Flow chart of the FRED method for analyzing the protein divergence landscape of functional categories. **(a) **We start from a matrix of all human genes with the conservation score (CS) in each of the 15 genomes analyzed. **(b) **First, all genes with a CS over 0 are ranked in each organism, and the highly ranked genes are shown in red and lowly ranked in blue following a gradient of colors. White cells mean that no ortholog/homolog is detected. Next, the genes are classified according to GO terms. **(c) **For each set of genes within a GO category, we calculate the median CS, and also select 10,000 sets of the same number of genes as in the GO category considered at random from the complete set of genes with GO annotation. **(d) **For each random set, we calculate the median CS. **(e) **From the 10,000 random sets we obtain the expected median CS and the standard error, which allow us to calculate the Z-score for the GO category under consideration. **(f) **This Z-score is then plotted in a matrix on a color-coded scale. Gray means no significant difference in the level of conservation compared to the background. A similar procedure is followed for the calculation of Z-scores for number of orthologs and homologs by counting the proportion of genes with homologs or orthologs in each set. Mmus, *Mus musculus*; Rnor, *Rattus norvegicus*; Cfam, *Canis familiaris*; Bta, *Bos taurus*; Mdom, *Monodelphis domestica*; Ggal, *Gallus gallus*; Xtro, *Xenopus tropicalis*; Drer, *Danio rerio*; Trub, *Takifugu rubripes*; Tnig, *Tetraodon nigroviridis*; Cint, *Ciona intestinalis*; Agam, *Anopheles gambiae*; Dmel, *Drosophila melanogaster*; Cele, *Caenorhabditis elegans*; Scer, *Saccharomyces cerevisiae*. All the results of these analyses for all GO categories are provided online in a searchable database at [28].

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