Silent mutation

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. (An online tool that can analyse a sequence of interest for possible mutations to create restriction sites is given in the External Links section.)

Recent results suggest that silent mutations can have an effect on subsequent protein structure and activity,.

Transfer RNA

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) 1000 times less UCC tRNA then UCU tRNA, the incorporation of serine happens a 1000 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.

Secondary Messenger RNA structure

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.

Examples

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.

See also

• Degeneracy of the genetic code
• Genealogical DNA test

References

• Chao HK, Hsiao KJ, Su TS (2001). "A silent mutation induces exon skipping in the phenylalanine hydroxylase gene in phenylketonuria". Hum Genet. 108 (1): 14–9. doi:10.1007/s004390000435. PMID 11214902.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Montera M, Piaggio F, Marchese C, Gismondi V, Stella A, Resta N, Varesco L, Guanti G, Mareni C (2001). "A silent mutation in exon 14 of the APC gene is associated with exon skipping in a FAP family". J Med Genet. 38 (12): 863–7. doi:10.1136/jmg.38.12.863. PMC 1734788. PMID 11768390.{{cite journal}}: CS1 maint: multiple names: authors list (link) Full text
• Chava Kimchi-Sarfaty, Jung Mi Oh, In-Wha Kim, Zuben E. Sauna, Anna Maria Calcagno, Suresh V. Ambudkar, Michael M. Gottesman (2007). "A "Silent" Polymorphism in the MDR1 Gene Changes Substrate Specificity". Science. 315 (5811): 525–528. doi:10.1126/science.1135308. PMID 17185560.{{cite journal}}: CS1 maint: multiple names: authors list (link) Abstract Summary Full Text

Chamary, J. V., and Laurence D. Hurst. "The price of silent mutations." Scientific American June 2009: 46-53. Print.

External links

• Overview article in Scientific American
• An online tool for silent mutagenesis
• Mueller lab - recoding viral genomes through silent mutagnesis