Restriction and recruitment-gene duplication and the origin and evolution of snake venom toxins.
Bottom Line: Our comparative transcriptomic analysis of these data reveals that snake venom does not evolve through the hypothesized process of duplication and recruitment of genes encoding body proteins.Thus, snake venom evolves through the duplication and subfunctionalization of genes encoding existing salivary proteins.These results highlight the danger of the elegant and intuitive "just-so story" in evolutionary biology.
Affiliation: School of Biological Sciences, Bangor University, United Kingdom.Show MeSH
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Mentions: Eukaryotic transcription factor binding sites are the result of a trade-off between the specificity offered by longer stretches of DNA and the robustness to mutation offered by shorter sequences and vary in length between 5 and greater than 30 nt, with an average length of 10 nt (Stewart et al. 2012). It has been estimated that eukaryotic promoters may contain 10–50 binding sites for 5–15 different transcription factors (Wray et al. 2003). The rarity of gene duplication, coupled with the low likelihood of evolving new combinations of transcription factor binding sites before the duplicated gene is nonfunctionalized by random mutations in coding sequences, should therefore make the process of duplication and recruitment of genes encoding physiological or body proteins into the venom gland exceedingly rare. How then do we reconcile this with the apparent widespread occurrence of this very process in the origin and evolution of snake venom? One possible alternative hypothesis is that many of the genes expressed in snake venom are in fact the result of the duplication of genes that were ancestrally expressed in multiple tissues, including the venom gland. Therefore following duplication these genes evolved through subfunctionalization, with one copy’s expression being restricted to the venom gland and the other maintaining the original, multi-tissue expression pattern (possibly with subsequent loss of expression of this paralog in the venom gland). This scenario of duplication and restriction, rather than duplication and recruitment (fig. 1) is more parsimonious as it requires only the loss of transcription factor binding sites, which may occur by random mutation of single base pairs or larger insertions or deletions (indels) that may delete or disrupt the existing transcriptional regulatory sequences. In order to differentiate between the two hypotheses gene expression data from nonvenom gland tissues in venomous and nonvenomous species are needed, something which has until now been missing. Here, we review the existing evidence for the duplication and recruitment of genes into the venom gland and carry out a comparative transcriptomic survey of gene expression in the venom glands and body tissues of a number of reptile species, including the painted saw-scaled viper (Echis coloratus), a medically important viperid with highly toxic venom; the corn snake (Pantherophis guttatus) a nonvenomous colubrid that kills its prey through constriction; the rough green snake (Opheodrys aestivus) a nonvenomous colubrid that grasps prey and simply swallows it; the royal or ball python (Python regius), a nonvenomous pythonid and member of the “primitive” superfamily, Henophidia, and the leopard gecko (Eublepharis macularius, Gekkonidae), a lizard that belongs to one of the most basal lineages of squamate reptiles. The phylogenetic position of Eu. macularius is particularly important, as it lies outside of the proposed clade of ancestrally venomous reptiles the “Toxicofera” (Vidal and Hedges 2005; Fry et al. 2006, 2013; Fry, Vidal, et al. 2009; Fry, Casewell, et al. 2012). Therefore, genes found in the salivary gland of this species can be taken to represent the ancestral squamate expression pattern. We also take advantage of available transcriptomic resources for body tissues in a number of other reptile species, including king cobra (Ophiophagus hannah) venom gland, accessory gland and pooled tissues (heart, lung, spleen, brain, testes, gall bladder, pancreas, small intestine, kidney, liver, eye, tongue, and stomach) (Vonk et al. 2013), garter snake (Thamnophis elegans) liver (Schwartz and Bronikowski 2013) and pooled tissue (brain, gonads, heart, kidney, liver, spleen and blood of males and females) (Schwartz et al. 2010), Burmese python (Python molurus bivittatus) pooled heart and liver (Castoe et al. 2011) and corn snake brain (Tzika et al. 2011).Fig. 1.—
Affiliation: School of Biological Sciences, Bangor University, United Kingdom.