Signatures of evolutionary functional divergence. Schematics of site-specific types I & II functional divergence between subfamilies of sequences. Left, type-I functional divergence in which a specific site is occupied by a conserved aspartate residue (D) in one lineage but occupied by many residues at the homologous site in the other lineage. Middle, type-II functional divergence in which a specific site is again occupied by a conserved aspartate residue (D) in one lineage while the homologous site in the other lineage is also conserved but occupied by a different residue (histidine, H). Right, no functional divergence associated with the replacements of aspartates and histidines. Functional inferences associated with these patterns require phylogenetic analysis otherwise they are indistinguishable from historical contingence (i.e., common ancestry).