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sasdfj asdkfasl {{Table|2=asdf}}{{User sandbox}}
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== me messing around with mutation article structure ==
{{short description|Alteration in the nucleotide sequence of a genome}}
{{Evolutionary biology|expanded=Process}}
{{Genetics sidebar}}
[[Image:Darwin Hybrid Tulip Mutation 2014-05-01.jpg|thumb|A tulip flower exhibiting a partially yellow petal due to a mutation in its genes]]
In [[biology]], a '''mutation''' is an alteration in the [[base sequence|nucleotide sequence]] of the [[genome]] of an [[organism]], [[virus]], or [[extrachromosomal DNA]].<ref>{{Cite web|url=https://www.nature.com/scitable/definition/mutation-8|title=mutation {{!}} Learn Science at Scitable|website=www.nature.com|language=en|access-date=2018-09-24}}</ref> Mutations result from errors during [[DNA replication]], [[mitosis]], and [[meiosis]] or other types of [[DNA repair#DNA damage|damage]] to [[DNA]] (such as [[pyrimidine dimer]]s that may be caused by exposure to radiation or [[carcinogens]]), which then may undergo error-prone repair (especially [[microhomology-mediated end joining]]<ref name="pmid25789972">{{cite journal | vauthors = Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC | title = Homology and enzymatic requirements of microhomology-dependent alternative end joining | journal = Cell Death & Disease | volume = 6 | issue = 3 | pages = e1697 | date = March 2015 | pmid = 25789972 | pmc = 4385936 | doi = 10.1038/cddis.2015.58 }}</ref>) or cause an error during other forms of repair<ref name="pmid24843013">{{cite journal | vauthors = Chen J, Miller BF, Furano AV | title = Repair of naturally occurring mismatches can induce mutations in flanking DNA | journal = eLife | volume = 3 | issue = | pages = e02001 | date = April 2014 | pmid = 24843013 | pmc = 3999860 | doi = 10.7554/elife.02001 }}</ref><ref name="pmid26033759">{{cite journal | vauthors = Rodgers K, McVey M | title = Error-Prone Repair of DNA Double-Strand Breaks | journal = Journal of Cellular Physiology | volume = 231 | issue = 1 | pages = 15–24 | date = January 2016 | pmid = 26033759 | pmc = 4586358 | doi = 10.1002/jcp.25053 }}</ref> or else may cause an error during replication ([[DNA repair#Translesion synthesis|translesion synthesis]]). Mutations may also result from [[Insertion (genetics)|insertion]] or [[Deletion (genetics)|deletion]] of segments of DNA due to [[mobile genetic elements]].<ref name="Bertram">{{cite journal | vauthors = Bertram JS | title = The molecular biology of cancer | journal = Molecular Aspects of Medicine | volume = 21 | issue = 6 | pages = 167–223 | date = December 2000 | pmid = 11173079 | doi = 10.1016/S0098-2997(00)00007-8 }}</ref><ref name="transposition764">{{cite journal | vauthors = Aminetzach YT, Macpherson JM, Petrov DA | title = Pesticide resistance via transposition-mediated adaptive gene truncation in Drosophila | journal = Science | volume = 309 | issue = 5735 | pages = 764–7 | date = July 2005 | pmid = 16051794 | doi = 10.1126/science.1112699 | bibcode = 2005Sci...309..764A }}</ref><ref name="Burrus">{{cite journal | vauthors = Burrus V, Waldor MK | title = Shaping bacterial genomes with integrative and conjugative elements | journal = Research in Microbiology | volume = 155 | issue = 5 | pages = 376–86 | date = June 2004 | pmid = 15207870 | doi = 10.1016/j.resmic.2004.01.012 }}</ref>

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]].

In [[multicellular organism]]s with dedicated [[Gamete|reproductive cell]]s, such as humans, only germline mutations - mutations in reproductive cells - can be passed on to offspring. Mutations in body cells ([[Somatic (biology)|somatic]] mutations)<ref name="Somatic_cell">{{cite encyclopedia|encyclopedia=Genome Dictionary|title=Somatic cell genetic mutation|url=https://theodora.com/genetics/#somaticcellgeneticmutation|accessdate=2010-06-06|date=June 30, 2007|publisher=Information Technology Associates|location=Athens, Greece|url-status=live|archiveurl=https://web.archive.org/web/20100224074045/http://www.theodora.com/genetics/#somaticcellgeneticmutation|archivedate=24 February 2010|df=dmy-all}}</ref> are not usually transmitted to descendants. *note: how to express difference between offspring of a cell (within a body) and offspring of the whole organism?*

Mutation can result in many different types of change in sequences. Mutations in [[gene]]s can either have no effect, alter the [[gene product|product of a gene]], or prevent the gene from functioning properly or completely. Mutations can also occur in [[Non-gene locus|nongenic region]]s. A 2007 study on [[genetic variation]]s between different [[species]] of ''[[Drosophila]]'' suggested that, if a mutation changes a [[protein]] produced by a gene, the result is likely to be harmful, with an estimated 70% of [[amino acid]] [[Polymorphism (biology)|polymorphism]]s that have damaging effects, and the remainder being either neutral or marginally beneficial.<ref name="Sawyer2007">{{cite journal | vauthors = Sawyer SA, Parsch J, Zhang Z, Hartl DL | title = Prevalence of positive selection among nearly neutral amino acid replacements in Drosophila | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 16 | pages = 6504–10 | date = April 2007 | pmid = 17409186 | pmc = 1871816 | doi = 10.1073/pnas.0701572104 | bibcode = 2007PNAS..104.6504S | author3 = Zhi Zhang }}</ref> 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.<ref name="Bertram" />

==Overview==
Mutations can involve the [[gene duplication|duplication]] of large sections of DNA, usually through [[genetic recombination]].<ref>{{cite journal | vauthors = Hastings PJ, Lupski JR, Rosenberg SM, Ira G | title = Mechanisms of change in gene copy number | journal = Nature Reviews. Genetics | volume = 10 | issue = 8 | pages = 551–64 | date = August 2009 | pmid = 19597530 | pmc = 2864001 | doi = 10.1038/nrg2593 | authorlink2 = James R. Lupski }}</ref> 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.<ref>{{cite book |last1=Carroll |first1=Sean B. |authorlink1=Sean B. Carroll |last2=Grenier |first2=Jennifer K. |last3=Weatherbee |first3=Scott D. | name-list-format = vanc |year=2005 |title=From DNA to Diversity: Molecular Genetics and the Evolution of Animal Design |edition=2nd |location=Malden, MA |publisher=[[Wiley-Blackwell|Blackwell Publishing]] |isbn=978-1-4051-1950-4 |lccn=2003027991 |oclc=53972564}}</ref> Most genes belong to larger [[gene family|gene families]] of shared ancestry, detectable by their [[sequence homology]].<ref>{{cite journal | vauthors = Harrison PM, Gerstein M | title = Studying genomes through the aeons: protein families, pseudogenes and proteome evolution | journal = Journal of Molecular Biology | volume = 318 | issue = 5 | pages = 1155–74 | date = May 2002 | pmid = 12083509 | doi = 10.1016/S0022-2836(02)00109-2 | authorlink2 = Mark Bender Gerstein }}</ref> 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 functions.<ref>{{cite journal | vauthors = Orengo CA, Thornton JM | title = Protein families and their evolution-a structural perspective | journal = Annual Review of Biochemistry | volume = 74 | pages = 867–900 | date = July 2005 | pmid = 15954844 | doi = 10.1146/annurev.biochem.74.082803.133029 | authorlink2 = Janet Thornton }}</ref><ref>{{cite journal | vauthors = Long M, Betrán E, Thornton K, Wang W | title = The origin of new genes: glimpses from the young and old | journal = Nature Reviews. Genetics | volume = 4 | issue = 11 | pages = 865–75 | date = November 2003 | pmid = 14634634 | doi = 10.1038/nrg1204 | author4 = Wen Wang }}</ref>

Here, [[protein domain]]s act as modules, each with a particular and independent function, that can be mixed together to produce genes encoding new proteins with novel properties.<ref>{{cite journal | vauthors = Wang M, Caetano-Anollés G | title = The evolutionary mechanics of domain organization in proteomes and the rise of modularity in the protein world | journal = Structure | volume = 17 | issue = 1 | pages = 66–78 | date = January 2009 | pmid = 19141283 | doi = 10.1016/j.str.2008.11.008 | authorlink2 = Gustavo Caetano-Anolles }}</ref> 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.<ref>{{cite journal | vauthors = Bowmaker JK | title = Evolution of colour vision in vertebrates | journal = Eye | volume = 12 | issue = Pt 3b | pages = 541–7 | date = May 1998 | pmid = 9775215 | doi = 10.1038/eye.1998.143 }}</ref> Another advantage of duplicating a gene (or even an entire genome) is that this increases [[Redundancy (engineering)|engineering redundancy]]; this allows one gene in the pair to acquire a new function while the other copy performs the original function.<ref>{{cite journal | vauthors = Gregory TR, Hebert PD | title = The modulation of DNA content: proximate causes and ultimate consequences | journal = Genome Research | volume = 9 | issue = 4 | pages = 317–24 | date = April 1999 | pmid = 10207154 | doi = 10.1101/gr.9.4.317 | authorlink1 = T. Ryan Gregory | authorlink2 = Paul D. N. Hebert | doi-broken-date = 2020-03-24 }}</ref><ref>{{cite journal | vauthors = Hurles M | title = Gene duplication: the genomic trade in spare parts | journal = PLOS Biology | volume = 2 | issue = 7 | pages = E206 | date = July 2004 | pmid = 15252449 | pmc = 449868 | doi = 10.1371/journal.pbio.0020206 }}</ref> Other types of mutation occasionally create new genes from previously [[noncoding DNA]].<ref>{{cite journal | vauthors = Liu N, Okamura K, Tyler DM, Phillips MD, Chung WJ, Lai EC | title = The evolution and functional diversification of animal microRNA genes | journal = Cell Research | volume = 18 | issue = 10 | pages = 985–96 | date = October 2008 | pmid = 18711447 | pmc = 2712117 | doi = 10.1038/cr.2008.278 }}</ref><ref>{{cite journal | vauthors = Siepel A | title = Darwinian alchemy: Human genes from noncoding DNA | journal = Genome Research | volume = 19 | issue = 10 | pages = 1693–5 | date = October 2009 | pmid = 19797681 | pmc = 2765273 | doi = 10.1101/gr.098376.109 | authorlink = Adam C. Siepel }}</ref>

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 (human)|chromosome 2]]; this fusion did not occur in the [[Lineage (evolution)|lineage]] of the other [[ape]]s, and they retain these separate chromosomes.<ref>{{cite journal | vauthors = Zhang J, Wang X, Podlaha O | title = Testing the chromosomal speciation hypothesis for humans and chimpanzees | journal = Genome Research | volume = 14 | issue = 5 | pages = 845–51 | date = May 2004 | pmid = 15123584 | pmc = 479111 | doi = 10.1101/gr.1891104 }}</ref> In evolution, the most important role of such chromosomal rearrangements may be to accelerate the divergence of a population into [[Speciation|new species]] by making populations less likely to interbreed, thereby preserving genetic differences between these populations.<ref>{{cite journal | vauthors = Ayala FJ, Coluzzi M | title = Chromosome speciation: humans, Drosophila, and mosquitoes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 Suppl 1 | issue = Suppl 1 | pages = 6535–42 | date = May 2005 | pmid = 15851677 | pmc = 1131864 | doi = 10.1073/pnas.0501847102 | bibcode = 2005PNAS..102.6535A | authorlink1 = Francisco J. Ayala }}</ref>

Sequences of DNA that can move about the genome, such as [[Transposable element|transposon]]s, make up a major fraction of the genetic material of plants and animals, and may have been important in the evolution of genomes.<ref>{{cite journal | vauthors = Hurst GD, Werren JH | title = The role of selfish genetic elements in eukaryotic evolution | journal = Nature Reviews Genetics | volume = 2 | issue = 8 | pages = 597–606 | date = August 2001 | pmid = 11483984 | doi = 10.1038/35084545 }}</ref> For example, more than a million copies of the [[Alu element|Alu sequence]] are present in the [[human genome]], and these sequences have now been recruited to perform functions such as regulating [[gene expression]].<ref>{{cite journal | vauthors = Häsler J, Strub K | title = Alu elements as regulators of gene expression | journal = Nucleic Acids Research | volume = 34 | issue = 19 | pages = 5491–7 | date = November 2006 | pmid = 17020921 | pmc = 1636486 | doi = 10.1093/nar/gkl706 }}</ref> 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.<ref name="transposition764" />

Nonlethal mutations accumulate within the [[gene pool]] and increase the amount of genetic variation.<ref name="Eyre-Walker07">{{cite journal | vauthors = Eyre-Walker A, Keightley PD | title = The distribution of fitness effects of new mutations | journal = Nature Reviews Genetics | volume = 8 | issue = 8 | pages = 610–8 | date = August 2007 | pmid = 17637733 | doi = 10.1038/nrg2146 | url = http://www.lifesci.sussex.ac.uk/home/Adam_Eyre-Walker/Website/Publications_files/EWNRG07.pdf | authorlink2 = Peter Keightley | url-status = live | archiveurl = https://web.archive.org/web/20160304195010/http://www.lifesci.sussex.ac.uk/home/Adam_Eyre-Walker/Website/Publications_files/EWNRG07.pdf | archivedate = 4 March 2016 | df = dmy-all }}</ref> 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 changes.

[[File:Prodryas.png|thumb|right|199px|''[[Prodryas persephone]]'', a Late [[Eocene]] butterfly]]
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 mutation]]s are defined as mutations whose effects do not influence the [[Fitness (biology)|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.<ref name=":4" /><ref>{{cite book | url = https://books.google.com/?id=ybeLBgAAQBAJ&pg=PA299&lpg=PA299&dq=t+is+believed+that+the+overwhelming+majority+of+mutations+have+no+significant+effect+on+an+organism's+fitness.#v=onepage&q=t%20is%20believed%20that%20the%20overwhelming%20majority%20of%20mutations%20have%20no%20significant%20effect%20on%20an%20organism's%20fitness.&f=false | title = Fundamentals of Polymer Physics and Molecular Biophysics | last = Bohidar | first = Himadri B. | name-list-format = vanc | date = January 2015 | publisher = Cambridge University Press | isbn = 978-1-316-09302-3 }}</ref>{{better source|note=Preferably a biology review paper or textbook|date=January 2017}} 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 cell]]s.

Beneficial mutations can improve reproductive success.<ref>{{Cite book|url=https://books.google.com/?id=sElrZSzoLYMC&pg=PA107&dq=Beneficial+mutations+can+improve+reproductive+success.#v=onepage&q=Beneficial%20mutations%20can%20improve%20reproductive%20success.&f=false|title=Dear Mr. Darwin: Letters on the Evolution of Life and Human Nature|last=Dover|first=Gabriel A.|last2=Darwin|first2=Charles | name-list-format = vanc |date=2000|publisher=University of California Press|isbn=9780520227903|language=en}}</ref><ref>{{Cite book|url=https://books.google.com/?id=OwBQCwAAQBAJ&pg=PA108&dq=Beneficial+mutations+can+improve+reproductive+success.#v=onepage&q=Beneficial%20mutations%20can%20improve%20reproductive%20success.&f=false|title=Genetics and Evolution of Infectious Diseases|last=Tibayrenc|first=Michel|date=2017-01-12|publisher=Elsevier|isbn=9780128001530|language=en}}</ref>

==Causes==
{{main|Mutagenesis}}
Four classes of mutations are (1) spontaneous mutations (molecular decay), (2) mutations due to error-prone replication bypass of [[DNA damage (naturally occurring)|naturally occurring DNA damage]] (also called error-prone translesion synthesis), (3) errors introduced during DNA repair, and (4) induced mutations caused by [[mutagen]]s. Scientists may also deliberately introduce [[mutant]] sequences through DNA manipulation for the sake of scientific experimentation.

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.<ref>{{cite web|url=https://www.npr.org/sections/health-shots/2017/03/23/521219318/cancer-is-partly-caused-by-bad-luck-study-finds|title=Cancer Is Partly Caused By Bad Luck, Study Finds|url-status=live|archiveurl=https://web.archive.org/web/20170713114206/http://www.npr.org/sections/health-shots/2017/03/23/521219318/cancer-is-partly-caused-by-bad-luck-study-finds|archivedate=13 July 2017|df=dmy-all}}</ref>

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.<ref>{{cite web|url=https://www.theguardian.com/science/2012/aug/22/older-fathers-genetic-mutations-research|title=Older fathers pass on more genetic mutations, study shows|first=Alok|last=Jha|date=22 August 2012|website=the Guardian}}</ref>

===Spontaneous mutation===

''Spontaneous mutations'' occur with non-zero probability even given a healthy, uncontaminated cell. They can be characterized by the specific change:<ref>{{cite web |url=http://www-personal.ksu.edu/~bethmont/mutdes.html#origins |title=Mutation, Mutagens, and DNA Repair |last=Montelone |first=Beth A. |name-list-format=vanc |year=1998 |website=www-personal.ksu.edu |accessdate=2015-10-02 |url-status=live |archiveurl=https://web.archive.org/web/20150926115801/http://www-personal.ksu.edu/~bethmont/mutdes.html#origins |archivedate=26 September 2015 |df=dmy-all }}</ref>

* [[Tautomer]]ism — A base is changed by the repositioning of a [[hydrogen]] atom, altering the hydrogen bonding pattern of that base, resulting in incorrect [[base pair]]ing during replication.
* [[Depurination]] — Loss of a [[purine]] base (A or G) to form an apurinic site ([[AP site]]).
* [[Deamination]] — [[Hydrolysis]] changes a normal base to an atypical base containing a [[Ketone|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 DNA base.
* [[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.
* [[Replication slippage]]

===Error-prone replication bypass===

There is increasing evidence that the majority of spontaneously arising mutations are due to error-prone replication ([[translesion synthesis]]) past DNA damage in the template strand. Naturally occurring oxidative 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 [[rat]]s.{{Citation needed|date=December 2019|reason=removed citation attributable to predatory publisher}} In [[mouse|mice]], the majority of mutations are caused by translesion synthesis.<ref>{{cite journal | vauthors = Stuart GR, Oda Y, de Boer JG, Glickman BW | title = Mutation frequency and specificity with age in liver, bladder and brain of lacI transgenic mice | journal = Genetics | volume = 154 | issue = 3 | pages = 1291–300 | date = March 2000 | pmid = 10757770 | pmc = 1460990 }}</ref> Likewise, in [[yeast]], Kunz et al.<ref>{{cite journal | vauthors = Kunz BA, Ramachandran K, Vonarx EJ | title = DNA sequence analysis of spontaneous mutagenesis in Saccharomyces cerevisiae | journal = Genetics | volume = 148 | issue = 4 | pages = 1491–505 | date = April 1998 | pmid = 9560369 | pmc = 1460101 }}</ref> found that more than 60% of the spontaneous single base pair substitutions and deletions were caused by translesion synthesis.

=== Errors introduced during DNA repair ===
{{See also|DNA damage (naturally occurring)|DNA repair}}
Although naturally occurring double-strand breaks occur at a relatively low frequency in DNA, their repair often causes mutation. [[Non-homologous end joining]] (NHEJ) is a major pathway for repairing double-strand breaks. NHEJ involves removal of a few [[nucleotide]]s 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.<ref>{{cite journal | vauthors = Lieber MR | title = The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway | journal = Annual Review of Biochemistry | volume = 79 | pages = 181–211 | date = July 2010 | pmid = 20192759 | pmc = 3079308 | doi = 10.1146/annurev.biochem.052308.093131 }}</ref>
[[File:Benzopyrene DNA adduct 1JDG.png|thumb|right|250px|A [[covalent]] [[adduct]] between the [[(+)-Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide|metabolite]] of [[Benzo(a)pyrene|benzo[''a'']pyrene]], the major [[mutagen]] in [[tobacco smoking|tobacco smoke]], and DNA<ref>Created from [http://www.rcsb.org/pdb/explore/explore.do?pdbId=1JDG PDB 1JDG] {{webarchive|url=https://web.archive.org/web/20151231235020/http://www.rcsb.org/pdb/explore/explore.do?pdbId=1JDG |date=31 December 2015 }}</ref>]]

=== Induced mutation ===

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:
* Chemicals
**[[Hydroxylamine]]
** [[Base analog]]s (e.g., [[Bromodeoxyuridine]] (BrdU))
** [[Alkylation|Alkylating agent]]s (e.g., [[ENU|''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 [[transition (genetics)|transition]]s, [[transversion]]s, or deletions.
**Agents that form [[DNA adduct]]s (e.g., [[ochratoxin A]])<ref>{{cite journal | vauthors = Pfohl-Leszkowicz A, Manderville RA | title = Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans | journal = Molecular Nutrition & Food Research | volume = 51 | issue = 1 | pages = 61–99 | date = January 2007 | pmid = 17195275 | doi = 10.1002/mnfr.200600137 }}</ref>
** DNA [[Intercalation (biochemistry)|intercalating]] agents (e.g., [[ethidium bromide]])
** [[Crosslinking of DNA|DNA crosslinkers]]
**[[File:Gene structure eukaryote 2 annotated.svg|thumb|242x242px|The transcriptional processes of splicing and translation of a eukaryotic gene]][[Oxidative stress|Oxidative damage]]
** [[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.
* Radiation
** [[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 [[DNA oxidation|oxidative damage to DNA]].<ref name="Kozmin">{{cite journal | vauthors = Kozmin S, Slezak G, Reynaud-Angelin A, Elie C, de Rycke Y, Boiteux S, Sage E | title = UVA radiation is highly mutagenic in cells that are unable to repair 7,8-dihydro-8-oxoguanine in Saccharomyces cerevisiae | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 38 | pages = 13538–43 | date = September 2005 | pmid = 16157879 | pmc = 1224634 | doi = 10.1073/pnas.0504497102 | bibcode = 2005PNAS..10213538K }}</ref>
** [[Ionizing radiation]]. Exposure to ionizing radiation, such as [[Gamma ray|gamma radiation]], can result in mutation, possibly resulting in cancer or death.

Whereas in former times mutations were assumed to occur by chance, or induced by mutagens, molecular mechanisms of mutation have been discovered in bacteria and across the tree of life. As S. Rosenberg states, "These mechanisms reveal a picture of highly regulated mutagenesis, up-regulated temporally by stress responses and activated when cells/organisms are maladapted to their environments—when stressed—potentially accelerating adaptation." <ref name=":5">{{cite journal | vauthors = Fitzgerald DM, Rosenberg SM | title = What is mutation? A chapter in the series: How microbes "jeopardize" the modern synthesis | journal = PLOS Genetics | volume = 15 | issue = 4 | pages = e1007995 | date = April 2019 | pmid = 30933985 | doi = 10.1371/journal.pgen.1007995 | pmc = 6443146 }}</ref> Since they are self-induced mutagenic mechanisms that increase the adaptation rate of organisms, they have some times been named as adaptive mutagenesis mechanisms, and include the SOS response in bacteria,<ref>{{cite journal | vauthors = Galhardo RS, Hastings PJ, Rosenberg SM | title = Mutation as a stress response and the regulation of evolvability | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 42 | issue = 5 | pages = 399–435 | date = 2007-01-01 | pmid = 17917874 | pmc = 3319127 | doi = 10.1080/10409230701648502 }}</ref> ectopic intrachromosomal recombination <ref>{{cite journal | vauthors = Quinto-Alemany D, Canerina-Amaro A, Hernández-Abad LG, Machín F, Romesberg FE, Gil-Lamaignere C | title = Yeasts acquire resistance secondary to antifungal drug treatment by adaptive mutagenesis | journal = PLOS One | volume = 7 | issue = 7 | pages = e42279 | date = 2012-07-31 | pmid = 22860105 | doi = 10.1371/journal.pone.0042279 | editor-first = Joy | editor-last = Sturtevant | pmc = 3409178 | bibcode = 2012PLoSO...742279Q }}</ref> and other chromosomal events such as duplications.<ref name=":5" />

== Classification by effect on structure ==
[[File:Chromosomes mutations-en.svg|thumb|right|301px|Five types of chromosomal mutations]]
[[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 sequence of a gene can be altered in a number of ways.<ref>{{cite web |last1=Rahman|first1=Nazneen|title=The clinical impact of DNA sequence changes|url=http://www.thetgmi.org/genetics/clinical-impact-dna-sequence-changes/|website=Transforming Genetic Medicine Initiative|accessdate=June 27, 2017|url-status=live|archiveurl=https://web.archive.org/web/20170804060005/http://www.thetgmi.org/genetics/clinical-impact-dna-sequence-changes/|archivedate=4 August 2017|df=dmy-all}}</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.

===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.
* 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 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 [[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:

==== Indel ====

*[[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]] or/Deficiency 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 mutations ====

*[[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 | 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 | authorlink = Ernst Freese | bibcode = 1959PNAS...45..622F | title = The Difference Between Spontaneous and Base-Analogue Induced Mutations of Phage T4 }}</ref> These changes are classified as transitions or transversions.<ref>{{cite journal |last=Freese |first=Ernst | name-list-format = vanc | 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 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). 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]].

==Functional effect==
<br />
=== Classifying by changes to mRNA translation ===
Mutations that occur in [[Coding region|coding regions]] of the genome can be categorized by their effect on mRNA translation.

'''[[Indel]] mutations:'''

*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 (biology)|translation]] from the original.<ref>{{cite encyclopedia|last=Hogan|first=C. Michael|editor-last=Monosson|editor-first=Emily|encyclopedia=[[Encyclopedia of Earth]]|title=Mutation|url=http://www.eoearth.org/view/article/159530/|accessdate=2015-10-08|date=October 12, 2010|publisher=Environmental Information Coalition, [[National Council for Science and the Environment]]|location=Washington, D.C.|oclc=72808636|url-status=live|archiveurl=https://web.archive.org/web/20151114055631/http://www.eoearth.org/view/article/159530/|archivedate=14 November 2015|df=dmy-all}}</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,'' <u>'''''and results only in changes in the amino acids that are coded for'''''</u>.

==== Substitution mutations: ====
[[File:Point mutations-en 4-17.png|thumb|451x451px|Illustration of different types of point 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 '''missense''' or '''nonsense''' 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|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 mutations, such as [[congenital adrenal hyperplasia]]. (See [[Stop codon]].)
***nonsense mutations can also be caused by non-point mutations - for example, an insertion or deletion mutation.

<br />
=== Effect on gene function ===
{{See also|Muller's morphs}}

*'''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 the [[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]]).
**An [[amorph (gene)|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.
*'''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 gain of function, including hypermorph (increased gene expression) 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 viruses."<ref>{{Cite news|url=https://www.usnews.com/news/news/articles/2017-12-19/us-lifts-funding-ban-on-studies-that-enhance-dangerous-germs|title=U.S. Lifts Funding Ban on Studies That Enhance Dangerous Germs|last=Steenhuysen|first=Julie|date=2017-12-19|work=U.S. News & World Report|access-date=2018-01-15}}</ref>
* Dominant negative mutations (also called [[Muller's morphs#Antimorph|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 [[Dominance (genetics)#Incomplete dominance|semi-dominant]] phenotype. In humans, dominant negative mutations have been implicated in cancer (e.g., mutations in genes [[p53]],<ref>{{cite journal | vauthors = Goh AM, Coffill CR, Lane DP | title = The role of mutant p53 in human cancer | journal = The Journal of Pathology | volume = 223 | issue = 2 | pages = 116–26 | date = January 2011 | pmid = 21125670 | doi = 10.1002/path.2784 | authorlink3 = David Lane (oncologist) }}</ref> [[Ataxia telangiectasia mutated|ATM]],<ref>{{cite journal | vauthors = Chenevix-Trench G, Spurdle AB, Gatei M, Kelly H, Marsh A, Chen X, Donn K, Cummings M, Nyholt D, Jenkins MA, Scott C, Pupo GM, Dörk T, Bendix R, Kirk J, Tucker K, McCredie MR, Hopper JL, Sambrook J, Mann GJ, Khanna KK | title = Dominant negative ATM mutations in breast cancer families | journal = Journal of the National Cancer Institute | volume = 94 | issue = 3 | pages = 205–15 | date = February 2002 | pmid = 11830610 | doi = 10.1093/jnci/94.3.205 | authorlink1 = Georgia Chenevix-Trench | citeseerx = 10.1.1.557.6394 }}</ref> [[CEBPA]]<ref>{{cite journal | vauthors = Paz-Priel I, Friedman A | title = C/EBPα dysregulation in AML and ALL | journal = Critical Reviews in Oncogenesis | volume = 16 | issue = 1–2 | pages = 93–102 | year = 2011 | pmid = 22150310 | pmc = 3243939 | doi = 10.1615/critrevoncog.v16.i1-2.90 | access-date = }}</ref> and [[Peroxisome proliferator-activated receptor gamma|PPARgamma]]<ref>{{cite journal | vauthors = Capaccio D, Ciccodicola A, Sabatino L, Casamassimi A, Pancione M, Fucci A, Febbraro A, Merlino A, Graziano G, Colantuoni V | title = A novel germline mutation in peroxisome proliferator-activated receptor gamma gene associated with large intestine polyp formation and dyslipidemia | journal = Biochimica et Biophysica Acta | volume = 1802 | issue = 6 | pages = 572–81 | date = June 2010 | pmid = 20123124 | doi = 10.1016/j.bbadis.2010.01.012 | access-date = }}</ref>). [[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]].<ref>{{cite journal | vauthors = McKusick VA | title = The defect in Marfan syndrome | journal = Nature | volume = 352 | issue = 6333 | pages = 279–81 | date = July 1991 | pmid = 1852198 | doi = 10.1038/352279a0 | bibcode = 1991Natur.352..279M | authorlink = Victor A. McKusick }}</ref> Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency.<ref>{{cite journal | vauthors = Judge DP, Biery NJ, Keene DR, Geubtner J, Myers L, Huso DL, Sakai LY, Dietz HC | title = Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome | journal = The Journal of Clinical Investigation | volume = 114 | issue = 2 | pages = 172–81 | date = July 2004 | pmid = 15254584 | pmc = 449744 | doi = 10.1172/JCI20641 }}</ref><ref>{{cite journal | vauthors = Judge DP, Dietz HC | title = Marfan's syndrome | journal = Lancet | volume = 366 | issue = 9501 | pages = 1965–76 | date = December 2005 | pmid = 16325700 | pmc = 1513064 | doi = 10.1016/S0140-6736(05)67789-6 }}</ref>
*[[Hypomorph]]s, after Mullerian classification, are characterized by altered gene products that acts with decreased [[gene expression]] compared to the [[wild type]] allele. Usually, hypomorphic mutations are recessive, but haploinsufficiency causes some alleles to be dominant.
*[[Neomorph]]s are characterized by the control of new [[protein]] product synthesis.
*[[Lethal allele|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.<ref>{{cite journal | vauthors = Ellis NA, Ciocci S, German J | 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>

<br />

==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 organism.
* A beneficial, or advantageous mutation increases the fitness of the organism.
* 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]],<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 | pmid = 8601499 | pmc = 1206892 | authorlink1 = Deborah Charlesworth | authorlink2 = 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 }}</ref> the maintenance of [[outcrossing]] [[sexual reproduction]] as opposed to [[inbreeding]]<ref>{{Cite book | vauthors = Bernstein H, Hopf FA, Michod RE | title = The molecular basis of the evolution of sex | journal = 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 | 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 | authors = 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 | authorlink2 = Michael Lynch (geneticist) }}</ref><ref>{{cite journal | vauthors = Barton NH, Keightley PD | 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 | authorlink1 = 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 }}</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 | 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 | authorlink5 = 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 }}</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|sequence data 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" />]]

* 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 | title = Bayesian analysis suggests that most amino acid replacements in Drosophila are driven by positive selection | journal = Journal of Molecular Evolution | volume = 57 Suppl 1 | issue = 1 | pages = S154–64 | date = August 2003 | pmid = 15008412 | doi = 10.1007/s00239-003-0022-3 | authorlink3 = 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 }}</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>{{cite journal | vauthors = Kimura M | 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 | authorlink = Motoo Kimura | bibcode = 1968Natur.217..624K }}</ref><ref name=":4">{{cite book |last=Kimura |first=Motoo |authorlink=Motoo Kimura | name-list-format = vanc |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 |ref=harv|title-link=The Neutral Theory of Molecular Evolution }}</ref> Hiroshi Akashi more recently 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 }}</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 |last=Gillespie |first=John H. | name-list-format = vanc | authorlink = 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 | pmid = 12702694 | pmc = 1462510 | authorlink = 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 | 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 | 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 }}</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===
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 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 |accessdate=2015-10-09 |date=June 14, 2012 |publisher=[[WebMD]] |location=New York |url-status=live |archiveurl=https://web.archive.org/web/20160304123903/http://www.medicinenet.com/script/main/art.asp?articlekey=33675 |archivedate=4 March 2016 |df=dmy-all }}</ref>
A [[wild type]] or homozygous non-mutated organism is one in which neither allele is mutated.

===Special classes===

*'''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|last=Alberts|publisher=Garland Science|year=2014|isbn=9780815344322|edition=6|location=|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=":0">{{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 = 2015-07-01 | pmid = 26281767 | doi = 10.1016/j.mrrev.2015.06.001 }}</ref> The permissive conditions may be [[Permissive temperature|temperature]],<ref name=":1">{{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 | pmid = 11454765 | url = http://www.genetics.org/content/158/3/1167 | pmc = 1461716 | url-status = live | archiveurl = https://web.archive.org/web/20170322014758/http://www.genetics.org/content/158/3/1167 | archivedate = 22 March 2017 | df = dmy-all }}</ref> certain chemicals,<ref name=":2">{{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 | doi = 10.1101/pdb.top069807 | pmc=4142476}}</ref> light<ref name=":2" /> or mutations in other parts of the [[genome]].<ref name=":0" /> [[In vivo|''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=":2" /> DNA Recombinase systems like [[Cre-Lox recombination|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=":2" /> 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 | doi = 10.1534/genetics.109.104794 | pmc=2746138}}</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=":1" />
*'''[[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 | authorlink2 = Stylianos Antonarakis }}</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.

==Inheritance, or, germline vs somatic cells==
[[File:Portulaca grandiflora mutant1.jpg|thumb|right|A mutation has caused this [[Portulaca grandiflora|moss rose]] plant to produce flowers of different colors. 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" /> which involve cells outside the dedicated reproductive group and which are not usually transmitted to descendants.

=== Germline ===
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.<ref>{{cite web|url=http://www.daisyfund.org/rb/about/genetics.html|title=''RB1'' Genetics|website=Daisy's Eye Cancer Fund|location=Oxford, UK|archiveurl=https://web.archive.org/web/20111126004753/http://www.daisyfund.org/rb/about/genetics.html|archivedate=2011-11-26|accessdate=2015-10-09}}</ref>

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 '''''[[wiktionary:de novo|de novo]]'' mutation'''.

=== Somatic ===
{{see also|Carcinogenesis|Loss of heterozygosity}}
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 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 cancer.''<ref>{{Cite news|url=https://www.britannica.com/science/somatic-mutation|title=somatic mutation {{!}} genetics|access-date=2017-03-31|url-status=live|archiveurl=https://web.archive.org/web/20170331122201/https://www.britannica.com/science/somatic-mutation|archivedate=31 March 2017|encyclopedia=Encyclopædia Britannica|df=dmy-all}}</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 name=":3">{{cite book|last=Hartl, Jones|first=Daniel L., Elizabeth W.|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|year=2017|title=Differences between germline and somatic mutation rates in humans and mice|journal=Nat Commun|volume=8|issue=|pages=15183|bibcode=2017NatCo...815183M|doi=10.1038/ncomms15183|pmc=5436103|pmid=28485371}}</ref>

==Disease causation==
Changes in DNA caused by mutation in a coding region of DNA can cause errors in protein sequence that may result in 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 DNA base sequence but do not change the function of the protein made by the gene. One study on the comparison of genes between different species of ''Drosophila'' suggests that if a mutation does change a protein, the mutation will most likely be harmful, with an estimated 70 percent of amino acid polymorphisms having damaging effects, and the remainder being either neutral or weakly beneficial.<ref name="Sawyer2007" /> However, studies have shown that only 7% of point mutations in noncoding DNA of yeast are deleterious and 12% in coding DNA are deleterious. The rest of the mutations are either neutral or slightly beneficial.<ref>{{cite journal | vauthors = Doniger SW, Kim HS, Swain D, Corcuera D, Williams M, Yang SP, Fay JC | title = A catalog of neutral and deleterious polymorphism in yeast | journal = PLOS Genetics | volume = 4 | issue = 8 | pages = e1000183 | date = August 2008 | pmid = 18769710 | pmc = 2515631 | doi = 10.1371/journal.pgen.1000183 | editor-first = Jonathan K. | last7 = Fay | editor-link = Jonathan K. Pritchard | author6 = Shiaw-Pyng Yang | first7 = Justin C. | editor-last = Pritchard | name-list-format = vanc}}</ref>

=== Inherited disorders ===
{{See also|Genetic disorder}}
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 [[DNA repair-deficiency 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.

A 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 DNA repair 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.

=== Role in carcinogenesis ===
{{See also|Carcinogenesis}}
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.<ref>{{cite journal|vauthors=Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M|date=June 1993|title=Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis|journal=Nature|volume=363|issue=6429|pages=558–61|bibcode=1993Natur.363..558I|doi=10.1038/363558a0|pmid=8505985}}</ref>

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 often 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.<ref>{{cite journal|author3=Rong H. Zhang|vauthors=Araten DJ, Golde DW, Zhang RH, Thaler HT, Gargiulo L, Notaro R, Luzzatto L|date=September 2005|title=A quantitative measurement of the human somatic mutation rate|journal=Cancer Research|volume=65|issue=18|pages=8111–7|doi=10.1158/0008-5472.CAN-04-1198|pmid=16166284}}</ref>

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 [[ultraviolet light|UV rays]], [[X-ray]]s 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

==Mutation rates==
{{Further|Mutation rate}}
[[Mutation rate]]s vary substantially across species, and the evolutionary forces that generally determine mutation are the subject of ongoing investigation.

The genomes of [[RNA virus]]es 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 [[HIV|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.

==Examples in humans/Beneficial mutations==
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 natural selection. Examples include the following:

'''HIV resistance''': a specific 32 base pair deletion in human [[CCR5]] ([[CCR5#CCR5-.CE.9432|CCR5-Δ32]]) confers [[HIV]] resistance to [[Zygosity|homozygotes]] and delays [[AIDS]] onset in heterozygotes.<ref>{{cite journal | vauthors = Sullivan AD, Wigginton J, Kirschner D | title = The coreceptor mutation CCR5Delta32 influences the dynamics of HIV epidemics and is selected for by HIV | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 18 | pages = 10214–9 | date = August 2001 | pmid = 11517319 | pmc = 56941 | doi = 10.1073/pnas.181325198 | bibcode = 2001PNAS...9810214S }}</ref> One possible explanation of the [[etiology]] of the relatively high frequency of CCR5-Δ32 in the [[Ethnic groups in Europe|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.<ref>{{cite episode |title=Mystery of the Black Death |url=https://www.pbs.org/wnet/secrets/mystery-black-death-background/1488/ |accessdate=2015-10-10 |series=[[Secrets of the Dead]] |network=[[PBS]] |date=October 30, 2002 |season=3 |number=2 |url-status=live |archiveurl=https://web.archive.org/web/20151012175528/http://www.pbs.org/wnet/secrets/mystery-black-death-background/1488/ |archivedate=12 October 2015 |df=dmy-all }} Episode background.</ref> 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 [[Evolutionary pressure|selective pressure]] on the CCR5 Delta 32 mutation was caused by [[smallpox]] instead of the bubonic plague.<ref>{{cite journal | vauthors = Galvani AP, Slatkin M | title = Evaluating plague and smallpox as historical selective pressures for the CCR5-Delta 32 HIV-resistance allele | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 25 | pages = 15276–9 | date = December 2003 | pmid = 14645720 | pmc = 299980 | doi = 10.1073/pnas.2435085100 | bibcode = 2003PNAS..10015276G | authorlink2 = Montgomery Slatkin }}</ref>

'''Malaria resistance''': 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 cell]]s. One-third of all [[Indigenous peoples|indigenous]] inhabitants of [[Sub-Saharan Africa]] carry the allele, because, in areas where [[malaria]] is common, there is a [[Evolution|survival value]] in carrying only a single sickle-cell allele ([[sickle cell trait]]).<ref>{{cite web |url=http://sicklecell.md/faq.asp |title=Frequently Asked Questions [FAQ's] |last=Konotey-Ahulu |first=Felix |website=sicklecell.md |url-status=live |archiveurl=https://web.archive.org/web/20110430031852/http://sicklecell.md/faq.asp |archivedate=30 April 2011 |df=dmy-all }}</ref> 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.

'''Antibiotic resistance''': Practically all bacteria develop antibiotic resistance when exposed to antibiotics. In fact, bacterial populations already have such mutations that get selected under antibiotic selection.<ref>{{cite journal | vauthors = Hughes D, Andersson DI | title = Evolutionary Trajectories to Antibiotic Resistance | journal = Annual Review of Microbiology | volume = 71 | pages = 579–596 | date = September 2017 | pmid = 28697667 | doi = 10.1146/annurev-micro-090816-093813 }}</ref> Obviously, such mutations are only beneficial for the bacteria but not for those infected.

'''[[Lactase persistence]]'''. A mutation allowed humans to express the enzyme [[lactase]] after they are naturally weaned from breast milk, allowing adults to digest [[lactose]], which is likely one of the most beneficial mutations in recent [[human evolution]].<ref>{{cite journal | vauthors = Ségurel L, Bon C | title = On the Evolution of Lactase Persistence in Humans | journal = Annual Review of Genomics and Human Genetics | volume = 18 | pages = 297–319 | date = August 2017 | pmid = 28426286 | doi = 10.1146/annurev-genom-091416-035340 }}</ref>

==Prion mutations==

[[Prion]]s 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.<ref>{{cite news |author=<!--Staff writer(s); no by-line.--> |title='Lifeless' prion proteins are 'capable of evolution' |url=http://news.bbc.co.uk/2/hi/health/8435320.stm |department=Health |work=[[BBC News Online]] |location=London |date=January 1, 2010 |accessdate=2015-10-10 |url-status=live |archiveurl=https://web.archive.org/web/20150925132138/http://news.bbc.co.uk/2/hi/health/8435320.stm |archivedate=25 September 2015 |df=dmy-all }}</ref> The human gene [[PRNP]] codes for the major prion protein, PrP, and is subject to mutations that can give rise to disease-causing prions.

<br />

== Evolution ==


section. what to include?
<br />
== History ==
{{main|Mutationism}}
[[File:Hugo de Vries (1848-1935), by Thérèse Schwartze (1851-1918).jpg|thumb|Dutch botanist [[Hugo de Vries]] making a painting of an [[Oenothera|evening primrose]], the plant which had apparently [[Mutationism|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 [[speciation|new species]], potentially instantaneously,<ref name="BowlerEclipse">{{cite book|author=Bowler, Peter J.|title=The Eclipse of Darwinism|date=1992|page=198|authorlink=Peter J. Bowler|origyear=1983}}</ref> in a sudden jump.<ref>{{cite book|last=Smocovitis|first=Vassiliki Betty|title=Unifying Biology: The Evolutionary Synthesis and Evolutionary Biology|journal=Journal of the History of Biology|publisher=Princeton University Press|year=1996|isbn=978-0-691-03343-3|volume=25|location=Princeton, NJ|p=56|doi=10.1007/bf01947504|lccn=96005605|oclc=34411399|pmid=11623198|issue=1}}</ref> This was envisaged as driving evolution, which was limited by the supply of mutations.

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.<ref>{{cite book|author1=Hallgrímsson, Benedikt|title=Variation: A Central Concept in Biology|author2=Hall, Brian K.|publisher=Academic Press|year=2011|page=18}}</ref> Darwin opposed saltation, insisting on [[phyletic gradualism|gradualism]] in evolution as [[uniformitarianism|in geology]]. In 1864, [[Albert von Kölliker]] revived Geoffroy's theory.<ref>[[Sewall Wright]]. (1984). ''Evolution and the Genetics of Populations: Genetics and Biometric Foundations Volume 1''. University of Chicago Press. p. 10</ref> In 1901 the [[genetics|geneticist]] [[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'',<ref name="DeVries1905">{{cite book|author=De Vries, Hugo|url=https://archive.org/details/speciesvarieties1904vrie|title=Species and Varieties: Their Origin by Mutation|year=1905|authorlink=Hugo de Vries}}</ref><ref name="BowlerEclipse" /> became a rival to Darwinism supported for a while by geneticists including [[William Bateson]],<ref name="Bateson1894">{{cite book|author=Bateson, William|url=https://archive.org/details/materialsforstu01bategoog|title=Materials for the Study of Variation, Treated with Especial Regard to Discontinuity in the Origin of Species|year=1894|authorlink=William Bateson}}</ref> [[Thomas Hunt Morgan]], and [[Reginald Punnett]].<ref>{{cite book|last1=Punnett|first1=Reginald C.|url=https://archive.org/details/in.ernet.dli.2015.32128|title=Mimicry in Butterflies|date=1915|publisher=Cambridge University Press|authorlink1=Reginald Punnett}}</ref><ref name="BowlerEclipse" />

Understanding of mutationism is clouded by the mid-20th century portrayal of the early mutationists by supporters of the [[Modern synthesis (20th century)|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]].<ref>{{cite book|author=Mayr, Ernst|title=What Makes Biology Unique?: Considerations on the Autonomy of a Scientific Discipline|publisher=Cambridge University Press|year=2007|authorlink=Ernst Mayr}}</ref><ref name="Provine2001">{{cite book|last=Provine|first=W. B.|title=The Origins of Theoretical Population Genetics, with a new afterword|publisher=University of Chicago Press, Chicago|year=2001|pages=56–107}}</ref><ref name="Stoltzfus_Cable_2014">{{cite journal|author1=Stoltzfus, A.|author2=Cable, K.|year=2014|title=Mendelian-Mutationism: The Forgotten Evolutionary Synthesis|journal=J Hist Biol|volume=47|issue=4|pages=501–546|doi=10.1007/s10739-014-9383-2|pmid=24811736}}</ref><ref name="Hull_1985">{{cite book|last=Hull|first=D. L.|title=The Darwinian Heritage|publisher=Princeton University Press|year=1985|editor-last=Kohn|editor-first=D.|pages=[https://archive.org/details/darwinianheritag00davi/page/773 773–812]|chapter=Darwinism as an historical entity: A historiographic proposal|chapter-url=https://archive.org/details/darwinianheritag00davi|chapter-url-access=registration}}</ref> However, the alignment of Mendelian genetics and natural selection began as early as 1902 with a paper by [[Udny Yule]],<ref>{{Cite journal|last1=Yule|first1=G. Udny|authorlink=Udny Yule|date=1902|title=Mendel's Laws and their probable relations to inter-racial heredity|journal=New Phytologist|volume=1|issue=10|pages=226–227|doi=10.1111/j.1469-8137.1902.tb07336.x}}</ref> 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.<ref name="Provine2001" /><ref name="Stoltzfus_Cable_2014" />

Mutationism, along with other alternatives to Darwinism like [[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.<ref name="Gould1982">Gould, S. J. (1982). "The uses of heresey; an introduction to Richard Goldschmidt's ''The Material Basis of Evolution''." [https://books.google.com/books?id=kAPLvAnp7KAC&lpg=PP1&pg=PR13 pp. xiii-xlii]. Yale University Press.</ref><ref>{{cite book|last=Ruse|first=Michael|url=https://archive.org/details/monadtomanconcep0000ruse|title=Monad to man: the Concept of Progress in Evolutionary Biology|date=1996|publisher=Harvard University Press|isbn=978-0-674-03248-4|pages=[https://archive.org/details/monadtomanconcep0000ruse/page/412 412–413]|authorlink=Michael Ruse|url-access=registration}}</ref> In 1987, [[Masatoshi Nei]] argued controversially that evolution was often mutation-limited.<ref name="Stoltzfus_on_Nei2014">{{Cite journal|author=A. Stoltzfus|year=2014|title=In search of mutation-driven evolution|journal=Evolution & Development|volume=16|pages=57–59|doi=10.1111/ede.12062}}</ref> Modern biologists such as [[Douglas J. Futuyma]] conclude that essentially all claims of evolution driven by large mutations can be explained by Darwinian evolution.<ref name="Futuyma">{{cite book|last1=Futuyma|first1=Douglas J.|url=https://www.springer.com/cda/content/document/cda_downloaddocument/9783319150444-c2.pdf?SGWID=0-0-45-1494358-p177219674|title=Can Modern Evolutionary Theory Explain Macroevolution?|date=2015|work=Macroevolution|publisher=Springer|editor1-last=Serrelli|editor1-first=E.|pages=29–85|authorlink1=Douglas J. Futuyma|editor2-last=Gontier|editor2-first=N.}}</ref>

==See also==
{{Columns-list|* [[Aneuploidy]]
* [[Antioxidant]]
* [[Budgerigar colour genetics]]
* [[Deletion (genetics)]]
* [[Ecogenetics]]
* [[Embryology]]
* [[Homeobox]]
* [[Polyploid]]y
* [[Robertsonian translocation]]
* [[Signature-tagged mutagenesis]]
* [[Somatic hypermutation]]
* [[TILLING (molecular biology)]]
* [[Trinucleotide repeat expansion]]
* [[Human somatic variations]]|colwidth=30em}}

== References ==
{{Reflist|30em}}

==External links==
{{Commons category|Mutations}}
*{{cite episode |title=Genetic Mutation |url=http://www.bbc.co.uk/programmes/b008drvm |accessdate=2015-10-18 |series=[[In Our Time (radio series)|In Our Time]] |first1=Steve |last1=Jones |authorlink=Steve Jones (biologist) |first2=Adrian |last2=Woolfson |first3=Linda |last3=Partridge | name-list-format = vanc |authorlink3=Linda Partridge |network=[[BBC Radio 4]] |date=December 6, 2007}}
*{{cite web |url=https://web.stanford.edu/group/hopes/cgi-bin/hopes_test/all-about-mutations/ |title=All About Mutations |last=Liou |first=Stephanie |date=February 5, 2011 |website=HOPES |publisher=[[Huntington's Disease Outreach Project for Education at Stanford]] |accessdate=2015-10-18}}
*{{cite web |url=http://grenada.lumc.nl/LSDB_list/lsdbs/AR |title=Locus Specific Mutation Databases |publisher=[[Leiden University Medical Center]] |location=Leiden, the Netherlands |accessdate=2015-10-18}}
*{{cite web |url=https://mutalyzer.nl/ |title=Welcome to the Mutalyzer website |publisher=Leiden University Medical Center |location=Leiden, the Netherlands |accessdate=2015-10-18}} — The [[Mutalyzer]] website.

{{Mutation}}
{{Chromosomal abnormalities}}
{{Evolution}}
{{Portal bar|Biology|Medicine|Evolutionary biology}}
{{Use dmy dates|date=July 2011}}

[[Category:Mutation| ]]
[[Category:Evolutionary biology]]
[[Category:Radiation health effects]]
[[Category:Molecular evolution]]

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