(CN) – Snakes roamed Earth on well-developed legs about 150 million years ago, until “Sonic hedgehog” came along.
That’s the conclusion of a study published Thursday, which details how a gene known as Sonic hedgehog disrupted a genetic circuit that drives limb growth in snakes – ultimately prompting serpentines to develop their trademark slither.
Three mutations in a genetic switch, known as an enhancer, that controlled the activity of the Sonic hedgehog gene stunted limb development in snakes by destroying a region of the enhancer where proteins bind to DNA, according to researchers from the University of Florida.
The team compared DNA sequences of snake and lizard genomes, finding that three mutations combine to affect the way genetic information is transcribed in embryonic pythons, stunting limb development.
The enhancer functions like a genetic “switch” that turns on the Sonic hedgehog gene during limb formation. Since three activators of the switch were deleted from pythons’ DNA, the Sonic hedgehog gene only flickers on before shutting off – ending the process of leg growth in the embryo.
“It’s exciting to know the precise nucleotide changes that are responsible for limb reduction,” study co-author Martin Cohn said.
While pythons and boa constrictors retain traces of leg structures, some snakes like cobras and vipers are completely limbless. The authors found that python embryos form leg “buds” and initiate the entire genetic program necessary to develop legs, but the process breaks down after the Sonic hedgehog gene switches off. This is why elements of the genetic material necessary for developing legs have remained after millions of years in certain snake species.
Other enhancers also remain intact, including those that enable the activity of a gene called Hoxd13 needed to develop hands and feet.
“The results tell us that python limb development progresses much further than we knew before. They make embryonic legs but the cells don’t complete the process of skeletal development,” Cohn said.
More completely limbless snakes show more extensive decay of the Sonic hedgehog limb enhancer. This helps explains how more advanced snakes ultimately lost their legs altogether, the researchers found.
The timeline of snakes developing legs have sparked multiple theories from scientists. Snake fossils estimated to be at least 90 million years old have led some researchers to believe that legs re-evolved in certain snakes, while others retained their limbs longer than other species.
Cohn believes that their discovery of a transitory leg skeleton in python embryos demonstrates the relics of ancestral snake legs and could have allowed the raw material for limbs to reappear.
“This surprising conservation and the specific modifications in the snake genome are a clear testament of their ancestry. Snakes clearly evolved from limbed ancestors and their genomes demonstrate this,” study co-author Francisca Leal said.
Their findings suggest the mutations that ultimately eliminated snake limbs likely began around 100 million years ago during the Upper Cretaceous period, according to genomic studies.
The team’s findings could also be applied to mouse and human models to look for mutations in the same genomic regions, as some of these transcription factor binding sites have not yet been discovered in mammals, Cohn said.
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