Convergent evolution of toxin resistance in animals

Abstract

Convergence is the phenomenon whereby similar phenotypes evolve independently in different lineages. One example is resistance to toxins in animals. Toxins have evolved many times throughout the tree of life. They disrupt molecular and physiological pathways in target species, thereby incapacitating prey or deterring a predator. In response, molecular resistance has evolved in many species exposed to toxins to counteract their harmful effects. Here, we review current knowledge on the convergence of toxin resistance using examples from a wide range of toxin families. We explore the evolutionary processes and molecular adaptations driving toxin resistance. However, resistance adaptations may carry a fitness cost if they disrupt the normal physiology of the resistant animal. Therefore, there is a trade-off between maintaining a functional molecular target and reducing toxin susceptibility. There are relatively few solutions that satisfy this trade-off. As a result, we see a small set of molecular adaptations appearing repeatedly in diverse animal lineages, a phenomenon that is consistent with models of deterministic evolution. Convergence may also explain what has been called 'autoresistance'. This is often thought to have evolved for self-protection, but we argue instead that it may be a consequence of poisonous animals feeding on toxic prey. Toxin resistance provides a unique and compelling model system for studying the interplay between trophic interactions, selection pressures and the molecular mechanisms underlying evolutionary novelties.

Keywords: co-evolutionary arms races; convergent evolution; deterministic evolution; functional constraint; molecular adaptation; toxin resistance.

Fig. 1

Well‐known examples of ecological contexts underpinning toxin resistance. (A–C) predator resistance, where a predator is resistant to the toxins of its prey. (A) The mongoose is known to predate on true cobras. (B) The grasshopper mouse preys on bark scorpions. (C) Garter snakes prey on toxic newts. (D) Prey resistance is resistance of a prey species to the toxins of a predator and is exemplified here by rattlesnakes preying on North American ground squirrels. (E) Autoresistance is where an animal is resistant to its own toxins. The example shown here is of true cobras that show resistance to cobra α‐neurotoxins.

Fig. 2

Convergent evolution of α‐neurotoxin resistance in animals. (A) Schematic representation (based on Kini, 2019) of the α‐1 muscle‐type nicotinic acetylcholine receptor (nAChR). Red circles indicate the position of the ligand‐binding domain of α‐neurotoxins in the nAChR. (B) Protein topology of an α‐subunit and a non‐α‐subunit of the muscle‐type nAChR. A–F indicate the loop structures at the extracellular domain in the respective subunits (Rahman et al., 2020). The black circle indicates the C‐loop involved in α‐neurotoxin binding. (C) Sequence alignment of the α1‐nAChR ligand‐binding domain. The reference amino acid sequence is from humans (Homo sapiens) and differences from this sequence are displayed for all other species. Substitutions associated with resistance are highlighted in coloured font. The asterisk (*) in Varanus exanthematicus indicates that the two substitutions shown are associated with reduced binding affinity (Jones, Harris & Fry, 2021). Tree topology based on Khan et al. (2020). Sequence accession numbers are provided in Table S5.

Fig. 3

Morphological exaptations and behavioural traits proposed to negate selection pressures for evolving molecular resistance in snake‐eating birds such as the secretary bird (Sagittarius serpentarius). This figure represents multiple examples of traits unique to birds, and particularly to snake‐eating birds, that might contribute to the prevention of snakebite envenomation. Drawing from an original photograph by Jason Shallcross, with permission.

Fig. 4

Resistance against pain‐inducing scorpion venom in grasshopper mouse (Onychomys torridus). (A) Protein topology of voltage‐gated Na + channel (Na_v 1.8). The black circle indicates the outer pore associated with scorpion‐venom binding in the Na_v 1.8 channel. Structure based on Shen et al. (2017). (B) Partial sequence alignment of the outer pore of the α‐subunit of domain II of the Na_v 1.8 channel. The reference amino acid sequence is from humans (Homo sapiens) and differences from this sequence are displayed for all other species. Substitutions associated with resistance are highlighted in bold. Tree topology based on TimeTree.org (Kumar et al., 2017). For sequence accession numbers, see Table S6.

Fig. 5

Convergent evolution of guanidinium toxin resistance in animals. (A) Protein topology of the voltage‐gated Na⁺ channel, Na_v 1.4. The black circles indicate the outer pores involved in guanidinium toxin binding. Structure based on Shen et al. (2017). (B) Partial sequence alignments of the outer pores of the voltage‐gated Na + channel Na_v 1.4. The reference amino acid sequence is from humans (Homo sapiens) and differences from this sequence are displayed for all other species. Substitutions associated with resistance are highlighted in bold, and their respective amino‐acid positions are numbered based on Na_v 1.4 from Homo sapiens. Tree topology based on TimeTree.org (Kumar et al., 2017) and taxon‐specific phylogenies (Geffeney et al., ; Feldman et al., ; Hanifin & Gilly, 2015). Key for the Thamnophis sirtalis populations: B, Benton County; W, Warrenton; WC, Willow Creek. For sequence accession numbers, see Table S7.

Fig. 6

Convergent evolution of cardiac glycoside resistance in animals. (A) Protein topology of the sodium–potassium pump (Na⁺/K⁺‐ATPase). The black circle indicates the H1–H2 extracellular loop that is involved in cardiac glycoside binding. Structure based on Bagrov, Shapiro & Fedorova (2009). (B) Sequence alignment of the H1–H2 extracellular domain of Na⁺/K⁺‐ATPase. The reference amino acid sequence is from humans (Homo sapiens) and differences from this sequence are displayed for all other species. Substitutions associated with resistance are highlighted in bold. Tree topology based on TimeTree.org (Kumar et al., 2017) and taxon‐specific phylogenies (Dobler et al., ; Ujvari et al., ; Mohammadi et al., 2016). For sequence accession numbers, see Table S8.

Fig. 7

Convergent evolution of epibatidine resistance in poison dart frogs. (A) Schematic representation (based on Kini, 2019) of the neural‐type nicotinic acetylcholine receptor [nAChR; (α4)₂(β2)₃]. Red circles indicate the ligand‐binding domain of epibatidine in the nAChR. (B) Protein topology of the α4‐subunit and the β2‐subunit of the neural‐type nAChR. A–F indicate the loop structures at the extracellular domain in the respective subunits (Rahman et al., 2020). The black circle indicates the E‐loop involving the ligand‐binding domain of epibatidine. (C) Sequence alignment of the β2‐nAChR ligand‐binding domain. The reference amino acid sequence is from humans (Homo sapiens) and differences from this sequence are displayed for all other species. Substitutions associated with resistance are highlighted in bold. Tree topology based on Tarvin et al. (2017). For sequence accession numbers, see Table S9.

Fig. 8

Hypothesised convergent evolutionary scenarios for autoresistance in poisonous animals. It is generally assumed that autoresistance is a self‐protection phenomenon. Here, we propose a three‐step evolution scenario for the origins of autoresistance: (1) predator resistance, followed by (2) sequestration of the toxin by the predator, and (3) exploitation of the toxin for defence. As this figure indicates, a similar three‐step process can be seen in diverse lineages, suggesting evolutionary convergence. The displayed examples include (A) pufferfish (family Tetraodontidae) feeding on TTX‐bearing flatworms, gastropods and echinoderms, (B) herbivorous insects feeding on CG‐containing plants, (C, D) poison dart frogs (family Dendrobatidae) feeding on toxic arthropods, (E) pitohui birds (Pitohui spp.) feeding on (among others) BTX‐bearing melyrid beetles, and (F) keelback snakes (Rhabdophis spp.) feeding on CG‐bearing anuran amphibians. BTX, batrachotoxin; CG, cardiac glycosides; TTX, tetrodotoxin.