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Review
, 59 (2), 149-61

Codon Bias as a Means to Fine-Tune Gene Expression

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Review

Codon Bias as a Means to Fine-Tune Gene Expression

Tessa E F Quax et al. Mol Cell.

Abstract

The redundancy of the genetic code implies that most amino acids are encoded by multiple synonymous codons. In all domains of life, a biased frequency of synonymous codons is observed at the genome level, in functionally related genes (e.g., in operons), and within single genes. Other codon bias variants include biased codon pairs and codon co-occurrence. Although translation initiation is the key step in protein synthesis, it is generally accepted that codon bias contributes to translation efficiency by tuning the elongation rate of the process. Moreover, codon bias plays an important role in controlling a multitude of cellular processes, ranging from differential protein production to protein folding. Here we review currently known types of codon bias and how they may influence translation. We discuss how understanding the principles of codon bias and translation can contribute to improved protein production and developments in synthetic biology.

Figures

Figure 1
Figure 1. Translation in the Ribosome and tRNA Structure
Cartoon of the ribosome (green) during translation of a mRNA (blue) with a wobbling codon-anticodon base pair encoding a leucine amino acid. A site, aminoacyl-tRNA site; E site, exit site; P site, peptidyl-tRNA site.
Figure 2
Figure 2. Different Types of Codon Bias
(A) Frequency bias will result in effective protein production when the frequency of used codons matches the cellular tRNA population. (B) Co-occurrence bias enhances protein expression, presumably because of tRNA recharging in the vicinity of the translating ribosome. (C) Pair bias is probably selected because of more optimal interactions of tRNAs in the A site and the P site.
Figure 3
Figure 3. Ribosome Density Profiling to Measure Translation
(A) Single-gene translation profiles based on ribosome density analysis are used to characterize intragenic fluctuations in translation elongation rates (e.g., corresponding to ramps of rare codons or pause sites at Shine-Dalgarno motifs). (B) Genome translation profiles based on ribosome density analysis provide insight in intergenic differences in translation efficiency (translatome) by normalizing gene specific ribosome densities to their mRNA abundance. Importantly, intergenic differences in translation efficiency can be identified only if similar translation elongation rates can be assumed (e.g., on the basis of a similar codon bias in the genes to compare).
Figure 4
Figure 4. Codon Landscapes and Intergenic Codon Bias
(A) The intragenic codon landscape can modulate the translation elongation rate, contributing to appropriate co-translational folding of the protein's secondary structure elements and domains. The red arrow indicates a stretch of rare codons encoding the red colored residues in the protein structure. Apart from a ramp sequence at 5′ end of the coding sequence, a valley in the codon landscape occurs between the two domains. The picture represents the bovine β-B2 crystallin and is adapted from Komar (2009). (B) Differential expression of genes residing in an operon is controlled by differential translation. This is accomplished mainly by enhanced initiation (as reflected by a higher ribosome density) and, to some extent, by adjusted elongation (as reflected by a more optimal codon bias). An example is shown of the operon encoding the CRISPR-associated Cascade complex from E. coli with uneven stoichiometry; cryo-electron microscopic structure is from Wiedenheft et al. (2011). (C) The expression of sets of functionally related genes can be co-regulated on the basis of their codon bias. The available pools of aminoacyl-tRNAs can specifically change under certain conditions, which lead to improved translation of genes with adapted codon bias. As an example, genes encoding amino acid biosynthesis pathways are shown, which contain many rare codons translated by tRNAs that remain highly charged during amino acid starvation.

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