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  • Review Article
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The evolutionary consequences of erroneous protein synthesis

Key Points

  • Protein synthesis is a complex, multistage process, and many things can go wrong along the way.

  • At present, our knowledge of protein-synthesis error rates is limited. But existing measurements indicate that protein synthesis is error prone in comparison with DNA replication.

  • A protein that has not been synthesized correctly may be non-functional or toxic. However, it may also have a new, beneficial function.

  • The synthesis of non-functional and toxic proteins imposes fitness costs on the organism. These costs generally increase with the expression level of a gene.

  • Many mechanisms seem to have evolved to minimize the costs of erroneous protein synthesis.

  • In some cases, organisms can take advantage of synthesis errors. For example, programmed frameshifts are sometimes used for expression regulation.

  • Cellular life is an inherently noisy process. Every gene produces a range of different protein variants, and organisms optimize and take advantage of the properties of the entire range.

Abstract

Error s in protein synthesis disrupt cellular fitness, cause disease phenotypes and shape gene and genome evolution. Experimental and theoretical results on this topic have accumulated rapidly in disparate fields, such as neurobiology, protein biosynthesis and degradation and molecular evolution, but with limited communication among disciplines. Here, we review studies of error frequencies, the cellular and organismal consequences of errors and the attendant long-range evolutionary responses to errors. We emphasize major areas in which little is known, such as the failure rates of protein folding, in addition to areas in which technological innovations may enable imminent gains, such as the elucidation of translational missense error frequencies. Evolutionary responses to errors fall into two broad categories: adaptations that minimize errors and their attendant costs and adaptations that exploit errors for the organism's benefit.

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Figure 1: Sources of errors in eukaryotic protein synthesis.
Figure 2: Alternative strategies for reducing protein misfolding.
Figure 3: Evolutionary exploitation of synthesis errors.

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Acknowledgements

This work was funded in part by the National Institutes of Health grants P50 GM068763 and R01 GM088344.

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Glossary

Kinetic misfolding

The failure of an error-free protein to assume its proper ground-state conformation or spontaneous loss of the ground-state conformation.

Gain of toxic function

Any event that causes a protein to generate a deleterious effect on the cell that expresses it. For example, a mutation that causes a protein to aggregate and become cytotoxic would be called a gain-of-toxic-function mutation.

Clean-up costs

Any fitness costs related to the production and degradation of non-functional protein.

Translational-accuracy selection

A selection pressure that causes genes or specific sites in genes to be encoded by high-fidelity codons — that is, codons that correspond to abundant tRNAs.

Selection for error mitigation

A selection pressure that causes genes or specific sites in genes to be encoded by codons that, when mistranslated, lead to the substitution of amino acids with limited deleterious effects.

Translational-robustness selection

A selection pressure that causes proteins to be tolerant to missense errors under translation. Translationally robust proteins fold and function even when mistranslated.

Stochastic misfolding

Misfolding of error-free polypeptides. Also see 'kinetic misfolding'.

Programmed frameshifting

Frameshifting that is required for the proper expression of a specific functional protein. The frequency with which ribosomes change the reading frame at programmed-frameshift sites is often tightly regulated.

Ribosome skipping

A mechanism used by certain picornaviruses to produce multiple peptides from a single ORF. A specific sequence (the 2A sequence) causes the translating ribosome to skip the formation of a peptide bond at the junction of the 2A sequence and the downstream sequence.

Look-ahead effect

The ability of organisms to sense the effect of potential future mutations if these mutations arise as errors under protein synthesis.

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Allan Drummond, D., Wilke, C. The evolutionary consequences of erroneous protein synthesis. Nat Rev Genet 10, 715–724 (2009). https://doi.org/10.1038/nrg2662

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