Functional Test of a Naturally Occurred Tumor Modifier Gene Provides Insights to Melanoma Development.

Occurrence of degenerative interactions is thought to serve as a mechanism underlying hybrid unfitness. However, the molecular mechanisms underpinning the genetic interaction and how they contribute to overall hybrid incompatibilities are limited to only a handful of examples. A vertebrate model organism, , is used to study hybrid dysfunction and it has been shown from this model that diseases, such as melanoma, can occur in certain interspecies hybrids. Melanoma development is due to hybrid inheritance of an oncogene, , and loss of a co-evolved tumor modifier. It was recently found that , a G protein-coupled receptor involved in cell adhesion, is a tumor regulator gene in naturally hybridizing species and . We hypothesized that one of the two parental alleles of is involved in regulation of cell proliferation, migration and melanomagenesis. Accordingly, we assessed the function of alleles from each parental species of the melanoma-bearing hybrids using cell proliferation and migration assays. In addition, we expressed each allele with the oncogene in transgenic medaka. We found that cells transfected with the exhibited decreased proliferation and migration compared to those with the allele. Moreover, allele of completely inhibited melanoma development in transgenic medaka, while expression did not exhibit melanoma suppressive activity in medaka. These findings showed that is a natural melanoma suppressor and provide new insight in melanoma etiology.