The Spawn of Medusa or Evolutionary Tinkering?

Living at the end of the world, Medusa, the creature with twisting serpents for hair, was such a vile looking creature that one look would turn a man to stone. Greek mythology purports that drops of blood from her severed head fell on the desert and gave rise to venomous snakes. While this account is compelling, venomous snakes predated the Greeks and until recently the exact origin of venom was just the source of speculation.

Picture 1: Medusa executed by Perseus painted by Peter Paul Rubens. Medusa was once a beautiful maiden who dared to compare her beauty to that of the god Minerva. Angered by this, Minerva turned her into a gorgon, and changed her hair into writhing snakes. Medusa was a terror until Perseus was able to sneak up while she was asleep, and by using his shield as a mirror to avoid a direct look at her, cut off her head.

Snakes are reptiles that have no legs and are strict carnivores which swallow their prey whole. Primitive snakes do not produce venom, but the advanced snakes of the superfamily Colubroidea contain all venomous snake species Venom molecules come in many forms that attach to proteins and receptors; blocking neurons, loosening the walls of blood vessels, and confusing the immune system. These toxins evolved from duplication events, which through the accumulation of mutations were recruited to the snakes’ venom weaponry. Although the venoms undergo variation in sequence and structure, the molecular scaffold of the ancestral protein is usually retained (Fry and Wuster 2004). By constructing the phylogenies of the toxin sequences, the resulting pattern of recruitment and diversification of the venoms can resolve the evolutionary history of snake venoms.

Figure 1: Phylogeny of the superfamily Colubroidea. “Colubridae” refers to the groups of snakes that lack front fangs. The 3FTx gene was believed to be exclusive to the Elapidae but it was recently discovered that it was recruited prior to the split between elapid and colubrine lineages. Viperidae is the most basal and elapidae is the most derived group.

The vipers and elapids are the most distantly related of all the Colubroidea lineages, so their recruitment of toxins can be informative to the clade as a whole (see Figure 1). Phylogenies were constructed by Fry and Wuster to resolve whether a single recruitment or independent recruitment events led to the presence of venom families in the both vipers and elapids. Of the eight toxin families analyzed, five were monophyletic to the exclusion of non-venom proteins, but were non-monophyletic among the vipers and elapid lineages. These genes, BPTI-Kunitz, CRISP, M12B, NGF, and GBL (see Figure 2) are indicative of a single early recruitment. The elapid and viperid PLA2 and natriurec peptides (see Figure 2) arose from independent recruitment events but are homologous in function. The cystatins remain unresolved as the phylogeny is consistent with both a single recruitment with losses and also multiple recruitment. The distance values indicate a single recruitment, placing the cystatins at the base of the clade (see Figure 2). The last common ancestor of the colubroid snakes had an arsenal of at least five and possibly six or more venom families existing in the vipers and elapids today.

Figure 2: The pattern of recruitment of toxin families present in both the viperids and elapids. The Cystatins remain unresolved. Recruitment events are represented by perpendicular gray bars.

With the evolutionary location of the recruitments resolved, the origin of the recruited genes was still unknown. Many scientists retain the idea that the venoms are modified saliva proteins.  Fry (2005) constructed phylogenies of amino acid sequences of the venoms and related non-venom proteins to discover the origin of the venoms. He discovered the toxin recruitment events occurred at least 24 times. After constructing the evolutionary trees of these 24 genes, Fry discovered that in only two cases did venom genes arise from salivary glands. The 22 other genes arose from genes originating in a variety of organs including the brain, trachea, heart, lung, spleen, and large intestine. Following gene duplication in one of these organs, a copy retains its function allowing the other to accumulate mutations. The mutated gene can then be recruited to producing proteins in the venom gland. Mutations that made venom more deadly not only increased the survival of the snakes but also ensured their strange status in myths and legends.


Fry, B.G. and Wüster, W. (2004) Assembling an arsenal: Origin and evolution of the snake venom proteome inferred from phylogenetic analysis of toxin sequences. Mol. Biol. Evol. 21: 870-883.

Fry, B. G. (2005) From genome to ‘venome’: molecular origin and evolution of the snake venom proteome inferred from phylogenetic analysis of toxin sequences and related body proteins. Genome Res. 15: 403– 420.

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