Monkeying around with venom: an increased resistance to α-neurotoxins supports an evolutionary arms race between Afro-Asian primates and sympatric cobras

Abstract

Background: Snakes and primates have a multi-layered coevolutionary history as predators, prey, and competitors with each other. Previous work has explored the Snake Detection Theory (SDT), which focuses on the role of snakes as predators of primates and argues that snakes have exerted a selection pressure for the origin of primates' visual systems, a trait that sets primates apart from other mammals. However, primates also attack and kill snakes and so snakes must simultaneously avoid primates. This factor has been recently highlighted in regard to the movement of hominins into new geographic ranges potentially exerting a selection pressure leading to the evolution of spitting in cobras on three independent occasions.

Results: Here, we provide further evidence of coevolution between primates and snakes, whereby through frequent encounters and reciprocal antagonism with large, diurnally active neurotoxic elapid snakes, Afro-Asian primates have evolved an increased resistance to α-neurotoxins, which are toxins that target the nicotinic acetylcholine receptors. In contrast, such resistance is not found in Lemuriformes in Madagascar, where venomous snakes are absent, or in Platyrrhini in the Americas, where encounters with neurotoxic elapids are unlikely since they are relatively small, fossorial, and nocturnal. Within the Afro-Asian primates, the increased resistance toward the neurotoxins was significantly amplified in the last common ancestor of chimpanzees, gorillas, and humans (clade Homininae). Comparative testing of venoms from Afro-Asian and American elapid snakes revealed an increase in α-neurotoxin resistance across Afro-Asian primates, which was likely selected against cobra venoms. Through structure-activity studies using native and mutant mimotopes of the α-1 nAChR receptor orthosteric site (loop C), we identified the specific amino acids responsible for conferring this increased level of resistance in hominine primates to the α-neurotoxins in cobra venom.

Conclusion: We have discovered a pattern of primate susceptibility toward α-neurotoxins that supports the theory of a reciprocal coevolutionary arms-race between venomous snakes and primates.

Keywords: Evolution; Neurotoxin; Primate; Resistance; Venom.

Fig. 1.

The effects of venom from the representative African cobra Naja mossambica against the nAChR orthosteric site mimotopes from seven clades of primates (see Additional file 1 for other African cobra species with congruent results). A Ancestral state reconstruction of the area under the curve (AUC) values of the binding of N. mossambica against the primate mimotopes. B Bar graphs represent the mean AUC values of the adjacent curve graphs. Statistical significance is indicated by matching letters with the colors of letter indicating the level of significance; brown p< 0.001, green p< 0.01, pink p< 0.05. C Curve graphs show the mean wavelength shift (nm) in light with binding of venoms over a 120-s association phase. The venom was tested in triplicate (n=3). Error bars on all graphs represent the SEM. AUC values were statistically analyzed using a one-way ANOVA with a Tukey’s comparisons multiple comparisons test comparing to the native mimotope. All raw data and statistical analyses outputs can be found in Additional file 2

Fig. 2.

The effects of venom from the Asian cobra Naja siamensis against the nAChR orthosteric site mimotopes from seven clades of primates (see additional file 1 for other Asian cobra species with congruent results). A Ancestral state reconstruction of the area under the curve (AUC) values of the binding of N. siamensis against the primate mimotopes. B Bar graphs represent the mean AUC values of the adjacent curve graphs. Statistical significance is indicated by matching letters with the colors of letter indicating the level of significance; brown p< 0.001, green p< 0.01, pink p< 0.05. C Curve graphs show the mean wavelength shift (nm) in light with binding of venoms over a 120-s association phase. The venom was tested in triplicate (n=3). Error bars on all graphs represent the SEM. AUC values were statistically analyzed using a one-way ANOVA with a Tukey’s comparisons multiple comparisons test comparing to the native mimotope. All raw data and statistical analyses outputs can be found in Additional file 2

Fig. 3.

The effects of venom from the American coral snake Micrurus browni against the nAChR orthosteric site mimotopes from seven clades of primates. A Ancestral state reconstruction of the area under the curve (AUC) values of the binding of M. browni against the primate mimotopes. B Bar graphs represent the mean AUC values of the adjacent curve graphs. C Curve graphs show the mean wavelength shift (nm) in light with binding of venoms over a 120-s association phase. The venom was tested in triplicate (n=3). Error bars on all graphs represent the SEM. No statistical significance was detected using a one-way ANOVA. All raw data and statistical analyses outputs can be found in Additional file 2

Fig. 4.

The effects of venom from the American coral snake Micrurus corallinus against the nAChR orthosteric site mimotopes from seven clades of primates. A Ancestral state reconstruction of the area under the curve (AUC) values of the binding of M. corallinus against the primate mimotopes. B Bar graphs represent the mean AUC values of the adjacent curve graphs. C Curve graphs show the mean wavelength shift (nm) in light with binding of venoms over a 120-s association phase. The venom was tested in triplicate (n=3). Error bars on all graphs represent the SEM. AUC values were statistically analyzed using a one-way ANOVA with a Tukey’s comparisons multiple comparisons test comparing to the native mimotope. A statistical significance is indicated by matching letters with the colors of letter indicating the level of significance; pink p< 0.01. All raw data and statistical analyses outputs can be found in Additional file 2

Fig. 5.

The effects of venom from a representative African cobra species (Naja mossambica) and a representative Asian cobra species (N. siamensis) against native and mutant Homininae mimotope sequences. A Amino acid sequences of native and mutant mimotopes. B Bar graphs represent the mean area under the curve (AUC) values of the adjacent curve graphs. Curve graphs show the mean wavelength (nm) shift in light with increased binding of venoms over a 120-s association phase. Each venom was tested in triplicate (n=3). Error bars on all graphs represent the SEM. AUC values were statistically analyzed using a one-way ANOVA with a Dunnett’s multiple comparisons post hoc test comparing to the native mimotope. A statistical significance is annotated above bars by ** (p< 0.01), *** (p< 0.001), or **** (p< 0.0001). All raw data and statistical analyses outputs can be found in Additional file 2