{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:16:58Z","timestamp":1791944218050,"version":"4.3.4"},"reference-count":99,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatitis B virus (HBV) genotype F is one of the most genetically divergent and evolutionarily ancient HBV lineages and predominantly circulates in indigenous and admixed populations of the Americas. Here, we performed a comprehensive evolutionary and inferred functional characterization of the HBV genotype F via the largest curated dataset of complete genomes. Phylogenomic reconstruction, recombination screening, and phylogenetic network analyses were integrated with codon-based selective pressure inference, surface protein posttranslational modification profiling, mutational analysis of antigenic regions, and reverse transcriptase (RT) drug resistance assessment. The HBV-F subgenotype exhibited a well-resolved phylogenetic structure and limited intragenotypic recombination, while intergenotypic recombination contributed substantially to reticulate evolutionary signals. Selective pressure analyses revealed strong purifying selection in replication-associated domains of the polymerase, in contrast to episodic adaptive evolution in surface-exposed and regulatory proteins, particularly the X protein. N-glycosylation sites in large surface proteins are highly conserved. Some mutations in the major hydrophilic region (MHR) were significantly detected, whereas RT drug resistance mutations were rare and followed canonical lamivudine-associated pathways. Collectively, these findings highlight the balance between deep evolutionary conservation and localized adaptive flexibility in shaping the HBV genotype F and provide a genotype-specific framework for interpreting viral fitness, immune interactions, and antiviral resistance.<\/jats:p>","DOI":"10.3390\/ijms27052284","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T10:24:34Z","timestamp":1772447074000},"page":"2284","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["From Genome Diversity to Inferred Functional Constraints: An Integrated Evolutionary Analysis of Hepatitis B Virus Genotype F"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1044-7450","authenticated-orcid":false,"given":"Ruy D.","family":"Chac\u00f3n","sequence":"first","affiliation":[{"name":"Department of Pathology, School of Veterinary Medicine, University of S\u00e3o Paulo, Av. Prof. Orlando M. Paiva, 87, S\u00e3o Paulo 05508-270, Brazil"},{"name":"Pathogen Genetics Research Group (PATHO-GEN), OMICS, Lima 15001, Peru"},{"name":"Immunology and Cancer Research Group (IMMUCA), OMICS, Lima 15001, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2912-1191","authenticated-orcid":false,"given":"Obert","family":"Mar\u00edn-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Pathogen Genetics Research Group (PATHO-GEN), OMICS, Lima 15001, Peru"},{"name":"Immunology and Cancer Research Group (IMMUCA), OMICS, Lima 15001, Peru"},{"name":"Departamento Acad\u00e9mico de Microbiolog\u00eda M\u00e9dica, Facultad de Medicina, Universidad Nacional Mayor de San Marcos, Lima 15081, Peru"},{"name":"Instituto de Investigaci\u00f3n de Ciencias Biol\u00f3gicas Antonio Raimondi (ICBAR), Facultad de Ciencias Biol\u00f3gicas, Universidad Nacional Mayor de San Marcos, Av. Carlos Germ\u00e1n Amezaga 375, Lima 15081, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8266-7631","authenticated-orcid":false,"given":"Jimmy","family":"Ango-Bedri\u00f1ana","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biocient\u00edfica SRL-Cl\u00ednica El Nazareno-Huamanga, Ayacucho 05001, Peru"},{"name":"Escuela Profesional de Medicina Humana, Universidad Nacional de San Crist\u00f3bal de Huamanga, Portal Independencia N\u00b0 57\u2013Huamanga, Ayacucho 05001, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9871-7058","authenticated-orcid":false,"given":"Homero","family":"Ango-Aguilar","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biocient\u00edfica SRL-Cl\u00ednica El Nazareno-Huamanga, Ayacucho 05001, Peru"},{"name":"Programa Acad\u00e9mico de Microbiolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Universidad Nacional de San Crist\u00f3bal de Huamanga, Portal Independencia N\u00b0 57\u2013Huamanga, Ayacucho 05001, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,28]]},"reference":[{"key":"ref_1","unstructured":"WHO (World Health Organization) (2024). 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