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Synonymous but not the same: the causes and consequences of codon bias

Nature Reviews Genetics volume 12, pages 32–42 (2011)Cite this article

Subjects

Key Points

  • Codon usage varies widely between species, between genes in a genome and between sites in a gene.

  • Explanations for natural variation in codon usage fall into two categories: mutational and selective.

  • Mutational mechanisms are responsible for most codon-usage variation between species; by contrast, selection for translation efficiency accounts for much of the systematic variation across a genome (except in mammals).

  • Translationally efficient codons may increase elongation rate, accuracy or both.

  • Rapid elongation should not be expected to influence protein yield per mRNA molecule for an endogenous gene, but it may be relevant for an overexpressed transgene.

  • The codons that provide efficient translation of an overexpressed transgene may differ from the efficient codons for an endogenous gene.

  • High-throughput measurements of endogenous mRNA levels, protein levels and ribosomal occupancies provide a detailed description of translation processes.

  • Libraries of randomized genes can elucidate design principles for efficient transgene expression, even without uncovering underlying mechanisms.

Abstract

Despite their name, synonymous mutations have significant consequences for cellular processes in all taxa. As a result, an understanding of codon bias is central to fields as diverse as molecular evolution and biotechnology. Although recent advances in sequencing and synthetic biology have helped to resolve longstanding questions about codon bias, they have also uncovered striking patterns that suggest new hypotheses about protein synthesis. Ongoing work to quantify the dynamics of initiation and elongation is as important for understanding natural synonymous variation as it is for designing transgenes in applied contexts.

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Figure 1: Codon bias within and between genomes.
Figure 2: Relationships between initiation rate, elongation rate, ribosome density and the rate of protein synthesis for endogenous genes.
Figure 3: Effects of mRNA secondary structure on translation initiation in bacteria.
Figure 4: The elongation rate may influence the rate of protein synthesis for an overexpressed gene.

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Acknowledgements

We thank L. Hurst and C. Wilke for helpful discussions. We apologize to those whose work we were unable to cite because of space constraints. G.K. acknowledges funding from the Wellcome Trust. J.B.P. acknowledges support from the Burroughs Wellcome Fund, the David and Lucile Packard Foundation, the James S. McDonnell Foundation, the Alfred P. Sloan Foundation, the Defense Advanced Research Projects Agency (HR0011-05-1-0057) and the US National Institute of Allergy and Infectious Diseases (2U54AI057168).

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  1. Department of Biology and Program in Applied Mathematics and Computational Science, University of Pennsylvania, 433 South University Avenue, Philadelphia, 19104, Pennsylvania, USA

    Joshua B. Plotkin

  2. Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Kings Buildings, Mayfield Road, EH9 3JR, Edinburgh, UK

    Grzegorz Kudla

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Glossary

Iso-accepting tRNAs

A subset of tRNAs that carry the same amino acid.

Negative selection

A form of natural selection that suppresses alternative genetic variants in favour of the wild type.

Horizontal gene transfer

The transfer of genetic material from one species into another.

Isochore

A large fragment of a chromosome that is characterized by homogeneous GC content.

Ribosomal pausing

A temporary arrest of the ribosome during translation elongation.

Effective population size

The number of individuals in a population that produce viable offspring.

Biased gene conversion

A recombination event in which one variant of genomic sequence is preferentially 'copied and pasted' onto another one.

Fourfold degenerate sites

Positions within the coding sequence of a gene at which all four nucleotides encode the same amino acid.

Shotgun proteomics

Methods of quantifying protein levels in a complex sample, typically using mass spectrometry.

Codon adaptation index

A measure of similarity between the codon usage of a gene and the average codon usage of highly expressed genes in a species.

RNA–seq

Quantitative analysis of RNA in a complex sample by high-throughput sequencing.

Ribosomal footprint

A fragment of mRNA that is protected by ribosomes from nuclease digestion in a ribosomal-profiling experiment.

Upstream ORFs

ORFs that are located 5′ from the primary ORF. They are thought to inhibit translation of the primary ORF.

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Plotkin, J., Kudla, G. Synonymous but not the same: the causes and consequences of codon bias. Nat Rev Genet 12, 32–42 (2011). https://doi.org/10.1038/nrg2899

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