A synonymous substitution (also called a silent substitution) 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. Synonymous substitutions and mutations affecting noncoding DNA are collectively known as silent mutations. A non-synonymous substitution results in a change in amino acid that may be arbitrarily further classified as conservative (change to an amino acid with similar physiochemical properties), semi-conservative (e.g. negative to positively charged amino acid), or radical (vastly different amino acid).
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Protein translation involves a set of twenty amino acids. Each of these amino acids is coded for by a sequence of three DNA base pairs called a codon. Because there are 64 possible codons, but only 20 amino acids (as well as a stop signal, 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. This is often referred to as redundancy of the genetic code. There are two mechanisms for redundancy: several different transfer RNAs can deliver the same amino acid, or one tRNA can have a non-standard "wobbly" 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.
Although mutation and substitution are often used interchangeably, there is a subtle but important difference. A nucleotide mutation is a base change (whether synonymous or non-synonymous) such that the mutant and wild-type forms coexist in a population. A nucleotide substitution is a base change between two populations. Thus, a mutation only becomes a substitution when the most recent common ancestor of the entire population carried that mutation . When all lineages carrying alternative mutations have died off, the remaining mutation is said to be fixed. Note that fixed mutations may never reach 100% frequency in the population, as further mutations at the same site may arise; these subsequent mutations, however, will all share a common ancestor which had the fixed mutation.
When a synonymous or silent mutation occurs, the change is often assumed to be neutral, meaning that it does not affect the fitness of the individual carrying the new gene to survive and reproduce. Redundancy of the genetic code provides some protection against the effect of mutations.
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,[1] in Saccharomyces cerevisiae those mutations have been shown to affect the protein secondary structure[2] and the adult flies showed lower ethanol tolerance.[3] 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.
Another reason why synonymous changes are not always silent 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.[4]
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