It’s a fable worthy of Aesop: Just how did the snake lose its legs? About 150 million years ago, the scaly reptiles were padding about on all-fours, until they then started to elongate and their limbs shrank. Now, a couple of independent studies have looked into exactly what genetic shift occurred to make this happen, and found that it is surprisingly simple.
It appears that a series of just three mutations in a region of DNA known as an enhancer, or genetic switch, are necessary for limb development to be halted. The enhancer in question is a target for the proteins that are needed to express a gene known rather wonderfully as Sonic hedgehog (the very same of Sega fame), which is itself related to the development of limbs. By altering the sequence of the enhancer, the mutations prevent the proteins from binding, and thus prevent the gene from working.
In one paper published in Current Biology, researchers found that the three mutations in the DNA of the python meant that the gene was not completely silenced, leading to the snakes to begin limb development, but that it was subsequently quickly turned off. In cobras, however, there are more than three mutations in the enhancer meaning that the gene never sees the light of day. This explains why in pythons and boas, they still retain what are known as “vestigial” limbs, little nubbins that form the beginnings of legs, while cobras and most other snakes have absolutely nothing.
Another study, published in Cell, also looked at the Sonic hedgehog (SHH) gene, and used CRISPR-Cas9 to edit the python enhancer into the genome of mouse embryos. These then developed to form small nubs instead of legs, confirming that the mutation in this section of DNA prevented the full development of limbs. Not only that, but the scientists then altered the snake DNA to fix the mutations, and then put that into mouse embryos, and found that the rodents legs developed normally.
The fact that it is seemingly so simple to turn on and turn off the section of DNA that controls the development of limbs is fascinating, because it could help explain the confusing number of fossil snakes that paradoxically have limbs when they should have already lost them. Some have suggested that different lineages of snakes lost their limbs at differing times, but these latest studies suggest that perhaps some groups actually managed to regrow them.