Abstract
Venom has only been recently discovered to be a basal trait of the Anguimorpha lizards. Consequently, very little is known about the timings of toxin recruitment events, venom protein molecular evolution, or even the relative physical diversifications of the venom system itself. A multidisciplinary approach was used to examine the evolution across the full taxonomical range of this ∼130 million-year-old clade. Analysis of cDNA libraries revealed complex venom transcriptomes. Most notably, three new cardioactive peptide toxin types were discovered (celestoxin, cholecystokinin, and YY peptides). The latter two represent additional examples of convergent use of genes in toxic arsenals, both having previously been documented as components of frog skin defensive chemical secretions. Two other novel venom gland-overexpressed modified versions of other protein frameworks were also recovered from the libraries (epididymal secretory protein and ribonuclease). Lectin, hyaluronidase, and veficolin toxin types were sequenced for the first time from lizard venoms and shown to be homologous to the snake venom forms. In contrast, phylogenetic analyses demonstrated that the lizard natriuretic peptide toxins were recruited independently of the form in snake venoms. The de novo evolution of helokinestatin peptide toxin encoding domains within the lizard venom natriuretic gene was revealed to be exclusive to the helodermatid/anguid subclade. New isoforms were sequenced for cysteine-rich secretory protein, kallikrein, and phospholipase A(2) toxins. Venom gland morphological analysis revealed extensive evolutionary tinkering. Anguid glands are characterized by thin capsules and mixed glands, serous at the bottom of the lobule and mucous toward the apex. Twice, independently this arrangement was segregated into specialized serous protein-secreting glands with thick capsules with the mucous lobules now distinct (Heloderma and the Lanthanotus/Varanus clade). The results obtained highlight the importance of utilizing evolution-based search strategies for biodiscovery and emphasize the largely untapped drug design and development potential of lizard venoms.
Highlights
Venom has only been recently discovered to be a basal trait of the Anguimorpha lizards
Toxin Transcript Types Recovered—BLAST analyses of transcripts recovered from the venom gland cDNA libraries identified seven protein types with sequence homology to previously characterized toxicoferan toxins (Table I)
Three toxin types previously only sequenced from snake venoms were recovered in this study: lectin, hyaluronidase, and veficolin (V. komodoensis)
Summary
Venom has only been recently discovered to be a basal trait of the Anguimorpha lizards. Phylogenetic analyses demonstrated that the lizard natriuretic peptide toxins were recruited independently of the form in snake venoms. Because of significant differences in anatomy of the venom delivery system and distant phylogenetic relatedness, it had been long assumed that the venom systems of snakes and helodermatid lizards were independently evolved [1,2,3]. Both lineages were recently revealed to be members of a clade (Toxicofera) that included several lineages of other lizards recently shown to be venomous [4, 5]. Diversification of Anguimorpha Lizard Venom System cally important species such as Heloderma (for example) may be clinically complex with symptoms, including extreme pain, acute local swelling, nausea, fever, faintness, myocardial infarction, tachycardia, hypotension, and inhibition of blood coagulation (6 –12)
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