{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T08:52:41Z","timestamp":1784796761250,"version":"3.55.0"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T00:00:00Z","timestamp":1657756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p><jats:italic>Enterovirus A<\/jats:italic> (<jats:italic>EV-A<\/jats:italic>) species cause hand, foot and mouth disease (HFMD), threatening the health of young children. Understanding the mutual codon usage pattern of the virus and its host(s) has fundamental and applied values. Here, through examining multiple codon usage parameters, we found that the codon usage bias among <jats:italic>EV-A<\/jats:italic> strains varies and is clade-specific. EVA76, EVA89, EVA90, EVA91 and EVA92, the unconventional clade of <jats:italic>EV-A<\/jats:italic> strains, show unique codon usage pattern relative to the two conventional clades, including EVA71, CVA16, CVA6 and CVA10, <jats:italic>etc.<\/jats:italic> Analyses of Effective Number of Codon (ENC), Correspondence Analysis (COA) and Parity Rule 2 (PR2), <jats:italic>etc.<\/jats:italic>, revealed that the codon usage patterns of <jats:italic>EV-A<\/jats:italic> strains are shaped by mutation pressure and natural selection. Based on the neutrality analysis, we determined the dominant role of natural selection in the formation of the codon usage bias of <jats:italic>EV-A<\/jats:italic>. In addition, we have determined the codon usage compatibility of potential hosts for <jats:italic>EV-A<\/jats:italic> strains using codon adaptation index (CAI), relative codon deoptimization index (RCDI) and similarity index (SiD) analyses, and found that <jats:italic>EV-A<\/jats:italic> showed host-specific codon adaptation patterns in different clades. Finally, we confirmed that the unique codon usage pattern of the unconventional clade affected protein expression level in human cell lines. In conclusion, we identified novel characteristics of codon usage bias in distinct <jats:italic>EV-A<\/jats:italic> clades associated with their host range, transmission and pathogenicity.<\/jats:p>","DOI":"10.3389\/fcimb.2022.941325","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T04:25:31Z","timestamp":1657772731000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Enterovirus A Shows Unique Patterns of Codon Usage Bias in Conventional Versus Unconventional Clade"],"prefix":"10.3389","volume":"12","author":[{"given":"Liyan","family":"Zeng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liuyao","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqing","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuye","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4527","DOI":"10.1093\/nar\/gku075","article-title":"The Influence of CpG and UpA Dinucleotide Frequencies on RNA Virus Replication and Characterization of the Innate Cellular Pathways Underlying Virus Attenuation and Enhanced Replication","volume":"42","author":"Atkinson","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0056642","article-title":"Causes and Implications of Codon Usage Bias in RNA Viruses","volume":"8","author":"Belalov","year":"2013","journal-title":"PLoS One"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1586\/14787210.2015.1058156","article-title":"Coxsackievirus A6: A New Emerging Pathogen Causing Hand, Foot and Mouth Disease Outbreaks Worldwide","volume":"13","author":"Bian","year":"2015","journal-title":"Expert Rev. Anti-Infect. Ther."},{"key":"B4","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.jcv.2010.02.002","article-title":"Co-Circulation of Coxsackieviruses A6 and A10 in Hand, Foot and Mouth Disease Outbreak in Finland","volume":"48","author":"Blomqvist","year":"2010","journal-title":"J. Clin. Virol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1093\/genetics\/129.3.897","article-title":"The Selection-Mutation-Drift Theory of Synonymous Codon Usage","volume":"129","author":"Bulmer","year":"1991","journal-title":"Genetics"},{"key":"B6","doi-asserted-by":"publisher","first-page":"6406","DOI":"10.1074\/jbc.M111.301622","article-title":"Molecular Determinants of Enterovirus 71 Viral Entry Cleft Around Gln-172 on VP1 Protein Interacts With Variable Region on Scavenge Receptor B 2","volume":"287","author":"Chen","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B7","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1007\/PL00006384","article-title":"An Evaluation of Measures of Synonymous Codon Usage Bias","volume":"47","author":"Comeron","year":"1998","journal-title":"J. Mol. Evol."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/srep18558","article-title":"A Novel Recombinant Enterovirus Type EV-A89 With Low Epidemic Strength in Xinjiang, China","volume":"5","author":"Fan","year":"2015","journal-title":"Sci. Rep."},{"key":"B9","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1198\/000313002533","article-title":"Corrgrams: Exploratory Displays for Correlation Matrices","volume":"56","author":"Friendly","year":"2002","journal-title":"Am. Stat."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1893","DOI":"10.1093\/nar\/8.9.1893","article-title":"Codon Frequencies in 119 Individual Genes Confirm Corsistent Choices of Degenerate Bases According to Genome Type","volume":"8","author":"Grantham","year":"1980","journal-title":"Nucleic Acids Res."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0005969","article-title":"Patterns of Oligonucleotide Sequences in Viral and Host Cell RNA Identify Mediators of the Host Innate Immune System","volume":"4","author":"Greenbaum","year":"2009","journal-title":"PloS One"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0168-1702(02)00309-X","article-title":"The Extent of Codon Usage Bias in Human RNA Viruses and its Evolutionary Origin","volume":"92","author":"Jenkins","year":"2003","journal-title":"Virus Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"4264","DOI":"10.1128\/jvi.64.9.4264-4273.1990","article-title":"Contrasts in Codon Usage of Latent Versus Productive Genes of Epstein-Barr Virus: Data and Hypotheses","volume":"64","author":"Karlin","year":"1990","journal-title":"J. Virol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2889","DOI":"10.1128\/jvi.68.5.2889-2897.1994","article-title":"Why is CpG Suppressed in the Genomes of Virtually All Small Eukaryotic Viruses But Not in Those of Large Eukaryotic Viruses","volume":"68","author":"Karlin","year":"1994","journal-title":"J. Virol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"3899","DOI":"10.1128\/jb.179.12.3899-3913.1997","article-title":"Compositional Biases of Bacterial Genomes and Evolutionary Implications","volume":"179","author":"Karlin","year":"1997","journal-title":"J. Bacteriol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1870","DOI":"10.1093\/molbev\/msw054","article-title":"MEGA7: Molecular Evolutionary Genetics Analysis Version 7.0 for Bigger Datasets","volume":"33","author":"Kumar","year":"2016","journal-title":"Mol. Biol. Evol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1038\/ni1028","article-title":"TLR9 Signals After Translocating From the ER to CpG DNA in the Lysosome","volume":"5","author":"Latz","year":"2004","journal-title":"Nat. Immunol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1016\/j.vaccine.2021.02.024","article-title":"Vaccine Candidates Generated by Codon and Codon Pair Deoptimization of Enterovirus A71 Protect Against Lethal Challenge in Mice","volume":"39","author":"Lee","year":"2021","journal-title":"Vaccine"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0096051","article-title":"Co-Circulation and Genomic Recombination of Coxsackievirus A16 and Enterovirus 71 During a Large Outbreak of Hand, Foot, and Mouth Disease in Central China","volume":"9","author":"Liu","year":"2014","journal-title":"PloS One"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.1016\/j.meegid.2011.02.018","article-title":"The Characteristics of the Synonymous Codon Usage in Enterovirus 71 Virus and the Effects of Host on the Virus in Codon Usage Pattern","volume":"11","author":"Liu","year":"2011","journal-title":"Infect. Genet. Evol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1099\/vir.0.060004-0","article-title":"Recombination Strategies and Evolutionary Dynamics of the Human Enterovirus A Global Gene Pool","volume":"95","author":"Lukashev","year":"2014","journal-title":"J. Gen. Virol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"336","DOI":"10.4238\/2014.January.21.1","article-title":"Overall Codon Usage Pattern of Enterovirus 71","volume":"13","author":"Ma","year":"2014","journal-title":"Genet. Mol. Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"360","DOI":"10.4161\/hv.27087","article-title":"Coxsackievirus A16: Epidemiology, Diagnosis, and Vaccine","volume":"10","author":"Mao","year":"2014","journal-title":"Hum. Vaccines Immunother."},{"key":"B24","doi-asserted-by":"publisher","first-page":"vev003","DOI":"10.1093\/ve\/vev003","article-title":"RDP4: Detection and Analysis of Recombination Patterns in Virus Genomes","volume":"1","author":"Martin","year":"2015","journal-title":"Virus Evol."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0169067","article-title":"African non-Human Primates Host Diverse Enteroviruses","volume":"12","author":"Mombo","year":"2017","journal-title":"PLoS One"},{"key":"B26","doi-asserted-by":"publisher","first-page":"9687","DOI":"10.1128\/JVI.00738-06","article-title":"Reduction of the Rate of Poliovirus Protein Synthesis Through Large-Scale Codon Deoptimization Causes Attenuation of Viral Virulence by Lowering Specific Infectivity","volume":"80","author":"Mueller","year":"2006","journal-title":"J. Virol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1093\/nar\/28.1.292","article-title":"Codon Usage Tabulated From International DNA Sequence Databases: Status for the Year 2000","volume":"28","author":"Nakamura","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1128\/JVI.00837-12","article-title":"Characterizing the Picornavirus Landscape Among Synanthropic Nonhuman Primates in Bangladesh 2007 to 2008","volume":"87","author":"Oberste","year":"2013","journal-title":"J. Virol."},{"key":"B29","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/978-1-4899-7448-8_11","article-title":"Enteroviruses and Parechoviruses: Echoviruses, Coxsackieviruses, and Others","volume-title":"Viral Infections of Humans","author":"Oberste","year":"2014"},{"key":"B30","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1099\/vir.0.80475-0","article-title":"Enteroviruses 76, 89, 90 and 91 Represent a Novel Group Within the Species Human Enterovirus A","volume":"86","author":"Oberste","year":"2005","journal-title":"J. Gen. Virol."},{"key":"B31","volume-title":"\"A Guide to Clinical Management and Public Health Response for Hand, Foot and Mouth Disease (HFMD)\"","year":"2011"},{"key":"B32","article-title":"Analysis of Codon Usage","author":"Peden","year":"1999"},{"key":"B33","doi-asserted-by":"publisher","first-page":"D593","DOI":"10.1093\/nar\/gkr859","article-title":"ViPR: An Open Bioinformatics Database and Analysis Resource for Virology Research","volume":"40","author":"Pickett","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"a031781","DOI":"10.1101\/cshperspect.a031781","article-title":"Hepatitis A Virus Codon Usage: Implications for Translation Kinetics and Capsid Folding","volume":"8","author":"Pint\u00f3","year":"2018","journal-title":"Cold Spring Harbor Perspect. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1745-6150-3-38","article-title":"CAIcal: A Combined Set of Tools to Assess Codon Usage Adaptation","volume":"3","author":"Puigb\u00f2","year":"2008","journal-title":"Biol. Direct."},{"key":"B36","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1098\/rstb.1995.0108","article-title":"DNA Sequence Evolution: The Sounds of Silence","volume":"349","author":"Sharp","year":"1995","journal-title":"Philos. Trans. R. Soc. London. Ser. B.: Biol. Sci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"7737","DOI":"10.1093\/nar\/14.19.7737","article-title":"Codon Usage in Regulatory Genes in Escherichia Coli Does Not Reflect Selection for \u2018Rare\u2019codons","volume":"14","author":"Sharp","year":"1986","journal-title":"Nucleic Acids Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1093\/nar\/15.3.1281","article-title":"The Codon Adaptation Index-a Measure of Directional Synonymous Codon Usage Bias, and its Potential Applications","volume":"15","author":"Sharp","year":"1987","journal-title":"Nucleic Acids Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1261\/rna.7640104","article-title":"Detection of Genome-Scale Ordered RNA Structure (GORS) in Genomes of Positive-Stranded RNA Viruses: Implications for Virus Evolution and Host Persistence","volume":"10","author":"Simmonds","year":"2004","journal-title":"Rna"},{"key":"B40","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1016\/j.chom.2018.03.019","article-title":"KREMEN1 Is a Host Entry Receptor for a Major Group of Enteroviruses","volume":"23","author":"Staring","year":"2018","journal-title":"Cell Host Microbe"},{"key":"B41","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.virusres.2008.07.027","article-title":"Cis-Active RNA Elements (CREs) and Picornavirus RNA Replication","volume":"139","author":"Steil","year":"2009","journal-title":"Virus Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"2653","DOI":"10.1073\/pnas.85.8.2653","article-title":"Directional Mutation Pressure and Neutral Molecular Evolution","volume":"85","author":"Sueoka","year":"1988","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1007\/BF00163236","article-title":"Intrastrand Parity Rules of DNA Base Composition and Usage Biases of Synonymous Codons","volume":"40","author":"Sueoka","year":"1995","journal-title":"J. Mol. Evol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/S0378-1119(99)00320-0","article-title":"Translation-Coupled Violation of Parity Rule 2 in Human Genes is Not the Cause of Heterogeneity of the DNA G+ C Content of Third Codon Position","volume":"238","author":"Sueoka","year":"1999","journal-title":"Gene"},{"key":"B45","doi-asserted-by":"publisher","first-page":"2273","DOI":"10.4049\/jimmunol.174.4.2273","article-title":"CpG RNA: Identification of Novel Single-Stranded RNA That Stimulates Human CD14+ CD11c+ Monocytes","volume":"174","author":"Sugiyama","year":"2005","journal-title":"J. Immunol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1016\/j.meegid.2017.06.004","article-title":"Synonymous Codon Usage Analysis of Hand, Foot and Mouth Disease Viruses: A Comparative Study on Coxsackievirus A6, A10, A16, and Enterovirus 71 From 2008 to 2015","volume":"53","author":"Su","year":"2017","journal-title":"Infect. Genet. Evol.: J. Mol. Epidemiol. Evol. Genet. Infect. Dis."},{"key":"B47","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1007\/s00705-012-1517-2","article-title":"Isolation and Genomic Characterization of Three Enterovirus 90 Strains in Shandong, China","volume":"158","author":"Tao","year":"2013","journal-title":"Arch. Virol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.meegid.2018.05.034","article-title":"The Adaptation of Codon Usage of+ ssRNA Viruses to Their Hosts","volume":"63","author":"Tian","year":"2018","journal-title":"Infect. Genet. Evol."},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02308-18","article-title":"Enterovirus A71 Containing Codon-Deoptimized VP1 and High-Fidelity Polymerase as Next-Generation Vaccine Candidate","volume":"93","author":"Tsai","year":"2019","journal-title":"J. Virol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1586\/14787210.2014.895666","article-title":"Update of Enterovirus 71 Infection: Epidemiology, Pathogenesis and Vaccine","volume":"12","author":"Wang","year":"2014","journal-title":"Expert Rev. Anti-infect. Ther."},{"key":"B51","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/1423-0127-21-31","article-title":"Animal Models of Enterovirus 71 Infection: Applications and Limitations","volume":"21","author":"Wang","year":"2014","journal-title":"J. Biomed. Sci."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1099\/jgv.0.001479","article-title":"Rules Governing Genetic Exchanges Among Viral Types From Different Enterovirus A Clusters","volume":"101","author":"Wang","year":"2020","journal-title":"J. Gen. Virol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1186\/1471-2148-10-253","article-title":"Codon Usage Bias and the Evolution of Influenza A Viruses. Codon Usage Biases of Influenza Virus","volume":"10","author":"Wong","year":"2010","journal-title":"BMC Evol. Biol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/0378-1119(90)90491-9","article-title":"The \u2018Effective Number of Codons\u2019 Used in a Gene","volume":"87","author":"Wright","year":"1990","journal-title":"Gene"},{"key":"B55","doi-asserted-by":"publisher","first-page":"1685","DOI":"10.1007\/s00705-011-1067-z","article-title":"The Complete Genome Sequence of an Enterovirus 76 Isolate in China Reveals a Recombination Event","volume":"156","author":"Xu","year":"2011","journal-title":"Arch. Virol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1038\/nm.1992","article-title":"Scavenger Receptor B2 is a Cellular Receptor for Enterovirus 71","volume":"15","author":"Yamayoshi","year":"2009","journal-title":"Nat. Med."},{"key":"B57","doi-asserted-by":"publisher","first-page":"19780","DOI":"10.3402\/ehtj.v6i0.19780","article-title":"Human Enterovirus 71 Epidemics: What's Next","volume":"6","author":"Yip","year":"2013","journal-title":"Emerg. Health Threat. J."},{"key":"B58","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1007\/s13337-014-0215-y","article-title":"Analysis of Synonymous Codon Usage in Enterovirus 71","volume":"25","author":"Zhang","year":"2014","journal-title":"VirusDisease"},{"key":"B59","doi-asserted-by":"publisher","first-page":"e00333","DOI":"10.1128\/JVI.00333-17","article-title":"Protective Efficacies of Formaldehyde-Inactivated Whole-Virus Vaccine and Antivirals in a Murine Model of Coxsackievirus A10 Infection","volume":"91","author":"Zhang","year":"2017","journal-title":"J. Virol."},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0077239","article-title":"The Distribution of Synonymous Codon Choice in the Translation Initiation Region of Dengue Virus","volume":"8","author":"Zhou","year":"2013","journal-title":"PLoS One"},{"key":"B61","doi-asserted-by":"publisher","first-page":"6400","DOI":"10.3390\/v7122947","article-title":"Epidemiological Research on Hand, Foot, and Mouth Disease in Mainland China","volume":"7","author":"Zhuang","year":"2015","journal-title":"Viruses"}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.941325\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T04:25:38Z","timestamp":1657772738000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.941325\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,14]]},"references-count":61,"alternative-id":["10.3389\/fcimb.2022.941325"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.941325","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,14]]},"article-number":"941325"}}