Research explains how snakes lost their limbs

February 7, 2019 by José Tadeu Arantes, FAPESP
Research explains how snakes lost their limbs
The study is part of an effort to understand how changes in the genome lead to changes in phenotypes . Credit: Jax Strong / Wikimedia

Snakes and lizards are reptiles that belong to the order Squamata. They share several traits but differ in one obvious respect: Snakes do not have limbs. The two suborders diverged more than 100 million years ago. Identification of the genetic factors involved in this loss of limbs is a focus of an article titled "Phenotype loss is associated with widespread divergence of the gene regulatory landscape in evolution," published by Juliana Gusson Roscito and collaborators in Nature Communications.

Another equally interesting focus of the article is eye degeneration in certain subterranean mammals. "We investigated these two cases in order to understand a much more general process, which is how genome changes during evolution lead to phenotype changes," Roscito said.

Currently working as a researcher at the Max Planck Institute for Molecular Cell Biology and Genetics in Dresden, Germany, Roscito's postdoctoral scholarship was linked to the thematic project "Comparative phylogeography, phylogeny, paleoclimate modeling and taxonomy of neotropical reptiles and amphibians," for which Miguel Trefaut Urbano Rodrigues is the principal investigator. Rodrigues is a professor at the University of São Paulo's Bioscience Institute (IB-USP) in Brazil and supervised Roscito's postdoctoral research. He is also a coauthor of the recently published article.

"The research consisted of an investigation of the genomes of several species of vertebrates, including the identification of genomic regions that changed only in snakes or subterranean mammals, while remaining unchanged in other species that have not lost their limbs or have normal eyes," Roscito said.

"In mammals with degenerated visual systems, we know several have been lost, such as those associated with the eye's crystalline lens and with the retina's photoreceptor cells. These genes underwent mutations during the evolutionary process. Eventually, they completely lost their functionality, meaning the capacity to encode proteins. But that's not what happened to snakes, which haven't lost the genes associated with limb formation. To be more precise, the study that sequenced the genome of a did detect the loss of one gene, but only one. Therefore, the approach we chose in our research consisted of investigating not the genes but the elements that regulate ."

Gene expression depends on for the information the gene contains to be transcribed into RNA (ribonucleic acid) and later translated into protein. This process is regulated by cis-regulatory elements (CREs), which are sequences of nucleotides in DNA (deoxyribonucleic acid) located near the genes they regulate. CREs control the spatiotemporal and quantitative patterns of gene expression.

"A regulatory element can activate or inhibit the expression of a gene in a certain part of the organism, such as the limbs, for example, while a different regulatory element can activate or inhibit the expression of the same gene in a different part, such as the head. If the gene is lost, it ceases to be expressed in both places and can often have a negative effect on the organism's formation.

However, if only one of the regulatory elements is lost, expression may disappear in one part while being conserved in the other," Roscito explained.

Tegu lizard

From a computational standpoint, CREs are not as easy to identify as genes. Genes have a characteristic syntax, with base pairs that show where the genes begin and end. This is not the case for CREs, so they have to be identified indirectly. This identification is normally based on the conservation of DNA sequences among many species.

"To detect the divergence of specific sequences in snakes, it's necessary to compare the genomes of snakes with the genomes of various reptiles and other vertebrates that have fully developed limbs. Genome sequences for reptiles with well-developed limbs are scarce, so we sequenced and assembled the genome of the fully limbed tegu lizard, Salvator merianae. This is the first species of the teiid lineage ever sequenced," the authors said.

"Using the tegu as a reference, we created an alignment of the genomes of several species, including two snakes (boa and python), three other limbed reptiles (green anole lizard, dragon lizard and gecko), three birds, an alligator, three turtles, 14 mammals, a frog, and a coelacanth. This alignment of 29 genomes was used as the basis for all further analyses."

The researchers identified more than 5,000 DNA regions that are considered candidate regulatory elements in several species. They then searched the large database using ingenious technical procedures that are described in detail in the article and obtained a set of CREs the mutation of which may have led to the disappearance of limbs in the ancestors of snakes.

"There are several studies concerning a well-known regulatory element that regulates a gene that, when modified, causes various defects in limbs. Snakes have mutations in this CRE. In a study published in 2016, the mouse CRE was replaced with the snake version, resulting in practically limbless descendants. This was a functional demonstration of a mechanism that may have led to limb loss in snakes. However, this CRE is only one of the regulatory elements for one of several genes that control formation," Roscito said.

"Our study extended the set of CREs. We showed that several other regulatory elements responsible for regulating many genes have mutated in snakes. The signature is far more comprehensive. An entire signaling cascade is affected."

Explore further: The warm and loving tegu lizard becomes a genetic resource

More information: Juliana G. Roscito et al, Phenotype loss is associated with widespread divergence of the gene regulatory landscape in evolution, Nature Communications (2018). DOI: 10.1038/s41467-018-07122-z

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1 / 5 (5) Feb 07, 2019
Wow. The snakes lost only 1 gene and then it prohibited them from growing any more legs? The Bible address that topic in Genesis when the snake was cursed, and afterwards it lost its ability to walk and had to slither on its belly from then on. Interesting parallels.
5 / 5 (5) Feb 07, 2019
@BA: IIRC, different types of snakes have lost their limbs at different times. Each seems to be associated with adaptation to habitats such as complex rocky landscapes, deep leaf-litter, life underground etc etc.

( I'd remind you about legless 'slow worms' which are not really snakes, and those real-skinny skinks which look 'half and half'. What did they do Biblically 'wrong' ?? )

FWIW, if this referenced work is but a regulatory gene, then a modest mutation the other way may restore limbs. Like the occasional whale reported with a pair of back legs...
5 / 5 (3) Feb 08, 2019
Wow. The snakes lost only 1 gene [irrelevant insertion of erroneous magic myth]

Without the Bronze Age mumbo jumbo, clearly that rare loss was the basis for modern science making the wow discovery that several CGE mechanisms were mainly responsible. The modifications would tend to preserve the limb genes (and, while not noted here, some of the pathways are also used to grow penis "limbs" . snakes have two)..
5 / 5 (3) Feb 08, 2019
Wow. The snakes lost only 1 gene and then it prohibited them from growing any more legs? The Bible address that topic in Genesis when the snake was cursed, and afterwards it lost its ability to walk and had to slither on its belly from then on. Interesting parallels.

It would be interesting to research how the Bible Worshipers lost their critical thinking abilities. Could it be a single defective gene that prevents the brain from developing normally? Interesting parallel.

5 / 5 (3) Feb 09, 2019
Research explains how snakes lost their limbs...

Simple carelessness, there's no point glossing over it.
5 / 5 (2) Feb 09, 2019
The Bible address that topic in Genesis...

Fascinating, does the bible have anything to say on quantum gravity?
Da Schneib
3 / 5 (2) Feb 09, 2019
Fascinating, does the bible have anything to say on quantum gravity?
Not to mention molecular biology.
Da Schneib
3.7 / 5 (3) Feb 09, 2019
It's amusing to see a bunch of nutjobs provide fairy-tale explanations of snakes' lack of legs from the Babble scrawled by the drunken stone age sheep herders about the super magic daddy in the sky.
4 / 5 (1) Feb 09, 2019
Well, fellows. You all know how I hate to be a contrarian buttinski...

Okay, you can stop laughing now. This is a grimly serious issue that I want to address.

I fear that the religious cracked-pottery have a legitimate point against Evolutionary Theory.

Obviously, they have failed to evolve past their ancestral fixation of worshiping Pharaoh as god-king.

& to prove it. Check out their utube sites for their practicing the sanctified traditional ceremonial sheep butt-fucking.

No wonder the price of lamb is so high! These tribal dolts are disrupting the normal mating habits of sheep. Causing the collapse of product to market. All we'll fet out of this? Are more trump voters!
5 / 5 (3) Feb 10, 2019
Fascinating, does the bible have anything to say on quantum gravity?
Not to mention molecular biology.

I thought it would be more prudent to use something that we don't know about ;¬)
3 / 5 (2) Feb 10, 2019
This fishy tail in finrot

Just as snakes did not come out of Africa
Humans did not come out of Africa
nor did humans evolve from chimps
humans like snakes
evolved from fish
our legs are our fins
our tail is a fishy tail
why do think when humans get stressed, they suffer from finrot
where do you think the fishy mermaid tails emerged
before the first animals crawled out the sea onto terra firma
fish were the first animals to evolve a backbone
our feet and hands are our flippers and tail and backbone evolved from fish
as snakes also evolved from fish
just as eels, also legless are at home in this fishy world
without fish evolving the first backbone
humans would be some slithering
slimy creature
as even snakes also evolved their backbone from fish
Snakes and humans evolved from Fish

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