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Recent large-scale metagenomic surveys have identified many diverse RNA viruses related to classical orthoflaviviruses and pestiviruses but quite different genome lengths and configurations, and with a hugely expanded host range that spans multiple animal phyla, including molluscs, cnidarians and stramenopiles,, and plants. Grouping of RNA-directed RNA polymerase (RdRP) hallmark gene sequences of flavivirus and \u2018flavi-like\u2019 viruses into four divergent clades and multiple lineages within them was congruent with helicase gene phylogeny, PPHMM profile comparisons, and comparison of RdRP protein structure predicted by AlphFold2. These results support their classification into the established order,\n                  <jats:italic>Amarillovirales<\/jats:italic>\n                  , in three families (\n                  <jats:italic>Flaviviridae, Pestiviridae<\/jats:italic>\n                  , and\n                  <jats:italic>Hepaciviridae<\/jats:italic>\n                  ), and 14 genera. This taxonomic framework informed by RdRP hallmark gene evolutionary relationships provides a stable reference from which major genome re-organisational events can be understood.\n                <\/jats:p>","DOI":"10.1101\/2025.01.17.632993","type":"posted-content","created":{"date-parts":[[2025,1,18]],"date-time":"2025-01-18T07:25:12Z","timestamp":1737185112000},"source":"Crossref","is-referenced-by-count":5,"title":["Integrated analysis of protein sequence and structure redefines viral diversity and the taxonomy of the\n                  <i>Flaviviridae<\/i>"],"prefix":"10.64898","author":[{"given":"Peter","family":"Simmonds","sequence":"first","affiliation":[{"name":"Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anamarija","family":"Butkovi\u0107","sequence":"additional","affiliation":[{"name":"Archaeal Virology Unit, Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, CNRS UMR6047, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe","family":"Grove","sequence":"additional","affiliation":[{"name":"MRC- University of Glasgow Centre for Virus Research, Glasgow, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1915-4993","authenticated-orcid":false,"given":"Richard","family":"Mayne","sequence":"additional","affiliation":[{"name":"Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8934-9193","authenticated-orcid":false,"given":"Jonathon C. 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