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Open Access Research article

From protein interactions to functional annotation: graph alignment in Herpes

Michal Kolář12, Michael Lässig13 and Johannes Berg13*

Author Affiliations

1 Institut für Theoretische Physik, Universität zu Köln, Zülpicher Straße 77, 50937 Köln, Germany

2 Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Vídeňská 1083, 14220 Praha, Czech Republic

3 Kavli Institute for Theoretical Physics, University of California, Santa Barbara, CA 93106-4030 Santa Barbara, USA

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BMC Systems Biology 2008, 2:90  doi:10.1186/1752-0509-2-90

Published: 28 October 2008



Sequence alignment is a prolific basis of functional annotation, but remains a challenging problem in the 'twilight zone' of high sequence divergence or short gene length. Here we demonstrate how information on gene interactions can help to resolve ambiguous sequence alignments. We compare two distant Herpes viruses by constructing a graph alignment, which is based jointly on the similarity of their protein interaction networks and on sequence similarity. This hybrid method provides functional associations between proteins of the two organisms that cannot be obtained from sequence or interaction data alone.


We find proteins where interaction similarity and sequence similarity are individually weak, but together provide significant evidence of orthology. There are also proteins with high interaction similarity but without any detectable sequence similarity, providing evidence of functional association beyond sequence homology. The functional predictions derived from our alignment are consistent with genomic position and gene expression data.


Our approach shows that evolutionary conservation is a powerful filter to make protein interaction data informative about functional similarities between the interacting proteins, and it establishes graph alignment as a powerful tool for the comparative analysis of data from highly diverged species.