No simple dependence between protein evolution rate and the number of protein-protein interactions: only the most prolific interactors tend to evolve slowly

BMC Evolutionary Biology No simple dependence between protein evolution rate and the number of protein-protein interactions: only the most prolific interactors tend to evolve slowly I King Jordan 0 Yuri I Wolf 0 Eugene V Koonin 0 0 Address: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health , Bethesda, MD 20894 Background: It has been suggested that rates of protein evolution are influenced, to a great extent, by the proportion of amino acid residues that are directly involved in protein function. In agreement with this hypothesis, recent work has shown a negative correlation between evolutionary rates and the number of protein-protein interactions. However, the extent to which the number of protein-protein interactions influences evolutionary rates remains unclear. Here, we address this question at several different levels of evolutionary relatedness. Results: Manually curated data on the number of protein-protein interactions among Saccharomyces cerevisiae proteins was examined for possible correlation with evolutionary rates between S. cerevisiae and Schizosaccharomyces pombe orthologs. Only a very weak negative correlation between the number of interactions and evolutionary rate of a protein was observed. Furthermore, no relationship was found between a more general measure of the evolutionary conservation of S. cerevisiae proteins, based on the taxonomic distribution of their homologs, and the number of protein-protein interactions. However, when the proteins from yeast were assorted into discrete bins according to the number of interactions, it turned out that 6.5% of the proteins with the greatest number of interactions evolved, on average, significantly slower than the rest of the proteins. Comparisons were also performed using protein-protein interaction data obtained with high-throughput analysis of Helicobacter pylori proteins. No convincing relationship between the number of protein-protein interactions and evolutionary rates was detected, either for comparisons of orthologs from two completely sequenced H. pylori strains or for comparisons of H. pylori and Campylobacter jejuni orthologs, even when the proteins were classified into bins by the number of interactions. Conclusion: The currently available comparative-genomic data do not support the hypothesis that the evolutionary rates of the majority of proteins substantially depend on the number of proteinprotein interactions they are involved in. However, a small fraction of yeast proteins with the largest number of interactions (the hubs of the interaction network) tend to evolve slower than the bulk of the proteins. - Background Rates of protein evolution vary greatly and may be influenced by a variety of factors. Recently, it has been demonstrated that the magnitude of the fitness effects associated with deleterious mutations in protein-coding genes (i.e. proteins' dispensability) correlates with rates of protein evolution [1,2]. Essential proteins or those that are less dispensable to an organism tend to evolve slower than those that are more dispensable. It has also been suggested that proteins' evolutionary rates are determined by the proportion of amino-acids that are critical to their function [3]. According to this intuitively plausible notion, proteins with a greater fraction of amino acid residues that play an essential role in the protein's function are predicted to evolve slower than those with a smaller fraction of such crucial residues. Consistent with this prediction, a negative correlation has been reported between protein evolutionary rates, which were determined from evolutionary distances between orthologous proteins from yeast Saccharomyces cerevisiae and the nematode Caenorhabditis elegans, and the number of protein-protein interactions (i.e., physical interactions determined, primarily, using the yeast two-hybrid system) proteins are involved in [4]. Yeast proteins that have a large number of interacting partners were found to have evolved slower, on average, than those with fewer interacting partners, and this was presumed to be due to the fact that proteins with more interacting partners have a greater fraction of residues directly involved in function. However, these same data indicate that less than 6% of the variance in evolutionary rates is explained by the variance in the number of protein-protein interactions, suggesting that the influence of the number of interacting partners on protein evolutionary rates might not be substantial. We sought to further investigate this phenomenon by examining the relationship between the number of proteinprotein interacting partners and protein evolutionary rates for the yeasts S. cerevisiae and Schizosaccharomyces pombe as well as for the proteobacteria Helicobacter pylori and Camplyobacter jejuni. Results and Discussion Evolutionary rates and protein-protein interactions: yeast A total of 1,879 pairs of orthologous proteins, one from S. cerevisiae and one from S. pombe, were identified (see Methods), and for 1,004 of these, there was data on protein-protein interactions of the S. cerevisiae member in the MIPS database [5]. For these 1,004 orthologous pairs, the number of protein-protein interactions detected for the S. cerevisiae protein was plotted against the calculated substitution rates between orthologs (Figure 1a). As with a previous survey that compared conserved S. cerevisiae and C. elegans orthologs [4], there is a negative correlation between the number of protein-protein interactions and the evolutionary rates. However, although this correlation is statistically significant (Table 1), the slope of the linear trend line (y = -0.012) fit to the data by least squares regression as well as the small r2 value (r2 = 0.0065) suggest that the influence of the number of interacting partners on rates of evolution is minor at best. Specifically, the r2 value indicates that less than 1% of the variation in substitution rates between orthologous proteins is explained by the variation in the number of protein-protein interactions. Furthermore, when only the most conserved ( 40% sequence identity), and thus most reliably identified, pairs of orthologous proteins were considered, the slope of the linear trend line as well as the r2 value decreased and the statistical significance disappeared (Figure 1b and Table 1). To account for the possibility that linear regression does not adequately reflect the structure of the data and the observed low correlation is due to a non-linear relationship between the number of interactions and evolutionary rate of a protein, we also calculated the rank correlation coefficients for these quantities. Under this approach, no statistically significant correlation was observed for either of the two analysed data sets (Table 1). It is tempting to speculate that the difference between the results obtained here and those reported previously [4] can be a (...truncated)