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Sequence alignment forms the basis of many methods for functional annotationby phylogenetic comparison, but becomes unreliable in the `twilight' regions ofhigh sequence divergence and short gene length. Here we perform a cross-speciescomparison of two herpesviruses, VZV and KSHV, with a hybrid method calledgraph alignment. The method is based jointly on the similarity of proteininteraction networks and on sequence similarity. In our alignment, we find openreading frames for which interaction similarity concurs with a low level ofsequence similarity, thus confirming the evolutionary relationship. Inaddition, we find high levels of interaction similarity between open readingframes without any detectable sequence similarity. The functional predictionsderived from this alignment are consistent with genomic position and geneexpression data.

From Protein Interactions to Functional Annotation: Graph Alignment in Herpes