The role of structural pleiotropy and regulatory evolution in the retention of heteromers of paralogs

Abstract

Gene duplication is a driver of the evolution of new functions. The duplication of genes encoding homomeric proteins leads to the formation of homomers and heteromers of paralogs, creating new complexes after a single duplication event. The loss of these heteromers may be required for the two paralogs to evolve independent functions. Using yeast as a model, we find that heteromerization is frequent among duplicated homomers and correlates with functional similarity between paralogs. Using in silico evolution, we show that for homomers and heteromers sharing binding interfaces, mutations in one paralog can have structural pleiotropic effects on both interactions, resulting in highly correlated responses of the complexes to selection. Therefore, heteromerization could be preserved indirectly due to selection for the maintenance of homomers, thus slowing down functional divergence between paralogs. We suggest that paralogs can overcome the obstacle of structural pleiotropy by regulatory evolution at the transcriptional and post-translational levels.

Determining the interaction status and evolutionary fate of duplicated homomeric proteins

“…Analyzing human, Arabidopsis, yeast and E. coli protein-protein interaction (PPI) data, [3] reported that most oligomeric paralogs diverged to form obligatory homomers. However, analysis of yeast, worm and fly, using both PPI data and oligomers of known structure, [2] indicated that heteromeric interactions dominate, a conclusion recently supported by [4] who analyzed yeast PPI data. We compared these studies and observed that these inconsistencies relate to three major factors.…”

“…Duplication is also ubiquitous and hence serves as the main source of new genes/proteins, as manifested by nearly half of all genes in a given genome being paralogs [1]. The duplication of genes encoding an oligomeric protein is of particular interest-the ancestral function may diverge alongside the oligomeric state thus providing new opportunities for evolutionary innovation [2][3][4][5].…”

“…Does protein function, or the source organism, for example, affect which fate dominates? Genome-scale studies [2][3][4] attempted to address the relative frequencies of these scenarios in model organisms, but their conclusions are inconsistent. Analyzing human, Arabidopsis, yeast and E. coli protein-protein interaction (PPI) data, [3] reported that most oligomeric paralogs diverged to form obligatory homomers.…”

“…First, different evolutionary scenarios were examined in different studies-e.g., ref. [3] did not consider the mixed homo/heteromers, and essentially none of these studies [2][3][4] consider hetero-others. Second, different interaction datasets were analyzed ranging from X-ray crystallographic structures (e.g., ref.…”

Coevolutionary Analysis of Protein Subfamilies by Sequence Reweighting

“…Indeed, coevolutionary analysis generally results in contacts predicted at the whole family level, thus predicting contact maps putatively formed by any member of the protein family. However, for large families consisting of multiple subgroups (or subfamilies), gene duplication and specialization lead to structural and functional variability of paralogous proteins sharing the overall same fold, but potentially carrying a sub-set of different contacts defining subfamily specificities [18,19]. Similarly, organisms with different genetic backgrounds and evolving in different environments will be subject to different fitness landscapes, thus not necessarily requiring the exact same structural and functional features, while still maintaining the same overall fold and function [20,21].…”