Burmese python and the DNA sequence associated with limb loss. (Eric Zamora/Florida Museum of Natural History and Martin J. Cohn/University of Florida)

What does it take to turn a lizard into a snake?

Turns out you don't need a wand and a lesson at Hogwarts, just a tiny genetic tweak. By making a simple switch more than 100 million years ago, ancient burrowing lizards became slithery and legless, giving rise to the first snakes.

That's according to studies published in the journals Current Biology and Cell this week. The first, by University of Florida researchers Francisca Leal and Martin J. Cohn, traces the particular molecular mechanism that prevents snake embryos from developing limbs. The second, based out of the Lawrence Berkeley National Lab, tested that mechanism by implanting it in a genetically modified mouse. The same simple genetic tweak can turn a mouse into a snake (or something snakelike), too.

The story of the first study begins in 1999, in the United Kingdom, where Cohn was a postdoctoral fellow researching this topic. He was particularly interested in a gene called sonic hedgehog (named by the father of a comic book fan), which is known to play a vital role in the differentiation and growth of body parts. The trouble was that Cohn didn't have any snakes himself, so he found himself traveling all over the country to pick up newly laid python eggs from various labs. (Pythons are more “primitive” snakes and are closer to their legged relatives than more recently evolved snakes like cobras.)

“Often it was the next day before I got them back to the lab to study them,” Cohn said. By that point, he couldn't find any evidence of sonic hedgehog being expressed in the tiny “limb buds,” or incipient limbs, that form in snake embryos where legs should be.

Fast forward 17 years. Cohn is a developmental biology professor and able to provide his students with all the snake eggs they need. He and his students also have at their disposal the entire sequenced genomes of several snake and lizard species, something that evolutionary developmental biologists like himself could only dream of in the 1990s.

Leal, a graduate student, took it upon herself to examine snake eggs at the very earliest stages of development, within the first 24 hours after they are laid. And she found what Cohn couldn't more than a decade ago: a tiny, weak flicker of sonic hedgehog activity in the limbs.

“That suggested two things,” Cohn said. “First was that the reason I never saw it was I never looked early enough. And second, it told us that the genomic machinery that controlled sonic hedgehog expression wasn’t completely lost.”

If sonic hedgehog still worked, there must be some other factor preventing it from staying on. Leal and Cohn turned their attention to a section of DNA known as ZRS. It's not a gene, but an enhancer — a regulatory sequence that helps the gene get expressed. Compared with the ZRS of a legged lizard called an anole, the python ZRS was missing several bits of code. When the researchers tested the purpose of those sections, they found that those were the sites where proteins bind to the enhancer to put it into action.

“It's as if you had a thumbprint reader on your iPhone, and the part of that reader that recognizes your print had been scratched off,” Cohn said. Without the print, the phone can't make the call to get sonic hedgehog to remain active. The snakes' incipient limbs never become more than a bundle of cells (though pythons still produce vestigial remnants that they use during mating).

On the other side of the country, at a lab in Berkeley, a separate team of scientists was looking at the same question. Noticing the same deletions in the ZRS enhancer that Cohn and Leal had found, they tried to reproduce them in a mouse. Using the genetic editing technique CRISPR, they inserted the ZRS sequences for pythons (primitive snakes), cobras (more advanced ones) and a variety of legged animals, including humans, platypuses and chickens.

Mice with the python version of ZRS developed stumpy, incomplete limbs. Those with the cobra version — which Cohn described as “degenerated to the point of being almost unrecognizable” — had no limbs at all. 

“We could follow in real time the evolutionary death of an enhancer,” co-author Axel Visel, of the Lawrence Berkeley National Laboratory, told the Atlantic.

Whether ZRS is the only factor in snakes' 100 million-year-old transition to leglessness still needs to be investigated. But it was almost certainly part of the process.

And to Cohn, the findings suggest something broader about “the power of comparative biology.” His experiment relied on understanding the genetics and the morphologies of several different species — pythons, cobras, mice, anoles — as did the research out of Berkeley.

No experiment that a human could design in the lab will approach the scale of biodiversity that exists naturally,” Cohn said. If scientists can reverse engineer the procedures that led to that diversity, they will have a handle on the mechanisms that shape our world. 

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