{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T12:07:28Z","timestamp":1788955648407,"version":"build-2803163510"},"reference-count":59,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2017,12,19]],"date-time":"2017-12-19T00:00:00Z","timestamp":1513641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>The Genome Aggregation Database presently contains &gt;120,000 human genomes. We searched in this database for the presence of mutations at the sites of tetanus (TeNT) and botulinum neurotoxins (BoNTs) cleavages of the three SNARE proteins: VAMP, SNAP-25 and Syntaxin. These mutations could account for some of the BoNT\/A resistant patients. At the same time, this approach was aimed at testing the possibility that TeNT and BoNT may have acted as selective agents in the development of resistance to tetanus or botulism. We found that mutations of the SNARE proteins are very rare and concentrated outside the SNARE motif required for the formation of the SNARE complex involved in neuroexocytosis. No changes were found at the BoNT cleavage sites of VAMP and syntaxins and only one very rare mutation was found in the essential C-terminus region of SNAP-25, where Arg198 was replaced with a Cys residue. This is the P1\u2019 cleavage site for BoNT\/A and the P1 cleavage site for BoNT\/C. We found that the Arg198Cys mutation renders SNAP-25 resistant to BoNT\/A. Nonetheless, its low frequency (1.8 \u00d7 10\u22125) indicates that mutations of SNAP-25 at the BoNT\/A cleavage site are unlikely to account for the existence of BoNT\/A resistant patients. More in general, the present findings indicate that tetanus and botulinum neurotoxins have not acted as selective agents during human evolution as it appears to have been the case for tetanus in rats and chicken.<\/jats:p>","DOI":"10.3390\/toxins9120404","type":"journal-article","created":{"date-parts":[[2017,12,19]],"date-time":"2017-12-19T10:48:40Z","timestamp":1513680520000},"page":"404","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["High Conservation of Tetanus and Botulinum Neurotoxins Cleavage Sites on Human SNARE Proteins Suggests That These Pathogens Exerted Little or No Evolutionary Pressure on Humans"],"prefix":"10.3390","volume":"9","author":[{"given":"Stefan","family":"Carle","sequence":"first","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4127-254X","authenticated-orcid":false,"given":"Marco","family":"Pirazzini","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58\/B, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6113-3857","authenticated-orcid":false,"given":"Ornella","family":"Rossetto","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58\/B, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Barth","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesare","family":"Montecucco","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58\/B, 35131 Padova, Italy"},{"name":"Institute for Neuroscience, National Research Council, Via Ugo Bassi 58\/B, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"Auton","year":"2015","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/nature11690","article-title":"Analysis of 6515 exomes reveals the recent origin of most human protein-coding variants","volume":"493","author":"Fu","year":"2013","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"159","DOI":"10.7326\/M17-0188","article-title":"The impact of whole-genome sequencing on the primary care and outcomes of healthy adult patients: A pilot randomized trial","volume":"167","author":"Vassy","year":"2017","journal-title":"Ann. 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