When reptile breeder Steve Sykes saw that two particular leopard geckos were up for auction in 2015, he knew he had to have them. The chubby lizards’ bodies were dappled with the black spots that gave their species its common name. And at eye level, they looked to be smiling. But unlike other members of Eublepharis macularius, these were “lemon frost” geckos: they were pastel yellow from the base of their head to the root of their tail, as if they had been dipped in lemon sherbet. A breeder had created this variety, also called a “morph,” just one generation earlier. The combination of rarity and beauty made the two geckos instantly appealing to Sykes. He purchased the pair and named them Mr. and Ms. Frosty.

Leopard geckos are among the most common reptile pets. Native to the Middle East and South Asia, they have been so successfully bred in captivity that most sold today are not sourced from the wild. Instead owners create and mix dozens of morphs through selective breeding and random luck.

“It’s a big deal when a brand-new base morph comes out, no matter what it is. So the fact that a lemon frost was available—that was definitely something that I wanted to add to my collection,” says Sykes, who owns a business called Geckos Etc. Herpetoculture. “I had no idea that there was any issue with this morph when I first got involved with it.”

The issue emerged with Mr. Frosty’s offspring. Sykes had bred the male with other leopard geckos he owned to produce more of the coveted lemon frosts. A year after the auction, he noticed small, white bumps growing on the bodies of some of the babies. Over time, he says, it became clear that these bumps were tumors. In fact, it turns out that more than 80 percent of the geckos with this morph suffer from a rare skin cancer that arises from pigment-producing cells called iridophores.

Closeup of the gecko Mr. Frosty on a blue background
“Lemon frost” leopard gecko named Mr. Frosty. Credit: L. Guo et al., in PLOS Genetics, 2021 and Steve Sykes

Sykes wanted to know if there was a way to breed lemon frosts to avoid this fate. Were the cancer and unique color somehow inextricably linked? Evolutionary geneticist Leonid Kruglyak of the University of California, Los Angeles, and his colleagues used Sykes’s geckos to crack the lemon frost genetic code—and found that a single gene controlled both the color and the cancer.

“There's been very little molecular genetic work done in reptiles, and so it's fantastic to see an instance where a group has been able to track down the genetic basis of a really interesting trait,” says Douglas Menke, a geneticist at the University of Georgia, who was consulted for the study but was not directly involved in the work.

This research could also open new avenues for studying human melanoma, an aggressive cancer of our pigment-producing cells. It is newly diagnosed in about 100,000 people in the U.S. each year and kills more than 7,000 annually.

Gecko Detective Work

In 2017, a short time after he discovered the lemon frost morph’s proclivity to tumors, Sykes says he got a call from Longhua Guo, a postdoctoral researcher at Kruglyak’s lab, who studies human genetics. Guo had seen photographs of leopard geckos online, and he became fascinated with how their genes control their vibrant and varied patterns. After a two-hour conversation, Guo says, Sykes convinced him to look into the lemon frost tumor mystery.

Because Sykes had already been breeding the geckos with the intent of selling them before he noticed the cancer, the researchers had access to dozens of Mr. Frosty’s children and grandchildren. They collected DNA samples by cutting off a small piece of a gecko’s tail or swabbing the inside of its cheek—relatively easy tasks, Guo says, because of the lizards’ relaxed temperament. Then, the team compared the sequenced genomes of the lemon frost geckos with an existing genome for a standard leopard gecko.

The results could not have been clearer: lemon frost geckos possessed one copy of a gene called SPINT1 that had mutated. Their other copy of that gene, as well as both copies in non-lemon-frost leopard geckos, did not have those differences in the DNA sequence.

“It turns out that SPINT1 can explain what is going on here because SPINT1 has been reported in zebra fish, in mice and in humans. [Mutations in the gene] are associated with skin-cell tumors,” Guo says. Looking at the lemon frosts’ tumors under a high-powered microscope revealed increased numbers of iridophores, which give some lizard scales a whitish appearance.

Guo and his team proposed that the mutated copy of SPINT1 causes lemon frost geckos to overproduce these cells. That overproduction would lead to a whiter overall background that would make the animals’ yellow color appear brighter and more visible—and that could also cause them to develop skin tumors later in life. The study, authored by Guo, Sykes, Kruglyak and their colleagues, was published on Thursday in PLOS Genetics.

A Frosty Model Organism

Researchers still do not know why some lemon frosts have more aggressive cancers than their siblings or why others (including Mr. Frosty himself) never develop visible tumors. “Why does gecko A develop no tumors at all while gecko B has very slight tumors that stay completely dormant for a very long time and gecko C has tumors that are very fast-growing and very active?” Sykes asks. “That’s always been a question for me.”

Answering this question may help scientists better understand how some cancers develop in humans, says Lara Urban, a conservation genomics research fellow at the University of Otago in New Zealand, who was not involved in the study. “I do think it will have an impact on cancer research, in that we understand the conservedness of this [SPINT1 genetic] pathway a little bit better now,” she says. “It will also be a potential new model organism for studying the development of skin cancer and contributing to actual therapeutic development.”

Perhaps there are tumor suppressor genes that keep the cancer at bay in some lizards but not others, Urban adds. And if the tumors are inevitable, they could exhibit certain chemical signatures that current methods do not detect. This raises the possibility of eventually creating diagnostics to catch preclinical melanoma in humans.

While the lemon frost morph might be bred as a research strain, Sykes says it is unlikely the lizards will ever be sold as hobbyist pets again.

“We’ve stopped breeding lemon frosts, and we have no intentions to start it up again in the future,” he says. “My goal is to produce beautiful, perfect, healthy geckos. And it doesn’t appear that it’s possible to separate the lemon frost gene from this tumor phenotype.”