Data from: Using Drosophila melanogaster to identify chemotherapy toxicity genes

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.