Melanoma loss-of-function mutants in xiphophorus caused by Xmrk-oncogene deletion and gene disruption by a transposable element

The overexpression of the Xmrk oncogene (ONC-Xmrk) in pigment cells of cert ain Xiphophorus hybrids has been found to be the primary change that result s in the formation of malignant melanoma. Spontaneous mutant stocks have be en isolated that have lost the ability to induce tumor formation when cross ed with Xiphophorus helleri. Two of these loss-of-function mutants were ana lyzed for genetic defects in ONC-Xmrk's. In the lof-1 mutant a novel transp osable element, TX-1, has jumped into ONC-Xmrk, leading to a disruption of the gene and a truncated protein product lacking the carboxyterminal domain of the receptor tyrosine kinase. TX-1 is obviously an active LTR-containin g retrotransposon in Xiphophorus that tvas nor found in other fish species outside the family Poeciliidae. Surprisingly, it does not encode ally prote in, suggesting the existence of a helper function for this retroelement. In the lof-2 mutant the entire ONC-Xmrk gene was found to be deleted. These d ata show that ONC-Xmrk is indeed the tumor-inducing gene of Xiphophorus and thus the critical constituent of the tumor (Tu) locus.