A comparison of sequences for evolutionary insight is best achieved by looking at the structural and functional (sub)units of proteins, the protein domains. By convention, domains are defined as conserved, functionally independent protein sequences, which bind or process ligands using a core structural motif [11] [12] [13] . Examples of domain modes of actions in signaling cascades for instance, are to connect different components into a larger complex or to bind signaling-molecules [14, 15] . Protein domains can usually fold independently, likely due to their relatively limited size, and are well known to behave as independent genetic elements within genomes [16, 17] . The sum of these features makes protein domains readily identifiable from raw nucleotide and amino acid sequences and many protein family resources (e.g., Superfamily and SMART [see Table 1 ]) indeed fully rely on such sequence similarity and motif identifications [18, 19] .