Function--structure analysis of proteins using covarion-based evolutionary approaches: Elongation factors

摘要

The divergent evolution of protein sequences from genomic databases can be analyzed by the use of different mathematical models. The most common treat all sites in a protein sequence as equally variable. More sophisticated models acknowledge the fact that purifying selection generally tolerates variable amounts of amino acid replacement at different positions in a protein sequence. In their "stationary" versions, such models assume that the replacement rate at individual positions re- mains constant throughout evolutionary history. "Nonstation- ary" covarion versions. however, allow the replacement rate at a position to vary in different branches of the evolutionary tree. Recently, statistical methods have been developed that high- light this type of variation in replacement rates. Here. we show how positions that have variable rates of divergence in different regions of a tree ("covarion behavior"), coupled with analyses of experimental three-dimensional structures, can provide ex- perimentally testable hypotheses that relate individual amino acid residues to specific functional differences in those branches. We illustrate this in the elongation factor family of proteins as a paradigm for applications of this type of analysis in functional genomics generally.