Differential selection after duplication in mammalian developmental genes.

Gene duplication provides the opportunity for subsequent refinement of distinct functions of the duplicated copies. Either through changes in coding sequence or changes in regulatory regions, duplicate copies appear to obtain new or tissue-specific functions. If this divergence were driven by natural selection, we would expect duplicated copies to have differentiated patterns of substitutions. We tested this hypothesis using genes that duplicated before the human/mouse split and whose orthologous relations were clear. The null hypothesis is that the number of amino acid changes between humans and mice was distributed similarly across different paralogs. We used a method modified from Tang and Lewontin to detect heterogeneity in the amino acid substitution pattern between those different paralogs. Our results show that many of the paralogous gene pairs appear to be under differential selection in the human/mouse comparison. The properties that led to diversification appear to have arisen before the split of the human and mouse lineages. Further study of the diverged genes revealed insights regarding the patterns of amino acid substitution that resulted in differences in function and/or expression of these genes. This approach has utility in the study of newly identified members of gene families in genomewide data mining and for contrasting the merits of alternative hypotheses for the evolutionary divergence of function of duplicated genes.