{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T01:02:23Z","timestamp":1781830943488,"version":"3.54.5"},"reference-count":86,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,7,9]],"date-time":"2020-07-09T00:00:00Z","timestamp":1594252800000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018537","name":"National Science and Technology Major Project","doi-asserted-by":"crossref","award":["2017ZX10104001"],"award-info":[{"award-number":["2017ZX10104001"]}],"id":[{"id":"10.13039\/501100018537","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100018537","name":"National Science and Technology Major Project","doi-asserted-by":"crossref","award":["2018ZX10713002"],"award-info":[{"award-number":["2018ZX10713002"]}],"id":[{"id":"10.13039\/501100018537","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100018537","name":"National Science and Technology Major Project","doi-asserted-by":"crossref","award":["2018ZX10305409-004-002"],"award-info":[{"award-number":["2018ZX10305409-004-002"]}],"id":[{"id":"10.13039\/501100018537","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100018537","name":"National Science and Technology Major Project","doi-asserted-by":"crossref","award":["2018ZX10711001"],"award-info":[{"award-number":["2018ZX10711001"]}],"id":[{"id":"10.13039\/501100018537","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Key Technologies R&D Program of the National Ministry of Science","award":["2018ZX10713002"],"award-info":[{"award-number":["2018ZX10713002"]}]},{"name":"the Key Technologies R&D Program of the National Ministry of Science","award":["2018ZX10713001-003"],"award-info":[{"award-number":["2018ZX10713001-003"]}]},{"DOI":"10.13039\/501100004826","name":"Beijing Natural Science Foundation","doi-asserted-by":"publisher","award":["L192014"],"award-info":[{"award-number":["L192014"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Hand, foot, and mouth disease (HFMD) is a common global epidemic. From 2008 onwards, many HFMD outbreaks caused by coxsackievirus A6 (CV-A6) have been reported worldwide. Since 2013, with a dramatically increasing number of CV-A6-related HFMD cases, CV-A6 has become the predominant HFMD pathogen in mainland China. Phylogenetic analysis based on the VP1 capsid gene revealed that subtype D3 dominated the CV-A6 outbreaks. Here, we performed a large-scale (near) full-length genetic analysis of global and Chinese CV-A6 variants, including 158 newly sequenced samples collected extensively in mainland China between 2010 and 2018. During the global transmission of subtype D3 of CV-A6, the noncapsid gene continued recombining, giving rise to a series of viable recombinant hybrids designated evolutionary lineages, and each lineage displayed internal consistency in both genetic and epidemiological features. The emergence of lineage \u2013A since 2005 has triggered CV-A6 outbreaks worldwide, with a rate of evolution estimated at 4.17\u2009\u00d7\u200910\u22123 substitutions site-1\u2009year\u22121 based on a large number of monophyletic open reading frame sequences, and created a series of lineages chronologically through varied noncapsid recombination events. In mainland China, lineage \u2013A has generated another two novel widespread lineages (\u2013J and \u2013L) through recombination within the enterovirus A gene pool, with robust estimates of occurrence time. Lineage \u2013A, \u2013J, and \u2013L infections presented dissimilar clinical manifestations, indicating that the conservation of the CV-A6 capsid gene resulted in high transmissibility, but the lineage-specific noncapsid gene might influence pathogenicity. Potentially important amino acid substitutions were further predicted among CV-A6 variants. The evolutionary phenomenon of noncapsid polymorphism within the same subtype observed in CV-A6 was uncommon in other leading HFMD pathogens; such frequent recombination happened in fast-spreading CV-A6, indicating that the recovery of deleterious genomes may still be ongoing within CV-A6 quasispecies. CV-A6-related HFMD outbreaks have caused a significant public health burden and pose a great threat to children\u2019s health; therefore, further surveillance is greatly needed to understand the full genetic diversity of CV-A6 in mainland China.<\/jats:p>","DOI":"10.1093\/ve\/veaa048","type":"journal-article","created":{"date-parts":[[2020,6,30]],"date-time":"2020-06-30T11:34:28Z","timestamp":1593516868000},"source":"Crossref","is-referenced-by-count":35,"title":["Genetic recombination in fast-spreading coxsackievirus A6 variants: a potential role in evolution and pathogenicity"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7053-3836","authenticated-orcid":false,"given":"Yang","family":"Song","sequence":"first","affiliation":[{"name":"WHO WPRO Regional Polio Reference Laboratory, National Health Commission Key Laboratory for Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, No. 155, Changbai Road, Changping District, Beijing, 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2692-5437","authenticated-orcid":false,"given":"Yong","family":"Zhang","sequence":"additional","affiliation":[{"name":"WHO WPRO Regional Polio Reference Laboratory, National Health Commission Key Laboratory for Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, No. 155, Changbai Road, Changping District, Beijing, 102206, China"},{"name":"Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhi","family":"Han","sequence":"additional","affiliation":[{"name":"WHO WPRO Regional Polio Reference Laboratory, National Health Commission Key Laboratory for Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, No. 155, Changbai Road, Changping District, Beijing, 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Xu","sequence":"additional","affiliation":[{"name":"Yunnan Center for Disease Control and Prevention, Kunming, Yunnan Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinbo","family":"Xiao","sequence":"additional","affiliation":[{"name":"WHO WPRO Regional Polio Reference Laboratory, National Health Commission Key Laboratory for Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, No. 155, Changbai Road, Changping District, Beijing, 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianjun","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong Center for Disease Control and Prevention, Jinan, Shandong Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxing","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong Center for Disease Control and Prevention, Jinan, Shandong Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfang","family":"Yang","sequence":"additional","affiliation":[{"name":"Shanxi Center for Disease Control and Prevention, Taiyuan, Shanxi Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuli","family":"Yu","sequence":"additional","affiliation":[{"name":"Hebei Center for Disease Control and Prevention, Shijiazhuang, Hebei Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deshan","family":"Yu","sequence":"additional","affiliation":[{"name":"Gansu Center for Disease Control and Prevention, Lanzhou, Gansu Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Chen","sequence":"additional","affiliation":[{"name":"Gansu Center for Disease Control and Prevention, Lanzhou, Gansu Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Huang","sequence":"additional","affiliation":[{"name":"Chongqing Center for Disease Control and Prevention, Chongqing City, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Center for Disease Control and Prevention, Beijing City, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Xie","sequence":"additional","affiliation":[{"name":"Tianjin Center for Disease Control and Prevention, Tianjin City, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanhuan","family":"Lu","sequence":"additional","affiliation":[{"name":"WHO WPRO Regional Polio Reference Laboratory, National Health Commission Key Laboratory for Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, No. 155, Changbai Road, Changping District, Beijing, 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianjiao","family":"Ji","sequence":"additional","affiliation":[{"name":"WHO WPRO Regional Polio Reference Laboratory, National Health Commission Key Laboratory for Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, No. 155, Changbai Road, Changping District, Beijing, 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Yang","sequence":"additional","affiliation":[{"name":"WHO WPRO Regional Polio Reference Laboratory, National Health Commission Key Laboratory for Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, No. 155, Changbai Road, Changping District, Beijing, 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Yan","sequence":"additional","affiliation":[{"name":"WHO WPRO Regional Polio Reference Laboratory, National Health Commission Key Laboratory for Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, No. 155, Changbai Road, Changping District, Beijing, 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangli","family":"Zhu","sequence":"additional","affiliation":[{"name":"WHO WPRO Regional Polio Reference Laboratory, National Health Commission Key Laboratory for Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, No. 155, Changbai Road, Changping District, Beijing, 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbo","family":"Xu","sequence":"additional","affiliation":[{"name":"WHO WPRO Regional Polio Reference Laboratory, National Health Commission Key Laboratory for Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, No. 155, Changbai Road, Changping District, Beijing, 102206, China"},{"name":"Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei Province, China"},{"name":"Anhui University of Science and Technology, Anhui Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,7,8]]},"reference":[{"key":"2021111805070282500_veaa048-B1","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.3390\/ijms20061256","article-title":"Advances in Antigenic Peptide-Based Vaccine and Neutralizing Antibodies against Viruses Causing Hand, Foot, and Mouth Disease","volume":"20","author":"Anasir","year":"2019","journal-title":"International Journal of Molecular Sciences"},{"key":"2021111805070282500_veaa048-B2","doi-asserted-by":"crossref","first-page":"e0127999","DOI":"10.1371\/journal.pone.0127999","article-title":"Seroepidemiology of Coxsackievirus A6, Coxsackievirus A16, and Enterovirus 71 Infections among Children and Adolescents in Singapore, 2008\u20132010","volume":"10","author":"Ang","year":"2015","journal-title":"PLoS One"},{"key":"2021111805070282500_veaa048-B3","doi-asserted-by":"crossref","first-page":"654","DOI":"10.3201\/eid2404.171298","article-title":"Emerging Coxsackievirus A6 Causing Hand, Foot and Mouth Disease, Vietnam","volume":"24","author":"Anh","year":"2018","journal-title":"Emerging Infectious Diseases"},{"key":"2021111805070282500_veaa048-B4","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/S0140-6736(74)91684-5","article-title":"Letter: New Enterovirus Type Associated with Epidemic of Aseptic 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Polioviruses, Coxsackieviruses, Echoviruses and Newer Enteroviruses'","author":"Bruu","year":"2002","journal-title":"A Practical Guide to Clinical Virology"},{"key":"2021111805070282500_veaa048-B7","doi-asserted-by":"crossref","first-page":"805","DOI":"10.15585\/mmwr.mm6429a8","article-title":"Atypical Presentations of Hand, Foot, and Mouth Disease Caused by Coxsackievirus A6\u2013Minnesota, 2014","volume":"64","author":"Buttery","year":"2015","journal-title":"Morbidity and Mortality Weekly Report"},{"key":"2021111805070282500_veaa048-B8","first-page":"213","article-title":"Notes from the Field: Severe Hand, Foot, and Mouth Disease Associated with Coxsackievirus A6 - Alabama","volume":"61","year":"2012","journal-title":"Morbidity and Mortality Weekly Report"},{"key":"2021111805070282500_veaa048-B9","doi-asserted-by":"crossref","first-page":"165","DOI":"10.33073\/pjm-2019-016","article-title":"Hand, Foot, and Mouth Disease Caused by Coxsackievirus A6: A Preliminary Report from Istanbul","volume":"68","author":"Ceylan","year":"2019","journal-title":"Polish Journal of Microbiology"},{"key":"2021111805070282500_veaa048-B10","doi-asserted-by":"crossref","first-page":"e01257","DOI":"10.1128\/JVI.01257-17","article-title":"A 3.0-Angstrom Resolution Cryo-Electron Microscopy Structure and Antigenic Sites of Coxsackievirus A6-like Particles","volume":"92","author":"Chen","year":"2018","journal-title":"Journal of Virology"},{"key":"2021111805070282500_veaa048-B11","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.virol.2009.12.007","article-title":"Analysis of Recombination and Natural Selection in Human Enterovirus 71","volume":"398","author":"Chen","year":"2010","journal-title":"Virology"},{"key":"2021111805070282500_veaa048-B12","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1097\/INF.0000000000000310","article-title":"An Atypical Dermatologic Presentation of a Child with Hand, Foot and Mouth Disease Caused by Coxsackievirus A6","volume":"33","author":"Chong","year":"2014","journal-title":"The Pediatric Infectious Disease Journal"},{"key":"2021111805070282500_veaa048-B13","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.ram.2018.05.003","article-title":"Atypical Hand, Foot, and Mouth Disease Caused by Coxsackievirus A6 in Argentina in 2015","volume":"51","author":"Cisterna","year":"2019","journal-title":"Revista Argentina de Microbiolog\u00eda"},{"key":"2021111805070282500_veaa048-B14","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1101\/gr.849004","article-title":"WebLogo: A Sequence Logo Generator","volume":"14","author":"Crooks","year":"2004","journal-title":"Genome Research"},{"key":"2021111805070282500_veaa048-B15","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1038\/nmeth.2109","article-title":"jModelTest 2: More Models, New Heuristics and Parallel Computing","volume":"9","author":"Darriba","year":"2012","journal-title":"Nature 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2013","volume":"69","author":"Han","year":"2014","journal-title":"Journal of Infection"},{"key":"2021111805070282500_veaa048-B22","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1111\/jpc.12708","article-title":"Outbreak of Variant Hand-Foot-and-Mouth Disease Caused by Coxsackievirus A6 in Auckland, New Zealand","volume":"50","author":"Hayman","year":"2014","journal-title":"Journal of Paediatrics and Child Health"},{"key":"2021111805070282500_veaa048-B23","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1080\/21645515.2018.1442997","article-title":"Five-Year Immunity Persistence following Immunization with Inactivated Enterovirus 71 Type (EV71) Vaccine in Healthy Children: A Further Observation","volume":"14","author":"Hu","year":"2018","journal-title":"Human Vaccines & Immunotherapeutics"},{"key":"2021111805070282500_veaa048-B24","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1136\/adc.55.8.583","article-title":"Outbreaks of Hand, Foot, and Mouth Disease 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High Incidence of Complication Disorders of Central Nervous System","volume":"55","author":"Ishimaru","year":"1980","journal-title":"Archives of Disease in Childhood"},{"key":"2021111805070282500_veaa048-B25","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.bsheal.2019.02.005","article-title":"Surveillance, Epidemiology, and Pathogen Spectrum of Hand, Foot, and Mouth Disease in Mainland of China from 2008 to 2017","volume":"1","author":"Ji","year":"2019","journal-title":"Biosafety and Health"},{"key":"2021111805070282500_veaa048-B26","doi-asserted-by":"crossref","first-page":"3182","DOI":"10.1109\/TIP.2012.2189578","article-title":"Posterior-Mean Super-Resolution with a Causal Gaussian Markov Random Field Prior","volume":"21","author":"Katsuki","year":"2012","journal-title":"IEEE Transactions on Image Processing"},{"key":"2021111805070282500_veaa048-B27","doi-asserted-by":"crossref","first-page":"8410","DOI":"10.1128\/JVI.00078-16","article-title":"Poliovirus Polymerase 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Coxsackievirus A6: A Clinico-Pathologic Study","volume":"43","author":"Laga","year":"2016","journal-title":"Journal of Cutaneous Pathology"},{"key":"2021111805070282500_veaa048-B31","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.jcv.2018.09.002","article-title":"Molecular Epidemiology of Coxsackievirus A6 Circulating in Hong Kong Reveals Common Neurological Manifestations and Emergence of Novel Recombinant Groups","volume":"108","author":"Lau","year":"2018","journal-title":"Journal of Clinical Virology"},{"key":"2021111805070282500_veaa048-B32","first-page":"26","article-title":"A Novel Enterovirus 71 (EV71) Virulence Determinant: The 69th Residue of 3C Protease Modulates Pathogenicity","volume":"7","author":"Li","year":"2017","journal-title":"Frontiers in Cellular and Infection Microbiology"},{"key":"2021111805070282500_veaa048-B33","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.virusres.2017.11.023","article-title":"Nonstructural Protein 2A 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Enterovirus","volume":"16","author":"Lin","year":"2015","journal-title":"BMC Genomics"},{"key":"2021111805070282500_veaa048-B37","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s11684-017-0605-9","article-title":"Landscape of Emerging and Re-Emerging Infectious Diseases in China: Impact of Ecology, Climate, and Behavior","volume":"12","author":"Liu","year":"2018","journal-title":"Frontiers of Medicine"},{"key":"2021111805070282500_veaa048-B38","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1099\/vir.0.19469-0","article-title":"Recombination in Uveitis-Causing Enterovirus Strains","volume":"85","author":"Lukashev","year":"2004","journal-title":"Journal of General Virology"},{"key":"2021111805070282500_veaa048-B39","doi-asserted-by":"crossref","first-page":"3281","DOI":"10.1099\/vir.0.81264-0","article-title":"Recombination in Circulating Human Enterovirus B: Independent Evolution of Structural and Non-Structural Genome 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