title: Using Drosophila melanogaster to identify chemotherapy toxicity genes.
abstract: The severity of the toxic side effects of chemotherapy shows a great deal of interindividual variability, and much of this variation is likely genetically based. Simple DNA tests predictive of toxic side effects could revolutionize the way chemotherapy is carried out. Due to the challenges in identifying polymorphisms that affect toxicity in humans, we use Drosophila fecundity following oral exposure to carboplatin, gemcitabine and mitomycin C as a model system to identify naturally occurring DNA variants predictive of toxicity. We use the Drosophila Synthetic Population Resource (DSPR), a panel of recombinant inbred lines derived from a multiparent advanced intercross, to map quantitative trait loci affecting chemotoxicity. We identify two QTL each for carboplatin and gemcitabine toxicity and none for mitomycin. One QTL is associated with fly orthologs of a priori human carboplatin candidate genes ABCC2 and MSH2, and a second QTL is associated with fly orthologs of human gemcitabine candidate genes RRM2 and RRM2B. The third, a carboplatin QTL, is associated with a posteriori human orthologs from solute carrier family 7A, INPP4A&B, and NALCN. The fourth, a gemcitabine QTL that also affects methotrexate toxicity, is associated with human ortholog GPx4. Mapped QTL each explain a significant fraction of variation in toxicity, yet individual SNPs and transposable elements in the candidate gene regions fail to singly explain QTL peaks. Furthermore, estimates of founder haplotype effects are consistent with genes harboring several segregating functional alleles. We find little evidence for nonsynonymous SNPs explaining mapped QTL; thus it seems likely that standing variation in toxicity is due to regulatory alleles.
authors.affiliation: University of California, Department of Ecology and Evolutionary Biology, Irvine, California 92697-2525 kingeg@missouri.edu.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: King
authors.affiliation: University of California, Department of Ecology and Evolutionary Biology, Irvine, California 92697-2525.
authors.forename: Galina
authors.initials: G
authors.lastname: Kislukhin
authors.affiliation: University of California, Department of Ecology and Evolutionary Biology, Irvine, California 92697-2525.
authors.forename: Kelli N
authors.initials: KN
authors.lastname: Walters
authors.affiliation: University of California, Department of Ecology and Evolutionary Biology, Irvine, California 92697-2525.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Long
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D016190:Carboplatin / Q000009:adverse effects; D004251:DNA Transposable Elements; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D005298:Fertility / Q000187:drug effects; D016685:Mitomycin / Q000009:adverse effects; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012097:Repressor Proteins / Q000235:genetics*; D012262:Ribonucleoside Diphosphate Reductase / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D016190:Carboplatin; D004251:DNA Transposable Elements; D003841:Deoxycytidine; D029721:Drosophila Proteins; D016685:Mitomycin; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012097:Repressor Proteins; D012262:Ribonucleoside Diphosphate Reductase; D015534:Trans-Activators; D000093542:Gemcitabine; C000715087:ABCC2 protein, human; C102933:tin protein, Drosophila; C093713:ribonucleotide reductase M2
keywords: Drosophila Synthetic Population Resource; MPP; Multiparent Advanced Generation Inter-Cross (MAGIC); Multiparental populations; advanced intercross line; chemotoxicity; complex traits; genetic heterogeneity; pharmacogenomics; quantitative trait loci