Synonymous Mutations as a Cause of Human Genetic Disease


The genetic code is degenerate, that is, several codons are translated into the same amino acid. Synonymous codon changes that do not alter the protein sequence were considered as having no functional consequence and referred to as ‘silent’. This viewpoint has changed drastically in the past decade. Studies in molecular evolution have established that in all organisms, synonymous codons are under selection pressure and consequently used with different frequencies. These observations have been complemented by biochemical, biophysical and genetic studies that provide mechanistic explanations of how such a codon bias is exploited by the translation machinery of cells to control gene expression, the efficiency of protein folding and the coordinated expression of functionally related gene families. Interest in this phenomenon has been heightened by the association between many synonymous mutations and human diseases. Thus, synonymous mutations, once considered innocuous are increasingly being demonstrated to be important in human diseases, evolution and biotechnology.

Key Concepts:

  • Synonymous codon changes do not change the amino acid sequence of the translated protein.

  • Until recently synonymous changes were thought to have no effect on the protein and were called silent.

  • New studies show that even synonymous nucleotide changes can affect protein folding and function.

  • Studies in molecular evolution show that even synonymous codons are under selection pressure.

  • Over 50 human diseases are associated with synonymous mutations.

  • Synonymous mutations can affect the splicing of precursor mRNAs.

  • Synonymous mutations can alter the secondary structure of the mRNA and thus affect mRNA stability.

  • Several codons encode the same amino acid but are not used with the same frequency, this is called codon bias.

  • Codon bias is used by the translation machinery to regulate the translation speed and accuracy.

Keywords: single nucleotide polymorphisms; synonymous mutations; codon bias; genetic code; genome‐wide association studies; protein folding; molecular evolution; ribosomal profiling

Figure 1.

How synonymous codon changes affect the structure and function of individual proteins. (a) The COMT protein is associated with pain sensitivity. Individuals with synonymous variant have high sensitivity to pain. The synonymous nucleotide change alters the mRNA secondary structure resulting in a more stable mRNA molecule but lower levels of the COMT protein which in turn results in higher pain sensitivity. (b) The multidrug transporter, Pgp effluxes numerous compounds out of cells, including chemotherapeutic agents. It is thus implicated in multidrug resistance during chemotherapy. The efflux of compounds can be modulated by compounds such as cyclosporine A and verapamil. A variant of Pgp does not show any difference in the drug‐efflux phenotype but does exhibit an altered response to the modulators. The variant gene differs from the wild type in that there are two synonymous changes and one nonsynonymous change. It has been demonstrated that the nonsynonymous change alone does not alter the phenotype. The synonymous changes are both less frequent codons which plausibly alter the speed of translation and result in the protein with the altered conformation. (c) The most common mutation in the CFTR protein is a deletion of Phe at position 508 (p.Phe508del). In the wild‐type protein, an Ile (position 507) precedes the Phe and the codons ATC and TTT encode these two amino acids. The mutation is the result of the removal of the last ‘C’ of the codon for Ile and the first two ‘Ts’ for the codon for Phe (c.507C>T). Thus besides the deletion of F508 (p.Phe508del) a new synonymous codon (for Ile, c.507C>T) is incorporated in the gene. If the synonymous change is reverted to the wild‐type codon even on the ΔF508 background mRNA folding and CFRT protein levels are corrected.

Figure 2.

Synonymous codon changes control protein levels, protein folding and protein function. (a) The pre‐mRNA contains noncoding introns and coding exons, the former are removed in a process called splicing to generate the mature mRNA. Codons in the exons carry signals that direct the accurate splicing of the pre‐mRNAs. Thus although synonymous changes in the coding regions do not affect the amino acid sequence of the translated protein they can disrupt spicing signals and result in an incorrectly spliced mRNA that misses one or more exons. (b) Synonymous codons changes can alter the stability of the mRNA. In general stable mRNAs are not easily degraded and result in higher protein levels. However, local stability near the 5′ end of the mRNA hinders the initiation of translation resulting in lower levels of protein. (c) Many proteins fold on the ribosome (cotranslational folding). In many instances different domains of a protein fold either faster or slower than others. In addition some domains are stabilised by other domains that occur downstream. Pause sites (i.e. synonymous codons that take longer to pass through the ribosome) control the speed of translation. In the example provided, a slow‐folding domain (A) is stabilised to A′ in the presence of the downstream domain B. If a ‘pause site’ occurs between A and B, then A will reach its conformation. However, if A has not reached its stable state interaction with the completely folded B will result in the A′ conformation. Thus, depending on the occurrence of a ‘pause site’ the final protein will have either one of two conformations, AB or A′B. (d) Rare codons occur much more frequently in the first 50–150 codons. These codons limit the speed of translation and thus prevent ribosomal congestion, which can reduce the number of misfolded protein molecules. (e) Another pattern commonly observed across genes (see text for details) is the so‐called autocorrelation. That is the same codons appear together for stretches of the gene. It is postulated that this permits the ‘reuse’ of tRNAs and thus enhances translation efficiency.



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Further Reading

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Sauna, Zuben E, and Kimchi‐Sarfaty, Chava(Dec 2013) Synonymous Mutations as a Cause of Human Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025173]