title: Medically important differences in snake venom composition are dictated by distinct postgenomic mechanisms.
abstract: Variation in venom composition is a ubiquitous phenomenon in snakes and occurs both interspecifically and intraspecifically. Venom variation can have severe outcomes for snakebite victims by rendering the specific antibodies found in antivenoms ineffective against heterologous toxins found in different venoms. The rapid evolutionary expansion of different toxin-encoding gene families in different snake lineages is widely perceived as the main cause of venom variation. However, this view is simplistic and disregards the understudied influence that processes acting on gene transcription and translation may have on the production of the venom proteome. Here, we assess the venom composition of six related viperid snakes and compare interspecific changes in the number of toxin genes, their transcription in the venom gland, and their translation into proteins secreted in venom. Our results reveal that multiple levels of regulation are responsible for generating variation in venom composition between related snake species. We demonstrate that differential levels of toxin transcription, translation, and their posttranslational modification have a substantial impact upon the resulting venom protein mixture. Notably, these processes act to varying extents on different toxin paralogs found in different snakes and are therefore likely to be as important as ancestral gene duplication events for generating compositionally distinct venom proteomes. Our results suggest that these processes may also contribute to altering the toxicity of snake venoms, and we demonstrate how this variability can undermine the treatment of a neglected tropical disease, snakebite.
authors.affiliation: Alistair Reid Venom Research Unit andMolecular Ecology and Evolution Group, School of Biological Sciences, Bangor University, Bangor LL57 2UW, United Kingdom; and n.r.casewell@liv.ac.uk.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Casewell
authors.affiliation: Bioinformatics Unit, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom;
authors.forename: Simon C
authors.initials: SC
authors.lastname: Wagstaff
authors.affiliation: Molecular Ecology and Evolution Group, School of Biological Sciences, Bangor University, Bangor LL57 2UW, United Kingdom; and.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wüster
authors.affiliation: Alistair Reid Venom Research Unit and.
authors.forename: Darren A N
authors.initials: DA
authors.lastname: Cook
authors.affiliation: Alistair Reid Venom Research Unit and.
authors.forename: Fiona M S
authors.initials: FM
authors.lastname: Bolton
authors.affiliation: Alistair Reid Venom Research Unit and.
authors.forename: Sarah I
authors.initials: SI
authors.lastname: King
authors.affiliation: Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, 11 46010 Valencia, Spain.
authors.forename: Davinia
authors.initials: D
authors.lastname: Pla
authors.affiliation: Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, 11 46010 Valencia, Spain.
authors.forename: Libia
authors.initials: L
authors.lastname: Sanz
authors.affiliation: Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, 11 46010 Valencia, Spain.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Calvete
authors.affiliation: Alistair Reid Venom Research Unit and.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harrison
mesh_terms: D000818:Animals; D003435:Crotalid Venoms / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D005786:Gene Expression Regulation / Q000502:physiology; D058069:Neglected Diseases / Q000188:drug therapy; D014176:Protein Biosynthesis / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D012909:Snake Bites / Q000188:drug therapy; D013045:Species Specificity; D014158:Transcription, Genetic / Q000502:physiology; D017819:Viperidae / Q000235:genetics / Q000378:metabolism
chemical_list: D003435:Crotalid Venoms; D020543:Proteome