Evolutionary origin, diversification and specialization of eukaryotic MutShomolog mismatch repair proteins

Most eubacteria, and all eukaryotes examined thus far, encode homologs of t he DNA mismatch repair protein MutS, Although eubacteria encode only one or two MutS-like proteins, eukaryotes encode at least six distinct MutS homol og (MSH) proteins, corresponding to conserved (orthologous) gene families. This suggests evolution of individual gene family lines of descent by sever al duplication/specialization events. Using quantitative phylogenetic analy ses (RASA, or relative apparent synapomorphy analysis), we demonstrate that comparison of complete MutS protein sequences, rather than highly conserve d C-terminal domains only, maximizes information about evolutionary relatio nships. We identify a novel, highly conserved middle domain, as well as cle arly delineate an N-terminal domain, previously implicated in mismatch reco gnition, that shows family-specific patterns of aromatic and charged amino acids. Our final analysis, in contrast to previous analyses of MutS-like se quences, yields a stable phylogenetic tree consistent with the known bioche mical functions of MutS/MSH proteins, that now assigns all known eukaryotic MSH proteins to a monophyletic group, whose branches correspond to the res pective specialized gene families, The rooted phylogenetic tree suggests th eir derivation from a mitochondrial MSH1-like protein, itself the descenden t of the MutS of a symbiont in a primitive eukaryotic precursor.