Genome-Wide Association Analysis of Oxidative Stress Resistance in Drosophila melanogaster
| Autor: | George F. Khan, Michael M. Magwire, Robert R. H. Anholt, Trudy F. C. Mackay, Allison L. Weber, Crystal L. Tabor |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Candidate gene Heredity Genome-wide association study medicine.disease_cause Toxicology 0302 clinical medicine Genetics 0303 health sciences Multidisciplinary biology Drosophila Melanogaster Vitamin K 3 Genomics Animal Models Vitamins Phenotypes Medicine Female Drosophila melanogaster Research Article Paraquat Science Neurogenesis Toxic Agents Quantitative Trait Loci Single-nucleotide polymorphism Quantitative trait locus Polymorphism Single Nucleotide 03 medical and health sciences Model Organisms Genetic variation medicine Genome-Wide Association Studies Animals Allele Biology 030304 developmental biology Quantitative Traits Complex Traits Herbicides DNA biology.organism_classification Oxidative Stress Genetics of Disease Pharmacogenomics 030217 neurology & neurosurgery Oxidative stress Population Genetics Genome-Wide Association Study |
| Zdroj: | PLoS ONE PLoS ONE, Vol 7, Iss 4, p e34745 (2012) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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