# Synonymous substitution > Mediated Wiki article. Canonical URL: https://mediated.wiki/source/Synonymous_substitution > Markdown URL: https://mediated.wiki/source/Synonymous_substitution.md > Source: https://en.wikipedia.org/wiki/Synonymous_substitution > Source revision: 1322492776 > License: Creative Commons Attribution-ShareAlike 4.0 International (https://creativecommons.org/licenses/by-sa/4.0/) {{Short description|Form of evolutionary mutation}} {{For|words related to "synonym"|Synonym (disambiguation) }} thumb|350px|Point substitution mutations of a codon, classified by their impact on protein sequence A '''synonymous substitution''' (often called a [''silent'' substitution](/source/Silent_substitution) though they are not always silent) is the [evolutionary](/source/evolutionary) [substitution](/source/Point_mutation) of one [base](/source/Base_pair) for another in an [exon](/source/exon) of a [gene](/source/gene) coding for a [protein](/source/protein), such that the produced [amino acid sequence](/source/amino_acid_sequence) is not modified. This is possible because the [genetic code](/source/genetic_code) is "[degenerate](/source/Codon_degeneracy)", meaning that some amino acids are coded for by more than one three-base-pair [codon](/source/codon); since some of the codons for a given amino acid differ by just one base pair from others coding for the same amino acid, a mutation that replaces the "normal" base by one of the alternatives will result in incorporation of the same amino acid into the growing [polypeptide chain](/source/polypeptide_chain) when the gene is translated. Synonymous substitutions and mutations affecting [noncoding DNA](/source/noncoding_DNA) are often considered [silent mutations](/source/silent_mutations); however, it is not always the case that the mutation is silent.{{cite journal | vauthors = Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM | title = A "silent" polymorphism in the MDR1 gene changes substrate specificity | journal = Science | volume = 315 | issue = 5811 | pages = 525–528 | date = January 2007 | pmid = 17185560 | doi = 10.1126/science.1135308 | s2cid = 15146955 | bibcode = 2007Sci...315..525K | url = https://zenodo.org/record/1230874 | doi-access = free }}{{cite journal | vauthors = Chamary JV, Parmley JL, Hurst LD | title = Hearing silence: non-neutral evolution at synonymous sites in mammals | journal = Nature Reviews. Genetics | volume = 7 | issue = 2 | pages = 98–108 | date = February 2006 | pmid = 16418745 | doi = 10.1038/nrg1770 | s2cid = 25713689 }}{{cite journal| vauthors = Goymer P |title=Synonymous mutations break their silence|journal=Nature Reviews Genetics|date=February 2007|volume=8|issue=2|page=92|doi=10.1038/nrg2056|s2cid=29882152|doi-access=free}}{{cite journal | vauthors = Zhou T, Ko EA, Gu W, Lim I, Bang H, Ko JH | title = Non-silent story on synonymous sites in voltage-gated ion channel genes | journal = PLOS ONE | volume = 7 | issue = 10 | article-number = e48541 | date = 31 October 2012 | pmid = 23119053 | pmc = 3485311 | doi = 10.1371/journal.pone.0048541 | doi-access = free | bibcode = 2012PLoSO...748541Z }}{{cite book | vauthors = Graur D |chapter=Single Base Mutation |chapter-url=http://nsmn1.uh.edu/dgraur/ArticlesPDFs/encyclopediahumangenome93.pdf |publisher=MacMillan |title=Nature Encyclopedia of the Human Genome |isbn=0-333-80386-8 |year=2003 | veditors = Cooper DN }} Since there are 22 codes for 64 codons, roughly we should expect a random substitution to be synonymous with probability about 22/64 = 34%. The actual value is around 20%.{{cite journal | vauthors = Kimura M | title = The rate of molecular evolution considered from the standpoint of population genetics | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 63 | issue = 4 | pages = 1181–1188 | date = August 1969 | pmid = 5260917 | pmc = 223447 | doi = 10.1073/pnas.63.4.1181 | bibcode = 1969PNAS...63.1181K | doi-access = free }} A synonymous mutation can affect [transcription](/source/Transcription_(genetics)), [splicing](/source/Splicing_(genetics)), [mRNA](/source/mRNA) transport, and [translation](/source/Translation_(biology)), any of which could alter the resulting [phenotype](/source/phenotype), rendering the synonymous mutation non-silent. The [substrate specificity](/source/substrate_specificity) of the [tRNA](/source/tRNA) to the rare codon can affect the timing of translation, and in turn the co-translational [folding of the protein](/source/Protein_folding). This is reflected in the [codon usage bias](/source/codon_usage_bias) that is observed in many [species](/source/species). A [nonsynonymous substitution](/source/nonsynonymous_substitution) results in a change in amino acid that may be arbitrarily further classified as conservative (a change to an amino acid with similar [physiochemical properties](/source/Physicochemical_properties)), semi-conservative (e.g. [negatively](/source/Anion) to [positively charged](/source/Cation) amino acid), or radical (vastly different amino acid). ==Degeneracy of the genetic code== Protein [translation](/source/translation_(genetics)) involves a set of twenty [amino acid](/source/amino_acid)s. Each of these amino acids is coded for by a sequence of three [DNA](/source/DNA) base pairs called a ''[codon](/source/codon)''. Because there are 64 possible codons, but only 20-22 [encoded amino acids](/source/Proteinogenic_amino_acid) (in nature) and a stop signal (i.e. up to three codons that do not code for any amino acid and are known as [stop codons](/source/stop_codons), indicating that translation should stop), some amino acids are coded for by 2, 3, 4, or 6 different codons. For example, the codons TTT and TTC both code for the amino acid [phenylalanine](/source/phenylalanine). This is often referred to as [''redundancy'' of the genetic code](/source/Genetic_code). There are two mechanisms for redundancy: several different transfer RNAs can deliver the same amino acid, or one [tRNA](/source/tRNA) can have a non-standard [wobble base](/source/wobble_base) in position three of the anti-codon, which recognises more than one base in the codon. In the above phenylalanine example, suppose that the base in position 3 of a TTT codon got substituted to a C, leaving the codon TTC. The amino acid at that position in the protein will remain a phenylalanine. Hence, the substitution is a synonymous one. == Evolution == When a synonymous or [silent mutation](/source/silent_mutation) occurs, the change is often assumed to be [neutral](/source/Neutral_theory_of_molecular_evolution), meaning that it does not affect the fitness of the individual carrying the new gene to survive and reproduce. Synonymous changes may not be neutral because certain codons are translated more efficiently (faster and/or more accurately) than others. For example, when a handful of synonymous changes in the fruit fly alcohol dehydrogenase gene were introduced, changing several codons to sub-optimal synonyms, production of the encoded enzyme was reduced{{cite journal | vauthors = Carlini DB, Stephan W | title = In vivo introduction of unpreferred synonymous codons into the Drosophila Adh gene results in reduced levels of ADH protein | journal = Genetics | volume = 163 | issue = 1 | pages = 239–243 | date = January 2003 | pmid = 12586711 | pmc = 1462401 | doi = 10.1093/genetics/163.1.239 }} and the adult flies showed lower ethanol tolerance.{{cite journal | vauthors = Carlini DB | title = Experimental reduction of codon bias in the Drosophila alcohol dehydrogenase gene results in decreased ethanol tolerance of adult flies | journal = Journal of Evolutionary Biology | volume = 17 | issue = 4 | pages = 779–785 | date = July 2004 | pmid = 15271077 | doi = 10.1111/j.1420-9101.2004.00725.x | doi-access = free }} Many organisms, from bacteria through animals, display biased use of certain synonymous codons. Such [codon usage bias](/source/codon_usage_bias) may arise for different reasons, some selective, and some neutral. In ''[Saccharomyces cerevisiae](/source/Saccharomyces_cerevisiae)'' synonymous codon usage has been shown to influence [mRNA](/source/Messenger_RNA) folding stability, with mRNA encoding different protein [secondary structure](/source/secondary_structure) preferring different codons.{{cite journal | vauthors = Kahali B, Basak S, Ghosh TC | title = Reinvestigating the codon and amino acid usage of S. cerevisiae genome: a new insight from protein secondary structure analysis | journal = Biochemical and Biophysical Research Communications | volume = 354 | issue = 3 | pages = 693–699 | date = March 2007 | pmid = 17258174 | doi = 10.1016/j.bbrc.2007.01.038 | bibcode = 2007BBRC..354..693K }} Another reason why synonymous changes are not always neutral is the fact that exon sequences close to exon-intron borders function as [RNA splicing](/source/RNA_splicing) signals. When the splicing signal is destroyed by a synonymous mutation, the exon does not appear in the final protein. This results in a truncated protein. One study found that about a quarter of synonymous variations affecting exon 12 of the [cystic fibrosis transmembrane conductance regulator](/source/cystic_fibrosis_transmembrane_conductance_regulator) gene result in that exon being skipped.{{cite journal | vauthors = Pagani F, Raponi M, Baralle FE | title = Synonymous mutations in CFTR exon 12 affect splicing and are not neutral in evolution | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 18 | pages = 6368–6372 | date = May 2005 | pmid = 15840711 | pmc = 1088389 | doi = 10.1073/pnas.0502288102 | doi-access = free | bibcode = 2005PNAS..102.6368P }}. == See also == *[Ka/Ks ratio](/source/Ka%2FKs_ratio) *[Missense mutation](/source/Missense_mutation) *[Nonsynonymous substitution](/source/Nonsynonymous_substitution) *[Point mutation](/source/Point_mutation) *[Expanded genetic code](/source/Expanded_genetic_code), where more than 20-22 natural encoded amino acids are used == References == {{Reflist}} {{Mutation}} {{MolecularEvolution}} {{MolBioGeneExp}} Category:Molecular evolution Category:Molecular biology Category:Protein biosynthesis Category:Gene expression Category:Mutation Category:Neutral theory --- Adapted from the Wikipedia article [Synonymous substitution](https://en.wikipedia.org/wiki/Synonymous_substitution) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Synonymous_substitution?action=history)). 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