Editing Mutation (section)

== Classification of types ==

=== By effect on structure ===
[[File:Chromosomes mutations-en.svg|thumb|right|301px|Five types of chromosomal mutations]]
[[File:Deletion Insertion Substitution-en.svg|thumb|right|301px|Types of small-scale mutations]]

The sequence of a gene can be altered in a number of ways.<ref>{{cite web| vauthors = Rahman N |title=The clinical impact of DNA sequence changes|url=http://www.thetgmi.org/genetics/clinical-impact-dna-sequence-changes/|website=Transforming Genetic Medicine Initiative|access-date=27 June 2017|url-status=dead|archive-url=https://web.archive.org/web/20170804060005/http://www.thetgmi.org/genetics/clinical-impact-dna-sequence-changes/|archive-date=4 August 2017}}</ref> 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.{{citation needed|date=February 2024}}

==== Large-scale mutations ====
{{See also|Chromosome abnormality}}

Large-scale mutations in [[chromosome|chromosomal]] structure include:
* Amplifications (or [[gene duplication]]s) or repetition of a chromosomal segment or presence of extra piece of a chromosome broken piece of a chromosome may become attached to a homologous or non-homologous chromosome so that some of the genes are present in more than two doses leading to multiple copies of all chromosomal regions, increasing the dosage of the genes located within them.
* [[Polyploidy]], duplication of entire sets of chromosomes, potentially resulting in a separate breeding population and [[speciation]].
* 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 gene]]s (e.g., [[Philadelphia chromosome|bcr-abl]]).
* Large scale changes to the structure of [[chromosome]]s called [[chromosomal rearrangement]] that can lead to a decrease of fitness but also to speciation in isolated, inbred populations. These include:
** [[Chromosomal translocation]]s: interchange of genetic parts from nonhomologous chromosomes.
** [[Chromosomal inversion]]s: reversing the orientation of a chromosomal segment.
** Non-homologous [[chromosomal crossover]].
** Interstitial deletions: an intra-chromosomal deletion that removes a segment of DNA from a single chromosome, thereby apposing previously distant genes. For example, cells isolated from a human [[astrocytoma]], a type of brain tumour, 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 [[Carcinogenesis|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 different alleles.

==== Small-scale mutations ====

Small-scale mutations affect a gene in one or a few nucleotides. (If only a single nucleotide is affected, they are called [[point mutation]]s.) Small-scale mutations include:
* [[Insertion (genetics)|Insertions]] add one or more extra nucleotides into the DNA. They are usually caused by [[transposable element]]s, or errors during replication of repeating elements. Insertions in the coding region of a gene may alter [[RNA splicing|splicing]] of the [[Messenger RNA|mRNA]] ([[splice site mutation]]), or cause a shift in the [[reading frame]] ([[Frameshift mutation|frameshift]]), both of which can significantly alter the [[gene product]]. Insertions can be reversed by excision of the transposable element.
* [[Deletion (genetics)|Deletions]] 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.
* [[Point mutation|Substitution mutations]], often caused by chemicals or malfunction of DNA replication, exchange a single nucleotide for another.<ref>{{cite journal | vauthors = Freese E | title = The Difference Between Spontaneous and Base-Analogue Induced Mutations of Phage T4 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 45 | issue = 4 | pages = 622–33 | date = April 1959 | pmid = 16590424 | pmc = 222607 | doi = 10.1073/pnas.45.4.622 | author-link = Ernst Freese | bibcode = 1959PNAS...45..622F | doi-access = free }}</ref> These changes are classified as transitions or transversions.<ref>{{cite journal | vauthors = Freese E | date = June 1959 |title=The specific mutagenic effect of base analogues on Phage T4 |journal=Journal of Molecular Biology |volume=1 |issue=2 |pages=87–105 |doi=10.1016/S0022-2836(59)80038-3}}</ref> 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 mispairing, or mutagenic base analogues 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). Point mutations are modifications of single base pairs of 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 gene functionality). As discussed [[#By impact on protein sequence|below]], point mutations that occur within the protein [[coding region]] of a gene may be classified as [[Synonymous substitution|synonymous]] or [[nonsynonymous substitution]]s, the latter of which in turn can be divided into [[Missense mutation|missense]] or [[nonsense mutations]].

=== By impact on protein sequence ===
[[File:Gene structure eukaryote 2 annotated.svg|alt=Diagram of the structure of a eukaryotic protein-coding gene, showing regulatory regions, introns, and coding regions. Four stages are shown: DNA, initial mRNA product, mature mRNA, and protein.|thumb|460x460px|The structure of a [[eukaryotic]] protein-coding gene. A mutation in the [[protein coding region]] (red) can result in a change in the amino acid sequence. Mutations in other areas of the gene can have diverse effects. Changes within [[regulatory sequence]]s (yellow and blue) can effect [[transcription (genetics)|transcriptional]] and [[Translation (biology)|translational]] regulation of [[gene expression]].]]
[[File:Point mutations-en.png|thumb|right|301px|Point mutations classified by impact on protein]]
[[File:Notable mutations.svg|301px|thumb|right|Selection of disease-causing mutations, in a standard table of the [[genetic code]] of [[amino acid]]s<ref>References for the image are found in Wikimedia Commons page at: [[Commons:File:Notable mutations.svg#References]].</ref>]]

The effect of a mutation on protein sequence depends in part on where in the genome it occurs, especially whether it is in a [[Coding region|coding]] or [[Non-coding DNA|non-coding region]]. Mutations in the non-coding [[regulatory sequence]]s of a gene, such as promoters, enhancers, and silencers, can alter levels of gene expression, but are less likely to alter the protein sequence. Mutations within [[intron]]s and in regions with no known biological function (e.g. [[pseudogene]]s, [[retrotransposon]]s) are generally [[Neutral mutation|neutral]], having no effect on phenotype – though intron mutations could alter the protein product if they affect mRNA splicing.

Mutations that occur in coding regions of the genome are more likely to alter the protein product, and can be categorized by their effect on amino acid sequence:
* A [[frameshift mutation]] is 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 (biology)|translation]] from the original.<ref>{{cite encyclopedia| vauthors = Hogan CM | veditors = Monosson E |encyclopedia=[[Encyclopedia of Earth]]|title=Mutation|url=http://www.eoearth.org/view/article/159530/|access-date=8 October 2015|date=12 October 2010|publisher=Environmental Information Coalition, [[National Council for Science and the Environment]]|location=Washington, D.C.|oclc=72808636|url-status=live|archive-url=https://web.archive.org/web/20151114055631/http://www.eoearth.org/view/article/159530/|archive-date=14 November 2015}}</ref> The earlier in the sequence the deletion or insertion occurs, the more altered the protein produced is. (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 following nucleotide).) By contrast, any insertion or deletion that is evenly divisible by three is termed an ''in-frame mutation''.
* A point substitution mutation results in a change in a single nucleotide and can be either synonymous or nonsynonymous.
** A [[synonymous substitution]] replaces a codon with another codon that codes for the same amino acid, so that the produced amino acid sequence is not modified. Synonymous mutations occur due to the [[Degeneracy (biology)|degenerate]] nature of the [[genetic code]]. If this mutation does not result in any phenotypic effects, then it is called [[Silent mutation|silent]], but not all synonymous substitutions are silent. (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, but these are not considered synonymous substitutions.)
** A [[nonsynonymous substitution]] replaces a codon with another codon that codes for a different amino acid, so that the produced amino acid sequence is modified. Nonsynonymous substitutions can be classified as nonsense or missense mutations:
*** A [[missense mutation]] changes a nucleotide 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 [[Superoxide dismutase|SOD1]]-mediated [[Amyotrophic lateral sclerosis|ALS]].<ref>{{cite journal|vauthors=Boillée S, Vande Velde C, Cleveland DW|s2cid=12968143|date=October 2006|title=ALS: a disease of motor neurons and their nonneuronal neighbors|journal=Neuron|volume=52|issue=1|pages=39–59|citeseerx=10.1.1.325.7514|doi=10.1016/j.neuron.2006.09.018|pmid=17015226}}</ref> On the other hand, if a missense mutation occurs in an amino acid codon that results in the use of a different, but chemically similar, amino acid, then sometimes little or no change is rendered in the protein. For example, a change from AAA to AGA will encode [[arginine]], a chemically similar molecule to the intended [[lysine]]. In this latter case the mutation will have little or no effect on phenotype and therefore be [[neutral mutation|neutral]].
*** 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 possibly a truncated, and often nonfunctional protein product. This sort of mutation has been linked to different diseases, such as [[congenital adrenal hyperplasia]]. (See [[Stop codon]].)

=== By effect on function ===
A mutation becomes an effect on function mutation when the exactitude of functions between a mutated protein and its direct interactor undergoes change. The interactors can be other proteins, molecules, nucleic acids, etc. There are many mutations that fall under the category of by effect on function, but depending on the specificity of the change the mutations listed below will occur.<ref>{{cite journal | vauthors = Reva B, Antipin Y, Sander C | title = Predicting the functional impact of protein mutations: application to cancer genomics | journal = Nucleic Acids Research | volume = 39 | issue = 17 | pages = e118 | date = September 2011 | pmid = 21727090 | pmc = 3177186 | doi = 10.1093/nar/gkr407 }}</ref>
* 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 (gene)|amorph]] or amorphic mutation in [[Muller's morphs]] schema. Phenotypes associated with such mutations are most often [[Dominance (genetics)|recessive]]. Exceptions are when the organism is [[Ploidy#Haploid and monoploid|haploid]], or when the reduced dosage of a normal gene product is not enough for a normal phenotype (this is called [[haploinsufficiency]]). A disease that is caused by a loss-of-function mutation is Gitelman syndrome and cystic fibrosis.<ref>{{cite journal | vauthors = Housden BE, Muhar M, Gemberling M, Gersbach CA, Stainier DY, Seydoux G, Mohr SE, Zuber J, Perrimon N | display-authors = 6 | title = Loss-of-function genetic tools for animal models: cross-species and cross-platform differences | journal = Nature Reviews. Genetics | volume = 18 | issue = 1 | pages = 24–40 | date = January 2017 | pmid = 27795562 | pmc = 5206767 | doi = 10.1038/nrg.2016.118 }}</ref>
* 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 [[Zygosity#Heterozygous|heterozygote]] containing the newly created allele as well as the original will express the new allele; genetically this defines the mutations as [[Dominance (genetics)|dominant]] phenotypes. Several of Muller's morphs correspond to the gain of function, including hypermorph (increased gene expression) and neomorph (novel function).
* Dominant negative mutations (also called anti-morphic 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 [[Dominance (genetics)#Incomplete dominance|semi-dominant]] phenotype. In humans, dominant negative mutations have been implicated in cancer (e.g., mutations in genes [[p53]], [[Ataxia telangiectasia mutated|ATM]], [[CEBPA]], and [[Peroxisome proliferator-activated receptor gamma|PPARgamma]]). [[Marfan syndrome]] is caused by mutations in the [[FBN1]] gene, located on [[Chromosome 15 (human)|chromosome 15]], which encodes fibrillin-1, a [[glycoprotein]] component of the [[extracellular matrix]]. Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency.
* Lethal mutations result in rapid organismal death when occurring during development and cause significant reductions of life expectancy for developed organisms. An example of a disease that is caused by a dominant lethal mutation is [[Huntington's disease]].
* Null mutations, also known as Amorphic mutations, are a form of loss-of-function mutations that completely prohibit the gene's function. The mutation leads to a complete loss of operation at the phenotypic level, also causing no gene product to be formed. [[Atopic dermatitis|Atopic eczema]] and dermatitis syndrome are common diseases caused by a null mutation of the gene that activates filaggrin.
* Suppressor mutations are a type of mutation that causes the double mutation to appear normally. In suppressor mutations the phenotypic activity of a different mutation is completely suppressed, thus causing the double mutation to look normal. There are two types of suppressor mutations, there are [[Epistasis|intragenic]] and extragenic suppressor mutations. Intragenic mutations occur in the gene where the first mutation occurs, while extragenic mutations occur in the gene that interacts with the product of the first mutation. A common disease that results from this type of mutation is [[Alzheimer's disease]].<ref>{{cite journal | vauthors = Eggertsson G, Adelberg EA | title = Map positions and specificities of suppressor mutations in Escherichia coli K-12 | journal = Genetics | volume = 52 | issue = 2 | pages = 319–340 | date = August 1965 | pmid = 5324068 | pmc = 1210853 | doi = 10.1093/genetics/52.2.319 }}</ref>
* Neomorphic mutations are a part of the gain-of-function mutations and are characterized by the control of new protein product synthesis. The newly synthesized gene normally contains a novel gene expression or molecular function. The result of the neomorphic mutation is the gene where the mutation occurs has a complete change in function.<ref>{{cite journal | vauthors = Takiar V, Ip CK, Gao M, Mills GB, Cheung LW | title = Neomorphic mutations create therapeutic challenges in cancer | journal = Oncogene | volume = 36 | issue = 12 | pages = 1607–1618 | date = March 2017 | pmid = 27841866 | pmc = 6609160 | doi = 10.1038/onc.2016.312 }}</ref>
* A back mutation or reversion is a point mutation that restores the original sequence and hence the original phenotype.<ref>{{cite journal | vauthors = Ellis NA, Ciocci S, German J | s2cid = 22290041 | title = Back mutation can produce phenotype reversion in Bloom syndrome somatic cells | journal = Human Genetics | volume = 108 | issue = 2 | pages = 167–73 | date = February 2001 | pmid = 11281456 | doi = 10.1007/s004390000447 }}</ref>

=== By effect on fitness (harmful, beneficial, neutral mutations) ===
{{See also|Fitness (biology)}}

In [[genetics]], it is sometimes useful to classify mutations as either '''{{vanchor|harmful}} or beneficial''' (or '''neutral'''):
* A harmful, or {{vanchor|deleterious}}, mutation decreases the fitness of the organism. Many, but not all mutations in [[essential gene]]s are harmful (if a mutation does not change the amino acid sequence in an essential protein, it is harmless in most cases).
* A beneficial, or advantageous mutation increases the fitness of the organism. Examples are mutations that lead to [[Antimicrobial resistance|antibiotic resistance]] in bacteria (which are beneficial for bacteria but usually not for humans).
* 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. In animals or plants, most mutations are neutral, given that the vast majority of their genomes is either non-coding or consists of repetitive sequences that have no obvious function ("[[Non-coding DNA|junk DNA]]").<ref>{{cite journal | vauthors = Doolittle WF, Brunet TD | title = On causal roles and selected effects: our genome is mostly junk | journal = BMC Biology | volume = 15 | issue = 1 | pages = 116 | date = December 2017 | pmid = 29207982 | pmc = 5718017 | doi = 10.1186/s12915-017-0460-9 | doi-access = free }}</ref>
'''Large-scale quantitative mutagenesis screens''', in which thousands of millions of mutations are tested, invariably find that a larger fraction of mutations has harmful effects but always returns a number of beneficial mutations as well. For instance, in a screen of all gene deletions in ''[[Escherichia coli|E. coli]]'', 80% of mutations were negative, but 20% were positive, even though many had a very small effect on growth (depending on condition).<ref>{{cite journal | vauthors = Nichols RJ, Sen S, Choo YJ, Beltrao P, Zietek M, Chaba R, Lee S, Kazmierczak KM, Lee KJ, Wong A, Shales M, Lovett S, Winkler ME, Krogan NJ, Typas A, Gross CA | display-authors = 6 | title = Phenotypic landscape of a bacterial cell | journal = Cell | volume = 144 | issue = 1 | pages = 143–56 | date = January 2011 | pmid = 21185072 | pmc = 3060659 | doi = 10.1016/j.cell.2010.11.052 }}</ref> Gene ''deletions'' involve removal of whole genes, so that point mutations almost always have a much smaller effect. In a similar screen in ''[[Streptococcus pneumoniae]]'', but this time with [[Transposable element|transposon]] insertions, 76% of insertion mutants were classified as neutral, 16% had a significantly reduced fitness, but 6% were advantageous.<ref>{{cite journal | vauthors = van Opijnen T, Bodi KL, Camilli A | title = Tn-seq: high-throughput parallel sequencing for fitness and genetic interaction studies in microorganisms | journal = Nature Methods | volume = 6 | issue = 10 | pages = 767–72 | date = October 2009 | pmid = 19767758 | pmc = 2957483 | doi = 10.1038/nmeth.1377 }}</ref>

This classification is obviously relative and somewhat artificial: a harmful mutation can quickly turn into a beneficial mutations when conditions change. Also, there is a gradient from harmful/beneficial to neutral, as many mutations may have small and mostly neglectable effects but under certain conditions will become relevant. Also, many traits are determined by hundreds of genes (or loci), so that each locus has only a minor effect. For instance, human height is determined by hundreds of genetic variants ("mutations") but each of them has a very minor effect on height,<ref>{{cite journal | vauthors = Allen HL, Estrada K, Lettre G, Berndt SI, Weedon MN, Rivadeneira F, etal | title = Hundreds of variants clustered in genomic loci and biological pathways affect human height | journal = Nature | volume = 467 | issue = 7317 | pages = 832–8 | date = October 2010 | pmid = 20881960 | pmc = 2955183 | doi = 10.1038/nature09410 | bibcode = 2010Natur.467..832L }}</ref> apart from the impact of [[nutrition]]. Height (or size) itself may be more or less beneficial as the huge range of sizes in animal or plant groups shows.

==== Distribution of fitness effects (DFE) ====

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]],<ref>{{cite journal | vauthors = Charlesworth D, Charlesworth B, Morgan MT | title = The pattern of neutral molecular variation under the background selection model | journal = Genetics | volume = 141 | issue = 4 | pages = 1619–32 | date = December 1995 | doi = 10.1093/genetics/141.4.1619 | pmid = 8601499 | pmc = 1206892 | author-link1 = Deborah Charlesworth | author-link2 = Brian Charlesworth }}</ref> the rate of [[Pathogenomics#Gene Loss / Genome Decay|genomic decay]],<ref>{{cite journal | vauthors = Loewe L | title = Quantifying the genomic decay paradox due to Muller's ratchet in human mitochondrial DNA | journal = Genetical Research | volume = 87 | issue = 2 | pages = 133–59 | date = April 2006 | pmid = 16709275 | doi = 10.1017/S0016672306008123 | doi-access = free }}</ref> the maintenance of [[outcrossing]] [[sexual reproduction]] as opposed to [[inbreeding]]<ref>{{Cite book | vauthors = Bernstein H, Hopf FA, Michod RE | title = Molecular Genetics of Development | chapter = The molecular basis of the evolution of sex | series = Advances in Genetics | volume = 24 | pages = 323–70 | year = 1987 | pmid = 3324702 | doi = 10.1016/s0065-2660(08)60012-7 | isbn = 9780120176243 }}</ref> and the evolution of [[sex]] and [[genetic recombination]].<ref>{{cite journal | vauthors = Peck JR, Barreau G, Heath SC | title = Imperfect genes, Fisherian mutation and the evolution of sex | journal = Genetics | volume = 145 | issue = 4 | pages = 1171–99 | date = April 1997 | doi = 10.1093/genetics/145.4.1171 | pmid = 9093868 | pmc = 1207886 }}</ref> DFE can also be tracked by tracking the skewness of the distribution of mutations with putatively severe effects as compared to the distribution of mutations with putatively mild or absent effect.<ref>{{cite journal | vauthors = Simcikova D, Heneberg P | title = Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 18577 | date = December 2019 | pmid = 31819097 | pmc = 6901466 | doi = 10.1038/s41598-019-54976-4 | bibcode = 2019NatSR...918577S }}</ref> In summary, the DFE plays an important role in predicting [[evolutionary dynamics]].<ref>{{cite journal | vauthors = Keightley PD, Lynch M | title = Toward a realistic model of mutations affecting fitness | journal = Evolution; International Journal of Organic Evolution | volume = 57 | issue = 3 | pages = 683–5; discussion 686–9 | date = March 2003 | pmid = 12703958 | doi = 10.1554/0014-3820(2003)057[0683:tarmom]2.0.co;2 | jstor = 3094781 | s2cid = 198157678 | author-link2 = Michael Lynch (geneticist) }}</ref><ref>{{cite journal | vauthors = Barton NH, Keightley PD | s2cid = 8934412 | title = Understanding quantitative genetic variation | journal = Nature Reviews Genetics | volume = 3 | issue = 1 | pages = 11–21 | date = January 2002 | pmid = 11823787 | doi = 10.1038/nrg700 | author-link1 = Nick Barton }}</ref> 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.<ref name="Sanjuán04">{{cite journal | vauthors = Sanjuán R, Moya A, Elena SF | title = The distribution of fitness effects caused by single-nucleotide substitutions in an RNA virus | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 22 | pages = 8396–401 | date = June 2004 | pmid = 15159545 | pmc = 420405 | doi = 10.1073/pnas.0400146101 | bibcode = 2004PNAS..101.8396S | doi-access = free }}</ref><ref>{{cite journal | vauthors = Carrasco P, de la Iglesia F, Elena SF | title = Distribution of fitness and virulence effects caused by single-nucleotide substitutions in Tobacco Etch virus | journal = Journal of Virology | volume = 81 | issue = 23 | pages = 12979–84 | date = December 2007 | pmid = 17898073 | pmc = 2169111 | doi = 10.1128/JVI.00524-07 }}</ref><ref>{{cite journal | vauthors = Sanjuán R | title = Mutational fitness effects in RNA and single-stranded DNA viruses: common patterns revealed by site-directed mutagenesis studies | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 365 | issue = 1548 | pages = 1975–82 | date = June 2010 | pmid = 20478892 | pmc = 2880115 | doi = 10.1098/rstb.2010.0063 }}</ref><ref>{{cite journal | vauthors = Peris JB, Davis P, Cuevas JM, Nebot MR, Sanjuán R | title = Distribution of fitness effects caused by single-nucleotide substitutions in bacteriophage f1 | journal = Genetics | volume = 185 | issue = 2 | pages = 603–9 | date = June 2010 | pmid = 20382832 | pmc = 2881140 | doi = 10.1534/genetics.110.115162 }}</ref> In ''[[Escherichia coli]]'', one study used [[transposon mutagenesis]] to directly measure the fitness of a random insertion of a derivative of [[Tn10]].<ref>{{cite journal | vauthors = Elena SF, Ekunwe L, Hajela N, Oden SA, Lenski RE | s2cid = 2267064 | title = Distribution of fitness effects caused by random insertion mutations in Escherichia coli | journal = Genetica | volume = 102–103 | issue = 1–6 | pages = 349–58 | date = March 1998 | pmid = 9720287 | doi = 10.1023/A:1017031008316 | author-link5 = Richard Lenski }}</ref> 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.<ref name="Hietpas11">{{cite journal | vauthors = Hietpas RT, Jensen JD, Bolon DN | title = Experimental illumination of a fitness landscape | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 19 | pages = 7896–901 | date = May 2011 | pmid = 21464309 | pmc = 3093508 | doi = 10.1073/pnas.1016024108 | bibcode = 2011PNAS..108.7896H | doi-access = free }}</ref> However, given that many mutations have effects too small to be detected<ref>{{cite journal | vauthors = Davies EK, Peters AD, Keightley PD | title = High frequency of cryptic deleterious mutations in Caenorhabditis elegans | journal = Science | volume = 285 | issue = 5434 | pages = 1748–51 | date = September 1999 | pmid = 10481013 | doi = 10.1126/science.285.5434.1748 }}</ref> and that mutagenesis experiments can detect only mutations of moderately large effect; DNA [[sequence analysis]] can provide valuable information about these mutations.

[[File:DFE in VSV.png|thumb|right|360px|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 (biology)|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.<ref name="Sanjuán04" />]]
* [[File:GOF diagram.png|thumb|This figure shows a simplified version of loss-of-function, switch-of-function, gain-of-function, and conservation-of-function mutations.]]Molecular sequence analysis: With rapid development of [[DNA sequencing]] 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.<ref>{{cite journal | vauthors = Loewe L, Charlesworth B | title = Inferring the distribution of mutational effects on fitness in Drosophila | journal = Biology Letters | volume = 2 | issue = 3 | pages = 426–30 | date = September 2006 | pmid = 17148422 | pmc = 1686194 | doi = 10.1098/rsbl.2006.0481 }}</ref><ref>{{cite journal | vauthors = Eyre-Walker A, Woolfit M, Phelps T | title = The distribution of fitness effects of new deleterious amino acid mutations in humans | journal = Genetics | volume = 173 | issue = 2 | pages = 891–900 | date = June 2006 | pmid = 16547091 | pmc = 1526495 | doi = 10.1534/genetics.106.057570 }}</ref><ref>{{cite journal | vauthors = Sawyer SA, Kulathinal RJ, Bustamante CD, Hartl DL | s2cid = 18051307 | title = Bayesian analysis suggests that most amino acid replacements in Drosophila are driven by positive selection | journal = Journal of Molecular Evolution | volume = 57 | issue = 1 | pages = S154–64 | date = August 2003 | pmid = 15008412 | doi = 10.1007/s00239-003-0022-3 | author-link3 = Carlos D. Bustamante | citeseerx = 10.1.1.78.65 | bibcode = 2003JMolE..57S.154S }}</ref><ref>{{cite journal | vauthors = Piganeau G, Eyre-Walker A | title = Estimating the distribution of fitness effects from DNA sequence data: implications for the molecular clock | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 18 | pages = 10335–40 | date = September 2003 | pmid = 12925735 | pmc = 193562 | doi = 10.1073/pnas.1833064100 | bibcode = 2003PNAS..10010335P | doi-access = free }}</ref> By examining DNA sequence differences within and between species, we are able to infer various characteristics of the DFE for neutral, deleterious and advantageous mutations.<ref name="Eyre-Walker07" /> 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 mutagenesis experiments.

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.<ref name="Kimura-1983">{{cite book | vauthors = Kimura M |author-link=Motoo Kimura |year=1983 |title=The Neutral Theory of Molecular Evolution |location=Cambridge, UK; New York |publisher=[[Cambridge University Press]] |isbn=978-0-521-23109-1 |lccn=82022225 |oclc=9081989 |title-link=The Neutral Theory of Molecular Evolution }}</ref><ref>{{cite journal | vauthors = Kimura M | s2cid = 4161261 | title = Evolutionary rate at the molecular level | journal = Nature | volume = 217 | issue = 5129 | pages = 624–6 | date = February 1968 | pmid = 5637732 | doi = 10.1038/217624a0 | author-link = Motoo Kimura | bibcode = 1968Natur.217..624K }}</ref> A later proposal by Hiroshi Akashi proposed a [[Multimodal distribution|bimodal]] model for the DFE, with modes centered around highly deleterious and neutral mutations.<ref>{{cite journal | vauthors = Akashi H | title = Within- and between-species DNA sequence variation and the 'footprint' of natural selection | journal = Gene | volume = 238 | issue = 1 | pages = 39–51 | date = September 1999 | pmid = 10570982 | doi = 10.1016/S0378-1119(99)00294-2 }}</ref> 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]].<ref name="Sanjuán04" /> 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.<ref name="Hietpas11" /> 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.<ref>{{cite journal | vauthors = Eyre-Walker A | title = The genomic rate of adaptive evolution | journal = Trends in Ecology & Evolution | volume = 21 | issue = 10 | pages = 569–75 | date = October 2006 | pmid = 16820244 | doi = 10.1016/j.tree.2006.06.015 | bibcode = 2006TEcoE..21..569E }}</ref> 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]]<ref>{{cite journal | vauthors = Gillespie JH | author-link = John H. Gillespie |date=September 1984 |title=Molecular Evolution Over the Mutational Landscape |journal=Evolution |volume=38 |issue=5 |pages=1116–1129 |doi=10.2307/2408444 |pmid=28555784 |jstor=2408444}}</ref> and [[H. Allen Orr]].<ref>{{cite journal | vauthors = Orr HA | title = The distribution of fitness effects among beneficial mutations | journal = Genetics | volume = 163 | issue = 4 | pages = 1519–26 | date = April 2003 | doi = 10.1093/genetics/163.4.1519 | pmid = 12702694 | pmc = 1462510 | author-link = H. Allen Orr }}</ref> They proposed that the distribution for advantageous mutations should be [[exponential decay|exponential]] under a wide range of conditions, which, in general, has been supported by experimental studies, at least for strongly selected advantageous mutations.<ref>{{cite journal | vauthors = Kassen R, Bataillon T | s2cid = 6954765 | title = Distribution of fitness effects among beneficial mutations before selection in experimental populations of bacteria | journal = Nature Genetics | volume = 38 | issue = 4 | pages = 484–8 | date = April 2006 | pmid = 16550173 | doi = 10.1038/ng1751 }}</ref><ref>{{cite journal | vauthors = Rokyta DR, Joyce P, Caudle SB, Wichman HA | s2cid = 20296781 | title = An empirical test of the mutational landscape model of adaptation using a single-stranded DNA virus | journal = Nature Genetics | volume = 37 | issue = 4 | pages = 441–4 | date = April 2005 | pmid = 15778707 | doi = 10.1038/ng1535 }}</ref><ref>{{cite journal | vauthors = Imhof M, Schlotterer C | title = Fitness effects of advantageous mutations in evolving Escherichia coli populations | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 3 | pages = 1113–7 | date = January 2001 | pmid = 11158603 | pmc = 14717 | doi = 10.1073/pnas.98.3.1113 | bibcode = 2001PNAS...98.1113I | doi-access = free }}</ref>

In general, it is accepted that the majority of mutations are neutral or deleterious, with advantageous mutations being rare; 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.<ref name="Eyre-Walker07" /> In addition, the DFE also differs between coding regions and [[Noncoding DNA|noncoding region]]s, with the DFE of noncoding DNA containing more weakly selected mutations.<ref name="Eyre-Walker07" />

=== By inheritance ===
[[File:Portulaca grandiflora mutant1.jpg|thumb|right|A mutation has caused this [[Portulaca grandiflora|moss rose]] plant to produce flowers of different colours. This is a [[Somatic (biology)|somatic]] mutation that may also be passed on in the [[germline]].]]
In [[multicellular organism]]s with dedicated [[Gamete|reproductive cell]]s, mutations can be subdivided into [[germline mutation]]s, which can be passed on to descendants through their reproductive cells, and [[Somatic (biology)|somatic]] mutations (also called acquired mutations),<ref name="Somatic_cell">{{cite encyclopedia |encyclopedia=Genome Dictionary |title=Somatic cell genetic mutation |url=https://theodora.com/genetics/#somaticcellgeneticmutation |access-date=6 June 2010 |date=30 June 2007 |publisher=Information Technology Associates |location=Athens, Greece |url-status=dead |archive-url=https://web.archive.org/web/20100224074045/http://www.theodora.com/genetics/#somaticcellgeneticmutation |archive-date=24 February 2010 }}</ref> which involve cells outside the dedicated reproductive group and which are not usually transmitted to descendants.

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 [[wild type]] or homozygous non-mutated organism is one in which neither allele is mutated.
* 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 heterozygosity|Compound heterozygous]] mutations or a genetic compound consists of two different mutations in the paternal and maternal alleles.<ref>{{cite encyclopedia |encyclopedia=MedTerms |title=Compound heterozygote |url=http://www.medicinenet.com/script/main/art.asp?articlekey=33675 |access-date=9 October 2015 |date=14 June 2012 |publisher=[[WebMD]] |location=New York |url-status=dead |archive-url=https://web.archive.org/web/20160304123903/http://www.medicinenet.com/script/main/art.asp?articlekey=33675 |archive-date=4 March 2016 }}</ref>

==== Germline mutation ====
{{Further|Germline mutation}}
A germline mutation in the reproductive cells of an individual 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 [[fertilization]], or continue from a previous constitutional mutation in a parent.<ref>{{cite web|url=http://www.daisyfund.org/rb/about/genetics.html|title=''RB1'' Genetics|website=Daisy's Eye Cancer Fund|location=Oxford, UK|archive-url=https://web.archive.org/web/20111126004753/http://www.daisyfund.org/rb/about/genetics.html|archive-date=26 November 2011|access-date=9 October 2015}}</ref> A germline mutation can be passed down through subsequent generations of organisms.

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 a dedicated germline. The distinction is also blurred in those animals that [[asexual reproduction|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 '''''[[wikt:de novo|de novo]]'' mutation'''.

==== Somatic mutation ====
{{main|Somatic mutation}}

A change in the genetic structure that is not inherited from a parent, and also not passed to offspring, is called a [[somatic cell|somatic]] mutation''.<ref name="Somatic_cell" />'' Somatic mutations are not inherited by an organism's offspring because they do not affect the [[germline]]. However, they are passed down to all the progeny of a mutated cell within the same organism during mitosis. A major section of an organism therefore might carry the same mutation. 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 cancer.''<ref>{{Cite encyclopedia|url=https://www.britannica.com/science/somatic-mutation|title=somatic mutation {{!}} genetics|access-date=31 March 2017|url-status=live|archive-url=https://web.archive.org/web/20170331122201/https://www.britannica.com/science/somatic-mutation|archive-date=31 March 2017|encyclopedia=Encyclopædia Britannica}}</ref>''

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 (fruit)|orange]].<ref>{{cite book | vauthors = Hartl L, Jones EW |url=https://archive.org/details/geneticsprincipl00hart/page/556|title=Genetics Principles and Analysis|publisher=Jones and Bartlett Publishers|year=1998|isbn=978-0-7637-0489-6|location=Sudbury, Massachusetts|pages=[https://archive.org/details/geneticsprincipl00hart/page/556 556]|url-access=registration}}</ref>

Human and mouse [[somatic cell]]s 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.<ref name="Milholland">{{cite journal | vauthors = Milholland B, Dong X, Zhang L, Hao X, Suh Y, Vijg J | title = Differences between germline and somatic mutation rates in humans and mice | journal = Nature Communications | volume = 8 | pages = 15183 | date = May 2017 | pmid = 28485371 | pmc = 5436103 | doi = 10.1038/ncomms15183 | bibcode = 2017NatCo...815183M }}</ref>

=== Special classes ===
<!-- This section is linked from [[Cat]] -->
* '''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).<ref>{{Cite book|title=Molecular Biology of the Cell| vauthors = Alberts B |publisher=Garland Science|year=2014|isbn=9780815344322|edition=6|pages=487}}</ref> These mutations are non-autonomous, as their manifestation depends upon presence of certain conditions, as opposed to other mutations which appear autonomously.<ref name="Chadov-2015">{{cite journal | vauthors = Chadov BF, Fedorova NB, Chadova EV | title = Conditional mutations in Drosophila melanogaster: On the occasion of the 150th anniversary of G. Mendel's report in Brünn | journal = Mutation Research/Reviews in Mutation Research | volume = 765 | pages = 40–55 | date = 1 July 2015 | pmid = 26281767 | doi = 10.1016/j.mrrev.2015.06.001 | bibcode = 2015MRRMR.765...40C }}</ref> The permissive conditions may be [[Permissive temperature|temperature]],<ref name="Landis-2001">{{cite journal | vauthors = Landis G, Bhole D, Lu L, Tower J | title = High-frequency generation of conditional mutations affecting Drosophila melanogaster development and life span | journal = Genetics | volume = 158 | issue = 3 | pages = 1167–76 | date = July 2001 | doi = 10.1093/genetics/158.3.1167 | pmid = 11454765 | pmc = 1461716 | url = http://www.genetics.org/content/158/3/1167 | url-status = dead | access-date = 21 March 2017 | archive-url = https://web.archive.org/web/20170322014758/http://www.genetics.org/content/158/3/1167 | archive-date = 22 March 2017 }}</ref> certain chemicals,<ref name="Gierut-2014">{{cite journal | vauthors = Gierut JJ, Jacks TE, Haigis KM | title = Strategies to achieve conditional gene mutation in mice | journal = Cold Spring Harbor Protocols | volume = 2014 | issue = 4 | pages = 339–49 | date = April 2014 | pmid = 24692485 | pmc = 4142476 | doi = 10.1101/pdb.top069807 }}</ref> light<ref name="Gierut-2014" /> or mutations in other parts of the [[genome]].<ref name="Chadov-2015" /> ''[[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.<ref>{{cite journal | vauthors = Spencer DM | title = Creating conditional mutations in mammals | journal = Trends in Genetics | volume = 12 | issue = 5 | pages = 181–7 | date = May 1996 | pmid = 8984733 | doi = 10.1016/0168-9525(96)10013-5 }}</ref> 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.<ref name="Gierut-2014" /> DNA Recombinase systems like [[Cre-Lox recombination]] used in association with [[Promoter (genetics)|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.<ref name="Gierut-2014" /> Certain [[intein]]s have been identified which splice only at certain permissive temperatures, leading to improper protein synthesis and thus, loss-of-function mutations at other temperatures.<ref>{{cite journal | vauthors = Tan G, Chen M, Foote C, Tan C | title = Temperature-sensitive mutations made easy: generating conditional mutations by using temperature-sensitive inteins that function within different temperature ranges | journal = Genetics | volume = 183 | issue = 1 | pages = 13–22 | date = September 2009 | pmid = 19596904 | pmc = 2746138 | doi = 10.1534/genetics.109.104794 }}</ref> 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.<ref name="Landis-2001" />
* '''[[Replication timing quantitative trait loci]]''' affects DNA replication.

=== Nomenclature ===
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 [[biologist]]s, 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 Human Genome Variation Society (HGVS) has developed the standard human sequence variant nomenclature,<ref name="paper45">{{cite journal | vauthors = den Dunnen JT, Antonarakis SE | title = Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion | journal = Human Mutation | volume = 15 | issue = 1 | pages = 7–12 | date = January 2000 | pmid = 10612815 | doi = 10.1002/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N | s2cid = 84706224 | author-link2 = Stylianos Antonarakis | doi-access = free }}</ref> which should be used by researchers and [[Genetic testing|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 [[Amino acid#Table of standard amino acid abbreviations and properties|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. D111X).
* Amino acid deletion (e.g., ΔF508) – The Greek letter Δ ([[delta (letter)|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.