Silent mutations are DNA mutations that do not result in a change to the amino acid sequence of a protein. They may occur in a non-coding region (outside of a gene or within an intron), or they may occur within an exon in a manner that does not alter the final amino acid sequence. The phrase silent mutation is often used interchangeably with the phrase synonymous mutation; however, synonymous mutations are a subcategory of the former, occurring only within exons.
Because silent mutations do not alter protein function they are often treated as though they are evolutionarily neutral. However, many organisms are known to exhibit codon usage biases, suggesting that there is selection for the use of particular codons due to translational stability. Silent mutations may also affect splicing, or transcriptional control.
In molecular cloning experiments, it can be useful to introduce silent mutations into a gene of interest in order to create or remove recognition sites for restriction enzymes.
Recent results suggest that silent mutations can have an effect on subsequent protein structure and activity.[1][2]
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Transfer RNA(tRNA) availability is one of the reasons that a silent mutation might not be silent at all. For every codon there's a different tRNA molecule. So there's a tRNA specifically for the codon UCU and another specifically for the codon UCC (and so on for all the codons). Both of those tRNA molecules carry the amino-acid serine to the ribosome that is translating a mRNA molecule. However, if there's (for example) a thousand times less UCC tRNA than UCU tRNA, then the incorporation of serine happens a thousand times slower when a mutation causes the codon to change from UCU to UCC. If it takes longer for the amino-acids to reach the ribosome, translation takes longer. This results in a lower expression of a certain gene with that 'silent' mutation. Also, if the ribosome has to wait too long, it might terminate translation prematurely.
Silent mutations change the secondary structure of RNA. Since RNA has a secondary structure that is not necessarily linear like that of DNA, the shape that goes along with the complementary bonding in the structure can have significant effects. For example, if the RNA molecule is not very stable, then it can be broken down quickly by enzymes in the cytoplasm. Alternatively, if the RNA molecule is too stable, and the complementary bonds are too strong for unpacking before translation, then the gene can also be under expressed.
Also, if the oncoming ribosome pauses because of a knot in the RNA, then the polypeptide can have time to fold into an unusual structure before the tRNA molecule has time to add another amino acid.
Steffen Mueller at the Stony Brook University designed a live virus vaccine in which the pathogen was engineered to have synonymous codons take the place of normally occurring ones in the genome. As a result, the vaccine was still able to infect and reproduce, albeit more slowly. Mice were vaccinated with this vaccine and they showed a resistance against the natural polio strain.
Mental disorders can be caused by silent mutations. One silent mutation causes the dopamine receptor D2 gene to be less stable and degrade faster, under expressing the gene.
Also, deviations from average pain sensitivity (APS) are caused by both an ATG to GTG mutation (nonsynonymous), and a CAT to CAC mutation (synonymous). Ironically, these two mutations are both shared by the Low pain sensitivity (LPS) and High pain sensitivity (HPS)gene. What distinguishes LPS from HPS is that LPS has an additional CTC to CTG silent mutation, while HPS does not and shares the CTC sequence at this location with APS.
| LPS | APS | HPS |
|---|---|---|
| CAC | CAT | CAC |
| CTG | CTC | CTC |
| GTG | ATG | GTG |
A silent mutation in the multidrug resistance 1 gene, which codes for a cellular membrane pump that expels drugs from the cell, can slow down translation in a specific location to allow the peptide chain to bend into an unusual conformation. Thus, the mutant pump is less functional.
Chamary, J. V., and Laurence D. Hurst. "The price of silent mutations." Scientific American June 2009: 46-53. Print.
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