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A Critique of the Toxicoferan Hypothesis

  • Adam D. Hargreaves
  • Abigail S. Tucker
  • John F. Mulley
Living reference work entry
Part of the Toxinology book series (TOXI)

Abstract

Historically, venom was believed to have evolved twice independently in squamate reptiles, once in the advanced snakes and once in venomous lizards. The presence of putative toxin proteins in the saliva of species usually regarded as non-venomous, and the expression of venom gene homologs in their salivary glands, led to the hypothesis that venom evolved a single time in reptiles. As the single, early origin of venom is synonymous with the Toxicofera clade (Serpentes, Anguimorpha and Iguania), it will subsequently be referred to as the Toxicofera hypothesis. This hypothesis has proved to be remarkably pervasive for almost a decade, but has until recently never been tested. Here, evidence used in support of the Toxicofera hypothesis is reviewed and critically evaluated. Taking into account both new and old data, it appears that this hypothesis is unsupported, and should be subject to further scrutiny and discussion. Finally, the implications of the rejection of the Toxicofera hypothesis are discussed, with respect to the knowledge of venom evolution in the Reptilia and also the practical implications of this knowledge.

Keywords

Toxicofera Reptiles Venom Oral glands Venom glands 

References

  1. Alper CA, Balavitch D. Cobra venom factor: evidence for its being altered cobra C3 (the third component of complement). Science. 1976;191:1275–6.CrossRefPubMedGoogle Scholar
  2. Anantharaman V, Aravind L, Koonin EV. Emergence of diverse biochemical activities in evolutionarily conserved structural scaffolds of proteins. Curr Opin Chem Biol. 2003;7:12–20.CrossRefPubMedGoogle Scholar
  3. Arbuckle K. Ecological function of venom in Varanus, with a compilation of dietary records from the literature. Biawak. 2009;3:46–56.Google Scholar
  4. Auffenberg W. The behavioral ecology of the Komodo monitor. Gainesville: University of Florida Press; 1981.Google Scholar
  5. Bonilla CA, Fiero MK, Seifert W. Comparative biochemistry and pharmacology of salivary gland secretions: I. Electrophoretic analysis of the proteins in the secretions from human parotid and reptilian parotid (Duvernoy’s) glands. J Chromatogr A. 1971;56:368–72.CrossRefGoogle Scholar
  6. Borek HA, Charlton NP. How not to train your dragon: a case of a Komodo dragon bite. Wilderness Environ Med. 2015;26(2):196–9.CrossRefPubMedGoogle Scholar
  7. Bull J, Jessop TS, Whiteley M. Deathly drool: evolutionary and ecological basis of septic bacteria in Komodo dragon mouths. PLoS One. 2010;5, e11097.PubMedCentralCrossRefPubMedGoogle Scholar
  8. Butte AJ, Dzau VJ, Glueck SB. Further defining housekeeping, or “maintenance,” genes Focus on “A compendium of gene expression in normal human tissues”. Physiol Genomics. 2001;7:95–6.PubMedGoogle Scholar
  9. Calvete JJ. Snake venomics: from the inventory of toxins to biology. Toxicon. 2013;75:44–62.CrossRefPubMedGoogle Scholar
  10. Calvete JJ, Escolano J, Sanz L. Snake venomics of Bitis species reveals large intragenus venom toxin composition variation: application to taxonomy of congeneric taxa. J Proteome Res. 2007;6:2732–45.CrossRefPubMedGoogle Scholar
  11. Casewell NR, Harrison RA, Wuster W, Wagstaff SC. Comparative venom gland transcriptome surveys of the saw-scaled vipers (Viperidae: Echis) reveal substantial intra-family gene diversity and novel venom transcripts. BMC Genomics. 2009;10:564.PubMedCentralCrossRefPubMedGoogle Scholar
  12. Casewell NR, Huttley GA, Wüster W. Dynamic evolution of venom proteins in squamate reptiles. Nat Commun. 2012;3:1066.CrossRefPubMedGoogle Scholar
  13. Casewell NR, Wüster W, Vonk FJ, Harrison RA, Fry BG. Complex cocktails: the evolutionary novelty of venoms. Trends Ecol Evol. 2013;28:219–29.CrossRefPubMedGoogle Scholar
  14. Casewell NR, Wagstaff SC, Wuster W, Cook DA, Bolton FM, King SI, Pla D, Sanz L, Calvete JJ, Harrison RA. Medically important differences in snake venom composition are dictated by distinct postgenomic mechanisms. Proc Natl Acad Sci U S A. 2014;111:9205–10.PubMedCentralCrossRefPubMedGoogle Scholar
  15. Cousin X, Créminon C, Grassi J, Méflah K, Cornu G, Saliou B, Bon S, Massoulié J, Bon C. Acetylcholinesterase from Bungarus venom: a monomeric species. FEBS Lett. 1996;387:196–200.CrossRefPubMedGoogle Scholar
  16. Crachi MT, Hammer LW, Hodgson WC. A pharmacological examination of venom from the Papuan taipan: (Oxyuranus scutellatus canni). Toxicon. 1999;37:1721–34.CrossRefPubMedGoogle Scholar
  17. Fry BG, Wüster W, Kini RM, Brusic V, Khan A, Venkataraman D, Rooney A. Molecular evolution and phylogeny of elapid snake venom three-finger toxins. J Mol Evol. 2003a;57:110–29.CrossRefPubMedGoogle Scholar
  18. Fry BG, Lumsden NG, Wüster W, Wickramaratna JC, Hodgson WC, Kini RM. Isolation of a neurotoxin (α-colubritoxin) from a nonvenomous colubrid: evidence for early origin of venom in snakes. J Mol Evol. 2003b;57:446–52.CrossRefPubMedGoogle Scholar
  19. Fry BG, Vidal N, Norman JA, Vonk FJ, Scheib H, Ramjan SR, Kuruppu S, Fung K, Hedges SB, Richardson MK. Early evolution of the venom system in lizards and snakes. Nature. 2006;439:584–8.CrossRefPubMedGoogle Scholar
  20. Fry BG, Wroe S, Teeuwisse W, van Osch MJ, Moreno K, Ingle J, McHenry C, Ferrara T, Clausen P, Scheib H, et al. A central role for venom in predation by Varanus komodoensis (Komodo Dragon) and the extinct giant Varanus (Megalania) priscus. Proc Natl Acad Sci U S A. 2009;106:8969–74.PubMedCentralCrossRefPubMedGoogle Scholar
  21. Fry BG, Winter K, Norman JA, Roelants K, Nabuurs RJ, van Osch MJ, Teeuwisse WM, van der Weerd L, McNaughtan JE, Kwok HF, et al. Functional and structural diversification of the Anguimorpha lizard venom system. Mol Cell Proteomics. 2010;9:2369–90.PubMedCentralCrossRefPubMedGoogle Scholar
  22. Fry BG, Scheib H, Junqueira de Azevedo ILM, Silva DA, Casewell NR. Novel transcripts in the maxillary venom glands of advanced snakes. Toxicon. 2012a;59:696–708.CrossRefPubMedGoogle Scholar
  23. Fry BG, Casewell NR, Wüster W, Vidal N, Young B, Jackson TN. The structural and functional diversification of the Toxicofera reptile venom system. Toxicon. 2012b;60:434–48.CrossRefPubMedGoogle Scholar
  24. Fry BG, Undheim EA, Ali SA, Jackson TN, Debono J, Scheib H, Ruder T, Morgenstern D, Cadwallader L, Whitehead D, et al. Squeezers and leaf-cutters: differential diversification and degeneration of the venom system in Toxicoferan reptiles. Mol Cell Proteomics. 2013;12:1881–99.PubMedCentralCrossRefPubMedGoogle Scholar
  25. Gibbs O. On the alleged occurrence of acetylcholine in the saliva. J Physiol. 1935;84:33–40.PubMedCentralCrossRefPubMedGoogle Scholar
  26. Guo T, Rudnick PA, Wang W, Lee CS, DeVoe DL, Balgley BM. Characterization of the human salivary proteome by capillary isoelectric focusing/nanoreversed-phase liquid chromatography coupled with ESI-tandem MS. J Proteome Res. 2006;5:1469–78.CrossRefPubMedGoogle Scholar
  27. Hargreaves AD, Swain MT, Logan DW, Mulley JF. Testing the Toxicofera: comparative transcriptomics casts doubt on the single, early evolution of the reptile venom system. Toxicon. 2014a;92:140–56.CrossRefPubMedGoogle Scholar
  28. Hargreaves AD, Swain MT, Hegarty MJ, Logan DW, Mulley JF. Restriction and recruitment-gene duplication and the origin and evolution of snake venom toxins. Genome Biol Evol. 2014b;6:2088–95.PubMedCentralCrossRefPubMedGoogle Scholar
  29. Harrison RA, Hargreaves A, Wagstaff SC, Faragher B, Lalloo DG. Snake envenoming: a disease of poverty. PLoS Negl Trop Dis. 2009;3, e569.PubMedCentralCrossRefPubMedGoogle Scholar
  30. Hsiang AY, Field DJ, Webster TH, Behlke ADB, Davis MB, Racicot RA, Gauthier JA. The origin of snakes: revealing the ecology, behavior, and evolutionary history of early snakes using genomics, phenomics, and the fossil record. BMC Evol Biol. 2015;15:87.PubMedCentralCrossRefPubMedGoogle Scholar
  31. Hu S, Xie Y, Ramachandran P, Ogorzalek Loo RR, Li Y, Loo JA, Wong DT. Large-scale identification of proteins in human salivary proteome by liquid chromatography/mass spectrometry and two-dimensional gel electrophoresis-mass spectrometry. Proteomics. 2005;5:1714–28.CrossRefPubMedGoogle Scholar
  32. Jansen DW. A possible function of the secretion of Duvernoy’s gland. Copeia. 1983;1983:262–4.CrossRefGoogle Scholar
  33. Jelinek GA, Tweed C, Lynch D, Celenza T, Bush B, Michalopoulos N. Cross reactivity between venomous, mildly venomous, and non-venomous snake venoms with the Commonwealth Serum Laboratories Venom Detection Kit. Emerg Med. 2004;16:459–64.CrossRefGoogle Scholar
  34. Junqueira-de-Azevedo ILM, Bastos CMV, Ho PL, Luna MS, Yamanouye N, Casewell NR. Venom-related transcripts from Bothrops jararaca tissues provide novel molecular insights into the production and evolution of snake venom. Mol Biol Evol. 2014;32:754–66.PubMedCentralCrossRefPubMedGoogle Scholar
  35. Kardong KV. Replies to Fry et al. (Toxicon 2012, 60/4, 434–448). Part B. Properties and biological roles of squamate oral products: the “venomous lifestyle” and preadaptation. Toxicon. 2012;60:964–6.CrossRefPubMedGoogle Scholar
  36. Kardong K, Weinstein S, Smith T. Reptile venom glands: form, function, and future. In: Mackessy S, editor. Handbook of venoms and toxins of reptiles. Boca Raton: CRC Press; 2009.Google Scholar
  37. Kasturiratne A, Wickremasinghe AR, de Silva N, Gunawardena NK, Pathmeswaran A, Premaratna R, Savioli L, Lalloo DG, de Silva HJ. The global burden of snakebite: a literature analysis and modelling based on regional estimates of envenoming and deaths. PLoS Med. 2008;5:e218.PubMedCentralCrossRefPubMedGoogle Scholar
  38. Kini RM, Doley R. Structure, function and evolution of three-finger toxins: mini proteins with multiple targets. Toxicon. 2010;56:855–67.CrossRefPubMedGoogle Scholar
  39. Kochva E. Development of the venom gland and trigeminal muscles in Vipera palaestinae. Cells Tissues Organs. 1963;52:49–89.CrossRefGoogle Scholar
  40. Kochva E. The development of the venom gland in the opisthoglyph snake Telescopus fallax with remarks on Thamnophis sirtalis (Colubridae, Reptilia). Copeia. 1965;1965:147–54.CrossRefGoogle Scholar
  41. Kochva E. Oral glands of the Reptilia. Biol Reptilia. 1978;8:43–161.Google Scholar
  42. Kochva E, Gans C. Salivary glands of snakes. Clin Toxicol. 1970;3:363–87.CrossRefPubMedGoogle Scholar
  43. Koludarov I, Sunagar K, Undheim EA, Jackson TN, Ruder T, Whitehead D, Saucedo AC, Mora GR, Alagon AC, King G. Structural and molecular diversification of the Anguimorpha lizard mandibular venom gland system in the arboreal species Abronia graminea. J Mol Evol. 2012;75:168–83.CrossRefPubMedGoogle Scholar
  44. Levy B, Appleton J. Effect of saliva on capillary permeability. J Dent Res. 1942;21:505–8.CrossRefGoogle Scholar
  45. Li M, Fry B, Kini RM. Eggs-only diet: its implications for the toxin profile changes and ecology of the marbled sea snake (Aipysurus eydouxii). J Mol Evol. 2005a;60:81–9.CrossRefPubMedGoogle Scholar
  46. Li M, Fry BG, Kini RM. Putting the brakes on snake venom evolution: the unique molecular evolutionary patterns of Aipysurus eydouxii (Marbled sea snake) phospholipase A2 toxins. Mol Biol Evol. 2005b;22:934–41.CrossRefPubMedGoogle Scholar
  47. Mackessy SP. Biochemistry and pharmacology of colubrid snake venoms. Toxin Rev. 2002;21:43–83.CrossRefGoogle Scholar
  48. Martin H. Étude de l’appareil glandulaire venimeux chez un embryon de Vipera aspis. Bull Soc Zool Fr. 1899;24:106–16.Google Scholar
  49. McCue MD. Cost of producing venom in three North American pitviper species. Copeia. 2006;2006:818–25.CrossRefGoogle Scholar
  50. Mebs D. Venomous and poisonous animals: a handbook for biologists, toxicologists and toxinologists, physicians and pharmacists. Stuttgart-Boca Raton: CRC Press Medpharm; 2002.Google Scholar
  51. Minton SA, Weinstein SA. Colubrid snake venoms: immunologic relationships, electrophoretic patterns. Copeia. 1987;1987:993–1000.CrossRefGoogle Scholar
  52. Nuchprayoon I, Garner P. Interventions for preventing reactions to snake antivenom. The Cochrane Library 1999; 4.Google Scholar
  53. Pawlak J, Mackessy SP, Fry BG, Bhatia M, Mourier G, Fruchart-Gaillard C, Servent D, Menez R, Stura E, Menez A, et al. Denmotoxin, a three-finger toxin from the colubrid snake Boiga dendrophila (Mangrove Catsnake) with bird-specific activity. J Biol Chem. 2006;281:29030–41.CrossRefPubMedGoogle Scholar
  54. Piskurek O, Austin CC, Okada N. Sauria SINEs: novel short interspersed retroposable elements that are widespread in reptile genomes. J Mol Evol. 2006;62:630–44.CrossRefPubMedGoogle Scholar
  55. Pough F, Andrews R, Cadle J, Crump M, Savitzky A, Wells K. Herpetology. 3rd ed. New Jersey: Prentice Hall; 2004.Google Scholar
  56. Pyron RA, Burbrink FT, Wiens JJ. A phylogeny and revised classification of Squamata, including 4161 species of lizards and snakes. BMC Evol Biol. 2013;13:93.PubMedCentralCrossRefPubMedGoogle Scholar
  57. Quijada-Mascarenas A, Wüster W. Recent advances in venomous snake systematics. In: Mackessy S, editor. Handbook of venoms and toxins of reptiles. Boca Raton: CRC Press; 2009.Google Scholar
  58. Reyes-Velasco J, Card DC, Andrew AL, Shaney KJ, Adams RH, Schield DR, Casewell NR, Mackessy SP, Castoe TA. Expression of venom gene homologs in diverse python tissues suggests a new model for the evolution of snake venom. Mol Biol Evol. 2015;32:173–83.CrossRefPubMedGoogle Scholar
  59. Ritonja A, Evans HJ, Machleidt W, Barrett AJ. Amino acid sequence of a cystatin from venom of the African puff adder (Bitis arietans). Biochem J. 1987;246:799–802.PubMedCentralCrossRefPubMedGoogle Scholar
  60. Saintgirons H. The cephalic exocrine glands of reptiles. 1. Anatomical and histological data. Annales des Sciences Naturelles-Zoologie et Biologie Animale. 1988;9:221–55.Google Scholar
  61. Shufeldt R. The poison apparatus of the Heloderma. Nature. 1891;43:514–15.CrossRefGoogle Scholar
  62. Simpson ID, Norris RL. Snakes of medical importance in India: is the concept of the “Big 4” still relevant and useful? Wilderness Environ Med. 2007;18:2–9.CrossRefPubMedGoogle Scholar
  63. Sunagar K, Fry BG, Jackson TN, Casewell NR, Undheim EA, Vidal N, Ali SA, King GF, Vasudevan K, Vasconcelos V. Molecular evolution of vertebrate neurotrophins: co-option of the highly conserved nerve growth factor gene into the advanced snake venom arsenal. PLoS One. 2013;8:e81827.PubMedCentralCrossRefPubMedGoogle Scholar
  64. Taub AM. Ophidian cephalic glands. J Morphol. 1966;118:529–41.CrossRefPubMedGoogle Scholar
  65. Taub AM. Comparative histological studies on Duvernoy’s gland of colubrid snakes. Bull Am Mus Nat Hist. 1967;138:1–50.Google Scholar
  66. Tucker AS. Salivary gland adaptations: modification of the glands for novel uses. Front Oral Biol. 2010;14:21–31.CrossRefPubMedGoogle Scholar
  67. Underwood G, Kochva E. On the affinities of the burrowing asps Atractaspis (Serpentes: Atractaspididae). Zool J Linn Soc. 1993;107:3–64.CrossRefGoogle Scholar
  68. Vidal N. Colubroid systematics: evidence for an early appearance of the venom apparatus followed by extensive evolutionary tinkering. Toxin Rev. 2002;21:21–41.CrossRefGoogle Scholar
  69. Vidal N, Hedges SB. Higher-level relationships of Caenophidian snakes inferred from four nuclear and mitochondrial genes. C R Biol. 2002;325:987–95.CrossRefPubMedGoogle Scholar
  70. Vidal N, Hedges SB. The phylogeny of squamate reptiles (lizards, snakes, and amphisbaenians) inferred from nine nuclear protein-coding genes. C R Biol. 2005;328:1000–8.CrossRefPubMedGoogle Scholar
  71. Vikrant S, Verma BS. Monitor lizard bite-induced acute kidney injury – a case report. Ren Fail. 2014;33:444–6.CrossRefGoogle Scholar
  72. Vonk FJ, Admiraal JF, Jackson K, Reshef R, de Bakker MA, Vanderschoot K, van den Berge I, van Atten M, Burgerhout E, Beck A. Evolutionary origin and development of snake fangs. Nature. 2008;454:630–3.CrossRefPubMedGoogle Scholar
  73. Vonk FJ, Casewell NR, Henkel CV, Heimberg AM, Jansen HJ, McCleary RJ, Kerkkamp HM, Vos RA, Guerreiro I, Calvete JJ, et al. The king cobra genome reveals dynamic gene evolution and adaptation in the snake venom system. Proc Natl Acad Sci U S A. 2013;110:20651–6.PubMedCentralCrossRefPubMedGoogle Scholar
  74. Wagstaff SC, Harrison RA. Venom gland EST analysis of the saw-scaled viper, Echis ocellatus, reveals novel α9 β1 integrin-binding motifs in venom metalloproteinases and a new group of putative toxins, renin-like aspartic proteases. Gene. 2006;377:21–32.Google Scholar
  75. Wagstaff SC, Sanz L, Juárez P, Harrison RA, Calvete JJ. Combined snake venomics and venom gland transcriptomic analysis of the ocellated carpet viper, Echis ocellatus. J Proteomics. 2009;71:609–23.CrossRefPubMedGoogle Scholar
  76. Weavers BW. Diet of the Lace Monitor Lizard (Varanus vadus) in south-eastern Australia. Aust Zool. 1989;25:83–5.CrossRefGoogle Scholar
  77. Weinstein SA, Keyler DE, White J. Replies to Fry et al. (Toxicon 2012, 60/4, 434–448). Part A. Analyses of squamate reptile oral glands and their products: a call for caution in formal assignment of terminology designating biological function. Toxicon. 2012;60:954–63.CrossRefPubMedGoogle Scholar
  78. White J, Weinstein SA. Reply to Vikrant and Verma about “Monitor Lizard Envenoming”. Renal Failure. 2015;37(4):1–2.CrossRefGoogle Scholar
  79. Whitton JL, Sheng N, Oldstone MB, McKee TA. A “string-of-beads” vaccine, comprising linked minigenes, confers protection from lethal-dose virus challenge. J Virol. 1993;67:348–52.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Adam D. Hargreaves
    • 1
  • Abigail S. Tucker
    • 2
  • John F. Mulley
    • 3
  1. 1.Department of ZoologyUniversity of OxfordOxfordUK
  2. 2.Department of Craniofacial Development and Stem Cell BiologyKing’s College London, Guy’s HospitalLondonUK
  3. 3.School of Biological SciencesBangor UniversityBangorUK

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