Synonymous substitution
Encyclopedia
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).
involves a set of twenty amino acid
s. 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.
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.
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 mutation
s.
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, in Saccharomyces cerevisiae
those mutations have been shown to affect the protein secondary structure
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.
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.
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
for another in an exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
of a gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
coding for a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, such that the produced amino acid sequence is not modified. Synonymous substitutions and mutations affecting noncoding DNA
Noncoding DNA
In genetics, noncoding DNA describes components of an organism's DNA sequences that do not encode for protein sequences. In many eukaryotes, a large percentage of an organism's total genome size is noncoding DNA, although the amount of noncoding DNA, and the proportion of coding versus noncoding...
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).
Degeneracy of the genetic code
Protein translationTranslation (genetics)
In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...
involves a set of twenty amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s. Each of these amino acids is coded for by a sequence of three DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
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
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
. 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.
Substitution versus mutation
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 ancestorMost recent common ancestor
In genetics, the most recent common ancestor of any set of organisms is the most recent individual from which all organisms in the group are directly descended...
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.
Synonymous substitutions and evolution
When a synonymous or silent mutationSilent 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 , or they may occur within an exon in a manner that does not alter the final amino acid sequence...
occurs, the change is often assumed to be neutral
Neutral theory of molecular evolution
The neutral theory of molecular evolution states that the vast majority of evolutionary changes at the molecular level are caused by random drift of selectively neutral mutants . The theory was introduced by Motoo Kimura in the late 1960s and early 1970s...
, 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 mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s.
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, in Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
those mutations have been shown to affect the protein secondary structure
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
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
Codon usage bias
Codon usage bias refers to differences in the frequency of occurrence of synonymous codons in coding DNA. A codon is a series of three nucleotides that encodes a specific amino acid residue in a polypeptide chain or for the termination of translation .There are 64 different codons but only 20...
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
RNA splicing
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
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.