Evolution of snake venom

Venom in snakes 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. 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. The common view of this history before 2014 was that venom originated just once among all Toxicofera approximately 170 million years ago, and then diversified into the wide range of venoms seen today. 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 subsequently lost the ability to produce venom, often due to a change in diet. The single-origin hypothesis suggests that the mechanism of evolution in most cases has been gene duplication followed by natural selection for adaptive traits. Some of the various 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. The idea that venom had a single evolutionary origin has been called into question by 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 a number of snake lineages. 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. 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 in multiple branches among Squamata approximately 100 million years ago. More recent studies using nuclear gene sequences found the presence of similar venom proteins in several lizards within a clade that was named 'Toxicofera'. This led to the theory that venom originated only once within the entire lineage approximately 170 million years ago. This ancestral venom consisted 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 American “rat snakes,” such as Pantherophis guttatus, lost their venom following the evolution of constriction as a means of prey capture. The independent evolution of constriction in the fish-eating aquatic genus Acrochordus also saw the degradation of the venom system. Two independent lineages, one terrestrial and one marine, that shifted to an egg-based diet, also possess the remnants of an atrophied venom system. The view that venom evolved just once has recently been called into doubt. 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, snake venom evolved independently in a number of lineages. 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. Castoe stated that the team 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 total messenger RNA in a cell). 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 (also referred to as 'colubroidian snakes'), thus suggesting that most venom evolution took place after this lineage diverged from other snakes. 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 (PLA2) 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 (or recombination between DNA sequences that are similar, but not alleles) 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. 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. 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.