From a mutational point of view, protein-protein interaction domains are different from other domains as well and this appears to be particularly true for the group of small, relatively promiscuous domains like SH3 and PDZ. These domains are promiscuous in the sense that they both tend to physically interact with a large number of ligands [79, 80] and are prone to move through the genome to recombine with many other domains. It has been found that particularly these domains evolve more slowly than non-promiscuous domains [70] . This likely stems from the fact that they are required to participate in many different interactions, which makes selection pressures more stringent and the appearance of the branches on phylogenetic trees relatively short and more difficult to assess when co-evolutionary data in terms of other domains in the same gene family or expression patterns is limited [42, 63] . Non-promiscuous domains on the other hand can quite easily evade the selection pressure by obtaining compensatory mutations either within themselves or their specific binding partner [70] .