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1. Molecular mechanisms underlying intraspecific variation in snake venom

   Amazonas, DR (January 2018, Journal of proteomics)

   Understanding the molecular mechanisms that underlie snake venom variability provides important clues for understanding how the biological functions of this powerful toxic arsenal evolve. Here we analyzed in detail individual transcripts and venom protein isoforms produced by five specimens of a venomous snake (Bothrops atrox) from two nearby but genetically distinct populations from the Brazilian Amazon rainforest showing functional similarities in venom properties. Individual variation was observed among the venoms of these specimens, but the overall abundance of each general toxin family was conserved both in transcripts and in venom protein levels. However, when expression of independent paralogues was analyzed, remarkable differences were observed within and among each toxin group both between individuals and between populations. Transcripts for functionally essential venom proteins (“housekeeping” proteins) are highly expressed in all specimens and show similar transcription/translation rates. In contrast, other paralogues show lower expression levels and the toxins they code for vary among different individuals. These results provide support for the idea that that expression and translational differences play a greater role in defining adaptive variation in venom phenotypes than does sequence variation in protein coding genes and that convergent adaptive venom phenotypes can be generated through different molecular mechanisms. 

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2. Ontogenetic Change in the Venom of Mexican Black-Tailed Rattlesnakes (Crotalus molossus nigrescens)

   https://doi.org/10.3390/toxins10120501  

   Borja, Miguel; Neri-Castro, Edgar; Pérez-Morales, Rebeca; Strickland, Jason; Ponce-López, Roberto; Parkinson, Christopher; Espinosa-Fematt, Jorge; Sáenz-Mata, Jorge; Flores-Martínez, Esau; Alagón, Alejandro; et al (December 2018, Toxins)

   null (Ed.)

   Ontogenetic changes in venom composition have important ecological implications due the relevance of venom in prey acquisition and defense. Additionally, intraspecific venom variation has direct medical consequences for the treatment of snakebite. However, ontogenetic changes are not well documented in most species. The Mexican Black-tailed Rattlesnake (Crotalus molossus nigrescens) is large-bodied and broadly distributed in Mexico. To document venom variation and test for ontogenetic changes in venom composition, we obtained venom samples from twenty-seven C. m. nigrescens with different total body lengths (TBL) from eight states in Mexico. The primary components in the venom were detected by reverse-phase HPLC, western blot, and mass spectrometry. In addition, we evaluated the biochemical (proteolytic, coagulant and fibrinogenolytic activities) and biological (LD50 and hemorrhagic activity) activities of the venoms. Finally, we tested for recognition and neutralization of Mexican antivenoms against venoms of juvenile and adult snakes. We detected clear ontogenetic venom variation in C. m. nigrescens. Venoms from younger snakes contained more crotamine-like myotoxins and snake venom serine proteinases than venoms from older snakes; however, an increase of snake venom metalloproteinases was detected in venoms of larger snakes. Venoms from juvenile snakes were, in general, more toxic and procoagulant than venoms from adults; however, adult venoms were more proteolytic. Most of the venoms analyzed were hemorrhagic. Importantly, Mexican antivenoms had difficulties recognizing low molecular mass proteins (<12 kDa) of venoms from both juvenile and adult snakes. The antivenoms did not neutralize the crotamine effect caused by the venom of juveniles. Thus, we suggest that Mexican antivenoms would have difficulty neutralizing some human envenomations and, therefore, it may be necessary improve the immunization mixture in Mexican antivenoms to account for low molecular mass proteins, like myotoxins. 

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3. Size Matters: An Evaluation of the Molecular Basis of Ontogenetic Modifications in the Composition of Bothrops jararacussu Snake Venom

   https://doi.org/10.3390/toxins12120791  

   Freitas-de-Sousa, Luciana A.; Nachtigall, Pedro G.; Portes-Junior, José A.; Holding, Matthew L.; Nystrom, Gunnar S.; Ellsworth, Schyler A.; Guimarães, Noranathan C.; Tioyama, Emilly; Ortiz, Flora; Silva, Bruno R.; et al (December 2020, Toxins)

   null (Ed.)

   Ontogenetic changes in venom composition have been described in Bothrops snakes, but only a few studies have attempted to identify the targeted paralogues or the molecular mechanisms involved in modifications of gene expression during ontogeny. In this study, we decoded B. jararacussu venom gland transcripts from six specimens of varying sizes and analyzed the variability in the composition of independent venom proteomes from 19 individuals. We identified 125 distinct putative toxin transcripts, and of these, 73 were detected in venom proteomes and only 10 were involved in the ontogenetic changes. Ontogenetic variability was linearly related to snake size and did not correspond to the maturation of the reproductive stage. Changes in the transcriptome were highly predictive of changes in the venom proteome. The basic myotoxic phospholipases A2 (PLA2s) were the most abundant components in larger snakes, while in venoms from smaller snakes, PIII-class SVMPs were the major components. The snake venom metalloproteinases (SVMPs) identified corresponded to novel sequences and conferred higher pro-coagulant and hemorrhagic functions to the venom of small snakes. The mechanisms modulating venom variability are predominantly related to transcriptional events and may consist of an advantage of higher hematotoxicity and more efficient predatory function in the venom from small snakes. 

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4. Gradual and Discrete Ontogenetic Shifts in Rattlesnake Venom Composition and Assessment of Hormonal and Ecological Correlates

   https://doi.org/10.3390/toxins12100659  

   Schonour, Richard B.; Huff, Emma M.; Holding, Matthew L.; Claunch, Natalie M.; Ellsworth, Schyler A.; Hogan, Michael P.; Wray, Kenneth; McGivern, James; Margres, Mark J.; Colston, Timothy J.; et al (October 2020, Toxins)

   null (Ed.)

   Ontogenetic shifts in venom occur in many snakes but establishing their nature as gradual or discrete processes required additional study. We profiled shifts in venom expression from the neonate to adult sizes of two rattlesnake species, the eastern diamondback and the timber rattlesnake. We used serial sampling and venom chromatographic profiling to test if ontogenetic change occurs gradually or discretely. We found evidence for gradual shifts in overall venom composition in six of eight snakes, which sometimes spanned more than two years. Most chromatographic peaks shift gradually, but one quarter shift in a discrete fashion. Analysis of published diet data showed gradual shifts in overall diet composition across the range of body sizes attained by our eight study animals, while the shifts in abundance of different prey classes varied in form from gradual to discrete. Testosterone concentrations were correlated with the change in venom protein composition, but the relationship is not strong enough to suggest causation. Venom research employing simple juvenile versus adult size thresholds may be failing to account for continuous variation in venom composition lifespan. Our results imply that venom shifts represent adaptive matches to dietary shifts and highlight venom for studies of alternative gene regulatory mechanisms. 

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5. Phylogenetically diverse diets favor more complex venoms in North American pitvipers

   https://doi.org/10.1073/pnas.2015579118  

   Holding, Matthew L.; Strickland, Jason L.; Rautsaw, Rhett M.; Hofmann, Erich P.; Mason, Andrew J.; Hogan, Michael P.; Nystrom, Gunnar S.; Ellsworth, Schyler A.; Colston, Timothy J.; Borja, Miguel; et al (April 2021, Proceedings of the National Academy of Sciences)

   The role of natural selection in the evolution of trait complexity can be characterized by testing hypothesized links between complex forms and their functions across species. Predatory venoms are composed of multiple proteins that collectively function to incapacitate prey. Venom complexity fluctuates over evolutionary timescales, with apparent increases and decreases in complexity, and yet the causes of this variation are unclear. We tested alternative hypotheses linking venom complexity and ecological sources of selection from diet in the largest clade of front-fanged venomous snakes in North America: the rattlesnakes, copperheads, cantils, and cottonmouths. We generated independent transcriptomic and proteomic measures of venom complexity and collated several natural history studies to quantify dietary variation. We then constructed genome-scale phylogenies for these snakes for comparative analyses. Strikingly, prey phylogenetic diversity was more strongly correlated to venom complexity than was overall prey species diversity, specifically implicating prey species’ divergence, rather than the number of lineages alone, in the evolution of complexity. Prey phylogenetic diversity further predicted transcriptomic complexity of three of the four largest gene families in viper venom, showing that complexity evolution is a concerted response among many independent gene families. We suggest that the phylogenetic diversity of prey measures functionally relevant divergence in the targets of venom, a claim supported by sequence diversity in the coagulation cascade targets of venom. Our results support the general concept that the diversity of species in an ecological community is more important than their overall number in determining evolutionary patterns in predator trait complexity. 

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