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Recent data indicate that the HEV genome contains a highly heterogeneous hypervariable region (HVR) that can tolerate extensive genomic rearrangements, especially among immunocompromised patients. These rearrangements can increase HEV replication in tissue-culture and have further been observed in HEV-infected patients. Insertions comprise either duplications of virus-derived sequences, or alternatively, host-derived sequence fragments and exhibit enrichment of specific amino acids and functional motifs. However, the molecular mechanisms driving these insertions, as well as their functional significance, remain largely unexplored. Given that sequences not required for infectivity or replication are typically rapidly eliminated in small RNA viruses such as HEV, the persistence of HVR\u00a0insertions suggests a potential biological role in HEV replication and\/or pathogenesis. This review summarizes our current understanding of the role of HVR insertions during HEV infection, as well as the potential mechanisms underlying these insertions. We further discuss the factors driving the selection of genomic insertions and speculate on\u00a0their functional role by analyzing over 650 publicly available HEV genotype 3 genome sequences and systematically cataloging identified insertions.<\/jats:p>","DOI":"10.1038\/s42003-026-11055-5","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:52:31Z","timestamp":1792651951000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatitis E virus genome plasticity: a marker of chronicity and therapy failure?"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5675-674X","authenticated-orcid":false,"given":"Saskia","family":"Janshoff","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leyla","family":"Sirkinti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian K.","family":"Nocke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa S.","family":"Bechtel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"G\u00f6mer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannick","family":"Br\u00fcggemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eike","family":"Steinmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3292-6671","authenticated-orcid":false,"given":"Richard J. 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