title: Genome-wide networks of amino acid covariances are common among viruses.
abstract: Coordinated variation among positions in amino acid sequence alignments can reveal genetic dependencies at noncontiguous positions, but methods to assess these interactions are incompletely developed. Previously, we found genome-wide networks of covarying residue positions in the hepatitis C virus genome (R. Aurora, M. J. Donlin, N. A. Cannon, and J. E. Tavis, J. Clin. Invest. 119:225-236, 2009). Here, we asked whether such networks are present in a diverse set of viruses and, if so, what they may imply about viral biology. Viral sequences were obtained for 16 viruses in 13 species from 9 families. The entire viral coding potential for each virus was aligned, all possible amino acid covariances were identified using the observed-minus-expected-squared algorithm at a false-discovery rate of ≤1%, and networks of covariances were assessed using standard methods. Covariances that spanned the viral coding potential were common in all viruses. In all cases, the covariances formed a single network that contained essentially all of the covariances. The hepatitis C virus networks had hub-and-spoke topologies, but all other networks had random topologies with an unusually large number of highly connected nodes. These results indicate that genome-wide networks of genetic associations and the coordinated evolution they imply are very common in viral genomes, that the networks rarely have the hub-and-spoke topology that dominates other biological networks, and that network topologies can vary substantially even within a given viral group. Five examples with hepatitis B virus and poliovirus are presented to illustrate how covariance network analysis can lead to inferences about viral biology.
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis, University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Donlin
authors.forename: Brandon
authors.initials: B
authors.lastname: Szeto
authors.forename: David W
authors.initials: DW
authors.lastname: Gohara
authors.forename: Rajeev
authors.initials: R
authors.lastname: Aurora
authors.forename: John E
authors.initials: JE
authors.lastname: Tavis
mesh_terms: D000595:Amino Acid Sequence; D019143:Evolution, Molecular; D016679:Genome, Viral; D016174:Hepacivirus / Q000737:chemistry / Q000235:genetics; D008969:Molecular Sequence Data; D010802:Phylogeny; D016415:Sequence Alignment; D014780:Viruses / Q000737:chemistry / Q000145:classification / Q000235:genetics*