Loss of a major venom toxin gene in a Western Diamondback rattlesnake population

The biochemical complexity and evolutionary diversity of snake venom composition reflects adaptation to the diversity of prey in their diets. However, the genetic mechanisms underlying the origins of this molecular diversity are not well understood. Here, we explored the potential extent of and genetic basis for venom protein variation in the widely-distributed Western Diamondback rattlesnake (Crotalus atrox). As in many rattlesnake venoms, metalloproteinases (SVMPs) are the major component of C. atrox venom, with three proteins belonging to three distinct major structural SVMP classes, MDC4, MAD3a, and MPO1, constituting the most abundant SVMPs. We found that while most venom proteins, including MDC4 and MAD3a, vary little among individuals, the MPO1 protein is completely absent from some animals, most commonly those from the western part of the species' geographic range. This distribution correlates with the previous finding of two distinct lineages within C. atrox and indicates that different ecological factors have shaped venom composition across the species' range. We further show that the loss of MPO1 expression is not due to down-regulation, but to independent inactivating mutations including whole gene deletions. The recurrent inactivation of a major toxin gene within a C. atrox subpopulation may reflect not only relaxed selection on the maintenance of MPO1 function, but that the loss of venom components may be favored if there is a metabolic cost to producing an ineffective toxin.