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These viruses replicate their genomes employing error-prone replicases. Thereby, they routinely generate a large \u2018cloud\u2019 of RNA genomes (quasispecies) which\u2014by trial and error\u2014comprehensively explore the sequence space available for functional RNA genomes that maintain the ability for efficient replication and immune escape. In this context, it is important to identify which RNA secondary structures in the sequence space of the HCV genome are conserved, likely due to functional requirements. Here, we provide the first genome-wide multiple sequence alignment (MSA) with the prediction of RNA secondary structures throughout all representative full-length HCV genomes. We selected 57 representative genomes by clustering all complete HCV genomes from the BV-BRC database based on k-mer distributions and dimension reduction and adding RefSeq sequences. We include annotations of previously recognized features for easy comparison to other studies. Our results indicate that mainly the core coding region, the C-terminal NS5A region, and the NS5B region contain secondary structure elements that are conserved beyond coding sequence requirements, indicating functionality on the RNA level. In contrast, the genome regions in between contain less highly conserved structures. The results provide a complete description of all conserved RNA secondary structures and make clear that functionally important RNA secondary structures are present in certain HCV genome regions but are largely absent from other regions. Full-genome alignments of all branches of\n                    <jats:italic>Hepacivirus C<\/jats:italic>\n                    are provided in the supplement.\n                  <\/jats:p>","DOI":"10.1038\/s41598-024-62897-0","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T04:03:58Z","timestamp":1719893038000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Comprehensive survey of conserved RNA secondary structures in full-genome alignment of Hepatitis C virus"],"prefix":"10.1038","volume":"14","author":[{"given":"Sandra","family":"Triebel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Lamkiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Ontiveros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blake","family":"Sweeney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5016-5191","authenticated-orcid":false,"given":"Peter F.","family":"Stadler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton I.","family":"Petrov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Niepmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manja","family":"Marz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,2]]},"reference":[{"key":"62897_CR1","unstructured":"Organization, W.\u00a0H. 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Gynecol. 142, 449\u2013456. https:\/\/doi.org\/10.1097\/AOG.0000000000005306 (2023).","journal-title":"Obstetr. Gynecol."},{"key":"62897_CR4","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinre.2020.101596","volume":"45","author":"F Roudot-Thoraval","year":"2021","unstructured":"Roudot-Thoraval, F. Epidemiology of hepatitis C virus infection. Clin. Res. Hepatol. Gastroenterol. 45, 101596. https:\/\/doi.org\/10.1016\/j.clinre.2020.101596 (2021).","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"62897_CR5","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1126\/science.2523562","volume":"244","author":"Q-L Choo","year":"1989","unstructured":"Choo, Q.-L. et al. Isolation of a cDNA cLone derived from a blood-borne non-A, non-B viral Hepatitis genome. Science 244, 359\u2013362. https:\/\/doi.org\/10.1126\/science.2523562 (1989).","journal-title":"Science"},{"key":"62897_CR6","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1126\/science.2496467","volume":"244","author":"G Kuo","year":"1989","unstructured":"Kuo, G. et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 244, 362\u2013364. https:\/\/doi.org\/10.1126\/science.2496467 (1989).","journal-title":"Science"},{"key":"62897_CR7","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1128\/jvi.65.3.1105-1113.1991","volume":"65","author":"A Takamizawa","year":"1991","unstructured":"Takamizawa, A. et al. Structure and organization of the hepatitis C virus genome isolated from human carriers. J. Virol. 65, 1105\u20131113. https:\/\/doi.org\/10.1128\/jvi.65.3.1105-1113.1991 (1991).","journal-title":"J. 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