A nonsynonymous substitution is a
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
that alters the
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
sequence of a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
. Nonsynonymous substitutions differ from
synonymous substitution
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 i ...
s, which do not alter amino acid sequences and are (sometimes)
silent mutation
Silent mutations are mutations in DNA that do not have an observable effect on the organism's phenotype. They are a specific type of neutral mutation. The phrase ''silent mutation'' is often used interchangeably with the phrase '' synonymous muta ...
s. As nonsynonymous substitutions result in a biological change in the organism, they are subject to
natural selection
Natural selection is the differential survival and reproduction of individuals due to differences in phenotype. It is a key mechanism of evolution, the change in the heritable traits characteristic of a population over generations. Cha ...
.
Nonsynonymous substitutions at a certain locus can be compared to the synonymous substitutions at the same locus to obtain the
Ka/Ks ratio. This ratio is used to measure the evolutionary rate of gene sequences. If a gene has lower levels of nonsynonymous than synonymous nucleotide substitution, then it can be inferred to be functional because a
Ka/Ks ratio < 1 is a hallmark of sequences that are being constrained to code for proteins.
Nonsynonymous substitutions are also referred to as replacement mutations.
Types
There are several common types of nonsynonymous substitutions.
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense m ...
s are nonsynonymous substitutions that arise from
point mutation
A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequence ...
s, mutations in a single nucleotide that result in the substitution of a different
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
, resulting in a change to the protein encoded.
Nonsense mutations are nonsynonymous substitutions that arise when a mutation in the DNA sequence causes a protein to terminate prematurely by changing the original amino acid to a
stop codon
In molecular biology (specifically protein biosynthesis), a stop codon (or termination codon) is a codon (nucleotide triplet within messenger RNA) that signals the termination of the translation process of the current protein. Most codons in mess ...
. Another type of mutation that deals with stop codons is known as a
nonstop mutation or readthrough mutation, which occurs when a stop codon is exchanged for an amino acid codon, causing the protein to be longer than specified.
Natural selection and the nearly neutral theory
Studies have shown that diversity among nonsynonymous substitutions is significantly lower than among synonymous substitutions. This is due to the fact that nonsynonymous substitutions are subject to much higher selective pressures than synonymous mutations. Motoo Kimura (1968) determined that calculated mutation rates were impossibly high, unless most of the mutations that occurred were either neutral or "nearly neutral".
He determined that if this were true,
genetic drift
Genetic drift, also known as allelic drift or the Wright effect, is the change in the frequency of an existing gene variant (allele) in a population due to random chance.
Genetic drift may cause gene variants to disappear completely and there ...
would be a more powerful factor in
molecular evolution
Molecular evolution is the process of change in the sequence composition of cellular molecules such as DNA, RNA, and proteins across generations. The field of molecular evolution uses principles of evolutionary biology and population genet ...
than natural selection. The "nearly neutral" theory proposes that molecular evolution acting on nonsynonymous substitutions is driven by mutation, genetic drift, and very weak natural selection, and that it is extremely sensitive to population size. In order to determine whether natural selection is taking place at a certain loci, the
McDonald–Kreitman test The McDonald–Kreitman test is a statistical test often used by evolutionary and population biologists to detect and measure the amount of adaptive evolution within a species by determining whether adaptive evolution has occurred, and the proportio ...
can be performed. The test consists of comparing ratios of synonymous and nonsynonymous genes between closely related species to the ratio of synonymous to nonsynonymous polymorphisms within species. If the ratios are the same, then
Neutral theory of molecular evolution
The neutral theory of molecular evolution holds that most evolutionary changes occur at the molecular level, and most of the variation within and between species are due to random genetic drift of mutant alleles that are selectively neutral. The ...
is true for that loci, and evolution is proceeding primarily through genetic drift. If there are more nonsynonymous substitutions between species than within a species, positive natural selection is occurring on beneficial alleles and natural selection is taking place.
Nonsynonymous substitutions have been found to be more common in loci involving pathogen resistance, reproductive loci involving sperm competition or egg-sperm interactions, and genes that have replicated and gained new functions, indicating that positive selection is taking place.
Research
Research on accurately modeling rates of mutation has been conducted for many years. A recent paper by Ziheng Yang and Rasmus Nielsen compared various methods and developed a new modeling method. They found that the new method was preferable for its smaller biases, which make it useful for large scale screening, but that the maximum-likelihood model was preferable in most scenarios because of its simplicity, and its flexibility in comparing multiple sequences while taking into account phylogeny.
Further research by Yang and Nielsen found that nonsynonymous to synonymous substitution ratios varied across loci in differing evolutionary lineages. During their study of nuclear loci of primates, even-toed ungulates, and rodents, they found that the ratio varied significantly at 22 of the 48 loci studied. This result provides strong evidence against a strictly neutral theory of
molecular evolution
Molecular evolution is the process of change in the sequence composition of cellular molecules such as DNA, RNA, and proteins across generations. The field of molecular evolution uses principles of evolutionary biology and population genet ...
, which states that mutations are mostly neutral or deleterious, and provides support for theories that include advantageous mutations.
See also
*
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense m ...
*
Nonsense mutation
References
External links
Synonymous and NonsynonymousutionsSimple Methods for Estimating the Numbers of Synonymous and Nonsynonymous Nucleotide Substitutions
{{MolBioGeneExp
Molecular biology
Mutation