title: Identification of combinatorial host-specific signatures with a potential to affect host adaptation in influenza A H1N1 and H3N2 subtypes.
abstract: The underlying strategies used by influenza A viruses (IAVs) to adapt to new hosts while crossing the species barrier are complex and yet to be understood completely. Several studies have been published identifying singular genomic signatures that indicate such a host switch. The complexity of the problem suggested that in addition to the singular signatures, there might be a combinatorial use of such genomic features, in nature, defining adaptation to hosts.
  
  
  
  We used computational rule-based modeling to identify combinatorial sets of interacting amino acid (aa) residues in 12 proteins of IAVs of H1N1 and H3N2 subtypes. We built highly accurate rule-based models for each protein that could differentiate between viral aa sequences coming from avian and human hosts. We found 68 host-specific combinations of aa residues, potentially associated to host adaptation on HA, M1, M2, NP, NS1, NEP, PA, PA-X, PB1 and PB2 proteins of the H1N1 subtype and 24 on M1, M2, NEP, PB1 and PB2 proteins of the H3N2 subtypes. In addition to these combinations, we found 132 novel singular aa signatures distributed among all proteins, including the newly discovered PA-X protein, of both subtypes. We showed that HA, NA, NP, NS1, NEP, PA-X and PA proteins of the H1N1 subtype carry H1N1-specific and HA, NA, PA-X, PA, PB1-F2 and PB1 of the H3N2 subtype carry H3N2-specific signatures. M1, M2, PB1-F2, PB1 and PB2 of H1N1 subtype, in addition to H1N1 signatures, also carry H3N2 signatures. Similarly M1, M2, NP, NS1, NEP and PB2 of H3N2 subtype were shown to carry both H3N2 and H1N1 host-specific signatures (HSSs).
  
  
  
  To sum it up, we computationally constructed simple IF-THEN rule-based models that could distinguish between aa sequences of avian and human IAVs. From the rules we identified HSSs having a potential to affect the adaptation to specific hosts. The identification of combinatorial HSSs suggests that the process of adaptation of IAVs to a new host is more complex than previously suggested. The present study provides a basis for further detailed studies with the aim to elucidate the molecular mechanisms providing the foundation for the adaptation process.
authors.affiliation: Department of Cell and Molecular Biology, Computational Biology and Bioinformatics, Science for Life Laboratory, Uppsala University, SE-751 24, Uppsala, Sweden.
authors.forename: Zeeshan
authors.initials: Z
authors.lastname: Khaliq
authors.affiliation: Department of Virology, Parasitology and Immunobiology (VIP), National Veterinary Institute (SVA), Uppsala, Sweden.|OIE Collaborating Centre for the Biotechnology-based Diagnosis of Infectious Diseases in Veterinary Medicine, Ulls väg 2B and 26, SE-756 89, Uppsala, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Leijon
authors.affiliation: OIE Collaborating Centre for the Biotechnology-based Diagnosis of Infectious Diseases in Veterinary Medicine, Ulls väg 2B and 26, SE-756 89, Uppsala, Sweden.|Department of Biomedical Sciences and Veterinary Public Health (BVF), Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
authors.forename: Sándor
authors.initials: S
authors.lastname: Belák
authors.affiliation: Department of Cell and Molecular Biology, Computational Biology and Bioinformatics, Science for Life Laboratory, Uppsala University, SE-751 24, Uppsala, Sweden. jan.komorowski@icm.uu.se.|Institute of Computer Science, Polish Academy of Sciences, 01-248, Warszawa, Poland. jan.komorowski@icm.uu.se.
authors.forename: Jan
authors.identifier: 0000-0002-0766-8789
authors.initials: J
authors.lastname: Komorowski
mesh_terms: D000222:Adaptation, Physiological; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000235:genetics; D000818:Animals; D019295:Computational Biology / Q000379:methods*; D058507:Host Specificity; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000502:physiology*; D053122:Influenza A Virus, H3N2 Subtype / Q000502:physiology*; D008958:Models, Molecular; D010802:Phylogeny; D016865:Reassortant Viruses / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D000596:Amino Acids; D014764:Viral Proteins
keywords: Combinatorial signatures; Host adaptation; Host-specific signatures; Influenza A virus; MCFS; Rosetta; Rough sets