In biology, a mutation is the permanent alteration of the nucleotide
sequence of the genome of an organism, virus, or extrachromosomal DNA
or other genetic elements.
Mutations result from errors during
DNA replication (especially during
Meiosis) or other types of damage to
DNA (such as may be caused by
exposure to radiation or carcinogens), which then may undergo
error-prone repair (especially microhomology-mediated end joining),
or cause an error during other forms of repair, or else may
cause an error during replication (translesion synthesis). Mutations
may also result from insertion or deletion of segments of
DNA due to
mobile genetic elements. Mutations may or may not produce
discernible changes in the observable characteristics (phenotype) of
an organism. Mutations play a part in both normal and abnormal
biological processes including: evolution, cancer, and the development
of the immune system, including junctional diversity.
The genomes of
RNA viruses are based on
RNA rather than DNA. The RNA
viral genome can be double stranded (as in DNA) or single stranded. In
some of these viruses (such as the single stranded human
immunodeficiency virus) replication occurs quickly and there are no
mechanisms to check the genome for accuracy. This error-prone process
often results in mutations.
Mutation can result in many different types of change in sequences.
Mutations in genes can either have no effect, alter the product of a
gene, or prevent the gene from functioning properly or completely.
Mutations can also occur in nongenic regions. One study on genetic
variations between different species of
Drosophila suggests that, if a
mutation changes a protein produced by a gene, the result is likely to
be harmful, with an estimated 70 percent of amino acid polymorphisms
that have damaging effects, and the remainder being either neutral or
marginally beneficial. Due to the damaging effects that mutations
can have on genes, organisms have mechanisms such as
DNA repair to
prevent or correct mutations by reverting the mutated sequence back to
its original state.
3.1 Spontaneous mutation
3.2 Error-prone replication bypass
3.3 Errors introduced during
3.4 Induced mutation
4 Classification of types
4.1 By effect on structure
4.1.1 Small-scale mutations
4.1.2 Large-scale mutations
4.2 By effect on function
4.3 By effect on fitness
4.3.1 Distribution of fitness effects
4.4 By impact on protein sequence
4.5 By inheritance
6 Harmful mutations
7 Beneficial mutations
9 Somatic mutations
10 Amorphic mutations
11 Hypomorphic and hypermorphic mutations
12 See also
14 External links
Mutations can involve the duplication of large sections of DNA,
usually through genetic recombination. These duplications are a
major source of raw material for evolving new genes, with tens to
hundreds of genes duplicated in animal genomes every million years.
Most genes belong to larger gene families of shared ancestry, known as
homology. Novel genes are produced by several methods, commonly
through the duplication and mutation of an ancestral gene, or by
recombining parts of different genes to form new combinations with new
Here, protein domains act as modules, each with a particular and
independent function, that can be mixed together to produce genes
encoding new proteins with novel properties. For example, the
human eye uses four genes to make structures that sense light: three
for cone cell or color vision and one for rod cell or night vision;
all four arose from a single ancestral gene. Another advantage of
duplicating a gene (or even an entire genome) is that this increases
engineering redundancy; this allows one gene in the pair to acquire a
new function while the other copy performs the original
function. Other types of mutation occasionally create new
genes from previously noncoding DNA.
Changes in chromosome number may involve even larger mutations, where
segments of the
DNA within chromosomes break and then rearrange. For
example, in the Homininae, two chromosomes fused to produce human
chromosome 2; this fusion did not occur in the lineage of the other
apes, and they retain these separate chromosomes. In evolution,
the most important role of such chromosomal rearrangements may be to
accelerate the divergence of a population into new species by making
populations less likely to interbreed, thereby preserving genetic
differences between these populations.
DNA that can move about the genome, such as transposons,
make up a major fraction of the genetic material of plants and
animals, and may have been important in the evolution of genomes.
For example, more than a million copies of the Alu sequence are
present in the human genome, and these sequences have now been
recruited to perform functions such as regulating gene expression.
Another effect of these mobile
DNA sequences is that when they move
within a genome, they can mutate or delete existing genes and thereby
produce genetic diversity.
Nonlethal mutations accumulate within the gene pool and increase the
amount of genetic variation. The abundance of some genetic changes
within the gene pool can be reduced by natural selection, while other
"more favorable" mutations may accumulate and result in adaptive
Prodryas persephone, a Late
For example, a butterfly may produce offspring with new mutations. The
majority of these mutations will have no effect; but one might change
the color of one of the butterfly's offspring, making it harder (or
easier) for predators to see. If this color change is advantageous,
the chances of this butterfly's surviving and producing its own
offspring are a little better, and over time the number of butterflies
with this mutation may form a larger percentage of the population.
Neutral mutations are defined as mutations whose effects do not
influence the fitness of an individual. These can increase in
frequency over time due to genetic drift. It is believed that the
overwhelming majority of mutations have no significant effect on an
organism's fitness.[better source needed] Also, DNA
repair mechanisms are able to mend most changes before they become
permanent mutations, and many organisms have mechanisms for
eliminating otherwise-permanently mutated somatic cells.
Beneficial mutations can improve reproductive success.
Main article: Mutationism
Hugo de Vries, making a painting of an evening primrose, the plant
which had apparently produced new forms by large mutations in his
experiments, by Thérèse Schwartze, 1918
Mutationism is one of several alternatives to evolution by natural
selection that have existed both before and after the publication of
Charles Darwin's 1859 book, On the Origin of Species. In the theory,
mutation was the source of novelty, creating new forms and new
species, potentially instantaneously, in a sudden jump. This
was envisaged as driving evolution, which was limited by the supply of
Before Darwin, biologists commonly believed in saltationism, the
possibility of large evolutionary jumps, including immediate
speciation. For example, in 1822 Étienne Geoffroy Saint-Hilaire
argued that species could be formed by sudden transformations, or what
would later be called macromutation. Darwin opposed saltation,
insisting on gradualism in evolution as in geology. In 1864, Albert
von Kölliker revived Geoffroy's theory. In 1901 the geneticist
Hugo de Vries
Hugo de Vries gave the name "mutation" to seemingly new forms that
suddenly arose in his experiments on the evening primrose Oenothera
lamarckiana, and in the first decade of the 20th century, mutationism,
or as de Vries named it mutationstheorie, became a rival to
Darwinism supported for a while by geneticists including William
Bateson, Thomas Hunt Morgan, and Reginald Punnett.
Understanding of mutationism is clouded by the mid-20th century
portrayal of the early mutationists by supporters of the modern
synthesis as opponents of Darwinian evolution and rivals of the
biometrics school who argued that selection operated on continuous
variation. In this portrayal, mutationism was defeated by a synthesis
of genetics and natural selection that supposedly started later,
around 1918, with work by the mathematician Ronald
Fisher. However, the alignment of Mendelian genetics
and natural selection began as early as 1902 with a paper by Udny
Yule, and built up with theoretical and experimental work in
Europe and America. Despite the controversy, the early mutationists
had by 1918 already accepted natural selection and explained
continuous variation as the result of multiple genes acting on the
same characteristic, such as height.
Mutationism, along with other alternatives to
Lamarckism and orthogenesis, was discarded by most biologists as they
came to see that Mendelian genetics and natural selection could
readily work together; mutation took its place as a source of the
genetic variation essential for natural selection to work on. However,
mutationism did not entirely vanish. In 1940, Richard Goldschmidt
again argued for single-step speciation by macromutation, describing
the organisms thus produced as "hopeful monsters", earning widespread
ridicule. In 1987,
Masatoshi Nei argued controversially that
evolution was often mutation-limited. Modern biologists such as
Douglas J. Futuyma conclude that essentially all claims of evolution
driven by large mutations can be explained by Darwinian evolution.
Main article: Mutagenesis
Four classes of mutations are (1) spontaneous mutations (molecular
decay), (2) mutations due to error-prone replication bypass of
DNA damage (also called error-prone translesion
synthesis), (3) errors introduced during
DNA repair, and (4) induced
mutations caused by mutagens. Scientists may also deliberately
introduce mutant sequences through
DNA manipulation for the sake of
One 2017 study claimed that 66% of cancer-causing mutations are
random, 29% are due to the environment (the studied population spanned
69 countries), and 5% are inherited.
Humans on average pass 60 new mutations to their children but fathers
pass more mutations depending on their age with every year adding two
new mutations to a child.
Spontaneous mutations occur with non-zero probability even given a
healthy, uncontaminated cell. They can be characterized by the
Tautomerism — A base is changed by the repositioning of a hydrogen
atom, altering the hydrogen bonding pattern of that base, resulting in
incorrect base pairing during replication.
Depurination — Loss of a purine base (A or G) to form an apurinic
site (AP site).
Hydrolysis changes a normal base to an atypical base
containing a keto group in place of the original amine group. Examples
include C → U and A → HX (hypoxanthine), which can be corrected by
DNA repair mechanisms; and 5MeC (5-methylcytosine) → T, which is
less likely to be detected as a mutation because thymine is a normal
Slipped strand mispairing — Denaturation of the new strand from the
template during replication, followed by renaturation in a different
spot ("slipping"). This can lead to insertions or deletions.
Error-prone replication bypass
There is increasing evidence that the majority of spontaneously
arising mutations are due to error-prone replication (translesion
DNA damage in the template strand. Naturally occurring
DNA damages arise at least 10,000 times per cell per day in
humans and 50,000 times or more per cell per day in rats. In mice,
the majority of mutations are caused by translesion synthesis.
Likewise, in yeast, Kunz et al. found that more than 60% of the
spontaneous single base pair substitutions and deletions were caused
by translesion synthesis.
Errors introduced during
DNA damage (naturally occurring) and
Although naturally occurring double-strand breaks occur at a
relatively low frequency in DNA, their repair often causes mutation.
Non-homologous end joining
Non-homologous end joining (NHEJ) is a major pathway for repairing
double-strand breaks. NHEJ involves removal of a few nucleotides to
allow somewhat inaccurate alignment of the two ends for rejoining
followed by addition of nucleotides to fill in gaps. As a consequence,
NHEJ often introduces mutations.
A covalent adduct between the metabolite of benzo[a]pyrene, the major
mutagen in tobacco smoke, and DNA
Induced mutations are alterations in the gene after it has come in
contact with mutagens and environmental causes.
Induced mutations on the molecular level can be caused by:
Base analogs (e.g.,
Alkylating agents (e.g., N-ethyl-N-nitrosourea (ENU)). These agents
can mutate both replicating and non-replicating DNA. In contrast, a
base analog can mutate the
DNA only when the analog is incorporated in
replicating the DNA. Each of these classes of chemical mutagens has
certain effects that then lead to transitions, transversions, or
Agents that form
DNA adducts (e.g., ochratoxin A)
DNA intercalating agents (e.g., ethidium bromide)
This figure depicts the following processes of transcription,
splicing, and translation of a eukaryotic gene.
Nitrous acid converts amine groups on A and C to diazo groups,
altering their hydrogen bonding patterns, which leads to incorrect
base pairing during replication.
Ultraviolet light (UV) (non-ionizing radiation). Two nucleotide bases
in DNA—cytosine and thymine—are most vulnerable to radiation that
can change their properties. UV light can induce adjacent pyrimidine
bases in a
DNA strand to become covalently joined as a pyrimidine
dimer. UV radiation, in particular longer-wave UVA, can also cause
oxidative damage to DNA.
Ionizing radiation. Exposure to ionizing radiation, such as gamma
radiation, can result in mutation, possibly resulting in cancer or
Classification of types
By effect on structure
Five types of chromosomal mutations.
Selection of disease-causing mutations, in a standard table of the
genetic code of amino acids.
The sequence of a gene can be altered in a number of ways. Gene
mutations have varying effects on health depending on where they occur
and whether they alter the function of essential proteins. Mutations
in the structure of genes can be classified into several types.
Small-scale mutations, affecting a gene in one or a few nucleotides,
Substitution mutations, often caused by chemicals or malfunction of
DNA replication, exchange a single nucleotide for another. These
changes are classified as transitions or transversions. Most
common is the transition that exchanges a purine for a purine (A ↔
G) or a pyrimidine for a pyrimidine, (C ↔ T). A transition can be
caused by nitrous acid, base mis-pairing, or mutagenic base analogs
such as BrdU. Less common is a transversion, which exchanges a purine
for a pyrimidine or a pyrimidine for a purine (C/T ↔ A/G). An
example of a transversion is the conversion of adenine (A) into a
cytosine (C). A point mutation are modifications of single base pairs
DNA or other small base pairs within a gene. A point mutation can
be reversed by another point mutation, in which the nucleotide is
changed back to its original state (true reversion) or by second-site
reversion (a complementary mutation elsewhere that results in regained
Point mutations that occur within the protein coding region of a gene
may be classified into a few kinds, depending upon what the erroneous
codon codes for:
Silent mutations, which code for the same (or a sufficiently similar)
Missense mutations, which code for a different amino acid.
Nonsense mutations, which code for a stop codon and can truncate the
Insertions add one or more extra nucleotides into the DNA. They are
usually caused by transposable elements, or errors during replication
of repeating elements. Insertions in the coding region of a gene may
alter splicing of the m
RNA (splice site mutation), or cause a shift in
the reading frame (frameshift), both of which can significantly alter
the gene product. Insertions can be reversed by excision of the
(Deletion remove one or more nucleotides from the DNA. Like
insertions, these mutations can alter the reading frame of the gene.
In general, they are irreversible: Though exactly the same sequence
might in theory be restored by an insertion, transposable elements
able to revert a very short deletion (say 1–2 bases) in any location
either are highly unlikely to exist or do not exist at all.
Large-scale mutations in chromosomal structure include:
Amplifications (or gene duplications) leading to multiple copies of
all chromosomal regions, increasing the dosage of the genes located
Deletions of large chromosomal regions, leading to loss of the genes
within those regions.
Mutations whose effect is to juxtapose previously separate pieces of
DNA, potentially bringing together separate genes to form functionally
distinct fusion genes (e.g., bcr-abl).
Large scale changes to the structure of chromosomes called chromosomal
rearrangement that can lead to a decrease of fitness but also to
speciation in isolated, inbred populations. These include:
Chromosomal translocations: interchange of genetic parts from
Chromosomal inversions: reversing the orientation of a chromosomal
Non-homologous chromosomal crossover.
Interstitial deletions: an intra-chromosomal deletion that removes a
DNA from a single chromosome, thereby apposing previously
distant genes. For example, cells isolated from a human astrocytoma, a
type of brain tumor, were found to have a chromosomal deletion
removing sequences between the Fused in Glioblastoma (FIG) gene and
the receptor tyrosine kinase (ROS), producing a fusion protein
(FIG-ROS). The abnormal FIG-ROS fusion protein has constitutively
active kinase activity that causes oncogenic transformation (a
transformation from normal cells to cancer cells).
Loss of heterozygosity: loss of one allele, either by a deletion or a
genetic recombination event, in an organism that previously had two
By effect on function
Loss-of-function mutations, also called inactivating mutations, result
in the gene product having less or no function (being partially or
wholly inactivated). When the allele has a complete loss of function
(null allele), it is often called an amorph or amorphic mutation in
Muller's morphs schema. Phenotypes associated with such mutations
are most often recessive. Exceptions are when the organism is haploid,
or when the reduced dosage of a normal gene product is not enough for
a normal phenotype (this is called haploinsufficiency).
Gain-of-function mutations, also called activating mutations, change
the gene product such that its effect gets stronger (enhanced
activation) or even is superseded by a different and abnormal
function. When the new allele is created, a heterozygote containing
the newly created allele as well as the original will express the new
allele; genetically this defines the mutations as dominant phenotypes.
Muller's morphs correspond to gain of function, including
hypermorph and neomorph. In December 2017, the U.S. government lifted
a temporary ban implemented in 2014 that banned federal funding for
any new "gain-of-function" experiments that enhance pathogens "such as
Avian influenza, SARS and the Middle East Respiratory Syndrome or MERS
Dominant negative mutations (also called antimorphic mutations) have
an altered gene product that acts antagonistically to the wild-type
allele. These mutations usually result in an altered molecular
function (often inactive) and are characterized by a dominant or
semi-dominant phenotype. In humans, dominant negative mutations have
been implicated in cancer (e.g., mutations in genes p53, ATM,
CEBPA and PPARgamma).
Marfan syndrome is caused by mutations
FBN1 gene, located on chromosome 15, which encodes fibrillin-1,
a glycoprotein component of the extracellular matrix. Marfan
syndrome is also an example of dominant negative mutation and
Hypomorphs, after Mullerian classification, are characterized by
altered gene products that acts with decreased gene expression
compared to the wild type allele.
Neomorphs are characterized by the control of new protein product
Lethal mutations are mutations that lead to the death of the organisms
that carry the mutations.
A back mutation or reversion is a point mutation that restores the
original sequence and hence the original phenotype.
By effect on fitness
See also: Fitness (biology)
In applied genetics, it is usual to speak of mutations as either
harmful or beneficial.
A harmful, or deleterious, mutation decreases the fitness of the
A beneficial, or advantageous mutation increases the fitness of the
organism. Mutations that promotes traits that are desirable, are also
called beneficial. In theoretical population genetics, it is more
usual to speak of mutations as deleterious or advantageous than
harmful or beneficial.
A neutral mutation has no harmful or beneficial effect on the
organism. Such mutations occur at a steady rate, forming the basis for
the molecular clock. In the neutral theory of molecular evolution,
neutral mutations provide genetic drift as the basis for most
variation at the molecular level.
A nearly neutral mutation is a mutation that may be slightly
deleterious or advantageous, although most nearly neutral mutations
are slightly deleterious.
Distribution of fitness effects
Attempts have been made to infer the distribution of fitness effects
(DFE) using mutagenesis experiments and theoretical models applied to
molecular sequence data. DFE, as used to determine the relative
abundance of different types of mutations (i.e., strongly deleterious,
nearly neutral or advantageous), is relevant to many evolutionary
questions, such as the maintenance of genetic variation, the rate
of genomic decay, the maintenance of outcrossing sexual
reproduction as opposed to inbreeding and the evolution of sex and
genetic recombination. In summary, the DFE plays an important role
in predicting evolutionary dynamics. A variety of approaches
have been used to study the DFE, including theoretical, experimental
and analytical methods.
Mutagenesis experiment: The direct method to investigate the DFE is to
induce mutations and then measure the mutational fitness effects,
which has already been done in viruses, bacteria, yeast, and
Drosophila. For example, most studies of the DFE in viruses used
site-directed mutagenesis to create point mutations and measure
relative fitness of each mutant. In Escherichia coli,
one study used transposon mutagenesis to directly measure the fitness
of a random insertion of a derivative of Tn10. In yeast, a
combined mutagenesis and deep sequencing approach has been developed
to generate high-quality systematic mutant libraries and measure
fitness in high throughput. However, given that many mutations
have effects too small to be detected and that mutagenesis
experiments can detect only mutations of moderately large effect; DNA
sequence data analysis can provide valuable information about these
The distribution of fitness effects (DFE) of mutations in vesicular
stomatitis virus. In this experiment, random mutations were introduced
into the virus by site-directed mutagenesis, and the fitness of each
mutant was compared with the ancestral type. A fitness of zero, less
than one, one, more than one, respectively, indicates that mutations
are lethal, deleterious, neutral, and advantageous.
Molecular sequence analysis: With rapid development of
technology, an enormous amount of
DNA sequence data is available and
even more is forthcoming in the future. Various methods have been
developed to infer the DFE from
DNA sequence data. By
DNA sequence differences within and between species, we are
able to infer various characteristics of the DFE for neutral,
deleterious and advantageous mutations. To be specific, the DNA
sequence analysis approach allows us to estimate the effects of
mutations with very small effects, which are hardly detectable through
One of the earliest theoretical studies of the distribution of fitness
effects was done by Motoo Kimura, an influential theoretical
population geneticist. His neutral theory of molecular evolution
proposes that most novel mutations will be highly deleterious, with a
small fraction being neutral. Hiroshi Akashi more recently
proposed a bimodal model for the DFE, with modes centered around
highly deleterious and neutral mutations. Both theories agree that
the vast majority of novel mutations are neutral or deleterious and
that advantageous mutations are rare, which has been supported by
experimental results. One example is a study done on the DFE of random
mutations in vesicular stomatitis virus. Out of all mutations,
39.6% were lethal, 31.2% were non-lethal deleterious, and 27.1% were
neutral. Another example comes from a high throughput mutagenesis
experiment with yeast. In this experiment it was shown that the
overall DFE is bimodal, with a cluster of neutral mutations, and a
broad distribution of deleterious mutations.
Though relatively few mutations are advantageous, those that are play
an important role in evolutionary changes. Like neutral mutations,
weakly selected advantageous mutations can be lost due to random
genetic drift, but strongly selected advantageous mutations are more
likely to be fixed. Knowing the DFE of advantageous mutations may lead
to increased ability to predict the evolutionary dynamics. Theoretical
work on the DFE for advantageous mutations has been done by John H.
Gillespie and H. Allen Orr. They proposed that the
distribution for advantageous mutations should be exponential under a
wide range of conditions, which, in general, has been supported by
experimental studies, at least for strongly selected advantageous
In general, it is accepted that the majority of mutations are neutral
or deleterious, with rare mutations being advantageous; however, the
proportion of types of mutations varies between species. This
indicates two important points: first, the proportion of effectively
neutral mutations is likely to vary between species, resulting from
dependence on effective population size; second, the average effect of
deleterious mutations varies dramatically between species. In
addition, the DFE also differs between coding regions and noncoding
regions, with the DFE of noncoding
DNA containing more weakly selected
By impact on protein sequence
A frameshift mutation is a mutation caused by insertion or deletion of
a number of nucleotides that is not evenly divisible by three from a
DNA sequence. Due to the triplet nature of gene expression by codons,
the insertion or deletion can disrupt the reading frame, or the
grouping of the codons, resulting in a completely different
translation from the original. The earlier in the sequence the
deletion or insertion occurs, the more altered the protein produced
For example, the code CCU GAC UAC CUA codes for the amino acids
proline, aspartic acid, tyrosine, and leucine. If the U in CCU was
deleted, the resulting sequence would be CCG ACU ACC UAx, which would
instead code for proline, threonine, threonine, and part of another
amino acid or perhaps a stop codon (where the x stands for the
In contrast, any insertion or deletion that is evenly divisible by
three is termed an in-frame mutation.
A nonsense mutation is a point mutation in a sequence of
results in a premature stop codon, or a nonsense codon in the
transcribed mRNA, and possibly a truncated, and often nonfunctional
protein product. This sort of mutation has been linked to different
mutations, such as congenital adrenal hyperplasia. (See Stop codon.)
Missense mutations or nonsynonymous mutations are types of point
mutations where a single nucleotide is changed to cause substitution
of a different amino acid. This in turn can render the resulting
protein nonfunctional. Such mutations are responsible for diseases
such as Epidermolysis bullosa, sickle-cell disease, and SOD1-mediated
A neutral mutation is a mutation that occurs in an amino acid codon
that results in the use of a different, but chemically similar, amino
acid. The similarity between the two is enough that little or no
change is often rendered in the protein. For example, a change from
AAA to AGA will encode arginine, a chemically similar molecule to the
Silent mutations are mutations that do not result in a change to the
amino acid sequence of a protein but do change the nucleotide
sequence, unless the changed amino acid is sufficiently similar to the
original. They may occur in a region that does not code for a protein,
or they may occur within a codon in a manner that does not alter the
final amino acid sequence.
Silent mutations are also called silent
substitutions, since they are not palpable changes as the changes in
phenotype. The phrase silent mutation is often used interchangeably
with the phrase synonymous mutation; however, synonymous mutations are
a subcategory of the former, occurring only within exons (and
necessarily exactly preserving the amino acid sequence of the
protein). Synonymous mutations occur due to the degenerate nature of
the genetic code. There can also be silent mutations in nucleotides
outside of the coding regions, such as the introns, because the exact
nucleotide sequence is not as crucial as it is in the coding regions.
A mutation has caused this moss rose plant to produce flowers of
different colors. This is a somatic mutation that may also be passed
on in the germline.
In multicellular organisms with dedicated reproductive cells,
mutations can be subdivided into germline mutations, which can be
passed on to descendants through their reproductive cells, and somatic
mutations (also called acquired mutations), which involve cells
outside the dedicated reproductive group and which are not usually
transmitted to descendants.
A germline mutation gives rise to a constitutional mutation in the
offspring, that is, a mutation that is present in every cell. A
constitutional mutation can also occur very soon after fertilisation,
or continue from a previous constitutional mutation in a parent.
The distinction between germline and somatic mutations is important in
animals that have a dedicated germline to produce reproductive cells.
However, it is of little value in understanding the effects of
mutations in plants, which lack dedicated germline. The distinction is
also blurred in those animals that reproduce asexually through
mechanisms such as budding, because the cells that give rise to the
daughter organisms also give rise to that organism's germline. A new
germline mutation not inherited from either parent is called a de novo
Diploid organisms (e.g., humans) contain two copies of each gene—a
paternal and a maternal allele. Based on the occurrence of mutation on
each chromosome, we may classify mutations into three types.
A heterozygous mutation is a mutation of only one allele.
A homozygous mutation is an identical mutation of both the paternal
and maternal alleles.
Compound heterozygous mutations or a genetic compound consists of two
different mutations in the paternal and maternal alleles.
A wild type or homozygous non-mutated organism is one in which neither
allele is mutated.
Conditional mutation is a mutation that has wild-type (or less severe)
phenotype under certain "permissive" environmental conditions and a
mutant phenotype under certain "restrictive" conditions. For example,
a temperature-sensitive mutation can cause cell death at high
temperature (restrictive condition), but might have no deleterious
consequences at a lower temperature (permissive condition). These
mutations are non-autonomous, as their manifestation depends upon
presence of certain conditions, as opposed to other mutations which
appear autonomously. The permissive conditions may be
temperature, certain chemicals, light or mutations in
other parts of the genome.
In vivo mechanisms like transcriptional
switches can create conditional mutations. For instance, association
of Steroid Binding Domain can create a transcriptional switch that can
change the expression of a gene based on the presence of a steroid
ligand. Conditional mutations have applications in research as
they allow control over gene expression. This is especially useful
studying diseases in adults by allowing expression after a certain
period of growth, thus eliminating the deleterious effect of gene
expression seen during stages of development in model organisms.
DNA Recombinase systems like Cre-Lox Recombination used in association
with promoters that are activated under certain conditions can
generate conditional mutations. Dual Recombinase technology can be
used to induce multiple conditional mutations to study the diseases
which manifest as a result of simultaneous mutations in multiple
genes. Certain inteins have been identified which splice only at
certain permissive temperatures, leading to improper protein synthesis
and thus, loss of function mutations at other temperatures.
Conditional mutations may also be used in genetic studies associated
with ageing, as the expression can be changed after a certain time
period in the organism's lifespan.
Replication timing quantitative trait loci affects
In order to categorize a mutation as such, the "normal" sequence must
be obtained from the
DNA of a "normal" or "healthy" organism (as
opposed to a "mutant" or "sick" one), it should be identified and
reported; ideally, it should be made publicly available for a
straightforward nucleotide-by-nucleotide comparison, and agreed upon
by the scientific community or by a group of expert geneticists and
biologists, who have the responsibility of establishing the standard
or so-called "consensus" sequence. This step requires a tremendous
scientific effort. Once the consensus sequence is known, the mutations
in a genome can be pinpointed, described, and classified. The
committee of the
Genome Variation Society (HGVS) has developed
the standard human sequence variant nomenclature, which should be
used by researchers and
DNA diagnostic centers to generate unambiguous
mutation descriptions. In principle, this nomenclature can also be
used to describe mutations in other organisms. The nomenclature
specifies the type of mutation and base or amino acid changes.
Nucleotide substitution (e.g., 76A>T) — The number is the
position of the nucleotide from the 5' end; the first letter
represents the wild-type nucleotide, and the second letter represents
the nucleotide that replaced the wild type. In the given example, the
adenine at the 76th position was replaced by a thymine.
If it becomes necessary to differentiate between mutations in genomic
DNA, mitochondrial DNA, and RNA, a simple convention is used. For
example, if the 100th base of a nucleotide sequence mutated from G to
C, then it would be written as g.100G>C if the mutation occurred in
genomic DNA, m.100G>C if the mutation occurred in mitochondrial
DNA, or r.100g>c if the mutation occurred in RNA. Note that, for
mutations in RNA, the nucleotide code is written in lower case.
Amino acid substitution (e.g., D111E) — The first letter is the one
letter code of the wild-type amino acid, the number is the position of
the amino acid from the N-terminus, and the second letter is the one
letter code of the amino acid present in the mutation. Nonsense
mutations are represented with an X for the second amino acid (e.g.
Amino acid deletion (e.g., ΔF508) — The Greek letter Δ (delta)
indicates a deletion. The letter refers to the amino acid present in
the wild type and the number is the position from the N terminus of
the amino acid were it to be present as in the wild type.
Mutation rates vary substantially across species, and the evolutionary
forces that generally determine mutation are the subject of ongoing
DNA caused by mutation can cause errors in protein
sequence, creating partially or completely non-functional proteins.
Each cell, in order to function correctly, depends on thousands of
proteins to function in the right places at the right times. When a
mutation alters a protein that plays a critical role in the body, a
medical condition can result. Some mutations alter a gene's
sequence but do not change the function of the protein made by the
gene. One study on the comparison of genes between different species
Drosophila suggests that if a mutation does change a protein, this
will probably be harmful, with an estimated 70 percent of amino acid
polymorphisms having damaging effects, and the remainder being either
neutral or weakly beneficial. Studies have shown that only 7% of
point mutations in noncoding
DNA of yeast are deleterious and 12% in
DNA are deleterious. The rest of the mutations are either
neutral or slightly beneficial.
If a mutation is present in a germ cell, it can give rise to offspring
that carries the mutation in all of its cells. This is the case in
hereditary diseases. In particular, if there is a mutation in a DNA
repair gene within a germ cell, humans carrying such germline
mutations may have an increased risk of cancer. A list of 34 such
germline mutations is given in the article
disorder. An example of one is albinism, a mutation that occurs in the
OCA1 or OCA2 gene. Individuals with this disorder are more prone to
many types of cancers, other disorders and have impaired vision. On
the other hand, a mutation may occur in a somatic cell of an organism.
Such mutations will be present in all descendants of this cell within
the same organism, and certain mutations can cause the cell to become
malignant, and, thus, cause cancer.
DNA damage can cause an error when the
DNA is replicated, and this
error of replication can cause a gene mutation that, in turn, could
cause a genetic disorder.
DNA damages are repaired by the
system of the cell. Each cell has a number of pathways through which
enzymes recognize and repair damages in DNA. Because
DNA can be
damaged in many ways, the process of
DNA repair is an important way in
which the body protects itself from disease. Once
DNA damage has given
rise to a mutation, the mutation cannot be repaired.
pathways can only recognize and act on "abnormal" structures in the
DNA. Once a mutation occurs in a gene sequence it then has normal DNA
structure and cannot be repaired.
Although mutations that cause changes in protein sequences can be
harmful to an organism, on occasions the effect may be positive in a
given environment. In this case, the mutation may enable the mutant
organism to withstand particular environmental stresses better than
wild-type organisms, or reproduce more quickly. In these cases a
mutation will tend to become more common in a population through
For example, a specific 32 base pair deletion in human CCR5
HIV resistance to homozygotes and delays AIDS
onset in heterozygotes. One possible explanation of the etiology
of the relatively high frequency of CCR5-Δ32 in the European
population is that it conferred resistance to the bubonic plague in
mid-14th century Europe. People with this mutation were more likely to
survive infection; thus its frequency in the population
increased. This theory could explain why this mutation is not
found in Southern Africa, which remained untouched by bubonic plague.
A newer theory suggests that the selective pressure on the
32 mutation was caused by smallpox instead of the bubonic plague.
An example of a harmful mutation is sickle-cell disease, a blood
disorder in which the body produces an abnormal type of the
oxygen-carrying substance hemoglobin in the red blood cells. One-third
of all indigenous inhabitants of
Sub-Saharan Africa carry the gene,
because, in areas where malaria is common, there is a survival value
in carrying only a single sickle-cell gene (sickle cell trait).
Those with only one of the two alleles of the sickle-cell disease are
more resistant to malaria, since the infestation of the malaria
Plasmodium is halted by the sickling of the cells that it infests.
Prions are proteins and do not contain genetic material. However,
prion replication has been shown to be subject to mutation and natural
selection just like other forms of replication. The human gene
PRNP codes for the major prion protein, PrP, and is subject to
mutations that can give rise to disease-causing prions.
Main article: Loss of heterozygosity
See also: Carcinogenesis
A change in the genetic structure that is not inherited from a parent,
and also not passed to offspring, is called a somatic mutation.
Somatic mutations are not inherited because they do not affect the
germline. These types of mutations are usually prompted by
environmental causes, such as ultraviolet radiation or any exposure to
certain harmful chemicals, and can cause diseases including
With plants, some somatic mutations can be propagated without the need
for seed production, for example, by grafting and stem cuttings. These
type of mutation have led to new types of fruits, such as the
"Delicious" apple and the "Washington" navel orange.
Human and mouse somatic cells have a mutation rate more than ten times
higher than the germline mutation rate for both species; mice have a
higher rate of both somatic and germline mutations per cell division
than humans. The disparity in mutation rate between the germline and
somatic tissues likely reflects the greater importance of genome
maintenance in the germline than in the soma.
An amorph, a term utilized by Muller in 1932, is a mutated allele,
which has lost the ability of the parent (whether wild type or any
other type) allele to encode any functional protein. An amorphic
mutation may be caused by the replacement of an amino acid that
deactivates an enzyme or by the deletion of part of a gene that
produces the enzyme.
Cells with heterozygous mutations (one good copy of gene and one
mutated copy) may function normally with the unmutated copy until the
good copy has been spontaneously somatically mutated. This kind of
mutation happens all the time in living organisms, but it is difficult
to measure the rate. Measuring this rate is important in predicting
the rate at which people may develop cancer.
Point mutations may arise from spontaneous mutations that occur during
DNA replication. The rate of mutation may be increased by mutagens.
Mutagens can be physical, such as radiation from UV rays, X-rays or
extreme heat, or chemical (molecules that misplace base pairs or
disrupt the helical shape of DNA). Mutagens associated with cancers
are often studied to learn about cancer and its prevention.
Hypomorphic and hypermorphic mutations
A hypomorphic mutation is a replacement of amino acids that would
hinder enzyme activity, which would reduce the enzyme level but not to
the point of complete loss. Usually, hypomorphic mutations are
recessive, but haploinsufficiency causes some alleles to be dominant.
A hypermorphic mutation changes the regulation of the gene and causes
it to overproduce the gene produce causing a greater than normal
enzyme levels. These type of alleles are dominant gain of function
type of alleles.
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Wikimedia Commons has media related to Mutations.
Jones, Steve; Woolfson, Adrian; Partridge, Linda (December 6, 2007).
"Genetic Mutation". In Our Time. BBC Radio 4. Retrieved
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Mutalyzer website". Leiden, the Netherlands: Leiden
University Medical Center. Retrieved 2015-10-18. — The
Mechanisms of mutation
Mutation with respect to structure
Mutation with respect to overall fitness
Nearly neutral mutation
Chromosome abnormalities (Q90–Q99, 758)
Warkany syndrome 2
Cat eye syndrome/
1q21.1 deletion syndrome/1q21.1 duplication syndrome/TAR syndrome
Cri du chat/
Chromosome 5q deletion syndrome
Miller–Dieker syndrome/Smith–Magenis syndrome
22q11.2 distal deletion syndrome
22q13 deletion syndrome
Prader–Willi syndrome (15)
Distal 18q-/Proximal 18q-
Turner syndrome (45,X)
Klinefelter syndrome (47,XXY)
XXYY syndrome (48,XXYY)
XXXY syndrome (48,XXXY)
Triple X syndrome
Triple X syndrome (47,XXX)
Tetrasomy X (48,XXXX)
Jacobs syndrome (47,XYY)
Burkitt's lymphoma t(8 MYC;14 IGH)
Follicular lymphoma t(14 IGH;18 BCL2)
Mantle cell lymphoma/
Multiple myeloma t(11 CCND1:14 IGH)
Anaplastic large-cell lymphoma
Anaplastic large-cell lymphoma t(2 ALK;5 NPM1)
Acute lymphoblastic leukemia
Philadelphia chromosome t(9 ABL; 22 BCR)
Acute myeloblastic leukemia with maturation
Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1)
Acute promyelocytic leukemia
Acute promyelocytic leukemia t(15 PML,17 RARA)
Acute megakaryoblastic leukemia
Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1)
Ewing's sarcoma t(11 FLI1; 22 EWS)
Synovial sarcoma t(x SYT;18 SSX)
Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB)
Myxoid liposarcoma t(12 DDIT3; 16 FUS)
Desmoplastic small-round-cell tumor
Desmoplastic small-round-cell tumor t(11 WT1; 22 EWS)
Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1)
Fragile X syndrome
XX male syndrome/46,XX testicular disorders of sex development
6; 9; 14; 15; 18; 20; 21, 22
Evolutionary history of life
Index of evolutionary biology articles
Outline of evolution
Timeline of evolution
Earliest known life forms
Evidence of common descent
Last universal common ancestor
Origin of life
Evolutionary developmental biology
dolphins and whales
Programmed cell death
Life cycles/nuclear phases
Tempo and modes
Renaissance and Enlightenment
Transmutation of species
On the Origin of Species
History of paleontology
The eclipse of Darwinism
History of molecular evolution
Extended evolutionary synthesis
Teleology in biology