title: Rules of co-occurring mutations characterize the antigenic evolution of human influenza A/H3N2, A/H1N1 and B viruses.
abstract: The human influenza viruses undergo rapid evolution (especially in hemagglutinin (HA), a glycoprotein on the surface of the virus), which enables the virus population to constantly evade the human immune system. Therefore, the vaccine has to be updated every year to stay effective. There is a need to characterize the evolution of influenza viruses for better selection of vaccine candidates and the prediction of pandemic strains. Studies have shown that the influenza hemagglutinin evolution is driven by the simultaneous mutations at antigenic sites. Here, we analyze simultaneous or co-occurring mutations in the HA protein of human influenza A/H3N2, A/H1N1 and B viruses to predict potential mutations, characterizing the antigenic evolution.
  
  
  
  We obtain the rules of mutation co-occurrence using association rule mining after extracting HA1 sequences and detect co-mutation sites under strong selective pressure. Then we predict the potential drifts with specific mutations of the viruses based on the rules and compare the results with the "observed" mutations in different years.
  
  
  
  The sites under frequent mutations are in antigenic regions (epitopes) or receptor binding sites.
  
  
  
  Our study demonstrates the co-occurring site mutations obtained by rule mining can capture the evolution of influenza viruses, and confirms that cooperative interactions among sites of HA1 protein drive the influenza antigenic evolution.
authors.affiliation: School of Computer Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore, Singapore.
authors.forename: Haifen
authors.initials: H
authors.lastname: Chen
authors.affiliation: School of Computer Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore, Singapore.
authors.forename: Xinrui
authors.initials: X
authors.lastname: Zhou
authors.affiliation: School of Computer Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore, Singapore.|Genome Institute of Singapore, A*STAR, Biopolis, 138672, Singapore, Singapore.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: School of Computer Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore, Singapore. asckkwoh@ntu.edu.sg.
authors.forename: Chee-Keong
authors.initials: CK
authors.lastname: Kwoh
mesh_terms: D019143:Evolution, Molecular; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics; D018963:Hepatitis Antigens / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics*; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics*; D009154:Mutation; D012641:Selection, Genetic
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D018963:Hepatitis Antigens
keywords: A/H3N2/H1N1 and B; Antigenic evolution; Co-occurring mutation; Influenza vaccine; Influenza virus