The Macromelanophore Locus and the Melanoma Oncogene Xmrk Are Separate Genetic Entities in the Genome of Xiphophorus

Fish of the genus Xiphophorus are polymorphic for black pigmentation patterns. Certain intra- or interspecific hybrids exhibit enhanced expression of these patterns, leading in many cases to malignant melanoma. Because no recombination was ever observed between the pattern information and the genetic predisposition to develop melanoma after hybridization, a “tumor gene” (Tu) was postulated that encodes both phenotypes. A dominant oncogene, ONC-Xmrk, was then found to be necessary and sufficient for the transforming function of Tu. Here we present molecular evidence that ONC-Xmrk and the pigment pattern information are encoded by separate, although intimately linked loci. No ONC-Xmrk gene was present in the 15 Xiphophorus strains investigated which exhibit no black pigmentation pattern. Five different patterns from Xiphophorus maculatus, X. evelynae, X. milleri, X. cortezi, and X. montezumae were associated with ONC-Xmrk and were melanomagenic, while fish of X. helleri, X. variatus, X. nezahualcoyotl, and X. montezumae with five other patterns had no ONC-Xmrk and consequently did not produce hybrid melanoma. These data provide evidence that ONC-Xmrk is sufficient for tumorigenesis in Xiphophorus hybrids, and that a separate, pigment pattern-encoding locus is closely linked to it.