Universal distribution of mutational effects on protein stability, uncoupling of protein robustness from sequence evolution and distinct evolutionary modes of prokaryotic and eukaryotic proteins

Guilhem Faure,Eugene V Koonin

doi:10.1088/1478-3975/12/3/035001

Guilhem Faure, Eugene V Koonin

Open Access

https://doi.org/10.1088/1478-3975/12/3/035001

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Abstract

Robustness to destabilizing effects of mutations is thought of as a key factor of protein evolution. The connections between two measures of robustness, the relative core size and the computationally estimated effect of mutations on protein stability (ΔΔG), protein abundance and the selection pressure on protein-coding genes (dN/dS) were analyzed for the organisms with a large number of available protein structures including four eukaryotes, two bacteria and one archaeon. The distribution of the effects of mutations in the core on protein stability is universal and indistinguishable in eukaryotes and bacteria, centered at slightly destabilizing amino acid replacements, and with a heavy tail of more strongly destabilizing replacements. The distribution of mutational effects in the hyperthermophilic archaeon Thermococcus gammatolerans is significantly shifted toward strongly destabilizing replacements which is indicative of stronger constraints that are imposed on proteins in hyperthermophiles. The median effect of mutations is strongly, positively correlated with the relative core size, in evidence of the congruence between the two measures of protein robustness. However, both measures show only limited correlations to the expression level and selection pressure on protein-coding genes. Thus, the degree of robustness reflected in the universal distribution of mutational effects appears to be a fundamental, ancient feature of globular protein folds whereas the observed variations are largely neutral and uncoupled from short term protein evolution. A weak anticorrelation between protein core size and selection pressure is observed only for surface residues in prokaryotes but a stronger anticorrelation is observed for all residues in eukaryotic proteins. This substantial difference between proteins of prokaryotes and eukaryotes is likely to stem from the demonstrable higher compactness of prokaryotic proteins.

Highlights

Protein-coding genes in any organismal lineage evolve at widely different rates, spanning a range of about three orders of magnitude [1, 2]
The coverage of the proteomes with protein structures varied from 0.5% for D. melanogaster to 19% for E. coli (Table 1; see Methods for details)
There was a significant negative correlation between the relative core size and protein abundance that was substantially more pronounced in bacteria than it was in eukaryotes, and in the former case, survived the correction for the universal correlation between abundance and dN/dS (Table 2)

Summary

Introduction

Protein-coding genes in any organismal lineage evolve at widely different rates, spanning a range of about three orders of magnitude [1, 2]. The distributions of the rates across sets of orthologous genes in diverse life forms, from bacteria to mammals, which reflect the relative rates of gene evolution, show a notably greater degree of conservation than the absolute rates [1, 2]. This observation inspired the universal pacemaker, a more general model of evolution, that postulates genome-wide, synchronous changes in the evolutionary rates of genes. The universal pacemaker model yields a better fit between thousands of individual gene trees and the species tree than the strict molecular clock model [8, 9]

Methods

Results

Discussion

Conclusion