Evolution of snake venom
and some lizards is a form of saliva that has been modified into venom over its evolutionary history. In snakes, venom has evolved to kill or subdue prey, as well as to perform other diet-related functions. While snakes occasionally use their venom in self defense, this is not believed to have had a strong effect on venom evolution. The evolution of venom is thought to be responsible for the enormous expansion of snakes across the globe.
The evolutionary history of snake venom is a matter of debate. Historically, snake venom was believed to have evolved once, at the base of the Caenophidia, or derived snakes. Molecular studies published beginning in 2006 suggested that venom originated just once among a putative clade of reptiles, called Toxicofera, approximately 170 million years ago. Under this hypothesis, the original toxicoferan venom was a very simple set of proteins that were assembled in a pair of glands. Subsequently, this set of proteins diversified in the various lineages of toxicoferans, including Serpentes, Anguimorpha, and Iguania: several snake lineages also lost the ability to produce venom. The Toxicoferan hypothesis was challenged by studies in the mid-2010s, including a 2015 study which found that venom proteins had homologs in many other tissues in the Burmese python. The study therefore suggested that venom had evolved independently in different reptile lineages, including once in the Caenophid snakes. Venom containing most extant toxin families is believed to have been present in the last common ancestor of the Caenophidia: these toxins subsequently underwent tremendous diversification, accompanied by changes in the morphology of venom glands and delivery systems.
Snake venom evolution is thought to be driven by an evolutionary arms race between venom proteins and prey physiology. The common mechanism of evolution is thought to be gene duplication followed by natural selection for adaptive traits. The adaptations produced by this process include venom more toxic to specific prey in several lineages, proteins that pre-digest prey, and a method to track down prey after a bite. These various adaptations of venom have also led to considerable debate about the definition of venom and venomous snakes. Changes in the diet of a lineage have been linked to atrophication of the venom.
Evolutionary history
The origin of venom is thought to have provided the catalyst for the rapid diversification of snakes in the Cenozoic period, particularly to the Colubridae and their colonization of the Americas. Scholars suggest that the reason for this huge expansion was the shift from a mechanical to a biochemical method of subduing prey. Snake venoms attack biological pathways and processes that are also targeted by venoms of other taxa; for instance, calcium channel blockers have been found in snakes, spiders, and cone snails, thus suggesting that venom exhibits convergent evolution. Venom is common among derived snake families. Venom containing most extant toxin families is believed to have been present in the last common ancestor of the Caenophidia, also called Colubroidea. These toxins subsequently underwent tremendous diversification, accompanied by changes in the morphology of venom glands and delivery systems. This diversification is linked to the rapid global radiation of the advanced snakes. The tubular or grooved fangs snakes use to deliver their venom to their target have evolved multiple times, and are an example of convergent evolution. The tubular fangs common to front-fanged snakes are believed to have evolved independently in Viperidae, Elapidae, and Atractaspidinae.Until the use of gene sequencing to create phylogenetic trees became practical, phylogenies were created on the basis of morphology. Such traditional phylogenies suggested that venom originated along multiple branches among Squamata approximately 100 million years ago: in the Caenophidia, or derived snakes, and in the lizard genus Heloderma. Studies using nuclear gene sequences in the mid-2000s and early 2010s found the presence of venom proteins in the lizard clades Anguimorpha and Iguania similar to those of snakes, and suggested that together with Serpentes, these formed a clade, which they named "Toxicofera". This led to the theory that venom originated only once within the entire lineage approximately 170 million years ago. This ancestral venom was described as consisting of a very simple set of proteins, assembled in a pair of glands. The venoms of the different lineages then diversified and evolved independently, along with their means of injecting venom into prey. This diversification included the independent evolution of front-fanged venom delivery from the ancestral rear-fanged venom delivery system. The single origin hypothesis also suggests that venom systems subsequently atrophied, or were completely lost, independently in a number of lineages. The phylogenetic position of Iguania within Toxicofera is supported by most molecular studies, but not by morphological ones.
The "Toxicoferan hypothesis" was subsequently challenged. A study performed in 2014 found that homologs of 16 venom proteins, which had been used to support the single origin hypothesis, were all expressed at high levels in a number of body tissues. The authors therefore suggested that previous research, which had found venom proteins to be conserved across the supposed Toxicoferan lineage, might have misinterpreted the presence of more generic "housekeeping" genes across this lineage, as a result of only sampling certain tissues within the reptiles' bodies. Therefore, the authors suggested that instead of evolving just once in an ancestral reptile, venom evolved independently in multiple lineages, including once prior to the radiation of the "advanced" snakes. A 2015 study found that homologs of the so-called "toxic" genes were present in numerous tissues of a non-venomous snake, the Burmese python. One of the authors stated that they had found homologs to the venom genes in many tissues outside the oral glands, where venom genes might be expected. This demonstrated the weaknesses of only analyzing transcriptomes. The team suggested that pythons represented a period in snake evolution before major venom development. The researchers also found that the expansion of venom gene families occurred mostly in highly venomous caenophidian snakes, thus suggesting that most venom evolution took place after this lineage diverged from other snakes. The debate over the Toxicoferan hypothesis is driven in part by disagreement over the definition of a venom. As of 2022, the Toxicoferan hypothesis remains a prevalent view.
Mechanisms of evolution
The primary mechanism for the diversification of venom is thought to be the duplication of gene coding for other tissues, followed by their expression in the venom glands. The proteins then evolved into various venom proteins through natural selection. This process, known as the birth-and-death model, is responsible for several of the protein recruitment events in snake venom. These duplications occurred in a variety of tissue types with a number of ancestral functions. Notable examples include 3FTx, ancestrally a neurotransmitter found in the brain, which has adapted into a neurotoxin that binds and blocks acetylcholine receptors. Another example is phospholipase A2 type IIA, ancestrally involved with inflammatory processes in normal tissue, which has evolved into venom capable of triggering lipase activity and tissue destruction. The change in function of PLA2, in particular, has been well documented; there is evidence of several separate gene duplication events, often associated with the origin of new snake species. Non-allelic homologous recombination induced by transposon invasion has been proposed as the mechanism of duplication of PLA2 genes in rattlesnakes, as an explanation for its rapid evolution. These venom proteins have also occasionally been recruited back into tissue genes.Gene duplication is not the only way that venom has become more diverse. There have been instances of new venom proteins generated by alternative splicing. The Elapid snake Bungarus fasciatus, for example, possesses a gene that is alternatively spliced to yield both a venom component and a physiological protein. Further diversification may have occurred by gene loss of specific venom components. For instance, the rattlesnake ancestor is believed to have had the PLA2 genes for a heterodimeric neurotoxin now found in Crotalus scutulatus, but those genes are absent in modern non-neurotoxic Crotalus species; the PLA2 genes for the Lys49-myotoxin supposedly existing in the common ancestor of rattlesnakes were also lost several times on recent lineages to extant species Domain loss has also been implicated in venom neofunctionalization. Investigation of the evolutionary history of viperid SVMP venom genes revealed repeated occasions of domain loss, coupled with significant positive selection in most of the phylogenetic branches where domain loss was thought to have occurred. Venom toxins have also evolved via the gene "hijacking" or "co-opting", or the change in function of unrelated genes. A 2021 study suggested that co-opting explained the evolution of most types of toxins, but not that of the toxins that are most abundant in snake venom.
Protein recruitment events have occurred at different points in the evolutionary history of snakes. For example, the 3FTX protein family is absent in the viperid lineage, suggesting that it was recruited into snake venom after the viperid snakes branched off from the remaining colubroidae. PLA2 is thought to have been recruited at least two separate times into snake venom, once in elapids and once in viperids, displaying convergent evolution of this protein into a toxin. A 2019 study suggested that gene duplication could have allowed different toxins to evolve independently, allowing snakes to experiment with their venom profiles and explore new and effective venom formulations. This was proposed as one of the ways snakes have diversified their venom formulations through millions of years of evolution. The various recruitment events had resulted in snake venom evolving into a very complex mixture of proteins. The venom of rattlesnakes, for example, includes nearly 40 different proteins from different protein families, and other snake venoms have been found to contain more than 100 distinct proteins. The composition of this mixture has been shown to vary geographically, and to be related to the prey species available in a certain region. Snake venom has generally evolved very quickly, with changes occurring faster in the venom than in the rest of the organism.