The Genetic Architecture of Methotrexate Toxicity Is Similar in Drosophila melanogaster and Humans

  • Kislukhin G
  • King E
  • Walters K
  • et al.
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Abstract

The severity of the toxic side effects of chemotherapy varies among patients and much of this variation is likely genetically based. Here, we use the model system Drosophila melanogaster to genetically dissect toxicity of methotrexate (MTX), a drug used primarily to treat childhood acute lymphoblastic leukemia and rheumatoid arthritis. We utilize the Drosophila Synthetic Population Resource (DSPR), a panel of recombinant inbred lines derived from a multiparent advanced intercross, and quantify MTX toxicity as a reduction in female fecundity. We identify three QTL affecting MTX toxicity; two co-localize with the fly orthologs of human genes believed to mediate MTX toxicity, and one is a novel MTX toxicity gene with a human ortholog. A fourth suggestive QTL spans a centromere. Local single marker association scans of candidate gene exons fail to implicate amino acid variants as the causative SNPs, and we therefore hypothesize the causative variation is regulatory. In addition, the effects at our mapped QTL do not conform to a simple biallelic pattern, suggesting multiple causative factors underlie the QTL mapping results. Consistent with this observation, no single SNP located in or near a candidate gene can explain the QTL mapping signal. Overall, our results validate D. melanogaster as a model for uncovering the genetic basis of chemotoxicity and suggest the genetic basis of MTX toxicity is due to a handful of genes each harboring multiple segregating regulatory factors.

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Kislukhin, G., King, E. G., Walters, K. N., Macdonald, S. J., & Long, A. D. (2013). The Genetic Architecture of Methotrexate Toxicity Is Similar in Drosophila melanogaster and Humans . G3: Genes|Genomes|Genetics, 3(8), 1301–1310. https://doi.org/10.1534/g3.113.006619

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