It is clear that some of the above characteristics are underappreciated in the phylogenetic analysis of linear amino acid sequences. Moreover, the effects of evolution extend even further than these aspects and entail transcriptional and translational regulation, intramolecular domain-domain interactions, gene modifications and post-translational protein modifications [88] [89] [90] [91] [92] [93] [94] [95] [96] . New methods are thus being developed to take into account that when sequences evolve, their close and distant functional relationships evolve in parallel. Correlations of mutations have already been found between residues of different proteins [97, 98] and compensating mutational changes at an interaction interface were shown to recover the instability of a complex [99] . These observations are evidence for the current evolutionary models for the protein-protein interaction (PPIs) networks that are being constructed through large-scale screens [100] [101] [102] . In these, a gene duplication or domain duplication (depending on the resolution of the network) implies the addition of a node, while the deletion of a gene or domain reduces the amount of links in the network (Fig. 3) . In the next step, extensive network rewiring may take place, driven by the effect of node addition or node loss in the network (i.e., the duplicability or essentiality of a domain/protein) and mutations in the domain-interaction interface [67, 74, [103] [104] [105] .