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-expectedsquared 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 genomewide 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. V iral genomes are usually small, and as a group, they are structurally very diverse. This places significant constraints on viral genetic coding patterns and leads to the variety of gene expression strategies and replication mechanisms that are summarized by Baltimore's seminal viral classification system (4). These constraints affect the selection pressures on viral genomes, often in ways not normally encountered by the genomes of cellular organisms. Although the effects of complex selective processes, such as epistasis and pleiotropy, on viral intragenomic interactions are partially understood in theoretical terms (24,33,37), observation of their effects on a genome-wide scale has proven difficult.The multiple-sequence alignments that underlie most genetic analyses assume that each position in an alignment is independent of all others, and hence, the alignments are blind to intragenomic dependencies. Such dependencies are clearly of major biological importance, because folding of proteins and RNAs brings distant residues into close proximity, so there is more information in sequence sets than standard analytical methods reveal. One method to find long-distance genetic interactions is to identify covariances among a collection of related sequences. Covariance is present when the identity of a residue at one position in a sequence is at l...

HCV Genome-Wide Genetic Analyses in Context of Disease Progression and Hepatocellular Carcinoma

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