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Determinants of the rate of protein sequence evolution

Nature Reviews Genetics volume 16, pages 409–420 (2015)Cite this article

Subjects

Key Points

  • Studying the rate of protein sequence evolution led to the foundation of the field of molecular evolution and continues to offer insights into the mechanism of evolution.

  • The evolutionary rate of a protein is only weakly influenced by the functional importance of the protein.

  • The expression level of a protein is a major determinant of its evolutionary rate.

  • Natural selection against molecular and cellular errors such as mistranslation, protein misfolding and protein misinteraction is a primary explanation of why highly expressed proteins evolve slowly.

  • The functional constraints on a protein include not only a constraint to maintain its physiological function but also a constraint to avoid toxicity, and both factors influence the evolutionary rate of the protein.

Abstract

The rate and mechanism of protein sequence evolution have been central questions in evolutionary biology since the 1960s. Although the rate of protein sequence evolution depends primarily on the level of functional constraint, exactly what determines functional constraint has remained unclear. The increasing availability of genomic data has enabled much needed empirical examinations on the nature of functional constraint. These studies found that the evolutionary rate of a protein is predominantly influenced by its expression level rather than functional importance. A combination of theoretical and empirical analyses has identified multiple mechanisms behind these observations and demonstrated a prominent role in protein evolution of selection against errors in molecular and cellular processes.

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Figure 1: The negative correlation between gene expression level and protein evolutionary rate (E–R anticorrelation) exists in all three domains of life.
Figure 2: Natural selection against errors in protein translation, folding and interaction can explain the E–R anticorrelation.
Figure 3: The expression cost hypothesis of the E–R anticorrelation.

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Acknowledgements

The authors thank X. Chen, W.-C. Ho, B. Moyers, J. Xu and three anonymous reviewers for comments. Research in the Zhang Lab on the topic reviewed here has been supported by the US National Institutes of Health.

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  1. Department of Ecology and Evolutionary Biology, University of Michigan, 830 North University Avenue, Ann Arbor, 48109, Michigan, USA

    Jianzhi Zhang & Jian-Rong Yang

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  1. Jianzhi Zhang
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Correspondence to Jianzhi Zhang.

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Supplementary information

Supplementary information S1 (box)

E-R anticorrelation for RNA genes (PDF 120 kb)

Supplementary information S2 (box)

Data sources for Figure 1 (PDF 174 kb)

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Glossary

Neutral theory

A theory of molecular evolution asserting that most variations of DNA and protein sequences within and between species are selectively neutral rather than adaptive.

Functional constraint

The extent to which random mutations are purged by natural selection owing to their deleterious effects on protein function.

Functional importance

The fitness advantage to an organism conferred by the function of a protein.

Molecular clock hypothesis

The hypothesis that the same protein evolves with an approximately constant rate over time and across different organisms.

Dispensability

The degree to which an organism can survive and reproduce when a given gene is removed.

Orthologous gene

A gene from a different species that originated by vertical descent from a single gene of the last common ancestor of these species.

Effective population size

(Denoted as Ne). A measure of the strength of random genetic drift in a population. The lower the Ne, the stronger the genetic drift. Ne is influenced by the census population size, breeding system and sex ratio, among other factors.

Protein misfolding

The process by which a protein structure assumes a non-native shape or conformation, which not only diminishes the physiological function of the protein but may also create cytotoxicity.

Preferred codon

A codon that is used more frequently than its synonymous codons in a genome sequence.

Mistranslated proteins

Nascent proteins in which incorrect amino acids have been incorporated during synthesis, which may be caused by incorrect charging of tRNAs by aminoacyl tRNA synthetases or incorrect acceptance of tRNAs by ribosomes.

Protein misinteraction

A non-native interaction between protein molecules that not only reduces the concentrations of freely available protein molecules but may also be toxic.

mRNA folding strength

A measure of the reduction in free energy of a folded mRNA molecule compared to its unfolded form.

Pleiotropic

Pertaining to pleiotropy: the phenomenon whereby one gene or one mutation affects multiple traits.

Designability

The number of protein sequences that adopt a protein structure.

Protein conformational diversity

The degree of structural variations of various native states of a protein.

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Zhang, J., Yang, JR. Determinants of the rate of protein sequence evolution. Nat Rev Genet 16, 409–420 (2015). https://doi.org/10.1038/nrg3950

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