How the snake lost its limbs

Over the past month, I feel like snakes have been chasing me. First of all, I came across this great video of snakes and iguanas on Planet earth II on BBC; I am going to place it at the end of this article as a reward for those interested and as mercy to those afraid of snakes. This Thanksgiving, I unexpectedly encountered a baby rattlesnake in my tracks on a crowded hike in San Diego; I rushed away from the site before the elders in its family made an appearance, finding a great reason to be thankful for!


A baby rattlesnake: look at the distinct ringed tail. (PC: Hrishikesh Pendurkar)

I am nervous and excited in equal parts to write this post. Nervous, as I am not a snake person; its nothing personal, but I confess these slithering creatures creep me out. However, like every unique topic, I am excited and curious about snakes. How did they evolve to be so different from other vertebrates and start slithering? Coincidentally, I came across a recent paper shedding light on a factor involved in the loss of snake limbs during evolution, and I thought it might be an interesting topic to touch upon.

An important fact about genetics is that just possessing a gene does not guarantee its expression. Many other factors can increase or decrease gene-expression. One such factor is an enhancer, a short DNA sequence that can bind to transcription factors and increase the expression of another gene. This story involves ZRS, an enhancer of a gene involved in limb development of animals. Researchers from Lawrence Berkeley National lab compared ZRS sequences of several organisms, including mice, humans, fish, and different types of snakes. They noticed that the sequence of ZRS was similar in most of these animals, including ‘primitive’ snakes like boa and python, which are older in the evolutionary timeline than advanced snakes like rattlesnake, cobra, and corn snake. Surprisingly, the ZRS sequences of advanced snakes were very different from the conserved sequences observed in other organisms.

To confirm if the functions of ZRS sequences from different organisms are different, the researchers used an advanced method called CRISPR-CAS technology (more on that later). Using this method, they could substitute the ZRS sequence of mice with that from human, python, cobra, or coelacanth fish. They showed that interchanging ZRS sequence of mouse with that from human or fish did not affect the limbs of the genetically modified mice. On the contrary, substitution with the cobra-ZRS sequence resulted in ‘serpentine mice’ – mice with short, truncated limbs. How would the sequence from python, which possesses remnant vestigial limbs affect the mice? Interestingly, this substitution resulted in a milder deformation of mice, i.e. they possessed limbs, but only with 2-3 digits. This implies that the enhancer is at least partly functional in basal snakes, and probably lost its function further down the evolutionary timeline.


(Top) A normal mouse, (bottom) mouse with ZRS sequence from cobra. Figure from the original paper (1)

My main goal behind choosing this paper was not just to highlight the findings. These are of course cogs in the wheel; important, but only a part of the whole picture. What I find amazing is that we now possess the technology to replace selective fragments of singular genes to test their functionality in animal models. The concept and application of gene manipulation with CRISPR-CAS at this level is a huge leap of progress. For those interested in knowing more about this method, here is great explanatory video.

Lastly, as promised, here is the video of snakes chasing a baby iguana in Galapagos islands, which I mentioned in the beginning. Enjoy Sir David Attenborough’s commentary that one cannot stop watching it, despite the guaranteed nightmares.

The video raises an interesting point regarding island habitats. The racer snakes are seen to chase the iguana in packs, a behavior quite atypical of snakes. Previously, I had also written about the advanced tool-using skills in crows  species specific to islands. I wonder if the behavior of snakes is also influenced specifically by the isolated environment of the island? Any ideas on what are other patterns are specific to island-inhabiting populations?

Original publication

  1. Kvon, Evgeny Z., et al. “Progressive Loss of Function in a Limb Enhancer during Snake Evolution.” Cell 167.3 (2016): 633-642.

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