If UCLA geneticists Leonid Kruglyak and Longhua Guo have anything to say about it, biological laboratories across the world may be using reptile models instead of mouse models in the future.
Unlike mice and zebrafish, genetic studies using reptiles are uncommon since their similarities to humans are few and far between. However, after working with leopard geckos, Kruglyak and Guo think the rare, brightly colored lizards could one serve as a biomedically relevant model for scientists studying human melanoma.
Kruglyak's lab at UCLA isn't a reptile lab, nor had his team previously studied leopard geckos. So, when an excited Guo suggested exploring the animals at a genetic level, it may have sounded like an odd request. Of course, odd is relative when Kruglyak himself has spent years examining yeast strains with unusual metabolism and roundworms that are resistant to certain drugs. It may have been a different animal but Guo’s proposal was ultimately the same as every project in the Kruglyak's lab—mapping a particular trait to a specific region in the genome.
In 2016, reptile breeder Steve Sykes began breeding an uncommonly white, black and yellow leopard gecko. But Stykes and his clients noticed a problem—over 80 percent of the geckos developed bulbous white skin tumors within the first 5 years of life. For some geckos, the tumors were so massive, they restricted movement. For others, infection was imminent if the tumors ruptured.
"It seemed likely that the same thing that was giving the geckos such unusual coloration was also causing the tumors," said Kruglyak.
With DNA from 500 leopard geckos, the team searched for specific regions that could be linked to certain color varieties. Specifically, they looked for a genetic hotspot that occurred only in the yellow, or Lemon Frost, geckos—and they found it.
The researchers mapped the Lemon Frost trait to a region that contained a single gene—called SPINT1—that was familiar to the geneticists.
In mice, deletion of SPINT1 leads to embryonic death, while increased expression leads to squamous cell carcinoma, the most aggressive type of nonmelanoma skin cancer. In zebrafish, reduced SPINT1 expression has been linked to hyperproliferation of basal cells in the skin, as well as enhanced proliferation of epithelial cells.
In humans, carcinoma tissues in vivo and carcinoma-derived cell lines in vitro have reduced SPINT1 on the cell membrane. The under-expression of SPINT1 in humans has been associated with a negative prognosis of skin and pancreatic cancer.
“The tumor suppressor function of SPINT1 establishes a potential link between [skin tumors] and regulation of white coloration in reptiles,” the researchers write in their paper, recently published in PLOS Genetics. “Our work suggests that cancer genes can play as important a role in [skin tumors] as they do in melanocytes and melanoma, and that Lemon Frost leopard geckos may serve as a disease model to study skin cutaneous melanoma.”
In future work, Guo wants to pursue the genetic basis of even more lizard colors, including two varieties called Blizzard and Patternless, which lack all colors and patterns. Perhaps this work will uncover additional findings potentially relevant to human health.
Photo: A California reptile shop began breeding Mr. Frosty in 2016 and produced a colony of lemon-yellow leopard geckos. The color variety was known as Lemon Frost. Credit: L. Guo et al./PLOS Genetics 2021/Steve Sykes