The origin and diversification of a novel protein family in venomous snakes

Abstract

The genetic origins of novelty are a central interest of evolutionary biology. Most new proteins evolve from preexisting proteins but the evolutionary path from ancestral gene to novel protein is challenging to trace, and therefore the requirements for and order of coding sequence changes, expression changes, or gene duplication are not clear. Snake venoms are important novel traits that are comprised of toxins derived from several distinct protein families, but the genomic and evolutionary origins of most venom components are not understood. Here, we have traced the origin and diversification of one prominent family, the snake venom metalloproteinases (SVMPs) that play key roles in subduing prey in many vipers. Genomic analyses of several rattlesnake (Crotalus) species revealed the SVMP family massively expanded from a single, deeply conserved adam28 disintegrin and metalloproteinase gene, to as many as 31 tandem genes in the Western Diamondback rattlesnake (Crotalus atrox) through a number of single gene and multigene duplication events. Furthermore, we identified a series of stepwise intragenic deletions that occurred at different times in the course of gene family expansion and gave rise to the three major classes of secreted SVMP toxins by sequential removal of a membrane-tethering domain, the cysteine-rich domain, and a disintegrin domain, respectively. Finally, we show that gene deletion has further shaped the SVMP complex within rattlesnakes, creating both fusion genes and substantially reduced gene complexes. These results indicate that gene duplication and intragenic deletion played essential roles in the origin and diversification of these novel biochemical weapons.

Some like it hot: population-specific adaptations in venom production to abiotic stressors in a widely distributed cnidarian

“…These massive shifts in Nv1 expression may be driven in part by its high copy number resulting in the production of this essential toxin to be highly dynamic. Similar patterns may be observed in other venomous lineages that also exhibit highly expanded gene families encoding toxins, such as metalloproteinases in rattlesnakes [40]. The investment of energy into heat response (e.g., production of numerous heat shock proteins, HSPs) appears to be traded-off with other high-cost physiological processes that do not contribute to survival under heat stress (e.g., venom production).…”

“…The investment of energy into heat response (e.g., production of numerous heat shock proteins, HSPs) appears to be traded-off with other high-cost physiological processes that do not contribute to survival under heat stress (e.g., venom production). It is hypothesized in both sea anemones [27] and snakes [40] that selection is acting on the expansion of gene families encoding toxins to drive increased protein production. Additionally, this mechanism may also allow for drastic and rapid shifts in toxin expression to meet biotic and abiotic factors.…”

An ancient, conserved gene regulatory network led to the rise of oral venom systems

“…Increasing the number of gene copies, especially in venom systems are crucial to bringing about evolutionary novelty (2,31,32). The meta-venom in habu comprises genes that have many copies, which could have played a role in evolution of the venom system in snakes (Supplementary table 4).…”

“…Incorporation of novel toxins has occurred relatively infrequently, and the process remains poorly understood at the transcriptional level. For example, recent insights into the evolution of snake venom metalloproteinases found that they are related to the mammalian adam28 gene (32,71). This gene is expressed in many tissues, but only weakly in the salivary glands of some species (72), and, furthermore, it is a transmembrane rather than a secreted protein.…”

“…This gene is expressed in many tissues, but only weakly in the salivary glands of some species (72), and, furthermore, it is a transmembrane rather than a secreted protein. While the series of sequential deletions necessary for the protein sequence to acquire toxicity have been revealed (32), the corresponding changes in gene expression accompanying them remain a mystery. Similarly, while the origin of phospholipases A2 has been traced to a common amniote ancestor, the steps required for its neofunctionalization remain obscure(73).…”