{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:35:20Z","timestamp":1787506520973,"version":"build-2736575974"},"reference-count":52,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T00:00:00Z","timestamp":1675296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Limnological Institute, Siberian Branch of the Russian Academy of Sciences","award":["121032300196-8"],"award-info":[{"award-number":["121032300196-8"]}]},{"name":"Irkutsk Antiplague Research Institute of Siberia and the Far East","award":["121032300196-8"],"award-info":[{"award-number":["121032300196-8"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We evaluated the temporal signal and substitution rate of tick-borne encephalitis virus (TBEV) using 276 complete open reading frame (ORF) sequences with known collection dates. According to a permutation test, the TBEV Siberian subtype (TBEV-S) data set has no temporal structure and cannot be applied for substitution rate estimation without other TBEV subtypes. The substitution rate obtained suggests that the common clade of TBEV (TBEV-common), including all TBEV subtypes and louping-ill virus (LIV), is characterized by the lowest rate (1.87 \u00d7 10\u22125 substitutions per site per year (s\/s\/y) or 1 nucleotide substitution per ORF per 4.9 years; 95% highest posterior density (HPD) interval, 1.3\u20132.4 \u00d7 10\u22125 s\/s\/y) among all tick-borne flaviviruses previously assessed. Within TBEV-common, the TBEV European subtype (TBEV-E) has the lowest substitution rate (1.3 \u00d7 10\u22125 s\/s\/y or 1 nucleotide substitution per ORF per 7.5 years; 95% HPD, 1.0\u20131.8 \u00d7 10\u22125 s\/s\/y) as compared with TBEV Far-Eastern subtype (3.0 \u00d7 10\u22125 s\/s\/y or 1 nucleotide substitution per ORF per 3.2 years; 95% HPD, 1.6\u20134.5 \u00d7 10\u22125 s\/s\/y). TBEV-common representing the species tick-borne encephalitis virus diverged 9623 years ago (95% HPD interval, 6373\u201313,208 years). The TBEV Baikalian subtype is the youngest one (489 years; 95% HPD, 291\u2013697 years) which differs significantly by age from TBEV-E (848 years; 95% HPD, 596\u20131112 years), LIV (2424 years; 95% HPD, 1572\u20133400 years), TBEV-FE (1936 years, 95% HPD, 1344\u20132598 years), and the joint clade of TBEV-S (2505 years, 95% HPD, 1700\u20133421 years) comprising Vasilchenko, Zausaev, and Baltic lineages.<\/jats:p>","DOI":"10.3390\/ijms24032921","type":"journal-article","created":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T02:35:10Z","timestamp":1675391710000},"page":"2921","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Dates and Rates of Tick-Borne Encephalitis Virus\u2014The Slowest Changing Tick-Borne Flavivirus"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4422-0497","authenticated-orcid":false,"given":"Artem N.","family":"Bondaryuk","sequence":"first","affiliation":[{"name":"Laboratory of Natural Focal Viral Infections, Irkutsk Antiplague Research Institute of Siberia and the Far East, 664047 Irkutsk, Russia"},{"name":"Limnological Institute, Siberian Branch of the Russian Academy of Sciences, 664033 Irkutsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5762-8817","authenticated-orcid":false,"given":"Nina V.","family":"Kulakova","sequence":"additional","affiliation":[{"name":"Department of Biodiversity and Biological Resources, Siberian Institute of Plant Physiology and Biochemistry, Siberian Branch of the Russian Academy of Sciences, 664033 Irkutsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1188-7351","authenticated-orcid":false,"given":"Olga I.","family":"Belykh","sequence":"additional","affiliation":[{"name":"Limnological Institute, Siberian Branch of the Russian Academy of Sciences, 664033 Irkutsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4534-3846","authenticated-orcid":false,"given":"Yurij S.","family":"Bukin","sequence":"additional","affiliation":[{"name":"Limnological Institute, Siberian Branch of the Russian Academy of Sciences, 664033 Irkutsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,2]]},"reference":[{"key":"ref_1","unstructured":"Dobler, G., Erber, W., Br\u00f6ker, M., and Schmitt, H.J. (2022). The TBE Book, Global Health Press. [5th ed.]."},{"key":"ref_2","unstructured":"Dobler, G., Erber, W., Br\u00f6ker, M., and Schmitt, H.J. (2022). The TBE Book, Global Health Press. [5th ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1146\/annurev.mi.44.100190.003245","article-title":"Flavivirus genome organization, expression, and replication","volume":"44","author":"Chambers","year":"1990","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_4","first-page":"53","article-title":"Characteristics of the Baikal Subtype of Tick-Borne Encephalitis Virus Circulating in Eastern Siberia","volume":"3","author":"Kozlova","year":"2018","journal-title":"Acta Biomed. Sci. East Sib. Biomed. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/s41426-018-0081-6","article-title":"A new subtype of eastern tick-borne encephalitis virus discovered in Qinghai-Tibet Plateau, China","volume":"7","author":"Dai","year":"2018","journal-title":"Emerg. Microbes Infect."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.meegid.2017.10.020","article-title":"New genetic lineage within the Siberian subtype of tick-borne encephalitis virus found in Western Siberia, Russia","volume":"56","author":"Tkachev","year":"2017","journal-title":"Infect. Genet. Evol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1900658","DOI":"10.2807\/1560-7917.ES.2019.24.47.1900658","article-title":"Detection of new endemic focus of tick-borne encephalitis virus (TBEV), Hampshire\/Dorset border, England, September 2019","volume":"24","author":"Holding","year":"2019","journal-title":"Eurosurveillance"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Deviatkin, A.A., Karganova, G.G., Vakulenko, Y.A., and Lukashev, A.N. (2020). TBEV Subtyping in Terms of Genetic Distance. Viruses, 12.","DOI":"10.3390\/v12111240"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1099\/vir.0.035766-0","article-title":"Rate of evolution and molecular epidemiology of tick-borne encephalitis virus in Europe, including two isolations from the same focus 44 years apart","volume":"93","author":"Sironen","year":"2012","journal-title":"J. Gen. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.virol.2006.09.015","article-title":"Genetic characterization of tick-borne flaviviruses: New insights into evolution, pathogenetic determinants and taxonomy","volume":"361","author":"Grard","year":"2007","journal-title":"Virology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"107411","DOI":"10.1016\/j.ympev.2022.107411","article-title":"Delimitation of the tick-borne flaviviruses. Resolving the tick-borne encephalitis virus and louping-ill virus paraphyletic taxa","volume":"169","author":"Bondaryuk","year":"2022","journal-title":"Mol. Phylogenet. Evol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Deviatkin, A.A., Kholodilov, I.S., Vakulenko, Y.A., Karganova, G.G., and Lukashev, A.N. (2020). Tick-Borne Encephalitis Virus: An Emerging Ancient Zoonosis?. Viruses, 12.","DOI":"10.3390\/v12020247"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1093\/molbev\/msv056","article-title":"The Performance of the Date-Randomization Test in Phylogenetic Analyses of Time-Structured Virus Data","volume":"32","author":"Duchene","year":"2015","journal-title":"Mol. Biol. Evol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"veaa061","DOI":"10.1093\/ve\/veaa061","article-title":"Temporal signal and the phylodynamic threshold of SARS-CoV-2","volume":"6","author":"Duchene","year":"2020","journal-title":"Virus Evol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3363","DOI":"10.1093\/molbev\/msaa163","article-title":"Bayesian Evaluation of Temporal Signal in Measurably Evolving Populations","volume":"37","author":"Duchene","year":"2020","journal-title":"Mol. Biol. Evol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Clark, J.J., Gilray, J., Orton, R.J., Baird, M., Wilkie, G., Filipe, A.D.S., Johnson, N., McInnes, C.J., Kohl, A., and Biek, R. (2020). Population genomics of louping ill virus provide new insights into the evolution of tick-borne flaviviruses. PLoS Negl. Trop. Dis., 14.","DOI":"10.1101\/2020.02.14.949230"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1098\/rstb.2010.0060","article-title":"Viral phylodynamics and the search for an \u2018effective number of infections\u2019","volume":"365","author":"Frost","year":"2010","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8663","DOI":"10.1128\/JVI.01013-12","article-title":"Revisiting the clinal concept of evolution and dispersal for the tick-borne flaviviruses by using phylogenetic and biogeographic analyses","volume":"86","author":"Heinze","year":"2012","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1016\/j.ttbdis.2019.06.006","article-title":"\u201c886-84-like\u201d tick-borne encephalitis virus strains: Intraspecific status elucidated by comparative genomics","volume":"10","author":"Adelshin","year":"2019","journal-title":"Ticks Tick Borne Dis."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Vogels, C.B.F., Brackney, D.E., Dupuis, A.P., Robich, R.M., Fauver, J.R., Brito, A.F., Williams, S.C., Anderson, J.F., Lubelczyk, C.B., and Lange, R.E. (2022). Phylogeographic reconstruction of the emergence and spread of Powassan virus in the northeastern United States. bioRxiv.","DOI":"10.1101\/2022.10.14.512245"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1002\/jmv.23856","article-title":"The deduced evolution history of Omsk hemorrhagic fever virus","volume":"86","author":"Karan","year":"2014","journal-title":"J. Med. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1038\/s41598-020-58242-w","article-title":"Phylogeography of Kyasanur Forest Disease virus in India (1957\u20132017) reveals evolution and spread in the Western Ghats region","volume":"10","author":"Yadav","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/s41426-018-0082-5","article-title":"Re-visiting the evolution, dispersal and epidemiology of Zika virus in Asia","volume":"7","author":"Pettersson","year":"2018","journal-title":"Emerg. Microbes Infect."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"45505","DOI":"10.1038\/srep45505","article-title":"Global evolutionary history and spatio-temporal dynamics of dengue virus type 2","volume":"7","author":"Wei","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Schuh, A.J., Ward, M.J., Brown, A.J., and Barrett, A.D. (2013). Phylogeography of Japanese encephalitis virus: Genotype is associated with climate. PLoS Negl. Trop. Dis., 7.","DOI":"10.1371\/journal.pntd.0002411"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7385","DOI":"10.1038\/s41598-017-07873-7","article-title":"Phylodynamics of Yellow Fever Virus in the Americas: New insights into the origin of the 2017 Brazilian outbreak","volume":"7","author":"Mir","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1038\/s41564-020-0771-4","article-title":"Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic","volume":"5","author":"Boni","year":"2020","journal-title":"Nat. Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"735","DOI":"10.3389\/fmicb.2020.00735","article-title":"The Phylodynamics of Seasonal Influenza A\/H1N1pdm Virus in China between 2009 and 2019","volume":"11","author":"Ma","year":"2020","journal-title":"Front. Microbiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/nature19827","article-title":"1970s and \u2018Patient 0\u2019 HIV-1 genomes illuminate early HIV\/AIDS history in North America","volume":"539","author":"Worobey","year":"2016","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1099\/0022-1317-79-5-981","article-title":"Tracing the origins of louping ill virus by molecular phylogenetic analysis","volume":"79","author":"McGuire","year":"1998","journal-title":"J. Gen. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Bondaryuk, A.N., Peretolchina, T.E., Romanova, E.V., Yudinceva, A.V., Andaev, E.I., and Bukin, Y.S. (2021). Phylogeography and Re-Evaluation of Evolutionary Rate of Powassan Virus Using Complete Genome Data. Biology, 10.","DOI":"10.3390\/biology10121282"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1111\/j.1755-0998.2011.02988.x","article-title":"Skyline-plot methods for estimating demographic history from nucleotide sequences","volume":"11","author":"Ho","year":"2011","journal-title":"Mol. Ecol. Resour."},{"key":"ref_33","first-page":"353","article-title":"The Little Ice Age in Scientific Perspective: Cold Spells and Caveats","volume":"44","author":"Hellmann","year":"2014","journal-title":"J. Interdiscip. Hist."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1126\/science.1177303","article-title":"Global signatures and dynamical origins of the Little Ice Age and Medieval Climate Anomaly","volume":"326","author":"Mann","year":"2009","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/j.0435-3676.2005.00242.x","article-title":"The \u2018little ice age\u2019: Re-evaluation of an evolving concept","volume":"87","author":"Matthews","year":"2016","journal-title":"Geogr. Ann. Ser. A Phys. Geogr."},{"key":"ref_36","first-page":"249","article-title":"Ecology and Environmental Degradation of Two Little Ice Age Earthlodge Villages in North Dakota: The Micromammal Evidence","volume":"95","author":"Semken","year":"2014","journal-title":"Wis. Archeol."},{"key":"ref_37","first-page":"313","article-title":"Post-glacial colonization of Europe by the wood mouse, Apodemus sylvaticus: Evidence of a northern refugium and dispersal with humans","volume":"120","author":"Herman","year":"2016","journal-title":"Biol. J. Linn. Soc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/sj.hdy.6800561","article-title":"So close and so different: Comparative phylogeography of two small mammal species, the yellow-necked fieldmouse (Apodemus flavicollis) and the woodmouse (Apodemus sylvaticus) in the Western Palearctic region","volume":"94","author":"Michaux","year":"2005","journal-title":"Heredity"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1007\/s11430-006-2027-4","article-title":"Humid Little Ice Age in arid central Asia documented by Bosten Lake, Xinjiang, China","volume":"49","author":"Chen","year":"2006","journal-title":"Sci. China Ser. D Earth Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1353\/jem.2013.0008","article-title":"Did the Little Ice Age Affect Indoor Climate and Comfort?: Re-theorizing Climate History and Architecture from the Early Modern Period","volume":"13","author":"Eriksdotter","year":"2013","journal-title":"J. Early Mod. Cult. Stud."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"107531","DOI":"10.1016\/j.quascirev.2022.107531","article-title":"The variable European Little Ice Age","volume":"287","author":"Wanner","year":"2022","journal-title":"Quat. Sci. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Heller, R., Chikhi, L., and Siegismund, H.R. (2013). The confounding effect of population structure on Bayesian skyline plot inferences of demographic history. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0062992"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"39","DOI":"10.17116\/molgen20213903139","article-title":"Phylogenetic analysis of European subtype strains of tick-borne encephalitis virus isolated in the territory of Siberia (Russia)","volume":"39","author":"Bondaryuk","year":"2021","journal-title":"Mol. Genet. Microbiol. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1093\/molbev\/msy073","article-title":"DAMBE7: New and Improved Tools for Data Analysis in Molecular Biology and Evolution","volume":"35","author":"Xia","year":"2018","journal-title":"Mol. Biol. Evol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1055-7903(02)00326-3","article-title":"An index of substitution saturation and its application","volume":"26","author":"Xia","year":"2003","journal-title":"Mol. Phylogenet. Evol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"vew007","DOI":"10.1093\/ve\/vew007","article-title":"Exploring the temporal structure of heterochronous sequences using TempEst (formerly Path-O-Gen)","volume":"2","author":"Rambaut","year":"2016","journal-title":"Virus Evol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/nmeth.4285","article-title":"ModelFinder: Fast model selection for accurate phylogenetic estimates","volume":"14","author":"Kalyaanamoorthy","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1093\/molbev\/msu300","article-title":"IQ-TREE: A fast and effective stochastic algorithm for estimating maximum-likelihood phylogenies","volume":"32","author":"Nguyen","year":"2015","journal-title":"Mol. Biol. Evol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Drummond, A.J., and Bouckaert, R.R. (2015). Bayesian Evolutionary Analysis with BEAST, Cambridge University Press.","DOI":"10.1017\/CBO9781139095112"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Bouckaert, R., Vaughan, T.G., Barido-Sottani, J., Duchene, S., Fourment, M., Gavryushkina, A., Heled, J., Jones, G., Kuhnert, D., and De Maio, N. (2019). BEAST 2.5: An advanced software platform for Bayesian evolutionary analysis. PLoS Comput. Biol., 15.","DOI":"10.1371\/journal.pcbi.1006650"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1093\/sysbio\/syy032","article-title":"Posterior summarization in Bayesian phylogenetics using tracer 1.7","volume":"67","author":"Rambaut","year":"2018","journal-title":"Syst. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1093\/molbev\/msi103","article-title":"Bayesian coalescent inference of past population dynamics from molecular sequences","volume":"22","author":"Drummond","year":"2005","journal-title":"Mol. Biol. Evol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2921\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:22:29Z","timestamp":1760120549000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2921"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,2]]},"references-count":52,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24032921"],"URL":"https:\/\/doi.org\/10.3390\/ijms24032921","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,2]]}}}