thumb|350px|Point substitution mutations of a codon, classified by their impact on protein sequence
A synonymous substitution (often called a silent substitution though they are not always silent) is the evolutionary substitution of one base for another in an exon of a gene coding for a protein, such that the produced amino acid sequence is not modified. This is possible because the genetic code is "degenerate", meaning that some amino acids are coded for by more than one three-base-pair 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 when the gene is translated. Synonymous substitutions and mutations affecting noncoding DNA are often considered silent mutations; however, it is not always the case that the mutation is silent.
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%.
A synonymous mutation can affect transcription, splicing, mRNA transport, and translation, any of which could alter the resulting phenotype, rendering the synonymous mutation non-silent. and the adult flies showed lower ethanol tolerance.
Many organisms, from bacteria through animals, display biased use of certain synonymous codons. Such codon usage bias may arise for different reasons, some selective, and some neutral. In Saccharomyces cerevisiae synonymous codon usage has been shown to influence mRNA folding stability, with mRNA encoding different protein secondary structure preferring different codons.
Another reason why synonymous changes are not always neutral is the fact that exon sequences close to exon-intron borders function as 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 gene result in that exon being skipped.
See also
- Ka/Ks ratio
- Missense mutation
- Nonsynonymous substitution
- Point mutation
- Expanded genetic code, where more than 20-22 natural encoded amino acids are used