Genome-Wide Association Analysis of Oxidative Stress Resistance in Drosophila melanogaster

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.

A conserved role for the 20S proteasome and Nrf2 transcription factor in oxidative-stress adaptation in mammals, C. elegans and D. melanogaster

“…Although it is clear that male flies consumed less than half as much of the sucrose/H 2 O 2 solution as did females (see supplementary material Fig.S1), we can think of no reason why this difference in ingestion would negatively affect proteolytic capacity. An alternative hypothesis is that the observed differences are due to sexual dimorphism in stress responses between male and female flies and, consistent with this idea, sexual dimorphism has previously been observed in thermotolerance and oxidative stress resistance in Drosophila (Sørensen et al, 2007;Waskar et al, 2009;Weber et al, 2012).…”

Using natural variation in Drosophila to discover previously unknown endoplasmic reticulum stress genes

“…Some of these ER stress candidates are within broad functional groups with previously known roles in ER stress. Of note, we identified four genes (CG11594, CG9003, RunxA, and CG11873) that had no prior known function in ER stress, but had been previously identified as candidate genes in oxidative stress response in the same DGRP lines (23). There are functional links between oxidative and ER stress (42), and the fact that these genes appeared as candidates in both processes suggests that there may be a genetic convergence of these two pathways in the DGRP.…”

“…association studies involving the DGRP (22,23), the minor allele frequency of a SNP was inversely proportional to the effect size of that SNP (Fig. S5).…”

“…Some of these candidates have functions not previously associated with ER stress, but others function in processes known to be important to the ER stress response. Examples of the latter include Golgi function (CG33298 and CG15611) (34,35), lipid metabolism (CG12428, bgm, Egm, CG9518, RdgA, and CG5162) (36)(37)(38)(39)(40)(41), and oxidative stress (CG11594, CG9003, RunxA, and CG11873) (23,42). In particular, an associated SNP 65 bp downstream of eIF-2β, the beta subunit of the eIF2 translation initiation factor (43), is particularly interesting.…”

Rare Variants in Hypermutable Genes Underlie Common Morphology and Growth Traits in WildSaccharomyces paradoxus

“…Toward this end, hundreds of studies have sought to map causal genes, using tests for allele sharing among affected but unrelated individuals. Against a backdrop of recent successes in fruit fly and plant populations (Atwell et al 2010;Brachi et al 2010;Chan et al 2011;Filiault and Maloof 2012;Mackay et al 2012;Magwire et al 2012;Weber et al 2012;Dunn et al 2013), association mapping in many systems has yielded loci that explain only a small part of the variation in a given trait across individuals (McCarthy et al 2008). The latter challenges have motivated the proposal that the bulk of common phenotypic variation may be attributable to rare, highly penetrant mutations (Dickson et al 2010;McClellan and King 2010; Veltman and Brunner 2012), including recurrent variation at hypermutable loci (Shen et al 1996;Chan et al 2010;Michaelson et al 2012).…”