Phylogenetic reconstruction of herpesvirus evolution is generally founded on amino acid sequence comparisons of specific proteins. These are relevant to the evolution of the specific gene (or set of genes), but the resulting phylogeny may vary depending on the particular sequence chosen for analysis (or comparison). In the first part of this report, we compare 13 herpesvirus genomes by using a new multidimensional methodology based on distance measures and partial orderings of dinucleotide relative abundances. The sequences were analyzed with respect to (i) genomic compositional extremes; (ii) total distances within and between genomes; (iii) partial orderings among genomes relative to a set of sequence standards; (iv) concordance correlations of genome distances; and (v) consistency with the alpha-, beta-, gammaherpesvirus classification. Distance assessments within individual herpesvirus genomes show each to be quite homogeneous relative to the comparisons between genomes. The gammaherpesviruses, Epstein-Barr virus (EBV), herpesvirus saimiri, and bovine herpesvirus 4 are both diverse and separate from other herpesvirus classes, whereas alpha- and betaherpesviruses overlap. The analysis revealed that the most central genome (closest to a consensus herpesvirus genome and most individual herpesvirus sequences of different classes) is that of human herpesvirus 6, suggesting that this genome is closest to a progenitor herpesvirus. The shorter DNA distances among alphaherpesviruses supports the hypothesis that the alpha class is of relatively recent ancestry. In our collection, equine herpesvirus 1 (EHV1) stands out as the most central alphaherpesvirus, suggesting it may approximate an ancestral alphaherpesvirus. Among all herpesviruses, the EBV genome is closest to human sequences. In the DNA partial orderings, the chicken sequence collection is invariably as close as or closer to all herpesvirus sequences than the human sequence collection is, which may imply that the chicken (or other avian species) is a more natural or more ancient host of herpesviruses. In the second part of this report, evolutionary relationships among the 13 herpesvirus genomes are evaluated on the basis of recent methods of amino acid alignment applied to four essential protein sequences. In this analysis, the alignment of the two betaherpesviruses (human cytomegalovirus versus human herpesvirus 6) shelved lower scores compared with alignments within alphaherpesviruses (i.e., among EHV1, herpes simplex virus type 1, varicella-zoster virus, pseudorabies virus type 1 and Marek's disease virus) and within gammaherpesviruses (EBV versus herpesvirus saimiri). Comparisons within the alpha class generally produced the highest alignment scores, with EHV1 and pseudorabies type 1 prominent, whereas herpes simplex virus type 1 versus varicella-zoster virus show the least similarity among the alpha sequences. The within-alpha, beta, and gamma class sequence similarity scores are generally 50 to 100% higher than the between-class sequence similarity scores. These results suggest that the betaherpesviruses separated earlier than the formation of the gamma class and that the alpha class may be of the most recent ancestry. By our methods, evolutionary relationships derived from genomic comparisons versus protein comparisons differ to some extent. The dinucleotide relative abundance distances appear to discriminate DNA structure specificity more than sequence specificity. The evolutionary development of genes among viruses (and species) is more dependent on each individual gene.
