title: Spatial, temporal and genetic dynamics of highly pathogenic avian influenza A (H5N1) virus in China.
abstract: BACKGROUND
  The spatial spread of H5N1 avian influenza, significant ongoing mutations, and long-term persistence of the virus in some geographic regions has had an enormous impact on the poultry industry and presents a serious threat to human health.
  
  
  METHODS
  We applied phylogenetic analysis, geospatial techniques, and time series models to investigate the spatiotemporal pattern of H5N1 outbreaks in China and the effect of vaccination on virus evolution.
  
  
  RESULTS
  Results showed obvious spatial and temporal clusters of H5N1 outbreaks on different scales, which may have been associated with poultry and wild-bird transmission modes of H5N1 viruses. Lead-lag relationships were found among poultry and wild-bird outbreaks and human cases. Human cases were preceded by poultry outbreaks, and wild-bird outbreaks were led by human cases. Each clade has gained its own unique spatiotemporal and genetic dominance. Genetic diversity of the H5N1 virus decreased significantly between 1996 and 2011; presumably under strong selective pressure of vaccination. Mean evolutionary rates of H5N1 virus increased after vaccination was adopted in China. A clear signature of positively selected sites in the clade 2.3.2 virus was discovered and this may have resulted in the emergence of clade 2.3.2.1.
  
  
  CONCLUSIONS
  Our study revealed two different transmission modes of H5N1 viruses in China, and indicated a significant role of poultry in virus dissemination. Furthermore, selective pressure posed by vaccination was found in virus evolution in the country.
authors.affiliation: State Key Laboratory of Remote Sensing Science, College of Global Change and Earth System Science, Beijing Normal University, Beijing, 100875, China. tianhuaiyu@gmail.com.
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China. cuiyujun.new@gmail.com.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Ministry of Education Key Laboratory for Biodiversity and Ecological Engineering, College of Life Sciences, Beijing Normal University, Beijing, 100875, China. donglu@bnu.edu.cn.
authors.forename: Lu
authors.initials: L
authors.lastname: Dong
authors.affiliation: Ministry of Education Key Laboratory for Earth System Modelling, Center for Earth System Science, Tsinghua University, Beijing, 100084, China. zhousenapril@gmail.com.
authors.forename: Sen
authors.initials: S
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Remote Sensing Science, College of Global Change and Earth System Science, Beijing Normal University, Beijing, 100875, China. xiaowenli627@126.com.|Ministry of Education Key Laboratory for Earth System Modelling, Center for Earth System Science, Tsinghua University, Beijing, 100084, China. xiaowenli627@126.com.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Remote Sensing Science, College of Global Change and Earth System Science, Beijing Normal University, Beijing, 100875, China. huangshanqian@gmail.com.
authors.forename: Shanqian
authors.initials: S
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China. ruifuyang@gmail.com.
authors.forename: Ruifu
authors.initials: R
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Remote Sensing Science, College of Global Change and Earth System Science, Beijing Normal University, Beijing, 100875, China. bingxu@tsinghua.edu.cn.|Ministry of Education Key Laboratory for Earth System Modelling, Center for Earth System Science, Tsinghua University, Beijing, 100084, China. bingxu@tsinghua.edu.cn.|Department of Geography, University of Utah, Salt Lake City, UT, 84112, USA. bingxu@tsinghua.edu.cn.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
mesh_terms: D000818:Animals; D000835:Animals, Wild; D002681:China / Q000453:epidemiology; D004196:Disease Outbreaks / Q000706:statistics & numerical data* / Q000662:veterinary; D019143:Evolution, Molecular; D014644:Genetic Variation; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000145:classification / Q000235:genetics / Q000302:isolation & purification; D005585:Influenza in Birds / Q000453:epidemiology* / Q000635:transmission / Q000821:virology*; D007251:Influenza, Human / Q000453:epidemiology* / Q000821:virology*; D010802:Phylogeny; D011200:Poultry; D014611:Vaccination