Mixing genomes of different species by hybridization can disrupt species-specific genetic interactions that were adapted and fixed within each species population. Such disruption can predispose the hybrids to abnormalities and disease that decrease the overall fitness of the hybrids and is therefore named as hybrid incompatibility. Interspecies hybridization between southern platyfish and green swordtails leads to lethal melanocyte tumorigenesis. This occurs in hybrids with tumor incidence following progeny ratio that is consistent with two-locus interaction, suggesting melanoma development is a result of negative epistasis. Such observations make Xiphophorus one of the only two vertebrate hybrid incompatibility examples in which interacting genes have been identified. One of the two interacting loci has been characterized as a mutant epidermal growth factor receptor. However, the other locus has not been identified despite over five decades of active research. Here we report the localization of the melanoma regulatory locus to a single gene, rab3d, which shows all expected features of the long-sought oncogene interacting locus. Our findings provide insights into the role of egfr regulation in regard to cancer etiology. Finally, they provide a molecular explainable example of hybrid incompatibility.

通过杂交混合不同物种的基因组会破坏在每个物种种群中适应并固定的物种特异性遗传相互作用。这种破坏会使杂种易患异常和疾病，从而降低了杂种的整体适应性，因此被称为杂种不相容性。南部白鳍鱼和绿色的剑尾鱼之间的种间杂交导致致命的黑素细胞肿瘤发生。这发生在后代比率与两个位点相互作用一致的肿瘤发生率的杂种中，表明黑色素瘤的发展是阴性上位的结果。这样的观察使Xiphophorus已鉴定出相互作用基因的仅有的两个脊椎动物杂种不相容性实例之一。两个相互作用的基因座之一已被表征为突变表皮生长因子受体。但是，尽管进行了五十多年的积极研究，但尚未确定其他基因座。在这里，我们报告黑色素瘤调节基因座定位到单个基因rab3d，该基因显示了长期寻找的癌基因相互作用基因座的所有预期特征。我们的发现为egfr调节在癌症病因学中的作用提供了见解。最后，它们提供了杂交不相容的分子可解释的例子。