World Library  
Flag as Inappropriate
Email this Article

Silent mutation

Article Id: WHEBN0001260905
Reproduction Date:

Title: Silent mutation  
Author: World Heritage Encyclopedia
Language: English
Subject: Mutation, Point mutation, MolecularEvolution, Dynamic mutation, Ka/Ks ratio
Collection: Molecular Evolution, Mutation
Publisher: World Heritage Encyclopedia

Silent mutation

Silent mutations are non-coding regions (outside of genes or within introns), or they may occur within exons. When they occur within exons they either do not result in a change to the amino acid sequence of a protein (a "synonymous substitution"), or result in the insertion of an alternative amino acid with similar properties to that of the original amino acid; in either case there is no significant change in phenotype. The phrase silent mutation is often used interchangeably with the phrase synonymous mutation; however, synonymous mutations only occur within exons, and are not always silent mutations.[1][2][3][4][5] Synonymous mutations can affect transcription, splicing, mRNA transport, and translation, any of which could alter phenotype, rendering the synonymous mutation non-silent.[3] The substrate specificity of the tRNA to the rare codon can affect the timing of translation, and in turn the co-translational folding of the protein.[1] This is reflected in the codon usage bias that is observed in many species. Mutations that cause the altered codon to produce an amino acid with similar functionality (e.g. a mutation producing leucine instead of isoleucine) are often classified as silent; if the properties of the amino acid are conserved, this mutation does not usually significantly affect protein function.[6]



  • Silent mutations and the genetic code 1
  • Transfer RNA 2
  • Structural consequences of silent mutations 3
  • Research and clinical applications 4
  • See also 5
  • References 6
  • External links 7

Silent mutations and the genetic code

Most amino acids are specified by multiple codons demonstrating that the genetic code is degenerate. Codons that code for the same amino acid are termed synonyms. Silent mutations are base substitutions that result in no change of the amino acid or amino acid functionality when the altered messenger RNA (mRNA) is translated. For example, if the codon AAA is altered to become AAG, the same amino acid – lysine – will be incorporated into the peptide chain. Silent mutations can also be produced by insertions or deletions, which cause a shift in the reading frame. An example of this is shown with modification to the sequence AUGAAAGAGACGU. If a deletion occurred at the sixth position, the sequence would be converted to AUGAAGAGACGU. If the reading frame begins at the first position of the peptide chain, in either sequence given, the amino acid following the start codon AUG would be lysine. Such frameshift mutations can lead to deleterious effects on the peptide chain, including insertion of different amino acids or premature truncation of the protein.[7]

Transfer RNA

Because silent mutations do not alter protein function they are often treated as though they are codon usage biases, suggesting that there is selection for the use of particular codons due to the need for translational stability. Transfer RNA (tRNA) availability is one of the reasons that silent mutations might not be as silent as conventionally believed.[8]

There is a different tRNA molecule for each codon. For example, there is a specific tRNA molecule for the codon UCU and another specific for the codon UCC, both of which code for the amino acid serine. In this instance, if there was a thousand times less UCC tRNA than UCU tRNA, then the incorporation of serine into a polypeptide chain would happen a thousand times more slowly when a mutation causes the codon to change from UCU to UCC. If amino acid transport to the ribosome is delayed, translation will be carried out at a much slower rate. This can result in lower expression of a particular gene containing that silent mutation if the mutation occurs within an exon. Additionally, if the ribosome has to wait too long to receive the amino acid, the ribosome could terminate translation prematurely.[6]

Structural consequences of silent mutations

I. Primary structure

A nonsynonymous mutation that occurs at the genomic or transcriptional levels is one that results in an alteration to the amino acid sequence in the protein product. A protein’s primary structure refers to its amino acid sequence. A substitution of one amino acid for another can impair protein function and structure, or its effects may be minimal or tolerated depending on how closely the properties of the amino acids involved in the swap correlate.[9] The premature insertion of a stop codon, a nonsense mutation, can alter the primary structure of a protein.[10] In this case, a truncated protein is produced. Protein function and folding is dependent on the position in which the stop codon was inserted and the amount and composition of the sequence lost.

Conversely, silent mutations are mutations in which the amino acid sequence is not altered.[10] Silent mutations lead to a change of one of the letters in the triplet code that represents a codon, but despite the single base change, the amino acid that is coded for remains unchanged or similar in biochemical properties. This is permitted by the degeneracy of the genetic code.

Historically, silent mutations were thought to be of little to no significance. However, recent research suggests that such alterations to the triplet code do effect protein translation efficiency and protein folding and function.[11][12]

II. Secondary structure

Silent mutations alter the secondary structure of mRNA. mRNA has a secondary structure that is not necessarily linear like that of DNA, thus the shape that accompanies complementary bonding in the structure can have significant effects. For example, if the mRNA molecule is relatively unstable, then it can be rapidly degraded by enzymes in the cytoplasm. If the RNA molecule is highly stable, and the complementary bonds are strong and resistant to unpacking prior to translation, then the gene may be underexpressed. Codon usage influences mRNA stability.[8]

If the oncoming ribosome pauses because of a knot in the RNA, then the polypeptide could potentially have enough time to fold into a non-native structure before the tRNA molecule can add another amino acid. Silent mutations may also affect splicing, or transcriptional control.

III. Tertiary structure

Silent mutations affect protein folding and function.[13] Recent research suggests that silent mutations can have an effect on subsequent protein structure and activity.[14][15] The timing and rate of protein folding can be altered, which can lead to functional impairments.[16]

Research and clinical applications

Silent mutations have been employed as an experimental strategy and can have clinical implications.

Steffen Mueller at the Stony Brook University designed a live vaccine for polio in which the virus was engineered to have synonymous codons replace naturally-occurring ones in the genome. As a result, the virus was still able to infect and reproduce, albeit more slowly. Mice that were vaccinated with this vaccine and exhibited resistance against the natural polio strain.

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.

Mental disorders can be caused by silent mutations. One silent mutation causes the dopamine receptor D2 gene to be less stable and degrade faster, underexpressing the gene.

A silent mutation in the multidrug resistance gene 1 (MDR1), 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.

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. LPS has an additional CTC to CTG silent mutation, while HPS does not and shares the CTC sequence at this location with APS [17]


See also


  1. ^ a b Kimchi-Sarfaty, C.; Oh, J. M.; Kim, I.-W.; Sauna, Z. E.; Calcagno, A. M.; Ambudkar, S. V.; Gottesman, M. M. (26 January 2007). "A "Silent" Polymorphism in the MDR1 Gene Changes Substrate Specificity". Science 315 (5811): 525–8.  
  2. ^ Chamary, JV; Parmley, JL; Hurst, LD (February 2006). "Hearing silence: non-neutral evolution at synonymous sites in mammals". Nature reviews. Genetics 7 (2): 98–108.  
  3. ^ a b Goymer, Patrick (February 2007). "Synonymous mutations break their silence". Nature Reviews Genetics 8 (2): 92.  
  4. ^ Zhou, Tong; Ko, Eun A.; Gu, Wanjun; Lim, Inja; Bang, Hyoweon; Ko, Jae-Hong; Uversky, Vladimir N. (31 October 2012). "Non-Silent Story on Synonymous Sites in Voltage-Gated Ion Channel Genes". PLoS ONE 7 (10): e48541.  
  5. ^ Graur, Dan (2003). "Single Base Mutation" (PDF). In Cooper, David N. Nature Encyclopedia of the Human Genome (PDF). MacMillan.  
  6. ^ a b Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter (2007). Molecular Biology of the Cell. Garland Science. p. 264.  
  7. ^ Watson, James D. (2008). Molecular Biology of the Gene (6th ed.). San Francisco: Pearson/Benjamin Cummings.  
  8. ^ a b Angov E (June 2011). "Codon usage: nature's roadmap to expression and folding of proteins". Biotechnol J 6 (6): 650–9.  
  9. ^ Teng S, Madej T, Panchenko A, Alexov E (March 2009). "Modeling effects of human single nucleotide polymorphisms on protein-protein interactions". Biophys. J. 96 (6): 2178–88.  
  10. ^ a b Strachan, Tom; Read, Andrew P. (1999). Human Molecular Genetics (2nd ed.). Wiley-Liss.  
  11. ^ Czech A, Fedyunin I, Zhang G, Ignatova Z (October 2010). "Silent mutations in sight: co-variations in tRNA abundance as a key to unravel consequences of silent mutations". Mol Biosyst 6 (10): 1767–72.  
  12. ^ Komar AA (August 2007). "Silent SNPs: impact on gene function and phenotype". Pharmacogenomics 8 (8): 1075–80.  
  13. ^ Kimchi-Sarfaty C, Oh JM, Kim IW, et al. (January 2007). "A "silent" polymorphism in the MDR1 gene changes substrate specificity". Science 315 (5811): 525–8.  
  14. ^ Komar AA (January 2007). "Genetics. SNPs, silent but not invisible". Science 315 (5811): 466–7.  
  15. ^ Beckman (22 December 2006). "The Sound of a Silent Mutation". News. Science/AAAS. 
  16. ^ Zhang Z, Miteva MA, Wang L, Alexov E (2012). "Analyzing effects of naturally occurring missense mutations". Comput Math Methods Med 2012: 805827.  
  17. ^ 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.   Full text

External links

  • Overview article — Chamary, J.V.; Hurst, Laurence D. (June 2009). "How Trivial DNA Changes Can Hurt Health". Scientific American. 
  • "WatCut: An on-line tool for restriction analysis, silent mutation scanning, and SNP-RFLP analysis". University of Waterloo. April 17, 2014. 
  • Mueller S, Coleman JR, Wimmer E (March 2009). "Putting synthesis into biology: a viral view of genetic engineering through de novo gene and genome synthesis". Chem. Biol. 16 (3): 337–47.  
This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.

Copyright © World Library Foundation. All rights reserved. eBooks from Project Gutenberg are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.