The document discusses the evolution of protein interaction networks by comparing networks across species. It finds that interactions change at a fast rate, with around 1% to 3% of interactions turning over per million years. Less specific interactions mediated by promiscuous domains evolve faster than more specific interactions. Functions related to immune response and transport show evidence of positive selection for fast interaction turnover. This dynamic interaction evolution may allow networks to search for optimal solutions to biological problems through mutations at the protein and network levels.

1. Pedro Beltrao & Luis Serrano EMBL-Heidelberg

4. Indirect measure of network evolution According to Wagner (2001), after 50My less than 20% of duplicates share interactions Wagner A (2001) The yeast protein interaction network evolves rapidly and contains few redundant duplicate genes. Mol Biol Evol 18: 1283-1292. Even without comparing interaction networks of different species it should be possible to gain insights into protein network evolution by studying gene duplications. Based on 13 interactions found within pairs of duplicated proteins, Wagner calculated a rate of 2.88×10 -6 new interactions per protein pair per My. Approximately 50 newly evolved interactions per million years . Duplication Divergence Interaction Lost Interaction Gain

5. Evolution of PINs Assign protein “age” by looking at the phylogenetic distribution of orthologs ~ 1By <~ 20 My S. cerevisiae S. bayanus C. glabrata K.lactis A.gossypii C.albicans D.hansenii Y.lipolytica N.crassa S.pombe Likely a recently duplicated gene Likely an ancestral protein

6. Evolution of PINs The interaction was inherited with the duplication The interaction was created or lost in one of the proteins after duplication OR poor coverage Rate = interactions between old and new + interactions between new proteins possible proteins pairs * divergence time Likely younger than 20My Homolog Older than 20My Duplication

7. Eukaryotic network evolution Eukaryotic interactomes have added new interaction in the recent evolutionary past at a rate on the order of 1 ×10 -5 new interactions per protein pair per My. Species studied D. melanogaster C. elegans S. cerevisiae H. sapiens Approximate divergence from reference species (My) 40 100 20 70 Older proteins with interactions 5761 1774 4190 6111 Recently duplicated proteins with interactions 788 412 514 266 Interactions to a new protein 3721 892 1207 729 Interactions gained or lost 3615 854 1120 623 Percentage of interactions conserved after duplication (%) 3 4 7 15 Rate for change of interactions (per protein pair per My) 1.86 ×10 -5 1.05 ×10 -5 2.45 ×10 -5 5.36 ×10 -6

8. Rate of addition of new interactions Percentage of inherited interactions Random interaction removal Random node removal Percentage of inherited interactions depends on network coverage The rate of change of interactions is mostly independent on network size.

11. Preferential turnover S. cerevisiae R 2 = 0.944 0.0E+00 2.0E-05 4.0E-05 6.0E-05 8.0E-05 1.0E-04 0 5 10 15 20 Number of protein interactions Rate of change D. melanogaster R 2 = 0.9701 0.0E+00 2.0E-05 4.0E-05 6.0E-05 8.0E-05 1.0E-04 0 5 10 15 20 Number of protein interactions Rate of change C. elegans R 2 = 0.9632 0.0E+00 2.0E-05 4.0E-05 6.0E-05 8.0E-05 1.0E-04 0 5 10 15 20 Number of protein interactions Rate of change H. sapiens R 2 = 0.9291 0.0E+00 1.0E-05 2.0E-05 3.0E-05 4.0E-05 0 5 10 15 20 Number of protein interactions Rate of change

13. Specificity and evolvability Protein specificity might be a factor determining likelihood of change of new interactions. Using iPfam , a database of structures with interacting protein domains (including crystal contacts), we binned protein binding domains with increasing number of interactions. We used the number of iPfam interactions as a proxy for binding specificity. 0.0E+00 4.0E-06 8.0E-06 1.2E-05 1.6E-05 2.0E-05 0 5 10 15 20 Average number of iPFAM interactions Rate of change

14. Specificity and evolvability Less specific interaction types evolve faster Using only the Human interactions network and excluding the high-throughput interactions. Selected “old” proteins that have promiscuous domains, selective domains or peptide binding domains.

16. Selection for interaction turnover Functions with higher rate of change than expected by their average n. of interactions