![Recent estimates of the human genome-wide mutation rate](https://upload.wikimedia.org/wikipedia/commons/6/65/Recent_estimates_of_the_human_genome-wide_mutation_rate.png)
In
genetics
Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar wor ...
, the mutation rate is the frequency of new
mutations in a single gene or organism over time. Mutation rates are not constant and are not limited to a single type of mutation; there are many different types of mutations. Mutation rates are given for specific classes of mutations.
Point mutations
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 ...
are a class of mutations which are changes to a single base.
Missense
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 mu ...
and
Nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the transcribed mRNA, and in leading to a truncated, incomplete, and usually nonfunctional protein produc ...
s are two subtypes of point mutations. The rate of these types of substitutions can be further subdivided into a mutation spectrum which describes the influence of the genetic context on the mutation rate.
There are several natural units of time for each of these rates, with rates being characterized either as mutations per base pair per cell division, per gene per generation, or per genome per generation. The mutation rate of an organism is an evolved characteristic and is strongly influenced by the genetics of each organism, in addition to strong influence from the environment. The upper and lower limits to which mutation rates can evolve is the subject of ongoing investigation. However, the mutation rate does vary over the
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...
. Over DNA, RNA or a single gene, mutation rates are changing.
When the mutation rate in humans increases certain health risks can occur, for example,
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
and other hereditary diseases. Having knowledge of mutation rates is vital to understanding the future of cancers and many hereditary diseases.
Background
Different genetic variants within a species are referred to as alleles, therefore a new mutation can create a new allele. In
population genetics
Population genetics is a subfield of genetics that deals with genetic differences within and between populations, and is a part of evolutionary biology. Studies in this branch of biology examine such phenomena as Adaptation (biology), adaptation, ...
, each allele is characterized by a selection coefficient, which measures the expected change in an allele's frequency over time. The selection coefficient can either be negative, corresponding to an expected decrease, positive, corresponding to an expected increase, or zero, corresponding to no expected change. The distribution of fitness effects of new mutations is an important parameter in population genetics and has been the subject of extensive investigation.
Although measurements of this distribution have been inconsistent in the past, it is now generally thought that the majority of mutations are mildly deleterious, that many have little effect on an organism's fitness, and that a few can be favorable.
Because of
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 ...
, unfavorable mutations will typically be eliminated from a population while favorable changes are generally kept for the next generation, and neutral changes accumulate at the rate they are created by mutations. This process happens by reproduction. In a particular generation the 'best fit' survive with higher probability, passing their genes to their offspring. The sign of the change in this probability defines mutations to be beneficial, neutral or harmful to organisms.
Measurement
An organism's mutation rates can be measured by a number of techniques.
One way to measure the mutation rate is by the fluctuation test, also known as the
Luria–Delbrück experiment. This experiment demonstrated that bacteria mutations occur in the absence of selection instead of the presence of selection.
This is very important to mutation rates because it proves experimentally mutations can occur without selection being a component—in fact, mutation and selection are completely distinc
evolutionary forces Different DNA sequences can have different propensities to mutation (see below) and may not occur randomly.
The most commonly measured class of mutations are substitutions, because they are relatively easy to measure with standard analyses of DNA sequence data. However substitutions have a substantially different rate of mutation (10
−8 to 10
−9 per generation for most cellular organisms) than other classes of mutation, which are frequently much higher (~10
−3 per generation for satellite DNA expansion/contraction).
Substitution rates
Many sites in an organism's genome may admit mutations with small fitness effects. These sites are typically called neutral sites. Theoretically mutations under no selection become
fixed
Fixed may refer to:
* ''Fixed'' (EP), EP by Nine Inch Nails
* ''Fixed'', an upcoming 2D adult animated film directed by Genndy Tartakovsky
* Fixed (typeface), a collection of monospace bitmap fonts that is distributed with the X Window System
* ...
between organisms at precisely the mutation rate. Fixed synonymous mutations, i.e.
synonymous substitutions, are changes to the sequence of a gene that do not change the protein produced by that gene. They are often used as estimates of that mutation rate, despite the fact that some synonymous mutations have fitness effects. As an example, mutation rates have been directly inferred from the whole genome sequences of experimentally evolved replicate lines of ''Escherichia coli'' B.
Mutation accumulation lines
A particularly labor-intensive way of characterizing the mutation rate is the mutation accumulation line.
Mutation accumulation lines have been used to characterize mutation rates with the
Bateman-Mukai Method and direct sequencing of well-studied experimental organisms ranging from intestinal bacteria (''
E. coli''), roundworms (''
C. elegans
''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (r ...
''), yeast (''
S. cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have bee ...
''), fruit flies (''
D. melanogaster
''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or "pomace fly". Starting with ...
''), and small ephemeral plants (''
A. thaliana
''Arabidopsis thaliana'', the thale cress, mouse-ear cress or arabidopsis, is a small flowering plant native to Eurasia and Africa. ''A. thaliana'' is considered a weed; it is found along the shoulders of roads and in disturbed land.
A winter a ...
'').
Variation in mutation rates
![Molecular evolution bamboos](https://upload.wikimedia.org/wikipedia/commons/3/3f/Molecular_evolution_bamboos.svg)
Mutation rates differ between species and even between different regions of the genome of a single species. These different rates of nucleotide substitution are measured in substitutions (
fixed mutations) per base pair per generation. For example, mutations in intergenic, or non-coding, DNA tend to accumulate at a faster rate than mutations in DNA that is actively in use in the organism (
gene expression). That is not necessarily due to a higher mutation rate, but to lower levels of
purifying selection
In natural selection, negative selection or purifying selection is the selective removal of alleles that are deleterious. This can result in stabilising selection through the purging of deleterious genetic polymorphisms that arise through random ...
. A region which mutates at predictable rate is a candidate for use as a
molecular clock
The molecular clock is a figurative term for a technique that uses the mutation rate of biomolecules to deduce the time in prehistory when two or more life forms diverged. The biomolecular data used for such calculations are usually nucleo ...
.
If the rate of neutral mutations in a sequence is assumed to be constant (clock-like), and if most differences between species are neutral rather than adaptive, then the number of differences between two different species can be used to estimate how long ago two species diverged (see
molecular clock
The molecular clock is a figurative term for a technique that uses the mutation rate of biomolecules to deduce the time in prehistory when two or more life forms diverged. The biomolecular data used for such calculations are usually nucleo ...
). In fact, the mutation rate of an organism may change in response to environmental stress. For example, UV light damages DNA, which may result in error prone attempts by the cell to perform
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
.
The human mutation rate is higher in the male germ line (sperm) than the female (egg cells), but estimates of the exact rate have varied by an order of magnitude or more. This means that a human genome accumulates around 64 new mutations per generation because each full generation involves a number of cell divisions to generate gametes.
Human mitochondrial DNA has been estimated to have mutation rates of ~3× or ~2.7×10
−5 per base per 20 year generation (depending on the method of estimation); these rates are considered to be significantly higher than rates of human genomic mutation at ~2.5×10
−8 per base per generation.
Using data available from whole genome sequencing, the human genome mutation rate is similarly estimated to be ~1.1×10
−8 per site per generation.
The rate for other forms of mutation also differs greatly from
point mutations
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 ...
. An individual
microsatellite locus often has a mutation rate on the order of 10
−4, though this can differ greatly with length.
Some sequences of DNA may be more susceptible to mutation. For example, stretches of DNA in human sperm which lack methylation are more prone to mutation.
In general, the mutation rate in unicellular
eukaryotes (and
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
) is roughly 0.003 mutations per genome per ''cell'' generation.
However, some species, especially the
ciliate
The ciliates are a group of alveolates characterized by the presence of hair-like organelles called cilia, which are identical in structure to eukaryotic flagella, but are in general shorter and present in much larger numbers, with a differen ...
of the genus ''
Paramecium
''
''Paramecium'' ( , ; also spelled ''Paramoecium'') is a genus of eukaryotic, unicellular ciliates, commonly studied as a representative of the ciliate group. ''Paramecia'' are widespread in freshwater, brackish, and marine environments and a ...
'' have an unusually low mutation rate. For instance, ''Paramecium tetraurelia'' has a base-substitution mutation rate of ~2 × 10
−11 per site per cell division. This is the lowest mutation rate observed in nature so far, being about 75× lower than in other eukaryotes with a similar genome size, and even 10× lower than in most prokaryotes. The low mutation rate in ''Paramecium'' has been explained by its transcriptionally silent
germ-line
In biology and genetics, the germline is the population of a multicellular organism's cells that pass on their genetic material to the progeny (offspring). In other words, they are the cells that form the egg, sperm and the fertilised egg. Th ...
nucleus
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
* Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucl ...
, consistent with the hypothesis that replication fidelity is higher at lower
gene expression levels.
The highest per base pair per generation mutation rates are found in viruses, which can have either RNA or DNA genomes. DNA viruses have mutation rates between 10
−6 to 10
−8 mutations per base per generation, and RNA viruses have mutation rates between 10
−3 to 10
−5 per base per generation.
Mutation spectrum
The mutation spectrum of an organism is the rate at which different types of mutations occur at different sites in the genome. The mutation spectrum matters because the rate alone gives a very incomplete picture of what is going on in a genome. For instance, mutations might occur at the same rate in two lineages, but the rate alone would not tell us if the mutations were all base substitutions in one lineage and all large-scale rearrangements in the other. Even within base substitutions, the spectrum can still be informative because a transition substitution is different from a transversion. The mutation spectrum also allows us to know whether mutations happen in
coding or
noncoding regions.
![TsTvMutation](https://upload.wikimedia.org/wikipedia/commons/b/b4/TsTvMutation.jpg)
There is a systematic difference in rates for
transitions (Alpha) and
transversion
Transversion, in molecular biology, refers to a point mutation in DNA in which a single (two ring) purine ( A or G) is changed for a (one ring) pyrimidine ( T or C), or vice versa. A transversion can be spontaneous, or it can be caused by i ...
s (Beta).
Evolution
The theory on the evolution of mutation rates identifies three principal forces involved: the generation of more deleterious mutations with higher mutation, the generation of more advantageous mutations with higher mutation, and the metabolic costs and reduced replication rates that are required to prevent mutations. Different conclusions are reached based on the relative importance attributed to each force. The optimal mutation rate of organisms may be determined by a trade-off between costs of a high mutation rate,
such as deleterious mutations, and the
metabolic costs of maintaining systems to reduce the mutation rate (such as increasing the expression of DNA repair enzymes.
or, as reviewed by Bernstein et al. having increased energy use for repair, coding for additional gene products and/or having slower replication). Secondly, higher mutation rates increase the rate of beneficial mutations, and evolution may prevent a lowering of the mutation rate in order to maintain optimal rates of adaptation.
As such, hypermutation enables some cells to rapidly adapt to changing conditions in order to avoid the entire population from becoming extinct.
Finally, natural selection may fail to optimize the mutation rate because of the relatively minor benefits of lowering the mutation rate, and thus the observed mutation rate is the product of neutral processes.
Studies have shown that treating
RNA viruses such as
poliovirus
A poliovirus, the causative agent of polio (also known as poliomyelitis), is a serotype of the species '' Enterovirus C'', in the family of ''Picornaviridae''. There are three poliovirus serotypes: types 1, 2, and 3.
Poliovirus is composed of a ...
with
ribavirin
Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, pe ...
produce results consistent with the idea that the viruses mutated too frequently to maintain the integrity of the information in their genomes.
This is termed
error catastrophe
Error catastrophe refers to the cumulative loss of genetic information in a lineage of organisms due to high mutation rates. The mutation rate above which error catastrophe occurs is called the error threshold. Both terms were coined by Manfred ...
.
The high mutation rate
HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
(Human Immunodeficiency Virus) of 3 x 10
−5 per base and generation, coupled with its short replication cycle leads to a high
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respons ...
variability, allowing it to evade the immune system.
See also
*
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 replication, DNA or viral repl ...
*
Critical mutation rate
*
Mutation frequency
*
Allele frequency
Allele frequency, or gene frequency, is the relative frequency of an allele (variant of a gene) at a particular locus in a population, expressed as a fraction or percentage. Specifically, it is the fraction of all chromosomes in the population tha ...
*
Rate of evolution
The rate of evolution is quantified as the speed of genetic or morphological change in a lineage over a period of time. The speed at which a molecular entity (such as a protein, gene, etc.) evolves is of considerable interest in evolutionary biolog ...
*
Genetics
Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar wor ...
*
Cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
References
External links
*
{{DEFAULTSORT:Mutation Rate
Mutation
Evolutionary biology
Temporal rates