Overview of experimental schema and hypotheses. Proteins that share functional/physical relationships have similar relative rates of evolution across the phylogeny, as shown in (A) with SMC5 and SMC6. The color scale along the bottom indicates the relative evolutionary rate (RER) of the specific protein for that species compared to the genome-wide average. A higher (red) RER indicates that the protein is evolving at a faster rate than the genome average for that branch. Conversely, a lower (blue) RER indicates that protein is evolving at a slower rate than the genome average. The ERC (right) is a Pearson correlation of the RERs for each shared branch of the gene pair. (B) Suppose the correlation in relative evolutionary rates between two proteins is due to compensatory coevolution and physical interactions. In that case, the correlation of their rates (ie. ERC value) would be higher for just the amino acids in the physically interacting domain. (C) Outline of experimental design. Created with Biorender.com

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Protein complexes and cellular pathways have significantly high average ERC. (A) The mean ERC values for 617 protein complexes (purple, median 5.366) and 125 cellular pathways (orange, median 4.597) versus the number of members contributing to the score. (B) Heat maps of the ERC scores for each protein pair in the motor proteins pathway (left) and SLIK complex (right). ERC for members of the motor proteins pathways that physically interact was set to NA (gray). (C) Scatter plots of the relative evolutionary rates for the top scoring pair from the motor proteins pathway (orange) and SLIK complex (purple).

Recreation of figure 1B with the COMA complex. The table shows the ERC values for each domain pair as labeled in the cartoon on the right. The domain pairs with physical interactions are highlighted in green.

ROC curve analysis of all 17 protein complexes. 12 of the 17 complexes have a ROC-AUC greater than 0.5. The SEC23/24 complex (bright green) has the highest ROC-AUC at 1, and the NUP84 complex (marigold) has the lowest AUC of 0.247. One-tailed Mann-Whitney U test, p < 0.05*, p<0.01**

Protein-vs-protein physically interacting domains do not consistently rank higher than non-physically interacting domains. The domains from individual protein pairs within each complex were ranked and the proportional ranking of the physically interacting domain was calculated. Each dot represents the proportional rank of the interacting domain pair for a protein pair, with colors representing the complexes. A score of 1 indicates that the physically interacting domains were ranked first. A score of 0 indicates that the physically interacting domains were ranked last. Permutation test, p<0.05 (bold), p<0.01 (bold and underlined)

Permutation p-value distribution of 617 protein complexes (top) and 125 pathways (bottom) when compared to a null distribution of 1000 samples.

Histogram of the Fisher transformed ERC values for all 12,552 orthologous genes in the 343 yeast dataset. Median = 0.953.