{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T09:39:14Z","timestamp":1786527554020,"version":"build-2736575974"},"reference-count":92,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["22-15-00230-\u041f"],"award-info":[{"award-number":["22-15-00230-\u041f"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"award":["22-15-00230-\u041f"],"award-info":[{"award-number":["22-15-00230-\u041f"]}],"id":[{"id":"https:\/\/ror.org\/03y2gwe85","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Bovine viral diarrhea virus (BVDV) is a pathogen of globally significance in cattle that has two biotypes: non-cytopathogenic (non-cp) and cytopathogenic (cp). The cp biotype arises from the non-cp through genome rearrangements, which frequently involve the insertion of host cellular RNA sequences, often accompanied by viral genome duplications. Here, we performed a systematic analysis of insertions across all complete BVDV genomes available in GenBank. Despite a 10-fold increase in available sequences over the past 10 years (from 59 to 670), the repertoire of known rearrangements associated with the cp phenotype has expanded only modestly, with insertions occurring predominantly at five conserved genomic hotspots. Notably, independent acquisitions of similar insertions\u2014such as DNAJC14 (Jiv), ubiquitin-like sequences, the NS4B-NS5A cleavage site, and the PYPDPQTLG motif\u2014in phylogenetically unrelated virus lineages reflect a limited number of permissive sites. Our analysis further demonstrates that many insertions are mosaic and suggests multiple recombination events that are poorly compatible with template switching by viral polymerase. Mechanistically, we propose that non-replicative recombination provides the most consistent explanation for the observed insertion patterns, particularly common coupling of cellular RNA acquisitions with viral sequence duplications. Both the steric proximity of virus replication to the endoplasmic reticulum and the RNA end requirements (2\u2032-3\u2032 cyclic phosphate and 5\u2032-OH) suggest that non-replicative recombination is likely mediated by the endoplasmic reticulum-associated IRE1 RNase and RtcB ligase, which are responsible for the alternative cytoplasmic splicing of cellular mRNA.<\/jats:p>","DOI":"10.3390\/v18080886","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T09:11:36Z","timestamp":1786525896000},"page":"886","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive Analysis of Insertions in BVDV and Implications for Non-Homologous Recombination Mechanisms"],"prefix":"10.3390","volume":"18","author":[{"given":"Fedor","family":"Perelygin","sequence":"first","affiliation":[{"name":"Martsinovsky Institute of Medical Parasitology, Tropical and Vector Borne Diseases, Sechenov First Moscow State Medical University, 119435 Moscow, Russia"},{"name":"Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2791-1835","authenticated-orcid":false,"given":"Yulia","family":"Aleshina","sequence":"additional","affiliation":[{"name":"Martsinovsky Institute of Medical Parasitology, Tropical and Vector Borne Diseases, Sechenov First Moscow State Medical University, 119435 Moscow, Russia"},{"name":"Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Chistiakova","sequence":"additional","affiliation":[{"name":"Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7297-040X","authenticated-orcid":false,"given":"Artem","family":"Orlov","sequence":"additional","affiliation":[{"name":"Martsinovsky Institute of Medical Parasitology, Tropical and Vector Borne Diseases, Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Lukashev","sequence":"additional","affiliation":[{"name":"Martsinovsky Institute of Medical Parasitology, Tropical and Vector Borne Diseases, Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.vetmic.2013.03.010","article-title":"Bovine Viral Diarrhea Virus (BVDV) Infections in Pigs","volume":"165","author":"Tao","year":"2013","journal-title":"Vet. 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