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... Show moreConvergence 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. Show less
We have examined sequences from the ligand-binding domain of the nicotinic acetyl choline receptor (nAChR) in 148 vertebrate species. We are in interested in this receptor because the α-neurotoxins... Show moreWe have examined sequences from the ligand-binding domain of the nicotinic acetyl choline receptor (nAChR) in 148 vertebrate species. We are in interested in this receptor because the α-neurotoxins of many venomous snakes binds to this receptor in its location at the neuromuscular junction in all vertebrates. Furthermore, some animals have evolved resistance to snake venoms and show modifications in the ligand binding domain of the nAChR which inhibit the binding of snake α-neurotoxins. Our analysis has shown that numerous vertebrate species, most of which were not previously known to possess α-neurotoxin resistance, do actually contain resistance-related modifications. These modifications are present in most of the taxa in our dataset, with the unexpected exclusion of the birds. It was particularly surprising to us that the snake-specialist predatory birds Circaetus pectoralis (black-chested snake eagle) and Sagittarius serpentarius (secretary bird) did not possess resistance modifications. There were also relatively few resistance-related mutations within the mammals. By contrast, there were multiple convergent evolutions of the well-characterised N-glycosylation motif within the squamate reptiles—particularly the snakes. We also identified a number of sites under positive selection, such as mutations to the proline subsite. Future functional testing will be needed to validate that these modifications do indeed confer resistance. To provide functional confirmation that resistance-related modifications do indeed reduce susceptibility to toxins, we used developmental bioassays. These assays showed that two species possessing resistance-related modifications of the nAChR (stickleback and bearded dragon) were less susceptible to the toxic effects of cobra venom than two species that lacked such modifications (zebrafish and chicken). In summary, we demonstrate that the range of mechanisms along with the phylogenetic distribution of resistance to snake α-neurotoxin appears to be more extensive than was previously appreciated. It also shows strong evidence of the convergent evolution of the same resistance mutations in independent linages. Our findings also support the notion that the mutations we have identified in this thesis may represent adaptive change in response to selective pressures exerted by α-neurotoxic snake venoms in an evolutionary arms race. Thus, we conclude that the evolutionary arms race between predator and prey appears to be a pervasive feature of the trophic interactions surrounding venomous snakes, which is shaping the molecular evolution of the nAChR in the vertebrates. Show less
Venomous snakes are important subjects of study in evolution, ecology, and biomedicine. Many venomous snakes have alpha-neurotoxins (alpha-neurotoxins) in their venom. These toxins bind the alpha-1... Show moreVenomous snakes are important subjects of study in evolution, ecology, and biomedicine. Many venomous snakes have alpha-neurotoxins (alpha-neurotoxins) in their venom. These toxins bind the alpha-1 nicotinic acetylcholine receptor (nAChR) at the neuromuscular junction, causing paralysis and asphyxia. Several venomous snakes and their predators have evolved resistance to alpha-neurotoxins. The resistance is conferred by steric hindrance from N-glycosylated asparagines at amino acids 187 or 189, by an arginine at position 187 that has been hypothesized to either electrostatically repulse positively charged neurotoxins or sterically interfere with alpha-neurotoxin binding, or proline replacements at positions 194 or 197 of the nAChR ligand-binding domain to inhibit alpha-neurotoxin binding through structural changes in the receptor. Here, we analyzed this domain in 148 vertebrate species, and assessed its amino acid sequences for resistance-associated mutations. Of these sequences, 89 were sequenced de novo. We find widespread convergent evolution of the N-glycosylation form of resistance in several taxa including venomous snakes and their lizard prey, but not in the snake-eating birds studied. We also document new lineages with the arginine form of inhibition. Using an in vivo assay in four species, we provide further evidence that N-glycosylation mutations reduce the toxicity of cobra venom. The nAChR is of crucial importance for normal neuromuscular function and is highly conserved throughout the vertebrates as a result. Our research shows that the evolution of alpha-neurotoxins in snakes may well have prompted arms races and mutations to this ancient receptor across a wide range of sympatric vertebrates. These findings underscore the inter-connectedness of the biosphere and the ripple effects that one adaption can have across global ecosystems. Show less
This first up date of the ASAS/EULAR recommendations on the management of ankylosing spondylitis (AS) is based on the original paper, a systematic review of existing recommendations and the... Show moreThis first up date of the ASAS/EULAR recommendations on the management of ankylosing spondylitis (AS) is based on the original paper, a systematic review of existing recommendations and the literature since 2005 and the discussion and agreement among 21 international experts, 2 patients and 2 physiotherapists in a meeting in February 2010. Each original bullet point was discussed in de tail and reworded if necessary. Decisions on new recommendations were made - if necessary after voting. The strength of the recommendations (SOR) was scored on an 11-point numerical rating scale after the meeting by email. These recommendations apply to patients of all ages that fulfill the modified NY criteria for AS, independent of extra-articular manifestations, and they take into account all drug and non-drug interventions related to AS. Four overarching principles were introduced, implying that one bullet has been moved to this section. There are now 11 bullet points including 2 new ones, one related to extra-articular manifestations and one to changes in the disease course. With a mean score of 9.1 (range 8-10) the SOR was generally very good. Show less
