An escapade with consequences

05/15/2020

Environmental pollution is responsible for matings between two fish species that usually don't mix. In their offspring, scientists have now identified genes relevant for the development of skin cancer.

When two species of a natural Xiphophorus population in Mexico mate, their offspring frequently exhibit large black skin lesions that turned out to be melanoma. (Image: Georg Schneider)

It is a popular aquarium fish and has been an established model in cancer research for around 100 years: Xiphophorus, the swordtail fish, is a species of live-bearing killifish which are native to Central America. Already in the 1920ies, geneticists discovered that the experimental interbreeding of related species frequently results in skin tumours in their offspring. Obviously, in these hybrids a gene that can initiate cancer runs out of control. The tumours correspond to human malignant melanoma.

Manfred Schartl, senior professor at the Department of Developmental Biochemistry of the University of Würzburg, has been studying these fish and the triggers of their tumour growth since his doctoral thesis. Together with scientists from USA and Mexico, he has now made a surprising discovery in Xiphophorus species living in the wild. This discovery provides new insights into the genetic principles of melanoma development which can be transferred to humans. The researchers present the results of their research in the latest issue of the journal Science.

Surprise find in Mexico

"One of my colleagues discovered a natural Xiphophorus population in Mexico where two species mate that don't usually do this," Manfred Schartl explains. This behaviour is probably caused by the increasing pollution of the water bodies in which the fish live. This impairs the females' sense of smell and thus their right choice of a mate. What piqued the scientists' interest is that their offspring frequently exhibit large black skin lesions that turned out to be melanoma – as in the case of the selective crossing experiments in the lab.

While looking for the causes of melanoma formation, the researchers found something in the fish genome. "The genome analysis of these fish showed a strong correlation between the occurrence of black spots and the activity of two regions on chromosome 21," Schartl explains. The first region harbours the so-called xmrk gene which is responsible for the first step of tumourigenesis. It is the same gene that was already identified as the melanoma inducing oncogene in the laboratory-bred fish. The second region contains another gene which is related to the tumour spreading into the surrounding tissue, the so-called melanosome transporter gene.

The needle tip in the haystack

The researchers also identified regions associated with the occurrence of melanoma on chromosome 5; one of it carries a gene called cd97. This gene was particularly active in cells of the melanotic tissue. This coincides with the fact that mammals, and this includes humans, too, have a gene comparable to cd97. This gene had already been found to be associated with metastasis and invasiveness of tumours in other cancer types.

"We have been looking for genes that influence cancer progression, the so-called tumour modifier genes, for a long time," Manfred Schartl says and adds that they have at least strong evidence pointing to this potential candidate now. Or, figuratively speaking: "While looking for the needle in the haystack, we have at least located the tip of the needle," the biochemist says. He adds that further steps will be necessary to verify the result by studies in cell cultures and conducting functional analyses in animal models to determine the specific relevance for melanoma in humans, too.

But why do fish that mate exclusively with members of their own species hardly ever get melanoma compared to offspring whose parents belong to two related species? "Normally, the fish have a tumour suppressor gene which keeps the melanoma in check," Manfred Schartl details. But if a fish mates with another species that does not have this gene in its genome, some offspring will lack this control function. As a result, black spots and melanoma can develop unchecked.

A building block in the evolution of new species

There is another reason why scientists are excited about the recently published research findings and this has nothing whatsoever to do with melanoma. "We identify genes in our work that are the basis of hybrid incompatibility in vertebrates," to quote the Science paper. This is based on the assumption that it is beneficial for the evolution of new species and their splitting if the members of the still closely related new species can no longer mate with each other so that they are unable to produce any more "hybrids", scientifically speaking.

To prevent such hybrids from surviving or at least from reproducing, a suitable genetic framework is necessary. So far, however, less than a dozen cases have been reported where individual genes trigger "incompatibilities" – too few to validate whether these processes share common genetic and evolutionary mechanisms. The scientists are intrigued to have successfully identified such genes during their research.

Original publication

Natural hybridization reveals incompatible alleles that cause melanoma in swordtail fish. Daniel L. Powell, Mateo García-Olazábal, Mackenzie Keegan, Patrick Reilly, Kang Du, Alejandra P. Díaz-Loyo, Shreya Banerjee, Danielle Blakkan, David Reich, Peter Andolfatto, Gil Rosenthal, Manfred Schartl, Molly Schumer, Science, DOI: 10.1126/science.aba5216