Network motif-based analysis of regulatory patterns in paralogous gene pairs

Current high-throughput experimental techniques make it feasible to infer gene regulatory interactions at the whole-genome level with reasonably good accuracy. Such experimentally inferred regulatory networks have become available for a number of simpler model organisms such as S. cerevisiae, and others. The availability of such networks provides an opportunity to compare gene regulatory processes at the whole genome level, and in particular, to assess similarity of regulatory interactions for homologous gene pairs either from the same or from different species. We present here a new technique for analyzing the regulatory interaction neighborhoods of paralogous gene pairs. Our central focus is the analysis of S. cerevisiae gene interaction graphs, which are of particular interest due to the ancestral whole-genome duplication (WGD) that allows to distinguish between paralogous transcription factors that are traceable to this duplication event and other paralogues. Similar analysis is also applied to E. coli and C. elegans networks. We compare paralogous gene pairs according to the presence and size of bi-fan arrays, classically associated in the literature with gene duplication, within other network motifs. We further extend this framework beyond transcription factor comparison to obtain topology-based similarity metrics based on the overlap of interaction neighborhoods applicable to most genes in a given organism. We observe that our network divergence metrics show considerably larger similarity between paralogues, especially those traceable to WGD. This is the case for both yeast and C. elegans, but not for E. coli regulatory network. While there is no obvious cross-species link between metrics, different classes of paralogues show notable differences in interaction overlap, with traceable duplications tending toward higher overlap compared to genes with shared protein families. Our findings indicate that divergence in paralogous interaction networks reflects a shared genetic origin, and that our approach may be useful for investigating structural similarity in the interaction networks of paralogous genes.