Department of Ecology and Evolutionary Biology, University of California, Irvine, Irvine, California 92697-2525, USA.
G3 (Bethesda). 2013 Aug 7;3(8):1301-10. doi: 10.1534/g3.113.006619.
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 the toxicity of methotrexate (MTX), a drug used primarily to treat childhood acute lymphoblastic leukemia and rheumatoid arthritis. We use the Drosophila Synthetic Population Resource, 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 quantitative trait loci (QTL) affecting MTX toxicity; two colocalize 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 single-nucleotide polymorphisms, 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 single-nucleotide polymorphism 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.
化疗的毒性副作用的严重程度在患者之间有所不同，而这种差异很大程度上是基于遗传的。在这里，我们使用黑腹果蝇模型系统来从遗传上剖析甲氨蝶呤（MTX）的毒性，MTX 是一种主要用于治疗儿童急性淋巴细胞白血病和类风湿性关节炎的药物。我们使用了 Drosophila Synthetic Population Resource，这是一个由多亲本先进互交衍生的重组近交系面板，并将 MTX 毒性量化为雌性生育力的降低。我们确定了三个影响 MTX 毒性的数量性状基因座（QTL）；其中两个与人类基因的果蝇同源物重合，这些基因被认为介导 MTX 毒性，另一个是与人类同源物的新型 MTX 毒性基因。第四个提示性 QTL 跨越着丝粒。候选基因外显子的单标记关联扫描未能将氨基酸变异体确定为致病的单核苷酸多态性，因此我们假设致病的变异体是调节性的。此外，我们映射到的 QTL 的效应不符合简单的双等位基因模式，这表明 QTL 映射结果的多个致病因素。与这一观察结果一致的是，没有一个位于候选基因内或附近的单一单核苷酸多态性可以解释 QTL 映射信号。总的来说，我们的结果验证了黑腹果蝇作为揭示化学毒性遗传基础的模型的有效性，并表明 MTX 毒性的遗传基础是由于少数几个基因，每个基因都携带有多个分离的调节因子。
