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Early evolution of the venom system in lizards and snakes

Nature volume 439, pages 584–588 (2006)Cite this article

Abstract

Among extant reptiles only two lineages are known to have evolved venom delivery systems, the advanced snakes and helodermatid lizards (Gila Monster and Beaded Lizard)1. Evolution of the venom system is thought to underlie the impressive radiation of the advanced snakes (2,500 of 3,000 snake species)2,3,4,5. In contrast, the lizard venom system is thought to be restricted to just two species and to have evolved independently from the snake venom system1. Here we report the presence of venom toxins in two additional lizard lineages (Monitor Lizards and Iguania) and show that all lineages possessing toxin-secreting oral glands form a clade, demonstrating a single early origin of the venom system in lizards and snakes. Construction of gland complementary-DNA libraries and phylogenetic analysis of transcripts revealed that nine toxin types are shared between lizards and snakes. Toxinological analyses of venom components from the Lace Monitor Varanus varius showed potent effects on blood pressure and clotting ability, bioactivities associated with a rapid loss of consciousness and extensive bleeding in prey. The iguanian lizard Pogona barbata retains characteristics of the ancestral venom system, namely serial, lobular non-compound venom-secreting glands on both the upper and lower jaws, whereas the advanced snakes and anguimorph lizards (including Monitor Lizards, Gila Monster and Beaded Lizard) have more derived venom systems characterized by the loss of the mandibular (lower) or maxillary (upper) glands. Demonstration that the snakes, iguanians and anguimorphs form a single clade provides overwhelming support for a single, early origin of the venom system in lizards and snakes. These results provide new insights into the evolution of the venom system in squamate reptiles and open new avenues for biomedical research and drug design using hitherto unexplored venom proteins.

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Figure 1: Relative glandular development and timing of toxin recruitment events mapped over the squamate reptile phylogeny.
Figure 2: Transverse section of Pogona barbata (Eastern Bearded Dragon) head to show relative arrangement of glands.
Figure 3: Bioactivity of V. varius (Lace Monitor) venom.
Figure 4: Comparative modelling of representative natriuretic peptides.

References

  1. Kochva, E. in Biology of the Reptilia Vol 8 (eds Gans, S. K. & Gans, C.) 43–162 (Academic, London, 1978)

    Google Scholar 

  2. Vidal, N. Colubroid systematics: evidence for an early appearance of the venom apparatus followed by extensive evolutionary tinkering. J. Toxicol. Toxin Rev. 21, 21–41 (2002)

    Article  Google Scholar 

  3. Vidal, N. & Hedges, S. B. Higher-level relationships of caenophidian snakes inferred from four nuclear and mitochondrial genes. C. R. Biol. 325, 987–995 (2002)

    Article  CAS  Google Scholar 

  4. Fry, B. G. et al. Isolation of a neurotoxin (alpha-colubritoxin) from a ‘non-venomous’ colubrid: evidence for early origin of venom in snakes. J. Mol. Evol. 57, 446–452 (2003)

    Article  ADS  CAS  Google Scholar 

  5. Fry, B. G. et al. LC/MS (liquid chromatography, mass spectrometry) analysis of Colubroidea snake venoms: evolutionary and toxinological implications. Rapid Commun. Mass Spectrom. 17, 2047–2062 (2003)

    Article  ADS  CAS  Google Scholar 

  6. Kochva, E. Development of the venom gland and trigeminal muscles in Vipera palaestinae. Acta Anat. 52, 49–89 (1963)

    Article  Google Scholar 

  7. Kochva, E. The development of the venom gland in the opisthoglyph snake Telescopus fallax with remarks on Thamnophis sirtalis (Colubridae, Reptilia). Copeia 2, 147–154 (1965)

    Article  Google Scholar 

  8. Kochva, E. The origin of snakes and evolution of the venom apparatus. Toxicon 25, 65–106 (1987)

    Article  CAS  Google Scholar 

  9. Kochva, E. Atractaspis (Serpentes, Atractaspididae) the Burrowing Asp; a multidisciplinary minireview. Bull. Nat. Hist. Mus. Lond. Zool. 68, 91–99 (2002)

    Google Scholar 

  10. Underwood, G. & Kochva, E. On the affinities of the burrowing asps Atractaspis (Serpentes: Atractaspididae). Zool. J. Linn. Soc. 107, 3–64 (1993)

    Article  Google Scholar 

  11. Underwood, G. in Venomous Snakes: Ecology, Evolution and Snakebite (eds Thorpe, R. S., Wüster, W. & Malhotra, A.) 1–13 (Symp. Zool. Soc. Lond. no. 70, Clarendon, Oxford, 1997)

    Google Scholar 

  12. Jackson, K. The evolution of venom-delivery systems in snakes. Zool. J. Linn. Soc. 137, 337–354 (2003)

    Article  Google Scholar 

  13. Fry, B. G. & Wüster, W. Assembling an arsenal: Origin and evolution of the snake venom proteome inferred from phylogenetic analysis of toxin sequences. Mol. Biol. Evol. 21, 870–883 (2004)

    Article  CAS  Google Scholar 

  14. Vidal, N. & Hedges, S. B. Molecular evidence for a terrestrial origin of snakes. Proc. R. Soc. Lond. B Suppl. 271, S226–S229 (2004)

    Article  CAS  Google Scholar 

  15. Townsend, T. M., Larson, A., Louis, E. & Macey, J. R. Molecular phylogenetics of Squamata: The position of snakes, Amphisbaenians, and Dibamids, and the root of the squamate tree. Syst. Biol. 53, 735–757 (2004)

    Article  Google Scholar 

  16. Gabe, M. & Saint Girons, H. Données histologiques sur les glandes salivaires des lépidosauriens. Mém. Mus. Natl Hist. Nat. Paris 58, 1–118 (1969)

    Google Scholar 

  17. Gabe, M. & Saint Girons, H. in Toxins of Animal and Plant Origin (eds de Vries, A. & Kochva, E.) 65–68 (Gordon & Breach, London, 1971)

    Google Scholar 

  18. Gygax, P. Entwicklung, Bau und Funktion der Giftdruse (Duvernoy's gland) von Natrix tessellata. Acta Trop. Zool. 28, 225–274 (1971)

    Google Scholar 

  19. Fry, B. G. From genome to ‘venome’: Molecular origin and evolution of the snake venom proteome inferred from phylogenetic analysis of toxin sequences and related body proteins. Genome Res. 15, 403–420 (2005)

    Article  CAS  Google Scholar 

  20. Fry, B. G. et al. Molecular evolution of elapid snake venom three finger toxins. J. Mol. Evol. 57, 110–129 (2003)

    Article  ADS  CAS  Google Scholar 

  21. Huang, T. F. & Chiang, H. S. Effect on human platelet aggregation of phospholipase A2 purified from Heloderma horridum (beaded lizard) venom. Biochim. Biophys. Acta 1211, 61–68 (1994)

    Article  CAS  Google Scholar 

  22. Fry, B. G. et al. Electrospray liquid chromatography/mass spectrometry fingerprinting of Acanthophis (death adder) venoms: taxonomic and toxinological implications. Rapid Commun. Mass Spectrom. 16, 600–608 (2002)

    Article  ADS  CAS  Google Scholar 

  23. Fry, B. G. et al. Novel natriuretic peptides from the venom of the inland taipan (Oxyuranus microlepidotus): Isolation, chemical and biological characterization. Biochem. Biophys. Res. Commun. 327, 1011–1015 (2005)

    Article  CAS  Google Scholar 

  24. Sopiev, O., Makeev, B. M., Kudryavtsev, S. B. & Makarov, A. N. A case of intoxication by a bite of the gray monitor (Varanus griseus). Izv. Akad. Nauk Turkm. SSR. Ser. Biol. Nauk 87, 78 (1987)

    Google Scholar 

  25. Gorelov, Y. U. K. About the toxicity of the saliva of the gray monitor. Izv. Akad. Nauk Turkm. SSR. Ser. Biol. Nauk 71, 74 (1971)

    Google Scholar 

  26. Pregill, G. K., Gauthier, J. A. & Greene, H. W. The evolution of Helodermatid squamates, with description of a new taxon and an overview of Varanoidea. Trans. San Diego Soc. Nat. Hist. 21, 167–202 (1986)

    Google Scholar 

  27. Norell, M. A., McKenna, M. C. & Novacek, M. J. Estesia mongoliensis, a new fossil varanoid from the Late Cretaceous Barun Goyot Formation of Mongolia. Am. Mus. Novit. 3045, 1–24 (1992)

    Google Scholar 

  28. Evans, S. E. At the feet of the dinosaurs: the origin, evolution and early diversification of squamate reptiles (Lepidosauria: Diapsida). Biol. Rev. Cambr. 78, 513–551 (2003)

    Article  Google Scholar 

  29. Guex, N. & Peitsch, M. C. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18, 2714–2723 (1997)

    Article  CAS  Google Scholar 

  30. Koradi, R., Billeter, M. & Wuthrich, K. MOLMOL: a program for display and analysis of macromolecular structures. J. Mol. Graph. 14(1M), 51–55 (1996)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the following persons and institutions who helped us or contributed tissue samples used in this study: A. Fry, Alice Springs Reptile Centre, Australian Reptile Park, M. A. G. de Bakker, R. L. Bezy, B. Branch, J. Campbell, N. Clemann, C. Clemente, C. Cicero, K. Daoues, A. S. Delmas, B. Demeter, J. Haberfield, A. Hassanin, Healesville Sanctuary, M. Hird, Louisiana State University Museum of Zoology, P. Moler, T. Moncuit, P. Moret, National Museum of Natural History Naturalis Leiden (J. W. Arntzen), T. Pappenfus, J.-C. Rage, C. Skliris, J. Smith, S. Sweet, Ultimate Reptiles (South Australia), University of California Museum of Vertebrate Zoology (Berkeley), J. Walker, R. Waters, J. Weigel and B. Wilson. We also thank A. Webb and T. Purcell for providing HPLC access; N. Williamson for help with preliminary mass spectrometry characterization; E. V. Grishin for help in obtaining the references in Russian; S. Edwards for comments; and T. van Wagner and V. Wexler for artwork. This work was funded by the Service de Systématique moléculaire of the Muséum National d'Histoire Naturelle, Institut de Systématique (N.V.) and by grants from the Australian Academy of Science (B.G.F.), Australian Geographic Society (B.G.F.), Australia & Pacific Science Foundation (B.G.F.), Australian Research Council (B.G.F.), CASS Foundation (B.G.F.), Commonwealth of Australia Department of Health and Aging (B.G.F.), Ian Potter Foundation (B.G.F.), International Human Frontiers Science Program Organisation (B.G.F.), Leiden University (F.J.V., M.K.R.), NASA Astrobiology Institute (S.B.H.), National Science Foundation (S.B.H.) and University of Melbourne (B.G.F.). We thank the relevant wildlife departments for granting the scientific permits for field collection of required specimens.

Author information

Authors and Affiliations

  1. Australian Venom Research Unit, Level 8, School of Medicine, University of Melbourne, Victoria, 3010, Parkville, Australia

    Bryan G. Fry & S. F. Ryan Ramjan

  2. Population and Evolutionary Genetics Unit, Museum Victoria, GPO Box 666E, Victoria, 3001, Melbourne, Australia

    Bryan G. Fry & Janette A. Norman

  3. Department of Biology and Astrobiology Research Center, 208 Mueller Lab, Pennsylvania State University, University Park, Pennsylvania, 16802-5301, USA

    Nicolas Vidal & S. Blair Hedges

  4. UMS 602, Taxonomie et collections, Reptiles-Amphibiens, Département Systématique et Évolution, Muséum National d'Histoire Naturelle, 25 Rue Cuvier, 75005, Paris, France

    Nicolas Vidal

  5. Institute of Biology, Leiden University, Kaiserstraat 63, PO Box 9516, 2300 RA, Leiden, The Netherlands

    Freek J. Vonk & Michael K. Richardson

  6. Department of Structural Biology and Bioinformatics, University of Geneva and Swiss Institute of Bioinformatics, Centre Médical Universitaire, 1 Rue Michel-Servet, 1211 4, Geneva, Switzerland

    Holger Scheib

  7. SBC Lab AG, Seebüelstrasse 26, 8185, Winkel, Switzerland

    Holger Scheib

  8. Monash Venom Group, Department of Pharmacology, Monash University, Clayton, 3800, Victoria, Australia

    Sanjaya Kuruppu & Wayne. C. Hodgson

  9. Molecular and Health Technologies, CSIRO, 343 Royal Parade, Victoria, 3010, Parkville, Australia

    Kim Fung

  10. Department of Pathology, University of Melbourne, Victoria, 3010, Parkville, Australia

    Vera Ignjatovic & Robyn Summerhayes

  11. Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Road, Victoria, 3052, Parkville, Australia

    Vera Ignjatovic & Robyn Summerhayes

  12. Department of Zoology, Tel Aviv University, 69978, Tel Aviv, Israel

    Elazar Kochva

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  1. Bryan G. Fry
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  14. Elazar Kochva
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Corresponding author

Correspondence to Bryan G. Fry.

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Competing interests

The sequences of the cDNA clones have been deposited in GenBank (accession numbers DQ139877–DQ139931 and DQ184481), as have the nuclear gene sequences (DQ119594–DQ119641). Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains 13 Supplementary Figures, including the molecular phylogenetic analysis of squamate nuclear genes, the phylogenetic analyses and sequence alignments of the toxin types analysed in this study as well as the liquid chromatography-mass spectrometry analysis of Varanus varius (Lace monitor) venom. (PDF 1238 kb)

Supplementary Methods

This file contains detailed descriptions of materials and methods not already described in the main article. (DOC 52 kb)

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Fry, B., Vidal, N., Norman, J. et al. Early evolution of the venom system in lizards and snakes. Nature 439, 584–588 (2006). https://doi.org/10.1038/nature04328

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