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RAVER in animal venoms. Three-dimensional homology models of various animal venom components depicting their molecular surface variability are presented. A color code is provided to depict sites experiencing evolutionary hypervariability and conservation. Positively selected sites are indicated in red  

RAVER in animal venoms. Three-dimensional homology models of various animal venom components depicting their molecular surface variability are presented. A color code is provided to depict sites experiencing evolutionary hypervariability and conservation. Positively selected sites are indicated in red  

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Understanding the nature and strength of natural selection that influences the evolution of genes is one of the major aspects of modern evolutionary biological studies. Animal venoms are complex cocktails of biologically active compounds that are secreted in a specialized gland and actively delivered to the target animal through the infliction of a...

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Understanding the nature and strength of natural selection that influences the evolution of genes is one of the major aspects of modern evolutionary biological studies. Animal venoms are complex cocktails of biologically active compounds that are secreted in a specialized gland and actively delivered to the target animal through the infliction of a...
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Toxin synergism is a complex biochemical phenomenon, where different animal venom proteins interact either directly or indirectly to potentiate toxicity to a level that is above the sum of the toxicities of the individual toxins. This provides the animals possessing venoms with synergistically enhanced toxicity with a metabolic advantage, since les...

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... Given that venom targets basal physiological processes such as the coagulation cascade (Serrano 2013) and neurotransmission sites (Fry et al. 2009), it may be that relatively few amino acid substitutions can refine venom targeting for divergent prey tissues. The further divergence in more ancient paralogs may reflect the combined effects of neutral evolution (Aird et al. 2017) and refinements to protein function not tied to prey specificity, such as structural stability of the protein (Sunagar et al. 2014), neofunctionalization for novel physiological targets (Whittington et al. 2018), and modifications during pairwise coevolution to avoid inhibitor molecules of resistant prey (Holding, Biardi, et al. 2016;Margres, Bigelow, et al. 2017). Broadly, diet expansion appears possible through sequence variation derived from multiple possible pathways rather than any specific type of variation. ...
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Understanding the joint roles of amino acid sequences variation of proteins and differential expression during adaptive evolution is a fundamental, yet largely unrealized, goal of evolutionary biology. Here, we use phylogenetic path analysis to analyze a comprehensive venom gland transcriptome dataset spanning three genera of pitvipers to identify the functional genetic basis of a key adaptation (venom complexity) linked to diet breadth. Analysis of gene family-specific patterns reveal that, for genes encoding two of the most important venom proteins (SVMPs and SVSPs), there are direct, positive relationships between sequence diversity, evenness of expression, and increased diet breadth. Further analysis of gene family diversification for these proteins showed no constraint on how individual lineages achieved toxin gene sequence diversity in terms of patterns of paralog diversification. In contrast, another major venom protein family (PLA2s) showed no relationship between venom molecular diversity and diet breadth. Additional analyses suggest that other molecular mechanisms-such as higher absolute levels of expression-are responsible for diet adaptation involving these venom proteins. Broadly, our findings argue that functional diversity generated through sequence and expression variation determine adaptation in key components of pitviper venoms, which mediate complex molecular interactions between the snakes and their prey.
... JFT gene duplication and subsequent alteration of function is consistent with previous studies that show venom genes can evolve through the duplication of physiologically important and conserved gene families, which undergo subfunctionalization (partition of ancestral function) or neofunctionalization (obtaining a new function) through various molecular evolutionary mechanisms (Sunagar et al. 2014). Previous work on anthozoans has shown that duplication plays an important role in the venom repertoire of this cnidarian group (Gacesa et al. 2015;Surm et al. 2019), and that duplicated toxins with similar or newly evolved functions may become differentially expressed in distinct tissues and/or across life stages (e.g., Surm et al. 2019). ...
... Our selection analyses suggest that the JFT family overall is under the influence of purifying (negative) selection across the JFT phylogeny and within individual JFT clades ( fig. 4) according to dN/dS calculations, which is consistent with previous studies that had lower taxonomic sampling for JFTs (Jouiaei, Sunagar, et al. 2015;Surm et al. 2019). Negative selection pressure can easily be explained by the functional constraint of these proteins to create cell membrane pores (Anderluh and Lakey 2008;Peraro and van der Goot 2016), and negative selection is generally observed across toxin families of early diverging venomous animals (Sunagar et al. 2014;Sunagar and Moran 2015). However, our expectation was that while purifying, selection may be occurring broadly across JFT sequences, a subset of genes (i.e., sites) along a subset of lineages may be undergoing positive selection, referred to as episodic positive selection (Murrell et al. 2012). ...
... Because the signal peptide region is under different selection regimes than the mature toxin sequences, the predicted signal peptide region was removed from putative JFTs prior to selection analyses (Sunagar et al. 2014). The overall synonymous to nonsynonymous substitutions (dN/dS) ratio values were evaluated using Analyze Codon Data analysis (hyphy acd, model ¼ MG94CUSTOMCF3X4) from HyPhy using all sequences for each data set derived from the phylogenetic analyses (i.e., JFT1, JFT2, JFT1b, JFT1c, and all JFTs). ...
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Many jellyfish species are known to cause a painful sting, but box jellyfish (class Cubozoa) are a well-known danger to humans due to exceptionally potent venoms. Cubozoan toxicity has been attributed to the presence and abundance of cnidarian specific pore-forming toxins called jellyfish toxins (JFTs), which are highly hemolytic and cardiotoxic. However, JFTs have also been found in other cnidarians outside of Cubozoa, and no comprehensive analysis of their phylogenetic distribution has been conducted to date. Here, we present a thorough annotation of jellyfish toxins from 147 cnidarian transcriptomes, and document 111 novel putative JFTs from over 20 species within Medusozoa. Phylogenetic analyses show that JFTs form two distinct clades, which we call JFT-1 and JFT-2. JFT-1 includes all known potent cubozoan toxins, as well as hydrozoan and scyphozoan representatives, some of which were derived from medically-relevant species. JFT-2 contains primarily uncharacterized jellyfish toxins. While our analyses detected broad purifying selection across JFTs, we found that a subset of cubozoan JFT-1 sequences are influenced by gene-wide episodic positive selection when compared to homologous toxins from other taxonomic groups. This suggests duplication followed by neofunctionalization or subfunctionalization as a potential mechanism for the highly potent venom in cubozoans. Additionally, published RNA-seq data from several medusozoan species indicates that JFTs are differentially expressed, spatially and temporally, between functionally distinct tissues. Overall, our findings suggest a complex evolutionary history of jellyfish toxins involving duplication and selection that may have led to functional diversification, including variability in toxin potency and specificity.
... Given their medical importance, snake venoms have fascinated humans since time immemorial, and have been extensively studied to date. Animal venoms can be chemically constituted by proteins, amino acids, carbohydrates, salts, and polyamines [1]. Snake venoms, however, are primarily proteinaceous. ...
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Snakebite is a neglected tropical disease that inflicts severe socioeconomic burden on developing countries by primarily affecting their rural agrarian populations. India is a major snakebite hotspot in the world, as it accounts for more than 58,000 annual snakebite mortalities and over three times that number of morbidities. The only available treatment for snakebite is a commercially marketed polyvalent antivenom, which is manufactured exclusively against the 'big four' Indian snakes. In this review, we highlight the influence of ecology and evolution in driving inter- and intra-specific venom variations in snakes. We describe the repercussions of this molecular variation on the effectiveness of the current generation Indian antivenoms in mitigating snakebite pathologies. We highlight the disturbing deficiencies of the conventional animal-derived antivenoms, and review next-generation recombinant antivenoms and other promising therapies for the efficacious treatment of this disease.
... Venom is an adaptive trait that has evolved multiple times across the animal kingdom to facilitate various ecological functions, including defence, predation, competition, or a combination thereof [1][2][3][4]. Given their medical relevance to humans in the form of snakebite, and the tremendous biodiscovery potential of their toxic molecules, snake venoms have received unparalleled research attention. ...
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Background Snake venom composition is dictated by various ecological and environmental factors, and can exhibit dramatic variation across geographically disparate populations of the same species. This molecular diversity can undermine the efficacy of snakebite treatments, as antivenoms produced against venom from one population may fail to neutralise others. India is the world’s snakebite hotspot, with 58,000 fatalities and 140,000 morbidities occurring annually. Spectacled cobra ( Naja naja ) and Russell’s viper ( Daboia russelii ) are known to cause the majority of these envenomations, in part due to their near country-wide distributions. However, the impact of differing ecologies and environment on their venom compositions has not been comprehensively studied. Methods Here, we used a multi-disciplinary approach consisting of venom proteomics, biochemical and pharmacological analyses, and in vivo research to comparatively analyse N . naja venoms across a broad region (>6000 km; seven populations) covering India’s six distinct biogeographical zones. Findings By generating the most comprehensive pan-Indian proteomic and toxicity profiles to date, we unveil considerable differences in the composition, pharmacological effects and potencies of geographically-distinct venoms from this species and, through the use of immunological assays and preclinical experiments, demonstrate alarming repercussions on antivenom therapy. We find that commercially-available antivenom fails to effectively neutralise envenomations by the pan-Indian populations of N . naja , including a complete lack of neutralisation against the desert Naja population. Conclusion Our findings highlight the significant influence of ecology and environment on snake venom composition and potency, and stress the pressing need to innovate pan-India effective antivenoms to safeguard the lives, limbs and livelihoods of the country’s 200,000 annual snakebite victims.
... Poisons, for example, are toxins that must be ingested, inhaled, or absorbed through the skin to harm their targets, while venoms inflict damage by being injected via a bite or a sting [1,2]. Furthermore, venoms, although implicated in a range of functions from being antimicrobial [3] to aiding in intrasexual combat [4], are typically classified as serving either to increase the feeding efficiency of the venomous animal or in deterring that animal's own enemies; i.e., in the binary roles of predation or defense [5][6][7][8][9]. These dual selection pressures have been compared broadly across taxonomic groups, with predation frequently cited as driving venom evolution and venom variability in cone snails [10,11] and snakes [12][13][14] (but see [15,16]), while predator deterrence is typically invoked to explain the venoms of echinoderms [17], bony fishes, and rays [18]. ...
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Pain, though unpleasant, is adaptive in calling an animal’s attention to potential tissue damage. A long list of animals representing diverse taxa possess venom-mediated, pain-inducing bites or stings that work by co-opting the pain-sensing pathways of potential enemies. Typically, such venoms include toxins that cause tissue damage or disrupt neuronal activity, rendering painful stings honest indicators of harm. But could pain alone be sufficient for deterring a hungry predator? Some venomologists have argued “no”; predators, in the absence of injury, would “see through” the bluff of a painful but otherwise benign sting or bite. Because most algogenic venoms are also toxic (although not vice versa), it has been difficult to disentangle the relative contributions of each component to predator deterrence. Southern grasshopper mice (Onychomys torridus) are voracious predators of arthropods, feeding on a diversity of scorpion species whose stings vary in painfulness, including painful Arizona bark scorpions (Centruroides sculpturatus) and essentially painless stripe-tailed scorpions (Paravaejovis spinigerus). Moreover, southern grasshopper mice have evolved resistance to the lethal toxins in bark scorpion venom, rendering a sting from these scorpions painful but harmless. Results from a series of laboratory experiments demonstrate that painful stings matter. Grasshopper mice preferred to prey on stripe-tailed scorpions rather than bark scorpions when both species could sting; the preference disappeared when each species had their stingers blocked. A painful sting therefore appears necessary for a scorpion to deter a hungry grasshopper mouse, but it may not always be sufficient: after first attacking and consuming a painless stripe-tailed scorpion, many grasshopper mice went on to attack, kill, and eat a bark scorpion even when the scorpion was capable of stinging. Defensive venoms that result in tissue damage or neurological dysfunction may, thus, be required to condition greater aversion than venoms causing pain alone.
... Venom evolution is assumed to be a key innovation that led to the evolutionary success 689 of venomous animal lineages (Pyron & Burbrink 2011;Sunagar et al. 2016) and a large body of 690 work is devoted towards understanding how venom evolves and responds to the environment 691 over time (Kordis & Gubensek 2000;Wong & Belov 2012;Casewell et al. 2013). However, the ...
... Venom is amongst such fascinating traits that has driven the predatory success of several lineages across the animal kingdom Fry et al., 2009a;Suranse et al., 2018). It is a complex cocktail of organic and inorganic compounds (e.g., peptides, polyamines, proteins, and salts) that is secreted in venom glands or venom producing cells, as in the case of cnidocytes in Cnidaria, and is distinguished from poisons in being actively delivered through a specialised apparatus to facilitate several quotidian functions of venomous organisms (Fry et al., 2009a;Sunagar et al., 2016). Research on venoms has advanced our understanding of the molecular mechanisms underlying the origin of new protein functions (neofunctionalization), diversification of multigene families, evolutionary dynamics of protein families, and coevolutionary biochemical arms races between prey and predatory animals (Brust et al., 2013;Casewell et al., 2011Casewell et al., , 2012Holding et al., 2016;Jansa and Voss, 2011;Martinson et al., 2017;Sunagar et al., 2013a;Vonk et al., 2013). ...
Article
Comprising of over a million described species of highly diverse invertebrates, Arthropoda is amongst the most successful animal lineages to have colonized aerial, terrestrial, and aquatic domains. Venom, one of the many fascinating traits to have evolved in various members of this phylum, has underpinned their adaptation to diverse habitats. Over millions of years of evolution, arthropods have evolved ingenious ways of delivering venom in their targets for self-defence and predation. The morphological diversity of venom delivery apparatus in arthropods is astounding, and includes extensively modified pedipalps, tail (telson), mouth parts (hypostome), fangs, appendages (maxillulae), proboscis, ovipositor (stinger), and hair (urticating bristles). Recent investigations have also unravelled an astonishing venom biocomplexity with molecular scaffolds being recruited from a multitude of protein families. Venoms are a remarkable bioresource for discovering lead compounds in targeted therapeutics. Several components with prospective applications in the development of advanced lifesaving drugs and environment friendly bio-insecticides have been discovered from arthropod venoms. Despite these fascinating features, the composition, bioactivity, and molecular evolution of venom in several arthropod lineages remains largely understudied. This review highlights the prevalence of venom, its mode of toxic action, and the evolutionary dynamics of venom in Arthropoda, the most speciose phylum in the animal kingdom.
... Several theories have been proposed to explain the molecular mechanisms that underpin the diversification of venoms. Venoms are generally known to experience 'positive Darwinian selection', which is characterised by the relatively increased accumulation of nonsynonymous mutations (or nucleotide substitutions that change the amino acid sequence) to synonymous mutations (or nucleotide substitutions that do not change the coded amino acid sequence) (Sunagar et al., 2016). Certain authors have speculated the role of DNA (deoxyribonucleic acid) polymerase as a 'mutase', resulting in an increased mutation rate in venom coding genes and, thus, driving the diversification of venom compositions -although, there is no evidence to support this. ...
Chapter
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Venomous animals and their venoms have intrigued mankind for millennia. Venoms are complex cocktails of chemically diverse components that disrupt the physiological functioning of the victim to aid the venom‐producing animal in defence and/or feeding. Despite evolving independently on at least 30 occasions in the animal kingdom, venom exhibits remarkable evolutionary convergence, both in composition and biochemical activity. Various factors, including geography, diet, predator pressure, evolutionary arms race and phylogenetic history, underpin the diversification of venoms. Certain venomous animals, particularly snakes, are medically important and are responsible for tens of thousands of permanent loss‐of‐function injuries and deaths in humans every year. At the same time, as venom harbours many bioactive and highly specific components, it has tremendous potential applications in the development of novel lifesaving therapeutics and environment‐friendly agrochemicals. Several wonder drugs based on venom proteins have saved millions of lives worldwide, and many others are in development. Key Concepts • Venom has evolved independently ∼30 times in the animal kingdom to assist the venom‐producing animal in self‐defence and/or prey capture. • A remarkable convergence can be observed in the composition and bioactivity of venoms. • While most animals modified their salivary glands into venom glands, the duck‐billed platypus and echidna evolved venom glands through the evolutionary tinkering of sweat glands. • Cnidarians evolved peculiar cell types to inject venom into their victims, while many hymenopterans have modified their ovipositors for venom injection. • The strong influence of positive Darwinian selection has driven the evolutionary diversification of venoms, while the structural integrity is conserved by purifying selection.
... The effectiveness of the process is linked to the effective population size, as in small populations the chances of fixation or elimination by random fluctuation are higher than in large ones. Luckily, more biologically realistic methods that are capable of detecting such episodes of selection at individual sites and/or lineages have been developed and are being constantly refined (e.g., the plethora of methods available in the HyPhy package (Kosakovsky Pond et al. 2005;Murrell et al. 2015)) and are now being applied to toxin evolution (Sunagar et al. 2015). ...
Chapter
Toxins represent one of the fastest evolving types of protein to be found in animal systems, sharing many of their features with other protein families that respond to extrinsic factors, such as those involved in immunity, and detecting and responding to the environment in which they live. However, studies on toxin genes have been lagging behind those on other gene families as until very recently, no fully sequenced genomes from venomous animals have been available. In this chapter, the molecular forces acting on toxin gene sequences are compared to those acting on other non-toxin genes, addressing in particular several features that have been stressed in the toxinological literature, i.e., their hypervariability, accelerated evolution, and apparent focal mutagenesis centering on the active site of the toxins. The accepted paradigm that the birth-and-death model underlies toxin multigene family evolution is challenged by studies that show both concerted evolution and birth-and-death can give rise to similar patterns following gene duplication and that both models may operate simultaneously. Much of the dynamics of gene duplication and the fate of duplicated genes seem to depend on the genomic and biological context in which they occur. Therefore, there is no reason to expect toxin-encoding genes from diverse animal groups to show common mechanisms of evolution.
... Venom is a hallmark example of animal evolution: the capacity to make and use toxins has arisen via natural selection multiple times in animals as diverse as corals, snails, spiders, snakes, and mammals (Casewell et al. 2013). This diversity within the animal tree of life is mirrored by diversity at the molecular and genetic level, as the proteins that make up venoms and the genes that specify these proteins evolve rapidly to fill diverse functional roles (Sunagar et al. 2016). Because of their remarkable molecular diversity, venoms are key, albeit challenging, resource for pharmacological discovery that contribute to the development of drugs that act as anti-tumor agents, heart stimulants, and therapies for neurological diseases (Harvey 2014). ...
... The biochemical diversity of venoms poses a compelling system in which to understand the genetic and molecular origin of diversity and the ecological and evolutionary impact of this diversity (Sunagar et al. 2016). This is best understood for snakes and other lineages which have been more completely studied because they have a direct impact on human health. ...