Convergent evolution of pain-inducing defensive venom components in spitting cobras

Abstract

Convergent evolution provides insights into the selective drivers underlying evolutionary change. Snake venoms, with a direct genetic basis and clearly defined functional phenotype, provide a model system for exploring the repeated evolution of adaptations. While snakes use venom primarily for predation, and venom composition often reflects diet specificity, three lineages of cobras have independently evolved the ability to spit venom at adversaries. Using gene, protein, and functional analyses, we show that the three spitting lineages possess venoms characterized by an up-regulation of phospholipase A2 (PLA2) toxins, which potentiate the action of preexisting venom cytotoxins to activate mammalian sensory neurons and cause enhanced pain. These repeated independent changes provide a fascinating example of convergent evolution across multiple phenotypic levels driven by selection for defense.

Anticoagulant Activity of Naja nigricollis Venom Is Mediated by Phospholipase A2 Toxins and Inhibited by Varespladib

“…Cytotoxic three-finger toxins (3FTxs) from N. atra and N. kaouthia venoms have been demonstrated to lyse erythrocytes [ 26 ], while the cytotoxic 3FTx complex hemextin AB identified from the venom of the closely related species Hemachatus haemachatus has been shown to inhibit the activity of the coagulation component factor VIIa [ 27 ]. The apparent synergy between PLA 2 s and 3FTxs in N. mossambica and H. haemachatus venom has been found to increase the potency of haemolytic venom activity [ 28 ], and perhaps cytolysis in general [ 29 ]. Some snake venom serine proteases (SVSPs), though not typically a major constituent of elapid venoms [ 30 ], can contribute to coagulant activity through the activation of clotting factors V/Va and VIII/VIIIa, thereby acting in a procoagulant manner [ 31 ].…”

“…Finally, snake venom metalloproteinases (SVMPs) from N. naja venom have been found to cause delays in clotting time through the hydrolysis of haemoglobin [ 33 ]. However, in combination, 3FTxs, PLA 2 s and SVMPs typically account for >95% of the total toxin content of the majority of cobra venoms [ 29 ], and thus identifying the key toxins responsible for anticoagulant venom effects remains challenging. Nonetheless, a recent study showed that the PLA 2 inhibitor varespladib was capable of effectively neutralising the anticoagulant activity of many Afro-Asian elapids, including N. nigricollis [ 34 ], suggesting that this toxin family may be of greatest importance.…”

“…The venom of N. nigricollis , like many elapid snakes [ 30 ], is predominantly composed of 3FTxs and PLA 2 s [ 29 , 35 ]. Crude N. nigricollis venom shows the ability to cleave fibrinogen [ 36 ] and inhibit platelet aggregation [ 37 ], but the primary toxin thought to be responsible for anticoagulation appears to be a multifunctional PLA 2 named “CM-IV”.…”

Duvernoy’s Gland Transcriptomics of the Plains Black-Headed Snake, Tantilla nigriceps (Squamata, Colubridae): Unearthing the Venom of Small Rear-Fanged Snakes

“…Venom has independently evolved over 100 times across the Tree of Life, amounting to more than 200,000 species which use this protein and peptide mixture for prey capture and predator defense [ 1 , 2 , 3 , 4 ]. Snakes have evolved several different venom delivery systems primarily for prey capture [ 5 , 6 ].…”

Special Issue: Evolutionary Ecology of Venom

“…Using a large sample of envenomations by a wide range of snakes, and the assumption that defensive venoms should invoke early pain to deter predators before damage is inflicted, Ward-Smith et al [ 19 ] tested the hypothesis that the defensive function has been important in venom evolution. They found no evidence that defense has been a pervasive influence in the evolution of venom in snakes overall, although interesting exceptions present fruitful avenues for further research [ 20 ].…”