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Nucleic Acids Research, 2000, Vol. 28, No. 2 463-471
© 2000 Oxford University Press

Evolutionary origin, diversification and specialization of eukaryotic MutS homolog mismatch repair proteins

Kevin M. Culligan1,2, Gilbert Meyer-Gauen2, James Lyons-Weiler3 and John B. Hays1,2,*

1Program in Molecular and Cellular Biology and 2Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA and 3Institute of Molecular Evolutionary Genetics and Department of Biology, Pennsylvania State University, University Park, PA 16802-5301, USA

Most eubacteria, and all eukaryotes examined thus far, encode homologs of the DNA mismatch repair protein MutS. Although eubacteria encode only one or two MutS-like proteins, eukaryotes encode at least six distinct MutS homolog (MSH) proteins, corresponding to conserved (orthologous) gene families. This suggests evolution of individual gene family lines of descent by several duplication/specialization events. Using quantitative phylogenetic analyses (RASA, or relative apparent synapomorphy analysis), we demonstrate that comparison of complete MutS protein sequences, rather than highly conserved C-terminal domains only, maximizes information about evolutionary relationships. We identify a novel, highly conserved middle domain, as well as clearly delineate an N-terminal domain, previously implicated in mismatch recognition, that shows family-specific patterns of aromatic and charged amino acids. Our final analysis, in contrast to previous analyses of MutS-like sequences, yields a stable phylogenetic tree consistent with the known biochemical functions of MutS/MSH proteins, that now assigns all known eukaryotic MSH proteins to a monophyletic group, whose branches correspond to the respective specialized gene families. The rooted phylogenetic tree suggests their derivation from a mitochondrial MSH1-like protein, itself the descendent of the MutS of a symbiont in a primitive eukaryotic precursor.

* To whom correspondence should be addressed at: Department of Environmental and Molecular Toxicology, Oregon State University, ALS 1007, Corvallis, OR 97331-7301, USA. Tel: +1 541 737 1777; Fax: +1 541 737 0947; Email: haysj@bcc.orst.edu Present address: Gilbert Meyer-Gauen, Plant Initiative, University of Nebraska–Lincoln, Lincoln, NE 68588-0665, USA The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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