR
authors.lastname: Anholt
mesh_terms: D000818:Animals; D004247:DNA / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006540:Herbicides / Q000633:toxicity; D008297:Male; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics*; D010269:Paraquat / Q000633:toxicity; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000187:drug effects / Q000235:genetics; D024483:Vitamin K 3 / Q000009:adverse effects; D014815:Vitamins / Q000009:adverse effects
chemical_list: D006540:Herbicides; D014815:Vitamins; D024483:Vitamin K 3; D004247:DNA; D010269:Paraquat