title: Genetic evolution of Human Enterovirus A71 subgenotype C4 in Shenzhen, China, 1998-2013.
abstract: Human Enterovirus A71 (EV-A71) is one of the severest enteroviruses that causes hand, foot, and mouth disease (HFMD) among children. This study identified the mutations of EV-A71 VP1 amino acid residues over a number of years and explored the possible association of identified mutations and HFMD epidemic outbreaks in Shenzhen, China.
  
  
  
  A total of 3760 stool specimens were collected from HFMD patients by Shenzhen Centers for Disease Control and Prevention (CDC) between 1998 and 2013. In total 289 VP1 strains were sequenced in this study, and amino acids mutation frequency was calculated. There were 2040 China nationwide sequences downloaded from Genebank as replication data.
  
  
  
  In our samples, 1036 subjects (27.6%) were EV-A71 infected. Three amino acid positions on VP1 protein were found to have high mutation prevalence. These are Q22H, S283T, and A289H. Site 22 showed a fast mutation fixation in the year 2008, at the time of the large scale epidemic outbreak in Shenzhen. Analysis of the nationwide data replicated the same trend of mutation prevalence of the three sites.
  
  
  
  The switching from Q to H on site 22 of the EV-A71 VP1 strain might be associated with the HFMD outbreak in Shenzhen in 2008. The identified amino acid sites 22, 283 and 289 provided information for developing anti-viral drugs against EV-A71 in the future.
authors.affiliation: Shenzhen Center for Disease Control and Prevention, Shenzhen, China; Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, China.
authors.forename: Yaqing
authors.initials: Y
authors.lastname: He
authors.affiliation: JC School of Public Health and Primary Care, the Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors.forename: Linjie
authors.initials: L
authors.lastname: Zou
authors.affiliation: JC School of Public Health and Primary Care, the Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors.forename: Marc Ka Chun
authors.initials: MKC
authors.lastname: Chong
authors.affiliation: JC School of Public Health and Primary Care, the Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors.forename: Ruoting
authors.initials: R
authors.lastname: Men
authors.affiliation: Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Xu
authors.affiliation: Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Xiangjie
authors.initials: X
authors.lastname: Yao
authors.affiliation: Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.affiliation: Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Huixia
authors.initials: H
authors.lastname: Xian
authors.affiliation: Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Min
authors.initials: M
authors.lastname: Luo
authors.affiliation: Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Jinquan
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Hanwu
authors.initials: H
authors.lastname: Ma
authors.affiliation: Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Qianjin
authors.initials: Q
authors.lastname: Feng
authors.affiliation: Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Shenzhen Center for Disease Control and Prevention, Shenzhen, China; Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: JC School of Public Health and Primary Care, the Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors.forename: Eng-Kiong
authors.initials: EK
authors.lastname: Yeoh
authors.affiliation: JC School of Public Health and Primary Care, the Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China; The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, China.
authors.forename: Benny Chung-Ying
authors.initials: BC
authors.lastname: Zee
authors.affiliation: Shenzhen Center for Disease Control and Prevention, Shenzhen, China; Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, China. Electronic address: yuanpingzhou@163.com.
authors.forename: Yuanping
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: The CityU Shenzhen Research Institute, Shenzhen, China; Department of Biomedical Science, the City University of Hong Kong, Hong Kong, China. Electronic address: mlhe7788@gmail.com.
authors.forename: Ming-Liang
authors.initials: ML
authors.lastname: He
authors.affiliation: JC School of Public Health and Primary Care, the Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China; The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, China. Electronic address: maggiew@cuhk.edu.hk.
authors.forename: Maggie Haitian
authors.initials: MH
authors.lastname: Wang
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D036022:Capsid Proteins / Q000235:genetics; D002648:Child; D002681:China / Q000453:epidemiology; D004196:Disease Outbreaks; D029821:Enterovirus A, Human / Q000235:genetics*; D004769:Enterovirus Infections / Q000453:epidemiology / Q000821:virology; D058872:Epidemics; D019143:Evolution, Molecular; D005243:Feces / Q000821:virology; D005260:Female; D005838:Genotype; D006232:Hand, Foot and Mouth Disease / Q000453:epidemiology / Q000821:virology*; D006801:Humans; D008297:Male; D009154:Mutation; D010802:Phylogeny; D017422:Sequence Analysis, DNA
chemical_list: D036022:Capsid Proteins; C442501:VP1 protein, Foot-and-mouth disease virus
keywords: EV-A71; HFMD; Hand-Foot-and-Mouth Disease; Mutation frequency; VP1