Transcriptional divergence plays a role in the rewiring of protein interaction networks after gene duplication.

Gene duplication plays a key role in the evolution of protein-protein interaction (PPI) networks. After a gene duplication event, paralogous proteins may diverge through the gain and loss of PPIs. This divergence can be explained by two non-exclusive mechanisms. First, mutations may accumulate in the coding sequences of the paralogs and affect their protein sequences, which can modify, for instance, their binding interfaces and thus their interaction specificity. Second, mutations may accumulate in the non-coding region of the genes and affect their regulatory sequences. The resulting changes in expression profiles can lead to paralogous proteins being differentially expressed and occurring in the cell with different sets of potential interaction partners. These changes could also alter splicing regulation and lead to the inclusion or exclusion of alternative exons. The evolutionary role of these regulatory mechanisms remains largely unexplored. We use bioinformatics analyses of existing PPI data and proteome-wide PPI screening to show that the divergence of transcriptional regulation between paralogs plays a significant role in determining their PPI specificity. Because many gene duplication events are followed by rapid changes in transcriptional regulation, our results suggest that PPI networks may be rewired by gene duplication, without the need for protein to diverge in their binding specificities. This article is part of a Special Issue entitled: From protein structures to clinical applications.