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The present study attempts to assess the genetic variability and evolutionary divergence among HEV genotypes. A vaccine promising capsid\u2010protein coding ORF\u20102 gene sequences of HEV was evaluated using phylogenetics, model\u2010based population genetic methods and principal component analysis. The analyses unveiled nine distinct clusters as subpopulations for six HEV genotypes. HEV\u20103 genotype samples stratified into four different subgroups, while HEV\u20104 stratified into three additional subclusters. Rabbit\u2010infectious HEV\u20103ra samples constitute a distinct cluster. Pairwise analysis identified marked genetic distinction of HEV\u20104c and HEV\u20104i subgenotypes compared to other genotypes. Numerous admixed, inter and intragenotype recombinant strains were detected. The MEME method identified several ORF\u20102 codon sites under positive selection. Some selection signatures lead to amino acid substitutions within ORF\u20102, resulting in altered physicochemical features. Moreover, a pattern of host\u2010specific adaptive signatures was identified among HEV genotypes. The analyses conclusively depict that recombination and episodic positive selection events have shaped the observed genetic diversity among different HEV genotypes. The significant genetic diversity and stratification of HEV\u20103 and HEV\u20104 genotypes into subgroups, as identified in the current study, are noteworthy and may have implications for the efficacy of anti\u2010HEV vaccines.<\/jats:p>","DOI":"10.1111\/jvh.13959","type":"journal-article","created":{"date-parts":[[2024,5,28]],"date-time":"2024-05-28T08:54:53Z","timestamp":1716886493000},"page":"524-534","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Genetic substructure and host\u2010specific natural selection trend across vaccine\u2010candidate <scp>ORF<\/scp>\u20102 capsid protein of <scp>hepatitis\u2010E<\/scp> virus"],"prefix":"10.1111","volume":"31","author":[{"given":"Nasir","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Biochemistry Abdul Wali Khan University Mardan  Mardan 23200 Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sehrish","family":"Kakakhel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Abdul Wali Khan University Mardan  Mardan 23200 Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul","family":"Malik","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy King Saud University  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiran","family":"Nigar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Abdul Wali Khan University Mardan  Mardan 23200 Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhail","family":"Akhtar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry A.T. 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