Molecular Biology and Evolution 19:1490-1500 (2002)
© 2002 Society for Molecular Biology and Evolution
Identification of Essential Amino Acid Changes in Paired Domain Evolution Using a Novel Combination of Evolutionary Analysis and In Vitro and In Vivo Studies
*Human Genetics Center, University of Texas-Houston;
Howard Hughes Medical Institute, University of Michigan Medical Center;
Department of Biology and Biochemistry, University of Houston;
Departments of Zoology and Genetics, Iowa State University;
||Department of Oral Biology, School of Dentistry, Medical College of Georgia;
¶Department of Ecology and Evolution, University of Chicago
Pax genes are defined by the presence of a paired box that encodes a DNA-binding domain of 128 amino acids. They are involved in the development of the central nervous system, organogenesis, and oncogenesis. The known Pax genes are divided into five groups within two supergroups. By means of a novel combination of evolutionary analysis, in vitro binding assays and in vivo functional analyses, we have identified the key residues that determine the differing DNA-binding properties of the two supergroups and of the Pax-2, 5, 8 and Pax-6 subgroups within supergroup I. The differences in binding properties between the two supergroups are largely caused by amino acid changes at residues 20 and 121 of the paired domain. Although the paired domains of the Pax-2, 5, 8 and the Pax-6 group differ by >19 amino acids, their distinct DNA-binding properties are determined almost completely by a single amino acid change. Thus, a small number of amino acid changes can account in large part for the divergence in binding properties among the known paired domains. Our approach for selecting candidate sites responsible for the functional divergence between genes should also be useful for studying other gene families.
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