The genetic architecture of methotrexate toxicity is similar in Drosophila melanogaster and humans.
The genetic architecture of methotrexate toxicity is similar in Drosophila melanogaster and humans.
复制标题
DOI：
10.1534/g3.113.006619
复制
发表时间：
2013-08-07
期刊：
影响因子：
--
通讯作者：
Long AD
中科院分区：
文献类型：
--
作者：
Kislukhin G;King EG;Walters KN;Macdonald SJ;Long AD
化疗毒副作用的严重程度因患者而异，而且这种差异很大程度上可能是基于遗传的。在这里，我们使用模型系统果蝇从基因角度剖析甲氨蝶呤（MTX）的毒性，甲氨蝶呤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。我们使用果蝇合成种群资源（一组源自多亲高级杂交的重组自交系），并将 MTX 毒性量化为雌性繁殖力的减少。我们确定了三个影响 MTX 毒性的数量性状基因座 (QTL)；两个与被认为介导 MTX 毒性的人类基因的果蝇直向同源物共定位，一个是具有人类直向同源物的新型 MTX 毒性基因。第四个暗示性 QTL 跨越着丝粒。候选基因外显子的局部单标记关联扫描未能将氨基酸变异暗示为致病单核苷酸多态性，因此我们假设致病变异是调节性的。此外，我们映射的 QTL 的效应不符合简单的双等位基因模式，表明 QTL 定位结果背后存在多种致病因素。与这一观察结果一致，位于候选基因内或附近的单个单核苷酸多态性不能解释 QTL 作图信号。总体而言，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，并表明 MTX 毒性的遗传基础是由少数基因造成的，每个基因都含有多个分离的调节因子。
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.