Conus Peptides: Biodiversity-based Discovery and Exogenomics (2006)

The venoms of the ∼700 species of predatory cone snails (genus Conus) are being systematically characterized. Each Conus species contains 100–200 small, highly structured venom peptides (colloquially known as conotoxins), which are synthesized and secreted in a venom duct (for overviews, see Refs. 1Olivera B.M. Annu. Rev. Ecol. Syst. 2002; 33: 25-47Crossref Scopus (186) Google Scholar, 2Olivera B.M. Rivier J. Clark C. Ramilo C.A. Corpuz G.P. Abogadie F.C. Mena E.E. Woodward S.R. Hillyard D.R. Cruz L.J. Science. 1990; 249: 257-263Crossref PubMed Scopus (514) Google Scholar, 3Terlau H. Olivera B.M. Physiol. Rev. 2004; 84: 41-68Crossref PubMed Scopus (804) Google Scholar). The biomedical potential of these small venom peptides is now well established; recent developments are summarized below. Additionally, the genetic basis and biological rationale for Conus peptide diversity is addressed. Conus peptide genes belong to a general class whose gene products are targeted to other organisms; the extensive molecular analysis carried out on the Conus genes revealed that these diversify extremely rapidly. Understanding this class of genes may require a specialized framework with features distinct from conventional genomics, which we will refer to as "exogenomics" (the gene products are targeted exogenously rather than endogenously). The interdisciplinary paradigm that has evolved for the systematic discovery of Conus venom peptides, if applied more broadly, should prove fruitful for generally exploring chemical diversity from the animal biodiversity that surrounds us. Six different Conus peptides have reached human clinical trials (Table 1); a significant milestone was the approval of a Conus peptide as a commercial drug for intractable pain by the Food and Administration in December 2004. The commercial product, Prialt (generically called ziconitide) is identical to the natural peptide produced by the magician's cone snail, Conus magus, originally designated ω-conotoxin MVIIA (4Olivera B.M. Drugs from the Sea. Karger, Basel2000: 74-85Crossref Google Scholar, 5Miljanich G.P. Curr. Med. Chem. 2004; 11: 3029-3040Crossref PubMed Scopus (472) Google Scholar, 6Olivera B.M. Gray W.R. Zeikus R. McIntosh J.M. Varga J. Rivier J. de Santos V. Cruz L.J. Science. 1985; 230: 1338-1343Crossref PubMed Scopus (641) Google Scholar, 7Staats P.S. Yearwood T. Charapata S.G. Presley R.W. Wallace M.S. Byas-Smith M. Fisher R. Bryce D.A. Mangieri E.A. Luther R.R. Mayo M. McGuire D. Ellis D. J. Am. Med. Assoc. 2004; 291: 63-70Crossref PubMed Scopus (546) Google Scholar). This is one of a class of peptides from fish-hunting cone snail venoms exhibiting high specificity for the N-type calcium channel (CaV2.2). Another peptide that acts by the same mechanism, ω-conotoxin GVIA from Conus geographus, is the most widely used Conus peptide in neuroscience, with ∼2000 research papers in the literature using this compound as a pharmacological tool (3Terlau H. Olivera B.M. Physiol. Rev. 2004; 84: 41-68Crossref PubMed Scopus (804) Google Scholar).TABLE 1Conus venom peptides with therapeutic potentialMolecular targetConus peptideTherapeutic applicationCompanyDevelopment stage reachedRef.aSee supplemental material for sequences and structures.N-type calcium channel (Cav2.2)ω-MVIIA (Prialt; zicontide)PainElan (Neurex)Approved by FDA 12/045Miljanich G.P. Curr. Med. Chem. 2004; 11: 3029-3040Crossref PubMed Scopus (472) Google Scholarω-CVID (AM336)PainAmradPhase 125Smith M.T. Cabot P.J. Ross F.B. Robertson A.D. Lewis R.J. Pain. 2002; 96: 119-127Abstract Full Text Full Text PDF PubMed Scopus (154) Google ScholarNeurotensin receptorContulakin-G (CGX-1160)PainCognetixPhase 126Allen J.W. Herbertsson K. McCumber D. Wagstaff J.D. Layer R.T. McCabe R.T. Yaksh T.L. Anesth. Analg. 2006; (in press)Google ScholarNorepinephrine transporterχ-MrIA (derivative) (Xen-2174)PainXenomePhase 127Nielsen C.K. Lewis R.J. Alewood D. Drinkwater R. Palant E. Patterson M. Yaksh T.L. McCumber D. Smith M.T. Pain. 2005; 118: 112-124Abstract Full Text Full Text PDF PubMed Scopus (88) Google ScholarNicotinic receptorsα-Vc1.1 (ACV-1)PainMetabolicPhase 128Satkunanathan N. Livett B. Gayler K. Sandall D. Down J. Khalil Z. Brain Res. 2005; 1059: 149-158Crossref PubMed Scopus (160) Google ScholarNMDAbN-Methyl-d-aspartate. receptorsConantokin-G (CGX-1007)Epilepsy; painCognetixPhase 129Malmberg A.B. Gilbert H. McCabe R.T. Basbaum A.I. Pain. 2003; 101: 109-116Abstract Full Text Full Text PDF PubMed Scopus (130) Google ScholarK+ channels (Kv1 subfamily)κ-PVIIA (CGX-1051)Myocardial infarctionCognetixPre-clinical8Lubbers N.L. Campbell T.J. Polakowski J.S. Bulaj G. Layer R.T. Moore J. Gross G.J. Cox B.F. J. Cardiovasc. Pharmacol. 2005; 46: 1-6Crossref PubMed Scopus (37) Google ScholarNa+ channelsμO-MrVIB (CGX-1002)PainCognetixPre-clinical30Bulaj G. Zhang M.M. Green B.R. Fiedler B. Layer R.T. Wei S. Nielsen J.S. Low S.J. Klein B.D. Wagstaff J.D. Chicoine L. Harty T.P. Terlau H. Yoshikami D. Olivera B.M. Biochemistry. 2006; 45: 7404-7414Crossref PubMed Scopus (84) Google Scholara See supplemental material for sequences and structures.b N-Methyl-d-aspartate. Open table in a new tab A high proportion of the first conopeptides characterized have reached clinical development; of the first 30 peptides purified from Conus venoms, 10% reached at least Phase 1 human clinical trials. A significant fraction of these Conus peptides in development are potential therapeutics for pain (see Table 1). Although pharmaceutical companies have mostly focused on opioids for treating severe pain, the analgesic Conus venom peptides in development work through five distinct mechanisms, of which none are opioid-based. One peptide, κ-PVIIA, a K+ channel blocker has been effective in decreasing cardiac damage in animal models of myocardial infarction (8Lubbers N.L. Campbell T.J. Polakowski J.S. Bulaj G. Layer R.T. Moore J. Gross G.J. Cox B.F. J. Cardiovasc. Pharmacol. 2005; 46: 1-6Crossref PubMed Scopus (37) Google Scholar, 9Zhang S.J. Yang X.M. Liu G.S. Cohen M.V. Pemberton K. Downey J.M. J. Cardiovasc. Pharmacol. 2003; 42: 764-771Crossref PubMed Scopus (34) Google Scholar). The diversity of analgesic conopeptides in Table 1 illustrates an important application of Conus peptides: identifying new pharmacological mechanisms. The N-type calcium channel had not been identified as a drug target for severe pain until ω-conotoxins were shown to be analgesic. Subsequently, small molecule drug candidates targeting N-type calcium channels were developed (10Hu L.Y. Ryder T.R. Rafferty M.F. Feng M.R. Lotarski S.M. Rock D.M. Sinz M. Stoehr S.J. Taylor C.P. Weber M.L. Bowersox S.S. Miljanich G.P. Millerman E. Wang Y.X. Szoke B.G. J. Med. Chem. 1999; 42: 4239-4249Crossref PubMed Scopus (41) Google Scholar, 11Snutch T.P. Zamponi G.W. Pajouhesh H. Pajouhesh H. Belardetti F. Neuromed Technologies I. 6. Neuromed, Vancouver BC, Canada2005: 1-12Google Scholar); some are now undergoing human clinical trials. Thus, even those Conus peptides not directly developed as therapeutics can be extremely valuable for identifying potential molecular targets for novel drugs. Conus venom peptides are being rapidly identified by using molecular cloning to deduce amino acid sequences. The continuously expanding data base provides an ever stronger case for extremely rapid diversification of genes encoding Conus peptides; each species has its own repertoire of 100–200 different venom peptides, distinct from that of any other species. Thus, living Conus are likely to express >70,000 different peptides in their venoms (3Terlau H. Olivera B.M. Physiol. Rev. 2004; 84: 41-68Crossref PubMed Scopus (804) Google Scholar). Most of this peptide diversity is generated by the greatly accelerated evolution of a few gene superfamilies; the nine superfamilies described to date are shown in Table 2; each Conus peptide gene encodes a precursor that typically has an N-terminal signal sequence of ∼25 amino acids, an intervening "pro" region (∼20–40 amino acids, depending on the gene superfamily), and at the C-terminal end, the mature toxin (10–40 amino acids for most superfamilies) in single copy (4Olivera B.M. Drugs from the Sea. Karger, Basel2000: 74-85Crossref Google Scholar). This rather conventional prepropeptide organization masks a striking and unconventional evolutionary pattern. Comparisons between superfamily genes from different Conus species reveal an extraordinary juxtaposition; signal sequences are conserved to an unprecedented degree but mature toxin regions are hypermutated (see Fig. 1). PCR primers designed from the conserved sequences make discovery of additional peptides in a superfamily using PCR straightforward. The predicted peptides can be chemically synthesized; for Conus peptides in the 10–25 amino acid size range, this is generally straightforward. One potential problem is the high frequency of post-translational modification in some Conus peptide families. The post-translational modification of Conus peptides was recently reviewed (12Buczek O. Bulaj G. Olivera B.M. Cell Mol. Life Sci. 2005; 62: 3067-3079Crossref PubMed Scopus (202) Google Scholar); more progress is needed to accurately predict post-translational modification a priori from cloned sequences.TABLE 2Conus venom peptide gene superfamiliesSuperfamily (Ref.)Cys pattern(s) (designated framework no.)Pharmacological familyaAdapted from Ref. 4; the individual conopeptide families and their targets are described in that review, which cites the primary literature.TargetaAdapted from Ref. 4; the individual conopeptide families and their targets are described in that review, which cites the primary literature.A (14Santos A.D. McIntosh J.M. Hillyard D.R. Cruz L.J. Olivera B.M. J. Biol. Chem. 2004; 279: 17596-17606Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar)CC-C-C(I/II)αNicotinic receptorsρα-Adrenergic receptorsA (16Teichert R.W. Rivier J. Dykert J. Cervini L. Gulyas J. Bulaj G. Ellison M. Olivera B.M. Toxicon. 2004; 44: 207-214Crossref PubMed Scopus (42) Google Scholar)CC-C-C-C-C(IV)αANicotinic receptorsκAK+ channels?M (15Corpuz G.P. Jacobsen R.B. Jimenez E.C. Watkins M. Walker C. Colledge C. Garrett J.E. McDougal O. Li W. Gray W.R. Hillyard D.R. Rivier J. McIntosh J.M. Cruz L.J. Olivera B.M. Biochemistry. 2005; 44: 8176-8186Crossref PubMed Scopus (82) Google Scholar)CC-C-C-CC(III)μNa+ channelsκMK+ channelsψNicotinic receptorsO (3Terlau H. Olivera B.M. Physiol. Rev. 2004; 84: 41-68Crossref PubMed Scopus (804) Google Scholar)C-C-CC-C-C(VI/VII)ωCa2+ channelsκK+ channelsδNa+ channelsT (31McIntosh J.M. Corpuz G.O. Layer R.T. Garrett J.E. Wagstaff J.D. Bulaj G. Vyazovkina A. Yoshikami D. Cruz L.J. Olivera B.M. J. Biol. Chem. 2000; 275: 32391-32397Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar)CC——CC(V)None definedUnknownT (32Walker C.S. Steel D. Jacobsen R.B. Lirazan M.B. Cruz L.J. Hooper D. Shetty R. de la Cruz R.C. Nielsen J.S. Zhou L.M. Bandyopadhyay P. Craig A.G. Olivera B.M. J. Biol. Chem. 1999; 274: 30664-30671Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar)CC——CXOCbThis Cys pattern was referred to as Framework X or as Framework I by different groups (22, 38).χCatecholamine transporterS (33Teichert R.W. Jimenez E.C. Olivera B.M. Biochemistry. 2005; 44: 7897-7902Crossref PubMed Scopus (42) Google Scholar, 34England L.J. Imperial J. Jacobsen R. Craig A.G. Gulyas J. Akhtar M. Rivier J. Julius D. Olivera B.M. Science. 1998; 281: 575-578Crossref PubMed Scopus (117) Google Scholar)C-C-C-C-C-C-C—C-C-C(VIII)σSerotonin (5HT3) receptorαSNicotinic receptorsP (35Lirazan M.B. Hooper D. Corpuz G.P. Ramilo C.A. Bandyopadhyay P. Cruz L.J. Olivera B.M. Biochemistry. 2000; 39: 1583-1588Crossref PubMed Scopus (65) Google Scholar)C-C-C-C-C-C(IX)None definedUnknownI1/I2 (36Buczek O. Yoshikami D. Watkins M. Bulaj G. Jimenez E.C. Olivera B.M. FEBS J. 2005; 272: 4178-4188Crossref PubMed Scopus (70) Google Scholar)C-C-CC-CC-C-C(XI)None definedK+ channelsJ (37Imperial J.S. Bansal P.S. Alewood P.F. Daly N.L. Craik D.J. Sporning A. Terlau H. Lopez-Vera E. Bandyopadhyay P. Olivera B.M. Biochemistry. 2006; (in press)PubMed Google Scholar)C-C-C-C(XIV)None definedK+ channels?a Adapted from Ref. 4Olivera B.M. Drugs from the Sea. Karger, Basel2000: 74-85Crossref Google Scholar; the individual conopeptide families and their targets are described in that review, which cites the primary literature.b This Cys pattern was referred to as Framework X or as Framework I by different groups (22McIntosh J.M. Gardner S. Luo S. Garrett J.E. Yoshikami D. Eur. J. Pharmacol. 2000; 393: 205-208Crossref PubMed Scopus (43) Google Scholar, 38Sharpe I.A. Gehrmann J. Loughnan M.L. Thomas L. Adams D.A. Atkins A. Palant E. Craik D.J. Adams D.J. Alewood P.F. Lewis R.J. Nat. Neurosci. 2001; 4: 902-907Crossref PubMed Scopus (219) Google Scholar). Open table in a new tab The mechanisms that underlie conopeptide gene hypermutation have not been elucidated. Although there is strong diversifying selection, the pattern and frequency of sequence changes suggest special mutational/recombination mechanisms targeting mature toxin regions preferentially (involvement of a mutagenic DNA polymerase has been specifically suggested) (13Conticello S.G. Gilad Y. Avidan N. Ben-Asher E. Levy Z. Fainzilber M. Mol. Biol. Evol. 2001; 18: 120-131Crossref PubMed Scopus (191) Google Scholar, 14Santos A.D. McIntosh J.M. Hillyard D.R. Cruz L.J. Olivera B.M. J. Biol. Chem. 2004; 279: 17596-17606Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). Notable genetic events that generated major groups of peptides in the A-superfamily have been described (14Santos A.D. McIntosh J.M. Hillyard D.R. Cruz L.J. Olivera B.M. J. Biol. Chem. 2004; 279: 17596-17606Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). In contrast to the mature peptide regions, other elements in Conus peptide genes are much more conserved (including some intronic regions). Signal sequences, usually the least conserved element of a secreted polypeptide, are so extremely conserved that unusual genetic events (such as gene conversion) seem likely to play a role in maintaining signal sequence conservation. Peptides of the same superfamily generally share a characteristic arrangement of Cys residues in the mature toxin region (the "Cys pattern"); each Cys pattern usually corresponds to a specific disulfide framework. However, in two gene superfamilies, each with a conserved Cys pattern, the disulfide connectivity changed as spacing of amino acids between Cys residues changed (15Corpuz G.P. Jacobsen R.B. Jimenez E.C. Watkins M. Walker C. Colledge C. Garrett J.E. McDougal O. Li W. Gray W.R. Hillyard D.R. Rivier J. McIntosh J.M. Cruz L.J. Olivera B.M. Biochemistry. 2005; 44: 8176-8186Crossref PubMed Scopus (82) Google Scholar, 16Teichert R.W. Rivier J. Dykert J. Cervini L. Gulyas J. Bulaj G. Ellison M. Olivera B.M. Toxicon. 2004; 44: 207-214Crossref PubMed Scopus (42) Google Scholar). Thus, although peptides in a gene superfamily usually have similar structures, groups of peptides with new disulfide scaffolds can occasionally evolve within a superfamily. How small peptides with multiple Cys residues are folded such that only one disulfide framework is formed in vivo is a fundamental issue not yet satisfactorily addressed; if oxidative folding is carried out in vitro, multiple disulfide isomers are generated; the peptide with the native scaffold must be purified from other folding isomers. Preliminary indications suggest that the "Pro" region of Conus peptide precursors contributes at least indirectly to facilitate correct folding (17Buczek O. Olivera B.M. Bulaj G. Biochemistry. 2004; 43: 1093-1101Crossref PubMed Scopus (51) Google Scholar, 18Bulaj G. Buczek O. Goodsell I. Jimenez E.C. Kranski J. Nielsen J.S. Garrett J.E. Olivera B.M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 14562-14568Crossref PubMed Scopus (75) Google Scholar). Conus peptide superfamilies have functionally differentiated; consequently, different peptides in the same superfamily may have different classes of physiological targets. Some examples are shown in Table 2; the M-superfamily includes the μ-conopeptide family (Na+ channel blockers), the κM-conopeptide family (K+ channel blockers), and the ψ-conopeptide family (non-competitive nicotinic receptor antagonists). These groups of peptides are genetically and structurally related with similar Cys patterns, disulfide scaffolds, and three-dimensional structures, but they have functionally diverged. In contrast, ligand sites of peptides in the same family are expected to be homologous (i.e. μ-conopeptide binding sites on various Na+ channel subtypes). However, within a single Conus peptide family, individual peptides may differ in targeting selectivity. α-Conopeptides are nicotinic receptor antagonists, but different α-conopeptides may target different receptor subtypes. Thus, a Conus peptide family can provide a ligand panel selective for different molecular isoforms of a general target class. An important corollary is that it is possible to change targeting specificity of Conus peptides by appropriate amino acid substitutions (for a specific example, see Ref. 19McIntosh J.M. Azam L. Staheli S. Dowell C. Lindstrom J.M. Kuryatov A. Garrett J.E. Marks M.J. Whiteaker P. Mol. Pharmacol. 2004; 65: 944-952Crossref PubMed Scopus (170) Google Scholar). Peptides that belong to different families may play analogous functional roles in different lineages of Conus species. Three different peptide families targeted to the KV1 subfamily of voltage-gated K+ channels, the κ-conotoxins, the conkunitzins (14Santos A.D. McIntosh J.M. Hillyard D.R. Cruz L.J. Olivera B.M. J. Biol. Chem. 2004; 279: 17596-17606Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar), and the κM conotoxins (18Bulaj G. Buczek O. Goodsell I. Jimenez E.C. Kranski J. Nielsen J.S. Garrett J.E. Olivera B.M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 14562-14568Crossref PubMed Scopus (75) Google Scholar), are completely unrelated genetically and structurally. Three different clades of fish-hunting cone snails each evolved peptides belonging to the three unrelated gene families for parallel physiological purposes (blocking the KV1 subfamily of K+ channels, as part of the "excitotoxic shock" strategy to rapidly immobilize fish prey) (20Imperial J.S. Silverton N. Olivera B.M. Bandyopadhyay P.K. Sporning A. Ferber M. Terlau H. Proceedings of the American Philosophical Society. 2006; (in press)Google Scholar, 21Terlau H. Shon K.J. Grilley M. Stocker M. Stuhmer W. Olivera B.M. Nature. 1996; 381: 148-151Crossref PubMed Scopus (252) Google Scholar). Although different clades of Conus species utilize different conopeptide families to inhibit the KV1 subfamily of K+ channels, all of these clades use the same family, the δ-conopeptides, to inhibit Na+ channel inactivation (20Imperial J.S. Silverton N. Olivera B.M. Bandyopadhyay P.K. Sporning A. Ferber M. Terlau H. Proceedings of the American Philosophical Society. 2006; (in press)Google Scholar). Thus some conopeptide families are found in a single clade comprising a few species, whereas others appear to be found in all ∼700 Conus species. In recent years, Conus peptide discovery has become more efficient by integrating phylogenetics into the discovery strategy. A prime example of systematic discovery using such a phylogenetically informed strategy has been the α-conopepide family peptides, which target nicotinic receptors. Some Conus species from which α-conotoxins have been characterized are shown in Fig. 1; major α-conopeptides from different species are shown. The first group analyzed were fish-hunting Conus belonging to one clade, the subgenus Pionoconus; the major α-conopeptides found belong to the same subfamily of α-conopeptides (the α3/5 subfamily) that specifically target the muscle nicotinic receptor subtype. Scanning different sequences of α3/5 subfamily peptides provides structure-function information; the pattern of amino acid conservation identifies the likely functionally important residues. By analyzing species less related to C. magus (in clades other than Pionoconus), other α-conopeptide subfamilies were identified. The worm-hunting species Conus imperialis, regius, and brunneus express peptides in the α4/3 subfamily, primarily targeted to homomeric nicotinic receptor subtypes (i.e. α7, α9, α10) (22McIntosh J.M. Gardner S. Luo S. Garrett J.E. Yoshikami D. Eur. J. Pharmacol. 2000; 393: 205-208Crossref PubMed Scopus (43) Google Scholar, 23Ellison M. McIntosh J.M. Olivera B.M. J. Biol. Chem. 2003; 278: 757-764Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 24Ellison M. Haberlandt C. Gomez-Casati M.E. Watkins M. Elgoyhen A.B. McIntosh J.M. Olivera B.M. Biochemistry. 2006; 45: 1511-1517Crossref PubMed Scopus (138) Google Scholar) instead of to the muscle subtype. Thus, a systematic sweep of biodiversity can be used to identify groups of peptides in the same family, which have diverged in target selectivity. Closely related species yield functionally homologous peptides; more divergent species express family members likely to have different (but related) molecular targets. This discovery strategy has provided the neuroscience community with a panel of α-conopeptides diagnostic for various nicotinic receptor subtypes. Every Conus species has a repertoire of 100–200 conopeptides with essentially no overlap between different species. The venom peptide families rapidly diversify. The conopeptide repertoire of a particular cone snail species mediates interactions between that species and its prey, predators, and competitors (2Olivera B.M. Rivier J. Clark C. Ramilo C.A. Corpuz G.P. Abogadie F.C. Mena E.E. Woodward S.R. Hillyard D.R. Cruz L.J. Science. 1990; 249: 257-263Crossref PubMed Scopus (514) Google Scholar). Thus venom peptide genes are sculpted by natural selection to the ecological singularities of the individual species. In any megadiverse group of related animals such as the cone snails, most of the genome would be expected to be largely conserved if the different species within the group were compared. In contrast, genes responsible for mediating interactions with other animals in the environment, such as the conopeptide genes, have to diversify rapidly because each species has its own ecological niche. The spectrum of biotic interactions of a species differs from that of all others; this is the perspective that rationalizes why a distinctive complement of venom peptides is found in each of the ∼700 different Conus species. Thus, the evolutionary history of such genes would be expected to be strikingly different from most of the rest of the genome, a hypothesis strongly supported by the accumulating data on Conus peptide genes. The rapidly diversifying genes encoding Conus peptides are, we believe, not at all unique in their evolutionary behavior; they are merely the first major class of such genes to have been characterized from a of related animal species. The rationale for why venom peptide genes rapidly diversify to the that in genes whose products on other animals in the will evolve extremely rapidly. other megadiverse animal rapidly diversifying genes should be a major genetic for The molecular genetic has been on a few and and these models provide a framework for genes that physiological Conus peptide genes are their gene products are exogenously Although the of different species in Conus is likely to be interactions with prey, predators, and competitors differ between species. The genes whose gene products on the of a different will be expected to a part of the genome greatly accelerated in its of is to this rapidly diversifying of the genome from the general class of genes by the particular to be to the evolution of the is accelerated may the to at a molecular The work on Conus peptide genes has revealed some and features an unprecedented of the of mature peptide regions with an conservation of signal sequences. these features be characteristic of genes in the of other megadiverse The unusual features of conopeptide genes may well be generally diagnostic of the of genes that diversify rapidly as genes comprising the these systematically differ in their organization from other genes, and to rapidly deduce and express or the gene products that they should into an that has potential for I and for their and this and J. and Cruz for that have generated the in this