{{short description|Clade of scaled reptiles}} {{automatic taxobox | name = Toxicoferans | fossil_range = {{fossilrange/linked|Bathonian|Present|ref=<ref>{{cite journal|last1=Marjanović|first1=D.|year=2021|title=The Making of Calibration Sausage Exemplified by Recalibrating the Transcriptomic Timetree of Jawed Vertebrates|journal=Frontiers in Genetics|volume=12|at=521693|doi=10.3389/fgene.2021.521693|doi-access=free |pmid=34054911 |pmc=8149952 }}</ref>}} | image = Mexican ridged nosed rattlesnake head.jpg | image_caption = Venomous snakes, such as the rattlesnake shown above, are the best-known venomous squamates | taxon = Toxicofera | authority = Vidal & Hedges, 2005 | subdivision_ranks = Subgroups | subdivision = * Anguimorpha * Iguania * Ophidia *†Mosasauria *†Polyglyphanodontia? *†Parviraptoridae? | synonyms = Pythonomorpha? }}
'''Toxicofera''' (Latin for "toxin-bearers") is a clade of scaled reptiles (squamates) that includes the Serpentes (snakes), Anguimorpha (monitor lizards, beaded lizards, and alligator lizards) and Iguania (iguanas, agamas, and chameleons). Toxicofera contains about 4,600 species (nearly 60%) of extant Squamata.<ref name="Fry2006">{{cite journal |doi=10.1038/nature04328 |pmid=16292255 |title=Early evolution of the venom system in lizards and snakes |journal=Nature |volume=439 |issue=7076 |pages=584–8 |year=2005 |last1=Fry |first1=Bryan G. |last2=Vidal |first2=Nicolas |last3=Norman |first3=Janette A. |last4=Vonk |first4=Freek J. |last5=Scheib |first5=Holger |last6=Ramjan |first6=S. F. Ryan |last7=Kuruppu |first7=Sanjaya |last8=Fung |first8=Kim |last9=Blair Hedges |first9=S. |last10=Richardson |first10=Michael K. |last11=Hodgson |first11=Wayne. C. |last12=Ignjatovic |first12=Vera |last13=Summerhayes |first13=Robyn |last14=Kochva |first14=Elazar |bibcode=2006Natur.439..584F |s2cid=4386245}}</ref> It encompasses all venomous reptile species, as well as numerous related non-venomous species. There is little morphological evidence to support this grouping; however, it has been recovered by all molecular analyses as of 2012.<ref>{{cite journal |doi=10.1016/j.crvi.2008.07.010 |pmid=19281946 |title=The molecular evolutionary tree of lizards, snakes, and amphisbaenians |journal=Comptes Rendus Biologies |volume=332 |issue=2–3 |pages=129–39 |year=2009 |last1=Vidal |first1=Nicolas |last2=Hedges |first2=S. Blair|s2cid=23137302 |url=https://comptes-rendus.academie-sciences.fr/biologies/articles/10.1016/j.crvi.2008.07.010/ |url-access=subscription }}</ref><ref>{{cite journal |doi=10.1186/1471-2148-13-93 |pmid=23627680 |pmc=3682911 |title=A phylogeny and revised classification of Squamata, including 4161 species of lizards and snakes |journal=BMC Evolutionary Biology |volume=13 |page=93 |year=2013 |last1=Pyron |first1=R. |last2=Burbrink |first2=Frank T. |last3=Wiens |first3=John J. |issue=1 |doi-access=free |bibcode=2013BMCEE..13...93P }}</ref><ref>{{cite journal |doi=10.1098/rsbl.2012.0703 |pmid=22993238 |pmc=3497141 |title=Resolving the phylogeny of lizards and snakes (Squamata) with extensive sampling of genes and species |journal=Biology Letters |volume=8 |issue=6 |pages=1043–6 |year=2012 |last1=Wiens |first1=J. J. |last2=Hutter |first2=C. R. |last3=Mulcahy |first3=D. G. |last4=Noonan |first4=B. P. |last5=Townsend |first5=T. M. |last6=Sites |first6=J. W. |last7=Reeder |first7=T. W.}}</ref>{{update inline|date=November 2023}}
== Cladistics == Toxicofera combines the following groups from traditional classification:<ref name="Fry2006" />
* Suborder Serpentes (snakes) * Suborder Iguania (iguanas, agamid lizards, chameleons, etc.) * Suborder Anguimorpha, consisting of: ** Family Varanidae (monitor lizards) ** Family Lanthanotidae (earless monitor lizard) ** Family Anguidae (alligator lizards, glass lizards, etc.) ** Family Helodermatidae (Gila monster and Mexican beaded lizard) ** Family Shinisauridae (Chinese crocodile lizard) ** Family Xenosauridae (knob-scaled lizards)
The relationship between these extant groups and a couple of extinct taxa are shown in the following cladogram, which is based on Reeder et al. (2015; Fig. 1).<ref name="Reeder2015">{{cite journal |doi=10.1371/journal.pone.0118199 |pmid=25803280 |pmc=4372529 |title=Integrated Analyses Resolve Conflicts over Squamate Reptile Phylogeny and Reveal Unexpected Placements for Fossil Taxa |journal=PLOS One |volume=10 |issue=3 |article-number=e0118199 |year=2015 |last1=Reeder |first1=Tod W. |last2=Townsend |first2=Ted M. |last3=Mulcahy |first3=Daniel G. |last4=Noonan |first4=Brice P. |last5=Wood |first5=Perry L. |last6=Sites |first6=Jack W. |last7=Wiens |first7=John J. |bibcode=2015PLoSO..1018199R |doi-access=free}}</ref> {{clade |label1='''Toxicofera''' |1={{clade |1={{clade |1=Serpentes 70 px |2={{extinct}}Mosasauria <span style="{{MirrorH}}">100 px</span> }} |2={{clade |1=Anguimorpha 70 px |2={{clade |1={{extinct}}Polyglyphanodontia 70 px |2=Iguania 70 px }} }} }} }}
Alongside these groups, Mosasauria, an extinct group including large marine reptiles primarily known from the Late Cretaceous, has been placed as part of the group. It has often been supposed that mosasaurs are most closely related to snakes, with the group containing the two dubbed Pythonomorpha, however, other studies have questioned this, finding that the closest relatives of mosasaurs are members of Varanoidea.<ref>{{Citation |last1=Polcyn |first1=Michael J. |title=Reassessing the Morphological Foundations of the Pythonomorph Hypothesis |date=2022-08-11 |work=The Origin and Early Evolutionary History of Snakes |pages=125–156 |editor-last=Gower |editor-first=David J. |url=https://www.cambridge.org/core/product/identifier/9781108938891%23CN-bp-7/type/book_part |access-date=2024-01-20 |edition=1 |publisher=Cambridge University Press |doi=10.1017/9781108938891.010 |isbn=978-1-108-93889-1 |last2=Augusta |first2=Bruno G. |last3=Zaher |first3=Hussam |editor2-last=Zaher |editor2-first=Hussam|url-access=subscription }}</ref> Polyglyphanodontia, a group of extinct herbivorous lizards known from the Cretaceous, have also been placed as part of this group in some studies as the sister group to Iguania, though other studies have instead suggested that they are most closely related to Teiioidea and thus placed outside Toxicofera.<ref name=":0">{{Cite journal |last1=Xing |first1=Lida |last2=Niu |first2=Kecheng |last3=Evans |first3=Susan E. |date=January 2023 |title=A new polyglyphanodontian lizard with a complete lower temporal bar from the Upper Cretaceous of southern China |journal=Journal of Systematic Palaeontology |language=en |volume=21 |issue=1 |doi=10.1080/14772019.2023.2281494 |issn=1477-2019|doi-access=free |bibcode=2023JSPal..2181494X }}</ref>
== Venom == {{Further|Evolution of snake venom}} Venom in squamates has historically been considered a rarity; while it has been known in Serpentes since ancient times, the actual percentage of snake species considered venomous was relatively small (around 25%).<ref name="Fry2009">{{cite journal |doi=10.1016/j.jprot.2009.01.009 |pmid=19457354 |title=Evolution and diversification of the Toxicofera reptile venom system |journal=Journal of Proteomics |volume=72 |issue=2 |pages=127–36 |year=2009 |last1=Fry |first1=Bryan G. |last2=Vidal |first2=Nicolas |last3=Van Der Weerd |first3=Louise |last4=Kochva |first4=Elazar |last5=Renjifo |first5=Camila}}</ref> Of the approximately 2,650 species of advanced snakes (Caenophidia), only the front-fanged species (≈650) were considered venomous by the anthropocentric definition. Following the classification of Helodermatidae in the 19th century, their venom was thought to have developed independently.<ref name="Fry2006" /> In snakes, the venom gland is in the upper jaw, but in helodermatids, it is found in the lower jaw.<ref name="Fry2006" /> The origin of venom in squamates was thus considered relatively recent in evolutionary terms and the result of convergent evolution among the seemingly-polyphyletic venomous snake families.{{citation needed|date=February 2012}}
In 2003 a study was published that described venom in snake subfamilies previously thought to lack it.<ref name="Fry2003">{{cite journal |doi=10.1007/s00239-003-2461-2 |pmid=12962311 |title=Molecular Evolution and Phylogeny of Elapid Snake Venom Three-Finger Toxins |journal=Journal of Molecular Evolution |volume=57 |issue=1 |pages=110–29 |year=2003 |last1=Fry |first1=B. G. |last2=Wüster |first2=W. |last3=Kini |first3=R. M. |last4=Brusic |first4=V. |last5=Khan |first5=A. |last6=Venkataraman |first6=D. |last7=Rooney |first7=A. P. |bibcode=2003JMolE..57..110F |citeseerx=10.1.1.539.324 |s2cid=12358977}}</ref> Further study claimed nearly all "non-venomous" snakes produce venom to a certain extent, suggesting a single, and thus far more ancient origin for venom in Serpentes than had been considered until then.<ref name="Fry2003-ratsnake">{{cite journal |doi=10.1007/s00239-003-2497-3 |pmid=14708577 |title=Isolation of a Neurotoxin (α-colubritoxin) from a Nonvenomous Colubrid: Evidence for Early Origin of Venom in Snakes |journal=Journal of Molecular Evolution |volume=57 |issue=4 |pages=446–52 |year=2003 |last1=Fry |first1=Bryan G. |last2=Lumsden |first2=Natalie G. |last3=Wüster |first3=Wolfgang |last4=Wickramaratna |first4=Janith C. |last5=Hodgson |first5=Wayne C. |last6=Manjunatha Kini |first6=R. |bibcode=2003JMolE..57..446F |s2cid=21055188}}</ref><ref name="Fry2004">{{cite journal |doi=10.1093/molbev/msh091 |pmid=15014162 |title=Assembling an Arsenal: Origin and Evolution of the Snake Venom Proteome Inferred from Phylogenetic Analysis of Toxin Sequences |journal=Molecular Biology and Evolution |volume=21 |issue=5 |pages=870–83 |year=2004 |last1=Fry |first1=B. G. |last2=Wüster |first2=W |doi-access=free}}</ref> As a practical matter, Fry cautioned:<ref>{{cite web |url=https://www.sciencedaily.com/releases/2003/12/031216075937.htm |title=Venom Hunt Finds 'Harmless' Snakes A Potential Danger |website=ScienceDaily |date=December 16, 2003}}</ref>
<blockquote> ''Some non-venomous snakes have been previously thought to have only mild 'toxic saliva'. But these results suggest that they actually possess true venoms. We even isolated from a rat snake'' [''Coelognathus radiatus'' (formerly known as ''Elaphe radiata'')<ref name="Fry2003-ratsnake" />]'', a snake common in pet stores, a typical cobra-style neurotoxin, one that is as potent as comparative toxins found in close relatives of the cobra. These snakes typically have smaller quantities of venom and lack fangs, but they can still deliver their venom via their numerous sharp teeth. But not all of these snakes are dangerous. It does mean, however, that we need to re-evaluate the relative danger of non-venomous snakes.'' </blockquote>
This prompted further research, which led to the discovery of venom (and venom genes) in species from groups which were not previously known to produce it, e.g. in Iguania (specifically ''Pogona barbata'' from the family Agamidae) and Varanidae (from ''Varanus varius'').<ref name="Fry2006" /> At the time, it was thought that this was the result of descent from a common venom-producing squamate ancestor; the hypothesis was described simply as the "venom clade" when first proposed to the scientific community.<ref name="Fry2006" /> The venom clade included Anguidae for phylogenetic reasons and adopted a previously suggested clade name: Toxicofera.<ref name="Vidal2005">{{cite journal |doi=10.1016/j.crvi.2005.10.001 |pmid=16286089 |title=The phylogeny of squamate reptiles (lizards, snakes, and amphisbaenians) inferred from nine nuclear protein-coding genes |journal=Comptes Rendus Biologies |volume=328 |issue=10–11 |pages=1000–8 |year=2005 |last1=Vidal |first1=Nicolas |last2=Hedges |first2=S. Blair|url=https://comptes-rendus.academie-sciences.fr/biologies/articles/10.1016/j.crvi.2005.10.001/ |url-access=subscription }}</ref>
This taxonomic rational, known currently as the "Toxicofera hypothesis," estimated that the common ancestral species that first developed venom in the venom clade lived on the order of 200 million years ago.<ref name="Fry2006" /> The venoms were thought to have evolved after genes normally active in various parts of the body duplicated and the copies found new use in the salivary glands,<ref name="Fry2003" /> though more recent research challenges the extent of this genetic recruitment to the venom system.<ref name=":1" />
Among snake families traditionally classified as venomous, the capacity seems to have evolved to extremes more than once by parallel evolution; 'non-venomous' snake lineages have either lost the ability to produce venom (but may still have lingering venom pseudogenes) or actually do produce venom in small quantities (e.g. 'toxic saliva'), likely sufficient to assist in small prey capture, but not normally causing harm to humans if bitten.{{citation needed|date=February 2012}}
The newly discovered diversity of squamate species producing venoms is a treasure trove for those seeking to develop new pharmaceutical drugs; many of these venoms lower blood pressure, for example.<ref name="Fry2006" /> Previously known venomous squamates have already provided the basis for medications such as Ancrod, Captopril, Eptifibatide, Exenatide and Tirofiban.{{citation needed|date=February 2012}}
The world's largest venomous lizard and the largest species of venomous land animal is the Komodo dragon.<ref name=":1">{{Cite journal |last=Hargreaves |first=Adam D. |last2=Swain |first2=Martin T. |last3=Hegarty |first3=Matthew J. |last4=Logan |first4=Darren W. |last5=Mulley |first5=John F. |date=August 2014 |title=Restriction and Recruitment—Gene Duplication and the Origin and Evolution of Snake Venom Toxins |url=https://academic.oup.com/gbe/article-lookup/doi/10.1093/gbe/evu166 |journal=Genome Biology and Evolution |language=en |volume=6 |issue=8 |pages=2088–2095 |doi=10.1093/gbe/evu166 |issn=1759-6653 |pmc=4231632 |pmid=25079342}}</ref>
=== Criticism === Other scientists such as Washington State University biologist Kenneth V. Kardong and toxicologists Scott A. Weinstein and Tamara L. Smith, have stated that the allegation of venom glands found in many of these animals "has had the effect of underestimating the variety of complex roles played by oral secretions in the biology of reptiles, produced a very narrow view of oral secretions and resulted in misinterpretation of reptilian evolution". According to these scientists "reptilian oral secretions contribute to many biological roles other than to quickly dispatch prey". These researchers concluded that, "Calling all in this clade venomous implies an overall potential danger that does not exist, misleads in the assessment of medical risks, and confuses the biological assessment of squamate biochemical systems".<ref name="Mackessy2009">{{cite book |last1=Weinstein |first1=Scott A. |last2=Smith |first2=Tamara L. |last3=Kardong |first3=Kenneth V. |editor=Stephen P. Mackessy |title=Handbook of Venoms and Toxins of Reptiles |chapter-url=https://books.google.com/books?id=x_vME799de4C&pg=PA84 |access-date=18 July 2013 |date=14 July 2009 |publisher=Taylor & Francis |isbn=978-1-4200-0866-1 |pages=76–84 |chapter=Reptile Venom Glands Form, Function, and Future |via=Google Books}}</ref>
More recent research has found that the majority of genes used to support the establishment of the Toxicofera clade were not uniquely expressed in venom and venom structures, but rather in multiple body structures and are likely to more closely reflect maintenance genes. This evidence, pointing to misinterpretation of phylogenetic trees and incomplete tissue sampling in formation of the Toxicofera hypothesis, places doubt on the assumption that the common ancestor of the clade was indeed venomous, and suggests instead that venom has evolved multiple times in reptiles.<ref>{{cite journal |doi=10.1016/j.toxicon.2014.10.004 |pmid=25449103 |title=Testing the Toxicofera: Comparative transcriptomics casts doubt on the single, early evolution of the reptile venom system |journal=Toxicon |volume=92 |pages=140–56 |year=2014 |last1=Hargreaves |first1=Adam D. |last2=Swain |first2=Martin T. |last3=Logan |first3=Darren W. |last4=Mulley |first4=John F. |bibcode=2014Txcn...92..140H |url=http://pure.aber.ac.uk/ws/files/5439440/Testing_the_Toxicofera_Comparative_transcriptomics_casts_doubt_on_the_single_early_evolution_of_the_reptile_venom_system.pdf}}</ref>
== References == {{Reflist}}
== External links == {{Commons category}} * [https://www.newscientist.com/article.ns?id=dn8331 Lizards' poisonous secret is revealed] November 16, 2005 * [http://www.livescience.com/animals/051117_lizard_venom.html The Surprising Origin of Venom Revealed] November 17, 2005 * [https://web.archive.org/web/20051125145127/http://www.corante.com/loom/archives/2005/11/21/which_came_first_the_snake_or_the_venom.php Which Came First, the Snake or the Venom?] November 21, 2005 * [https://www.sciencedaily.com/releases/2005/11/051122183250.htm Genealogy of scaly reptiles rewritten by new research] November 22, 2005 * [http://venomdoc.com/ Venomdoc Homepage], [https://web.archive.org/web/20080430215414/http://www.venomdoc.com/downloads/ Downloads] * [https://www.pbs.org/wnet/nature/venomcure/venom.html The Venom Cure: The Power of Poison] {{Webarchive|url=https://web.archive.org/web/20080725220955/https://www.pbs.org/wnet/nature/venomcure/venom.html |date=2008-07-25 }} * [http://www.nature.com/nature/podcast/v438/n7066/nature-2005-11-17.mp3 Nature Podcast November 17, 2005] (segment on the venom clade begins approximately 22 minutes into the program)
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Category:Toxicofera Category:Squamata Category:Toxicology Category:Phylogenetics Category:Evolutionary biology Category:Venomous reptiles Category:Taxa named by Nicolas Vidal