View source for Biology:Mutation

{{Short description|Alteration in the nucleotide sequence of a genome}}
{{Genetics sidebar}}
[[File:Darwin Hybrid Tulip Mutation 2014-05-01.jpg|thumb|A red [[Biology:Tulip|tulip]] exhibiting a partially yellow petal due to a mutation in its genes]]
[[File:RagwurzDoppelblueteH1b.jpg|thumb|Mutation with double bloom in the Langheck Nature Reserve near Nittel, Germany]]
In [[Biology:Biology|biology]], a '''mutation''' is an alteration in the [[Biology:Nucleic acid sequence|nucleic acid sequence]] of the [[Biology:Genome|genome]] of an organism, [[Biology:Virus|virus]], or [[Biology:Extrachromosomal DNA|extrachromosomal DNA]].<ref>{{Cite web|publisher=Nature Education |url= https://www.nature.com/scitable/definition/mutation-8|title=mutation {{!}} Learn Science at Scitable|website=Nature|language=en|access-date=24 September 2018}}</ref> Viral genomes contain either [[Biology:DNA|DNA]] or [[Biology:RNA|RNA]]. Mutations result from errors during [[Biology:DNA replication|DNA]] or [[Biology:Viral replication|viral replication]], [[Biology:Mitosis|mitosis]], or [[Biology:Meiosis|meiosis]] or other types of [[Biology:DNA repair#DNA damage|damage]] to DNA (such as [[Biology:Pyrimidine dimer|pyrimidine dimer]]s caused by exposure to [[Physics:Ultraviolet|ultraviolet]] radiation), which then may undergo error-prone repair (especially [[Biology:Microhomology-mediated end joining|microhomology-mediated end joining]]),<ref>{{cite journal | vauthors = Sfeir A, Symington LS | title = Microhomology-Mediated End Joining: A Back-up Survival Mechanism or Dedicated Pathway? | journal = Trends in Biochemical Sciences | volume = 40 | issue = 11 | pages = 701–714 | date = November 2015 | pmid = 26439531 | pmc = 4638128 | doi = 10.1016/j.tibs.2015.08.006 }}</ref> 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 | pages = e02001 | date = April 2014 | pmid = 24843013 | pmc = 3999860 | doi = 10.7554/elife.02001 | doi-access = free }}</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 cause an error during replication ([[Biology:DNA repair#Translesion synthesis|translesion synthesis]]). Mutations may also result from [[Biology:Insertion (genetics)|insertion]] or [[Biology:Deletion (genetics)|deletion]] of segments of DNA due to [[Biology:Mobile genetic elements|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 | s2cid = 24155688 }}</ref><ref name="transposition764">{{cite journal | vauthors = Aminetzach YT, Macpherson JM, Petrov DA | s2cid = 11640993 | 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 | doi-access = free }}</ref>

Mutations may or may not produce detectable changes in the observable characteristics ([[Biology:Phenotype|phenotype]]) of an organism. Mutations play a part in both normal and abnormal biological processes including: [[Biology:Evolution|evolution]], [[Medicine:Cancer|cancer]], and the development of the [[Biology:Immune system|immune system]], including [[Biology:Junctional diversity|junctional diversity]]. Mutation is the ultimate source of all [[Biology:Genetic variation|genetic variation]], providing the raw material on which evolutionary forces such as [[Biology:Natural selection|natural selection]] can act.

Mutation can result in many different types of change in sequences. Mutations in [[Biology:Gene|gene]]s can have no effect, alter the [[Biology:Gene product|product of a gene]], or prevent the gene from functioning properly or completely. Mutations can also occur in non-genic regions. A 2007 study on [[Biology:Genetic variation|genetic variation]]s between different [[Biology:Species|species]] of ''[[Biology:Drosophila|Drosophila]]'' suggested that, if a mutation changes a [[Biology:Protein|protein]] produced by a gene, the result is likely to be harmful, with an estimated 70% of [[Chemistry:Amino acid|amino acid]] [[Biology:Polymorphism|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 | doi-access = free }}</ref> Due to the damaging effects that mutations can have on genes, organisms have mechanisms such as [[Biology:DNA repair|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 [[Biology:Gene duplication|duplication]] of large sections of DNA, usually through [[Biology:Genetic recombination|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 | author-link2 = 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 | vauthors = Carroll SB, Grenier JK, Weatherbee SD |author-link1=Sean B. Carroll |year=2005 |title=From DNA to Diversity: Molecular Genetics and the Evolution of Animal Design |edition=2nd |location=Malden, MA |publisher=[[Company:Wiley-Blackwell|Blackwell Publishing]] |isbn=978-1-4051-1950-4 |lccn=2003027991 |oclc=53972564}}</ref> Most genes belong to larger [[Biology:Gene family|gene families]] of shared ancestry, detectable by their [[Biology:Sequence homology|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 | author-link2 = 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 | author-link2 = 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 | s2cid = 33999892 }}</ref>

Here, [[Biology:Protein domain|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 |  doi-access = free }}</ref> For example, the [[Biology:Human eye|human eye]] uses four genes to make structures that sense light: three for [[Biology:Cone cell|cone cell]] or [[Color vision|color vision]] and one for [[Biology:Rod cell|rod cell]] or night vision; all four arose from a single ancestral gene.<ref>{{cite journal | vauthors = Bowmaker JK | s2cid = 12851209 | 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 | doi-access = free }}</ref> Another advantage of duplicating a gene (or even an entire genome) is that this increases [[Engineering: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 | s2cid = 16791399 | author-link1 = T. Ryan Gregory | author-link2 = Paul D. N. Hebert | doi-access = free }}</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 | doi-access = free }}</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 | author-link = Adam C. Siepel }}</ref>

Changes in [[Biology:Chromosome|chromosome]] number may involve even larger mutations, where segments of the DNA within chromosomes break and then rearrange. For example, in the [[Biology:Homininae|Homininae]], two chromosomes fused to produce human chromosome 2; this fusion did not occur in the [[Biology:Lineage (evolution)|lineage]] of the other [[Biology:Ape|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 [[Biology: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 | issue = Suppl 1 | pages = 6535–42 | date = May 2005 | pmid = 15851677 | pmc = 1131864 | doi = 10.1073/pnas.0501847102 | bibcode = 2005PNAS..102.6535A |  doi-access = free }}</ref>

Sequences of DNA that can move about the genome, such as [[Biology: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 | s2cid = 2715605 | 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 [[Biology:Alu element|Alu sequence]] are present in the [[Biology:Human genome|human genome]], and these sequences have now been recruited to perform functions such as regulating [[Biology:Gene expression|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 [[Biology:Gene pool|gene pool]] and increase the amount of genetic variation.<ref name="Eyre-Walker07">{{cite journal | vauthors = Eyre-Walker A, Keightley PD | s2cid = 10868777 | 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 |  url-status = dead | archive-url = https://web.archive.org/web/20160304195010/http://www.lifesci.sussex.ac.uk/home/Adam_Eyre-Walker/Website/Publications_files/EWNRG07.pdf | archive-date = 4 March 2016 | access-date = 6 September 2010 }}</ref> The abundance of some genetic changes within the gene pool can be reduced by [[Biology:Natural selection|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 [[Biology:Butterfly|butterfly]] may produce [[Biology:Offspring|offspring]] with new mutations. The majority of these mutations will have no effect; but one might change the [[Color|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.

[[Biology:Neutral mutation|Neutral mutation]]s are defined as mutations whose effects do not influence the [[Biology:Fitness|fitness]] of an individual. These can increase in frequency over time due to [[Biology:Genetic drift|genetic drift]]. It is believed that the overwhelming majority of mutations have no significant effect on an organism's fitness.<ref name="Kimura-1983" /><ref>{{cite book | url = https://books.google.com/books?id=ybeLBgAAQBAJ&q=t+is+believed+that+the+overwhelming+majority+of+mutations+have+no+significant+effect+on+an+organism's+fitness.&pg=PA299 | title = Fundamentals of Polymer Physics and Molecular Biophysics | vauthors = Bohidar HB | date = January 2015 | publisher = Cambridge University Press | isbn = 978-1-316-09302-3 }}</ref> 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 [[Biology:Somatic cell|somatic cell]]s.

Beneficial mutations can improve reproductive success.<ref>{{Cite book|url=https://books.google.com/books?id=sElrZSzoLYMC&pg=PA107|title=Dear Mr. Darwin: Letters on the Evolution of Life and Human Nature| vauthors = Dover GA, Darwin C |date=2000|publisher=University of California Press|isbn=9780520227903|language=en}}</ref><ref>{{Cite book|url=https://books.google.com/books?id=OwBQCwAAQBAJ&pg=PA108|title=Genetics and Evolution of Infectious Diseases| vauthors = Tibayrenc M | date=12 January 2017|publisher=Elsevier|isbn=9780128001530|language=en}}</ref>

==Causes==
{{main|Biology:Mutagenesis}}
Four classes of mutations are (1) spontaneous mutations (molecular decay), (2) mutations due to error-prone replication bypass of [[Biology: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 [[Physics:Mutagen|mutagen]]s. Scientists may also deliberately introduce [[Biology:Mutant|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 news|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|newspaper=NPR.org|url-status=live|archive-url=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|archive-date=13 July 2017}}</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 | vauthors = Jha A |date=22 August 2012|website=The Guardian}}</ref>

===Spontaneous mutation===

''Spontaneous mutations'' occur with non-zero probability even given a healthy, uncontaminated cell. Naturally occurring oxidative DNA damage is estimated to occur 10,000 times per cell per day in humans and 100,000 times per cell per day in [[Biology:Rat|rat]]s.<ref>{{cite journal | vauthors = Ames BN, Shigenaga MK, Hagen TM | title = Oxidants, antioxidants, and the degenerative diseases of aging | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 17 | pages = 7915–22 | date = September 1993 | pmid = 8367443 | pmc = 47258 | doi = 10.1073/pnas.90.17.7915 | bibcode = 1993PNAS...90.7915A | doi-access = free }}</ref> Spontaneous mutations 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 | vauthors = Montelone BA |year=1998 |website=www-personal.ksu.edu |access-date=2 October 2015 |url-status=dead |archive-url=https://web.archive.org/web/20150926115801/http://www-personal.ksu.edu/~bethmont/mutdes.html#origins |archive-date=26 September 2015 }}</ref>
* [[Chemistry:Tautomer|Tautomer]]ism – A base is changed by the repositioning of a [[Chemistry:Hydrogen|hydrogen]] atom, altering the hydrogen bonding pattern of that base, resulting in incorrect [[Biology:Base pair|base pair]]ing during replication.<ref>{{cite journal | vauthors = Slocombe L, Al-Khalili JS, Sacchi M | title = Quantum and classical effects in DNA point mutations: Watson-Crick tautomerism in AT and GC base pairs | journal = Physical Chemistry Chemical Physics | volume = 23 | issue = 7 | pages = 4141–4150 | date = February 2021 | pmid = 33533770 | doi = 10.1039/D0CP05781A| issn=1463-9076 | bibcode = 2021PCCP...23.4141S | s2cid = 231788542 | doi-access = free }}</ref> Theoretical results suggest that [[Physics:Proton tunneling|proton tunneling]] is an important factor in the spontaneous creation of GC [[Chemistry:Tautomer|tautomer]]s.<ref>{{Cite journal | vauthors = Slocombe L, Sacchi M, Al-Khalili J |date=2022-05-05 |title=An open quantum systems approach to proton tunnelling in DNA |url=https://www.nature.com/articles/s42005-022-00881-8 |journal=Communications Physics |language=en |volume=5 |issue=1 |page=109 |doi=10.1038/s42005-022-00881-8 |arxiv=2110.00113 |bibcode=2022CmPhy...5..109S |s2cid=238253421 |issn=2399-3650}}</ref>
* [[Biology:Depurination|Depurination]] – Loss of a [[Chemistry:Purine|purine]] base (A or G) to form an apurinic site ([[Biology:AP site|AP site]]).
* [[Biology:Deamination|Deamination]] – [[Chemistry:Hydrolysis|Hydrolysis]] changes a normal base to an atypical base containing a [[Chemistry:Ketone|keto]] group in place of the original [[Chemistry:Amine|amine]] group. Examples include C → U and A → HX ([[Chemistry:Hypoxanthine|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 [[Chemistry:Thymine|thymine]] is a normal DNA base.
* [[Biology:Slipped strand mispairing|Slipped strand mispairing]] – Denaturation of the new strand from the template during replication, followed by renaturation in a different spot ("slipping"). This can lead to insertions or deletions.

===Error-prone replication bypass===

There is increasing evidence that the majority of spontaneously arising mutations are due to error-prone replication (translesion synthesis) past DNA damage in the template strand. In [[Biology: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 | doi = 10.1093/genetics/154.3.1291 | pmid = 10757770 | pmc = 1460990 }}</ref> Likewise, in [[Biology:Yeast|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 | doi = 10.1093/genetics/148.4.1491 | 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 ===
Although naturally occurring double-strand breaks occur at a relatively low frequency in DNA, their repair often causes mutation. [[Biology:Non-homologous end joining|Non-homologous end joining]] (NHEJ) is a major pathway for repairing double-strand breaks. NHEJ involves removal of a few [[Biology:Nucleotide|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 [[Chemistry:Covalent|covalent]] adduct between the metabolite of benzo[''a'']pyrene, the major mutagen in 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
** [[Chemistry:Hydroxylamine|Hydroxylamine]]
** [[Chemistry:Base analog|Base analog]]s (e.g., [[Chemistry:Bromodeoxyuridine|Bromodeoxyuridine]] (BrdU))
** [[Chemistry:Alkylation|Alkylating agent]]s (e.g., [[Chemistry: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 [[Biology:Transition (genetics)|transition]]s, [[Biology:Transversion|transversion]]s, or deletions.
** Agents that form [[Medicine:DNA adduct|DNA adduct]]s (e.g., [[Chemistry:Ochratoxin A|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 [[Chemistry:Intercalation (biochemistry)|intercalating]] agents (e.g., [[Chemistry:Ethidium bromide|ethidium bromide]])
** [[Biology:Crosslinking of DNA|DNA crosslinkers]]
** [[Biology:Oxidative stress|Oxidative damage]]
** [[Chemistry:Nitrous acid|Nitrous acid]] converts amine groups on A and C to [[Chemistry:Diazo|diazo]] groups, altering their hydrogen bonding patterns, which leads to incorrect base pairing during replication.
* Radiation
** [[Physics:Ultraviolet|Ultraviolet]] light (UV) (including [[Physics:Non-ionizing radiation|non-ionizing radiation]]). Two nucleotide bases in DNA—[[Chemistry:Cytosine|cytosine]] and thymine—are most vulnerable to radiation that can change their properties. UV light can induce adjacent [[Chemistry:Pyrimidine|pyrimidine]] bases in a DNA strand to become covalently joined as a [[Biology:Pyrimidine dimer|pyrimidine dimer]]. UV radiation, in particular longer-wave UVA, can also cause [[Chemistry: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 | doi-access = free }}</ref>
** [[Physics:Ionizing radiation|Ionizing radiation]]. Exposure to ionizing radiation, such as [[Physics: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="Fitzgerald-2019">{{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 | doi-access = free }}</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 = 1 January 2007 | 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 = 31 July 2012 | pmid = 22860105 | doi = 10.1371/journal.pone.0042279 | veditors = Sturtevant J | pmc = 3409178 | bibcode = 2012PLoSO...742279Q | doi-access = free }}</ref> and other chromosomal events such as duplications.<ref name="Fitzgerald-2019" />

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

The sequence of a gene can be altered in a number of ways.<ref>{{cite web| vauthors = Rahman N |title=The clinical impact of DNA sequence changes|url=http://www.thetgmi.org/genetics/clinical-impact-dna-sequence-changes/|website=Transforming Genetic Medicine Initiative|access-date=27 June 2017|url-status=dead|archive-url=https://web.archive.org/web/20170804060005/http://www.thetgmi.org/genetics/clinical-impact-dna-sequence-changes/|archive-date=4 August 2017}}</ref> Gene mutations have varying effects on health depending on where they occur and whether they alter the function of essential proteins.
Mutations in the structure of genes can be classified into several types.

==== Large-scale mutations ====

Large-scale mutations in [[Biology:Chromosome|chromosomal]] structure include:
* Amplifications (or [[Biology:Gene duplication|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.
* [[Biology:Polyploidy|Polyploidy]], duplication of entire sets of chromosomes, potentially resulting in a separate breeding population and [[Biology:Speciation|speciation]].
* Deletions of large chromosomal regions, leading to loss of the genes within those regions.
* Mutations whose effect is to juxtapose previously separate pieces of DNA, potentially bringing together separate genes to form functionally distinct [[Biology:Fusion gene|fusion gene]]s (e.g., bcr-abl).
* Large scale changes to the structure of [[Biology:Chromosome|chromosome]]s called [[Biology:Chromosomal rearrangement|chromosomal rearrangement]] that can lead to a decrease of fitness but also to speciation in isolated, inbred populations. These include:
** [[Biology:Chromosomal translocation|Chromosomal translocation]]s: interchange of genetic parts from nonhomologous chromosomes.
** [[Biology:Chromosomal inversion|Chromosomal inversion]]s: reversing the orientation of a chromosomal segment.
** Non-homologous [[Biology:Chromosomal crossover|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 [[Medicine:Glioblastoma|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 [[Biology:Carcinogenesis|oncogenic]] transformation (a transformation from normal cells to cancer cells).
* [[Biology:Loss of heterozygosity|Loss of heterozygosity]]: loss of one [[Biology:Allele|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 [[Biology:Point mutation|point mutation]]s.) Small-scale mutations include:
* [[Biology:Insertion (genetics)|Insertions]] add one or more extra nucleotides into the DNA. They are usually caused by [[Biology:Transposable element|transposable element]]s, or errors during replication of repeating elements. Insertions in the coding region of a gene may alter [[Biology:RNA splicing|splicing]] of the [[Biology:Messenger RNA|mRNA]] ([[Biology:Splice site mutation|splice site mutation]]), or cause a shift in the [[Biology:Reading frame|reading frame]] ([[Biology:Frameshift mutation|frameshift]]), both of which can significantly alter the [[Biology:Gene product|gene product]]. Insertions can be reversed by excision of the transposable element.
* [[Biology:Deletion (genetics)|Deletions]] remove one or more nucleotides from the DNA. Like insertions, these mutations can alter the reading frame of the gene. In general, they are irreversible: Though exactly the same sequence might, in theory, be restored by an insertion, transposable elements able to revert a very short deletion (say 1–2 bases) in ''any'' location either are highly unlikely to exist or do not exist at all.
* [[Biology:Point mutation|Substitution mutations]], often caused by chemicals or malfunction of DNA replication, exchange a single nucleotide for another.<ref>{{cite journal | vauthors = Freese E | title = The Difference Between Spontaneous and Base-Analogue Induced Mutations of Phage T4 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 45 | issue = 4 | pages = 622–33 | date = April 1959 | pmid = 16590424 | pmc = 222607 | doi = 10.1073/pnas.45.4.622 |  bibcode = 1959PNAS...45..622F | doi-access = free }}</ref> These changes are classified as transitions or transversions.<ref>{{cite journal | vauthors = Freese E | date = June 1959 |title=The specific mutagenic effect of base analogues on Phage T4 |journal=Journal of Molecular Biology |volume=1 |issue=2 |pages=87–105 |doi=10.1016/S0022-2836(59)80038-3}}</ref> Most common is the transition that exchanges a purine for a purine (A ↔ G) or a [[Chemistry:Pyrimidine|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 [[Chemistry:Adenine|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 below, point mutations that occur within the protein [[Biology:Coding region|coding region]] of a gene may be classified as [[Biology:Synonymous substitution|synonymous]] or [[Biology:Nonsynonymous substitution|nonsynonymous substitution]]s, the latter of which in turn can be divided into [[Biology:Missense mutation|missense]] or nonsense mutations.

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

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

Mutations that occur in coding regions of the genome are more likely to alter the protein product, and can be categorized by their effect on amino acid sequence:
* A [[Biology:Frameshift mutation|frameshift mutation]] is caused by insertion or deletion of a number of nucleotides that is not evenly divisible by three from a DNA sequence. Due to the triplet nature of gene expression by codons, the insertion or deletion can disrupt the reading frame, or the grouping of the codons, resulting in a completely different [[Biology:Translation|translation]] from the original.<ref>{{cite encyclopedia| vauthors = Hogan CM | veditors = Monosson E |encyclopedia=[[Encyclopedia of Earth]]|title=Mutation|url=http://www.eoearth.org/view/article/159530/|access-date=8 October 2015|date=12 October 2010|publisher=Environmental Information Coalition, National Council for Science and the Environment|location=Washington, D.C.|oclc=72808636|url-status=live|archive-url=https://web.archive.org/web/20151114055631/http://www.eoearth.org/view/article/159530/|archive-date=14 November 2015}}</ref> The earlier in the sequence the deletion or insertion occurs, the more altered the protein produced is. (For example, the code CCU GAC UAC CUA codes for the amino acids proline, aspartic acid, tyrosine, and leucine. If the U in CCU was deleted, the resulting sequence would be CCG ACU ACC UAx, which would instead code for proline, threonine, threonine, and part of another amino acid or perhaps a [[Biology:Stop codon|stop codon]] (where the x stands for the following nucleotide).) By contrast, any insertion or deletion that is evenly divisible by three is termed an ''in-frame mutation''.
* A point substitution mutation results in a change in a single nucleotide and can be either synonymous or nonsynonymous.
** A [[Biology:Synonymous substitution|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 [[Biology:Degeneracy|degenerate]] nature of the [[Biology:Genetic code|genetic code]]. If this mutation does not result in any phenotypic effects, then it is called [[Biology: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 [[Biology:Nonsynonymous substitution|nonsynonymous substitution]] replaces a codon with another codon that codes for a different amino acid, so that the produced amino acid sequence is modified. Nonsynonymous substitutions can be classified as nonsense or missense mutations:
*** A [[Biology:Missense mutation|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 [[Medicine:Epidermolysis bullosa|Epidermolysis bullosa]], sickle-cell disease, and [[Biology:Superoxide dismutase|SOD1]]-mediated [[Medicine:Amyotrophic lateral sclerosis|ALS]].<ref>{{cite journal|vauthors=Boillée S, Vande Velde C, Cleveland DW|s2cid=12968143|date=October 2006|title=ALS: a disease of motor neurons and their nonneuronal neighbors|journal=Neuron|volume=52|issue=1|pages=39–59|citeseerx=10.1.1.325.7514|doi=10.1016/j.neuron.2006.09.018|pmid=17015226}}</ref> On the other hand, if a missense mutation occurs in an amino acid codon that results in the use of a different, but chemically similar, amino acid, then sometimes little or no change is rendered in the protein. For example, a change from AAA to AGA will encode [[Chemistry:Arginine|arginine]], a chemically similar molecule to the intended [[Chemistry:Lysine|lysine]]. In this latter case the mutation will have little or no effect on phenotype and therefore be [[Biology:Neutral mutation|neutral]].
*** A [[Biology:Nonsense mutation|nonsense mutation]] is a point mutation in a sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the transcribed mRNA, and possibly a truncated, and often nonfunctional protein product. This sort of mutation has been linked to different diseases, such as [[Medicine:Congenital adrenal hyperplasia|congenital adrenal hyperplasia]]. (See [[Biology:Stop codon|Stop codon]].)

===By effect on function===
A mutation becomes an effect on function mutation when the exactitude of functions between a mutated protein and its direct interactor undergoes change. The interactors can be other proteins, molecules, nucleic acids, etc. There are many mutations that fall under the category of by effect on function, but depending on the specificity of the change the mutations listed below will occur.<ref>{{cite journal | vauthors = Reva B, Antipin Y, Sander C | title = Predicting the functional impact of protein mutations: application to cancer genomics | journal = Nucleic Acids Research | volume = 39 | issue = 17 | pages = e118 | date = September 2011 | pmid = 21727090 | pmc = 3177186 | doi = 10.1093/nar/gkr407 }}</ref>
* Loss-of-function mutations, also called inactivating mutations, result in the gene product having less or no function (being partially or wholly inactivated). When the allele has a complete loss of function ([[Biology:Null allele|null allele]]), it is often called an [[Biology:Amorph (gene)|amorph]] or amorphic mutation in [[Biology:Muller's morphs|Muller's morphs]] schema. Phenotypes associated with such mutations are most often [[Biology:Dominance (genetics)|recessive]]. Exceptions are when the organism is [[Biology: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 [[Biology:Haploinsufficiency|haploinsufficiency]]). A disease that is caused by a loss-of-function mutation is Gitelman syndrome and cystic fibrosis.<ref>{{cite journal | vauthors = Housden BE, Muhar M, Gemberling M, Gersbach CA, Stainier DY, Seydoux G, Mohr SE, Zuber J, Perrimon N | display-authors = 6 | title = Loss-of-function genetic tools for animal models: cross-species and cross-platform differences | journal = Nature Reviews. Genetics | volume = 18 | issue = 1 | pages = 24–40 | date = January 2017 | pmid = 27795562 | pmc = 5206767 | doi = 10.1038/nrg.2016.118 }}</ref>
* [[Biology:Gain-of-function research|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 [[Biology:Zygosity#Heterozygous|heterozygote]] containing the newly created allele as well as the original will express the new allele; genetically this defines the mutations as [[Biology:Dominance (genetics)|dominant]] phenotypes. Several of Muller's morphs correspond to the gain of function, including hypermorph (increased gene expression) and neomorph (novel function).
* Dominant negative mutations (also called anti-morphic mutations) have an altered gene product that acts antagonistically to the wild-type allele. These mutations usually result in an altered molecular function (often inactive) and are characterized by a dominant or [[Biology:Dominance (genetics)#Incomplete dominance|semi-dominant]] phenotype. In humans, dominant negative mutations have been implicated in cancer (e.g., mutations in genes [[Biology:P53|p53]], ATM, [[Biology:CEBPA|CEBPA]], and [[Biology:Peroxisome proliferator-activated receptor gamma|PPARgamma]]). [[Medicine:Marfan syndrome|Marfan syndrome]] is caused by mutations in the FBN1 gene, located on chromosome 15, which encodes fibrillin-1, a [[Chemistry:Glycoprotein|glycoprotein]] component of the [[Biology:Extracellular matrix|extracellular matrix]]. Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency.
* Lethal mutations result in rapid organismal death when occurring during development and cause significant reductions of life expectancy for developed organisms. An example of a disease that is caused by a dominant lethal mutation is [[Medicine:Huntington's disease|Huntington's disease]].
* Null mutations, also known as Amorphic mutations, are a form of loss-of-function mutations that completely prohibit the gene's function. The mutation leads to a complete loss of operation at the phenotypic level, also causing no gene product to be formed. [[Medicine:Atopic dermatitis|Atopic eczema]] and dermatitis syndrome are common diseases caused by a null mutation of the gene that activates filaggrin.
* Suppressor mutations are a type of mutation that causes the double mutation to appear normally. In suppressor mutations the phenotypic activity of a different mutation is completely suppressed, thus causing the double mutation to look normal. There are two types of suppressor mutations, there are [[Biology:Epistasis|intragenic]] and extragenic suppressor mutations. Intragenic mutations occur in the gene where the first mutation occurs, while extragenic mutations occur in the gene that interacts with the product of the first mutation. A common disease that results from this type of mutation is [[Medicine:Alzheimer's disease|Alzheimer's disease]].<ref>{{cite journal | vauthors = Eggertsson G, Adelberg EA | title = Map positions and specificities of suppressor mutations in Escherichia coli K-12 | journal = Genetics | volume = 52 | issue = 2 | pages = 319–340 | date = August 1965 | pmid = 5324068 | pmc = 1210853 | doi = 10.1093/genetics/52.2.319 }}</ref>
* Neomorphic mutations are a part of the gain-of-function mutations and are characterized by the control of new protein product synthesis. The newly synthesized gene normally contains a novel gene expression or molecular function. The result of the neomorphic mutation is the gene where the mutation occurs has a complete change in function.<ref>{{cite journal | vauthors = Takiar V, Ip CK, Gao M, Mills GB, Cheung LW | title = Neomorphic mutations create therapeutic challenges in cancer | journal = Oncogene | volume = 36 | issue = 12 | pages = 1607–1618 | date = March 2017 | pmid = 27841866 | pmc = 6609160 | doi = 10.1038/onc.2016.312 }}</ref>
* A back mutation or reversion is a point mutation that restores the original sequence and hence the original phenotype.<ref>{{cite journal | vauthors = Ellis NA, Ciocci S, German J | s2cid = 22290041 | title = Back mutation can produce phenotype reversion in Bloom syndrome somatic cells | journal = Human Genetics | volume = 108 | issue = 2 | pages = 167–73 | date = February 2001 | pmid = 11281456 | doi = 10.1007/s004390000447 }}</ref>

===By effect on fitness (harmful, beneficial, neutral mutations)===

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

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

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

[[File:DFE in VSV.png|thumb|right|360px|The distribution of fitness effects (DFE) of mutations in vesicular stomatitis virus. In this experiment, random mutations were introduced into the virus by site-directed mutagenesis, and the fitness of each mutant was compared with the ancestral type. A fitness of zero, less than one, one, more than one, respectively, indicates that mutations are lethal, deleterious, neutral, and advantageous.<ref name="Sanjuán04" />]]
* [[File:GOF diagram.png|thumb|This figure shows a simplified version of loss-of-function, switch-of-function, gain-of-function, and conservation-of-function mutations.]]Molecular sequence analysis: With rapid development of [[Biology:DNA sequencing|DNA sequencing]] technology, an enormous amount of DNA sequence data is available and even more is forthcoming in the future. Various methods have been developed to infer the DFE from DNA sequence data.<ref>{{cite journal | vauthors = Loewe L, Charlesworth B | title = Inferring the distribution of mutational effects on fitness in Drosophila | journal = Biology Letters | volume = 2 | issue = 3 | pages = 426–30 | date = September 2006 | pmid = 17148422 | pmc = 1686194 | doi = 10.1098/rsbl.2006.0481 }}</ref><ref>{{cite journal | vauthors = Eyre-Walker A, Woolfit M, Phelps T | title = The distribution of fitness effects of new deleterious amino acid mutations in humans | journal = Genetics | volume = 173 | issue = 2 | pages = 891–900 | date = June 2006 | pmid = 16547091 | pmc = 1526495 | doi = 10.1534/genetics.106.057570 }}</ref><ref>{{cite journal | vauthors = Sawyer SA, Kulathinal RJ, Bustamante CD, Hartl DL | s2cid = 18051307 | title = Bayesian analysis suggests that most amino acid replacements in Drosophila are driven by positive selection | journal = Journal of Molecular Evolution | volume = 57 | issue = 1 | pages = S154–64 | date = August 2003 | pmid = 15008412 | doi = 10.1007/s00239-003-0022-3 |  citeseerx = 10.1.1.78.65 | bibcode = 2003JMolE..57S.154S }}</ref><ref>{{cite journal | vauthors = Piganeau G, Eyre-Walker A | title = Estimating the distribution of fitness effects from DNA sequence data: implications for the molecular clock | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 18 | pages = 10335–40 | date = September 2003 | pmid = 12925735 | pmc = 193562 | doi = 10.1073/pnas.1833064100 | bibcode = 2003PNAS..10010335P | doi-access = free }}</ref> By examining DNA sequence differences within and between species, we are able to infer various characteristics of the DFE for neutral, deleterious and advantageous mutations.<ref name="Eyre-Walker07" /> To be specific, the DNA sequence analysis approach allows us to estimate the effects of mutations with very small effects, which are hardly detectable through mutagenesis experiments.

One of the earliest theoretical studies of the distribution of fitness effects was done by [[Biography:Motoo Kimura|Motoo Kimura]], an influential theoretical population [[Biology:Geneticist|geneticist]]. His neutral theory of [[Biology:Molecular evolution|molecular evolution]] proposes that most novel mutations will be highly deleterious, with a small fraction being neutral.<ref name="Kimura-1983">{{cite book | vauthors = Kimura M |year=1983 |title=The Neutral Theory of Molecular Evolution |location=Cambridge, UK; New York |publisher={{wipe|Cambridge University Press}} |isbn=978-0-521-23109-1 |lccn=82022225 |oclc=9081989 |title-link=The Neutral Theory of Molecular Evolution }}</ref><ref>{{cite journal | vauthors = Kimura M | s2cid = 4161261 | title = Evolutionary rate at the molecular level | journal = Nature | volume = 217 | issue = 5129 | pages = 624–6 | date = February 1968 | pmid = 5637732 | doi = 10.1038/217624a0 | author-link = Motoo Kimura | bibcode = 1968Natur.217..624K }}</ref> A later proposal by Hiroshi Akashi proposed a [[Multimodal distribution|bimodal]] model for the DFE, with modes centered around highly deleterious and neutral mutations.<ref>{{cite journal | vauthors = Akashi H | title = Within- and between-species DNA sequence variation and the 'footprint' of natural selection | journal = Gene | volume = 238 | issue = 1 | pages = 39–51 | date = September 1999 | pmid = 10570982 | doi = 10.1016/S0378-1119(99)00294-2 }}</ref> Both theories agree that the vast majority of novel mutations are neutral or deleterious and that advantageous mutations are rare, which has been supported by experimental results. One example is a study done on the DFE of random mutations in vesicular stomatitis virus.<ref name="Sanjuán04" /> Out of all mutations, 39.6% were lethal, 31.2% were non-lethal deleterious, and 27.1% were neutral. Another example comes from a high throughput mutagenesis experiment with yeast.<ref name="Hietpas11" /> In this experiment it was shown that the overall DFE is bimodal, with a cluster of neutral mutations, and a broad distribution of deleterious mutations.

Though relatively few mutations are advantageous, those that are play an important role in evolutionary changes.<ref>{{cite journal | vauthors = Eyre-Walker A | title = The genomic rate of adaptive evolution | journal = Trends in Ecology & Evolution | volume = 21 | issue = 10 | pages = 569–75 | date = October 2006 | pmid = 16820244 | doi = 10.1016/j.tree.2006.06.015 }}</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 [[Biography:John H. Gillespie|John H. Gillespie]]<ref>{{cite journal | vauthors = Gillespie JH | 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 [[Biography:H. Allen Orr|H. Allen Orr]].<ref>{{cite journal | vauthors = Orr HA | title = The distribution of fitness effects among beneficial mutations | journal = Genetics | volume = 163 | issue = 4 | pages = 1519–26 | date = April 2003 | doi = 10.1093/genetics/163.4.1519 | pmid = 12702694 | pmc = 1462510 | author-link = H. Allen Orr }}</ref> They proposed that the distribution for advantageous mutations should be [[Exponential decay|exponential]] under a wide range of conditions, which, in general, has been supported by experimental studies, at least for strongly selected advantageous mutations.<ref>{{cite journal | vauthors = Kassen R, Bataillon T | s2cid = 6954765 | title = Distribution of fitness effects among beneficial mutations before selection in experimental populations of bacteria | journal = Nature Genetics | volume = 38 | issue = 4 | pages = 484–8 | date = April 2006 | pmid = 16550173 | doi = 10.1038/ng1751 }}</ref><ref>{{cite journal | vauthors = Rokyta DR, Joyce P, Caudle SB, Wichman HA | s2cid = 20296781 | title = An empirical test of the mutational landscape model of adaptation using a single-stranded DNA virus | journal = Nature Genetics | volume = 37 | issue = 4 | pages = 441–4 | date = April 2005 | pmid = 15778707 | doi = 10.1038/ng1535 }}</ref><ref>{{cite journal | vauthors = Imhof M, Schlotterer C | title = Fitness effects of advantageous mutations in evolving Escherichia coli populations | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 3 | pages = 1113–7 | date = January 2001 | pmid = 11158603 | pmc = 14717 | doi = 10.1073/pnas.98.3.1113 | bibcode = 2001PNAS...98.1113I | doi-access = free }}</ref>

In general, it is accepted that the majority of mutations are neutral or deleterious, with advantageous mutations being rare; however, the proportion of types of mutations varies between species. This indicates two important points: first, the proportion of effectively neutral mutations is likely to vary between species, resulting from dependence on [[Biology:Effective population size|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 regions, with the DFE of noncoding DNA containing more weakly selected mutations.<ref name="Eyre-Walker07" />

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

Diploid organisms (e.g., humans) contain two copies of each gene—a paternal and a maternal allele. Based on the occurrence of mutation on each chromosome, we may classify mutations into three types. A [[Biology:Wild type|wild type]] or homozygous non-mutated organism is one in which neither allele is mutated.
* A heterozygous mutation is a mutation of only one allele.
* A homozygous mutation is an identical mutation of both the paternal and maternal alleles.
* [[Biology:Compound heterozygosity|Compound heterozygous]] mutations or a genetic compound consists of two different mutations in the paternal and maternal alleles.<ref>{{cite encyclopedia |encyclopedia=MedTerms |title=Compound heterozygote |url=http://www.medicinenet.com/script/main/art.asp?articlekey=33675 |access-date=9 October 2015 |date=14 June 2012 |publisher=[[Company:WebMD|WebMD]] |location=New York |url-status=dead |archive-url=https://web.archive.org/web/20160304123903/http://www.medicinenet.com/script/main/art.asp?articlekey=33675 |archive-date=4 March 2016 }}</ref>

==== Germline mutation ====
{{Further|Biology:Germline mutation}}
A germline mutation in the reproductive cells of an individual gives rise to a ''constitutional mutation'' in the offspring, that is, a mutation that is present in every cell. A constitutional mutation can also occur very soon after [[Biology:Fertilisation|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|archive-url=https://web.archive.org/web/20111126004753/http://www.daisyfund.org/rb/about/genetics.html|archive-date=26 November 2011|access-date=9 October 2015}}</ref> A germline mutation can be passed down through subsequent generations of organisms.

The distinction between germline and somatic mutations is important in animals that have a dedicated germline to produce reproductive cells. However, it is of little value in understanding the effects of mutations in plants, which lack a dedicated germline. The distinction is also blurred in those animals that reproduce asexually through mechanisms such as [[Biology:Budding|budding]], because the cells that give rise to the daughter organisms also give rise to that organism's germline.

A new germline mutation not inherited from either parent is called a '''''de novo'' mutation'''.

====Somatic mutation====
{{main article|Biology:Somatic mutation}}

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

With plants, some somatic mutations can be propagated without the need for seed production, for example, by [[Earth:Grafting|grafting]] and stem cuttings. These type of mutation have led to new types of fruits, such as the "Delicious" [[Biology:Apple|apple]] and the "Washington" navel orange.<ref>{{cite book | vauthors = Hartl L, Jones EW |url=https://archive.org/details/geneticsprincipl00hart/page/556|title=Genetics Principles and Analysis|publisher=Jones and Bartlett Publishers|year=1998|isbn=978-0-7637-0489-6|location=Sudbury, Massachusetts|pages=[https://archive.org/details/geneticsprincipl00hart/page/556 556]|url-access=registration}}</ref>

Human and mouse [[Biology:Somatic cell|somatic cell]]s have a mutation rate more than ten times higher than the [[Biology:Germline|germline]] mutation rate for both species; mice have a higher rate of both somatic and germline mutations per [[Biology:Cell division|cell division]] than humans. The disparity in mutation rate between the germline and somatic tissues likely reflects the greater importance of [[Biology:Genome|genome]] maintenance in the germline than in the soma.<ref name="Milholland">{{cite journal | vauthors = Milholland B, Dong X, Zhang L, Hao X, Suh Y, Vijg J | title = Differences between germline and somatic mutation rates in humans and mice | journal = Nature Communications | volume = 8 | pages = 15183 | date = May 2017 | pmid = 28485371 | pmc = 5436103 | doi = 10.1038/ncomms15183 | bibcode = 2017NatCo...815183M }}</ref>

===Special classes===
<!-- This section is linked from [[Biology:Cat|Cat]] -->
* '''Conditional mutation''' is a mutation that has wild-type (or less severe) phenotype under certain "permissive" environmental conditions and a mutant phenotype under certain "restrictive" conditions. For example, a temperature-sensitive mutation can cause cell death at high temperature (restrictive condition), but might have no deleterious consequences at a lower temperature (permissive condition).<ref>{{Cite book|title=Molecular Biology of the Cell| vauthors = Alberts B |publisher=Garland Science|year=2014|isbn=9780815344322|edition=6|pages=487}}</ref> These mutations are non-autonomous, as their manifestation depends upon presence of certain conditions, as opposed to other mutations which appear autonomously.<ref name="Chadov-2015">{{cite journal | vauthors = Chadov BF, Fedorova NB, Chadova EV | title = Conditional mutations in Drosophila melanogaster: On the occasion of the 150th anniversary of G. Mendel's report in Brünn | journal = Mutation Research/Reviews in Mutation Research | volume = 765 | pages = 40–55 | date = 1 July 2015 | pmid = 26281767 | doi = 10.1016/j.mrrev.2015.06.001 }}</ref> The permissive conditions may be temperature,<ref name="Landis-2001">{{cite journal | vauthors = Landis G, Bhole D, Lu L, Tower J | title = High-frequency generation of conditional mutations affecting Drosophila melanogaster development and life span | journal = Genetics | volume = 158 | issue = 3 | pages = 1167–76 | date = July 2001 | doi = 10.1093/genetics/158.3.1167 | pmid = 11454765 | pmc = 1461716 | url = http://www.genetics.org/content/158/3/1167 | url-status = dead | access-date = 21 March 2017 | archive-url = https://web.archive.org/web/20170322014758/http://www.genetics.org/content/158/3/1167 | archive-date = 22 March 2017 }}</ref> certain chemicals,<ref name="Gierut-2014">{{cite journal | vauthors = Gierut JJ, Jacks TE, Haigis KM | title = Strategies to achieve conditional gene mutation in mice | journal = Cold Spring Harbor Protocols | volume = 2014 | issue = 4 | pages = 339–49 | date = April 2014 | pmid = 24692485 | pmc = 4142476 | doi = 10.1101/pdb.top069807 }}</ref> light<ref name="Gierut-2014" /> or mutations in other parts of the [[Biology:Genome|genome]].<ref name="Chadov-2015" /> ''[[Biology: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="Gierut-2014" /> DNA Recombinase systems like [[Biology:Cre-Lox recombination|Cre-Lox recombination]] used in association with [[Biology:Promoter (genetics)|promoters]] that are activated under certain conditions can generate conditional mutations. Dual Recombinase technology can be used to induce multiple conditional mutations to study the diseases which manifest as a result of simultaneous mutations in multiple genes.<ref name="Gierut-2014" /> Certain [[Biology:Intein|intein]]s have been identified which splice only at certain permissive temperatures, leading to improper protein synthesis and thus, loss-of-function mutations at other temperatures.<ref>{{cite journal | vauthors = Tan G, Chen M, Foote C, Tan C | title = Temperature-sensitive mutations made easy: generating conditional mutations by using temperature-sensitive inteins that function within different temperature ranges | journal = Genetics | volume = 183 | issue = 1 | pages = 13–22 | date = September 2009 | pmid = 19596904 | pmc = 2746138 | doi = 10.1534/genetics.109.104794 }}</ref> Conditional mutations may also be used in genetic studies associated with ageing, as the expression can be changed after a certain time period in the organism's lifespan.<ref name="Landis-2001" />
* '''[[Biology:Replication timing quantitative trait loci|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|biologist]]s, who have the responsibility of establishing the ''standard'' or so-called "consensus" sequence. This step requires a tremendous scientific effort. Once the consensus sequence is known, the mutations in a genome can be pinpointed, described, and classified. The committee of the Human Genome Variation Society (HGVS) has developed the standard human sequence variant nomenclature,<ref name="paper45">{{cite journal | vauthors = den Dunnen JT, Antonarakis SE | title = Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion | journal = Human Mutation | volume = 15 | issue = 1 | pages = 7–12 | date = January 2000 | pmid = 10612815 | doi = 10.1002/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N | s2cid = 84706224 |  doi-access = free }}</ref> which should be used by researchers and [[Medicine: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 [[Biology:Genomic DNA|genomic DNA]], [[Biology:Mitochondrial DNA|mitochondrial DNA]], and [[Biology:RNA|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 [[Chemistry: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 [[Biology:N-terminus|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) indicates a deletion. The letter refers to the amino acid present in the wild type and the number is the position from the N terminus of the amino acid were it to be present as in the wild type.

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

In '''humans''', the [[Biology:Mutation rate|mutation rate]] is about 50–90 ''de novo'' mutations per genome per generation, that is, each human accumulates about 50–90 novel mutations that were not present in his or her parents. This number has been established by [[Biology:DNA sequencing|sequencing]] thousands of human trios, that is, two parents and at least one child.<ref>{{cite journal | vauthors = Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K | display-authors = 6 | title = Parental influence on human germline de novo mutations in 1,548 trios from Iceland | journal = Nature | volume = 549 | issue = 7673 | pages = 519–522 | date = September 2017 | pmid = 28959963 | doi = 10.1038/nature24018 | s2cid = 205260431 | bibcode = 2017Natur.549..519J }}</ref>

The genomes of [[Biology:RNA virus|RNA virus]]es are based on [[Biology:RNA|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 [[Biology: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.

The rate of de novo mutations, whether germline or somatic, vary among organisms.<ref>{{cite journal |last1=Bromham |first1=Lindell |title=WHy do species very in their rate of molecular evolution? |date=2009 |volume=5 |issue=3 |pages=401–404 |journal=Biology Letters |doi=10.1098/rsbl.2009.0136 |pmid=19364710 |pmc=2679939 }}</ref> Individuals within the same species can even express varying rates of mutation.<ref name="The population genetics of mutation">{{cite journal |last1=Loewe |first1=Laurence |last2=Hill |first2=William G. |title=The population genetics of mutations: good, bad, and indifferent |journal=Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences |date=2010 |volume=365 |issue=1544 |pages=1153–1167 |publisher=Philosophical transactions of the Royal Society of London |doi=10.1098/rstb.2009.0317 |pmid=20308090 |pmc=2871823 }}</ref> Overall, rates of de novo mutations are low compared to those of inherited mutations, which categorizes them as rare forms of [[Biology:Genetic variation|genetic variation]].<ref>{{cite journal |last1=Mohiuddin |first1=Mohiuddin |last2=Kooy |first2=R. Frank |last3=Pearson |first3=Christopher E. |title=DE novo mutations, genetic mosaicism, and genetic disease |journal=Frontiers in Genetics |date=2022 |volume=13 |doi=10.3389/fgene.2022.983668 |doi-access=free |pmid=36226191 |pmc=9550265 }}</ref> Many observations of de novo mutation rates have associated higher rates of mutation correlated to paternal age. In sexually reproducing organisms, the comparatively higher frequency of cell divisions in the parental sperm donor germline drive conclusions that rates of de novo mutation can be tracked along a common basis. The frequency of error during the DNA replication process of [[Biology:Gametogenesis|gametogenesis]], especially amplified in the rapid production of sperm cells, can promote more opportunities for de novo mutations to replicate unregulated by DNA repair machinery.<ref>{{cite journal |last1=Mohiuddin |first1=Mohiuddin |last2=Kooy |first2=R. Frank |last3=Pearson |first3=Christopher E. |title=De novo mutations, genetic mosaicism, and genetic disease |journal=Frontiers in Genetics |date=2022 |volume=13 |doi=10.3389/fgene.2022.983668 |doi-access=free |pmid=36226191 |pmc=9550265 }}</ref> This claim combines the observed effects of increased probability for mutation in rapid [[Biology:Spermatogenesis|spermatogenesis]] with short periods of time between cellular divisions that limit the efficiency of repair machinery.<ref>{{cite journal |last1=Acuna-Hidalgo |first1=Rocio |last2=Veltman |first2=Joris A. |last3=Hoischen |first3=Alexander |title=New insights into the generation and role of de novo mutations in health and disease |date=2016 |journal=Genome Biology |volume=17 |issue=1 |page=241 |doi=10.1186/s13059-016-1110-1 |doi-access=free |pmid=27894357 |pmc=5125044 }}</ref> Rates of de novo mutations that affect an organism during its development can also increase with certain environmental factors. For example, certain intensities of exposure to radioactive elements can inflict damage to an organism's genome, heightening rates of mutation. In humans, the appearance of [[Medicine:Skin cancer|skin cancer]] during one's lifetime is induced by overexposure to UV radiation that causes mutations in the cellular and skin genome.<ref>{{cite journal |last1=Ikehata |first1=Hironobu |last2=Ono |first2=Tetsuya |title=The mechanisms of UV mutagenesis |url=https://pubmed.ncbi.nlm.nih.gov/21436607/ |journal=Journal of Radiation Research |date=2011 |volume=52 |issue=2 |pages=115–125 |publisher=J Radiat Res |doi=10.1269/jrr.10175 |pmid=21436607 |bibcode=2011JRadR..52..115I |access-date=9 December 2023}}</ref>

===Randomness of mutations===
There is a widespread assumption that mutations are (entirely) "random" with respect to their consequences (in terms of probability). This was shown to be wrong as mutation frequency can vary across regions of the genome, with such [[Biology:DNA repair|DNA repair]]- and mutation-biases being associated with various factors. For instance, biologically important regions were found to be protected from mutations and mutations beneficial to the studied plant were found to be more likely – i.e. mutation is "non-random in a way that benefits the plant".<ref>{{cite news |title=Study challenges evolutionary theory that DNA mutations are random |url=https://phys.org/news/2022-01-evolutionary-theory-dna-mutations-random.html |access-date=12 February 2022 |work=U.C. Davis |language=en}}</ref><ref>{{cite journal | vauthors = Monroe JG, Srikant T, Carbonell-Bejerano P, Becker C, Lensink M, Exposito-Alonso M, Klein M, Hildebrandt J, Neumann M, Kliebenstein D, Weng ML, Imbert E, Ågren J, Rutter MT, Fenster CB, Weigel D | display-authors = 6 | title = Mutation bias reflects natural selection in Arabidopsis thaliana | journal = Nature | volume = 602 | issue = 7895 | pages = 101–105 | date = February 2022 | pmid = 35022609 | pmc = 8810380 | doi = 10.1038/s41586-021-04269-6 | bibcode = 2022Natur.602..101M }}</ref> Additionally, previous experiments typically used to demonstrate mutations being random with respect to fitness (such as the Fluctuation Test and [[Biology:Replica plating|Replica plating]]) have been shown to only support the weaker claim that those mutations are random with respect to external selective constraints, not fitness as a whole.<ref>{{cite journal |doi=10.1007/s10441-023-09464-8 |author=Bartlett, J. |title=Random with Respect to Fitness or External Selection? An Important but Often Overlooked Distinction |journal=Acta Biotheoretica |volume=71 |issue=2 |date=2023 |page=12 |pmid=36933070 |s2cid=257585761 }}</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. 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" /> Some mutations alter a gene's DNA base sequence but do not change the protein made by the gene.  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 | veditors = Pritchard JK |  doi-access = free }}</ref>

=== Inherited disorders ===
If a mutation is present in a [[Biology:Germ cell|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 [[Medicine:DNA repair-deficiency disorder|DNA repair-deficiency disorder]]. An example of one is albinism, a mutation that occurs in the ''[[Medicine:Oculocutaneous albinism type I|OCA1]]'' or ''[[Biology:OCA2|OCA2]]'' gene. Individuals with this disorder are more prone to many types of cancers, other disorders and have impaired vision.

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 ===
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. The accumulation of certain mutations over generations of somatic cells is part of cause of [[Biology:Malignant transformation|malignant transformation]], from normal cell to cancer cell.<ref>{{cite journal|vauthors=Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M|s2cid=4254940|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 loss-of-function 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 | vauthors = Araten DJ, Golde DW, Zhang RH, Thaler HT, Gargiulo L, Notaro R, Luzzatto L | title = A quantitative measurement of the human somatic mutation rate | journal = Cancer Research | volume = 65 | issue = 18 | pages = 8111–7 | date = September 2005 | pmid = 16166284 | doi = 10.1158/0008-5472.CAN-04-1198 | doi-access = free }}</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 UV rays, [[Physics:X-ray|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.

==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 [[Biology:CCR5|CCR5]] ([[Biology:CCR5#CCR5-Δ32|CCR5-Δ32]]) confers [[Biology:HIV|HIV]] resistance to [[Biology: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 | doi-access = free }}</ref> One possible explanation of the [[Philosophy:Etiology|etiology]] of the relatively high frequency of CCR5-Δ32 in the European population is that it conferred resistance to the [[Medicine:Bubonic plague|bubonic plague]] in mid-14th century [[Earth:Europe|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/ |access-date=10 October 2015 |series=Secrets of the Dead |network=PBS |date=30 October 2002 |season=3 |number=2 |url-status=live |archive-url=https://web.archive.org/web/20151012175528/http://www.pbs.org/wnet/secrets/mystery-black-death-background/1488/ |archive-date=12 October 2015}} Episode background.</ref> This theory could explain why this mutation is not found in [[Place:Southern Africa|Southern Africa]], which remained untouched by bubonic plague. A newer theory suggests that the [[Biology:Evolutionary pressure|selective pressure]] on the CCR5 Delta 32 mutation was caused by [[Medicine:Smallpox|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 |  doi-access = free }}</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 [[Biology:Hemoglobin|hemoglobin]] in the [[Biology:Red blood cell|red blood cell]]s. One-third of all indigenous inhabitants of [[Place:Sub-Saharan Africa|Sub-Saharan Africa]] carry the allele, because, in areas where [[Medicine:Malaria|malaria]] is common, there is a [[Biology:Evolution|survival value]] in carrying only a single sickle-cell allele ([[Medicine:Sickle cell trait|sickle cell trait]]).<ref>{{cite web |url=http://sicklecell.md/faq.asp |title=Frequently Asked Questions [FAQ's] | vauthors = Konotey-Ahulu F |website=sicklecell.md |url-status=dead |archive-url=https://web.archive.org/web/20110430031852/http://sicklecell.md/faq.asp |archive-date=30 April 2011 |access-date=16 April 2010 }}</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 ''[[Biology:Plasmodium|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 | doi-access = free }}</ref> Obviously, such mutations are only beneficial for the bacteria but not for those infected.

'''[[Biology:Lactase persistence|Lactase persistence]]'''. A mutation allowed humans to express the enzyme [[Biology:Lactase|lactase]] after they are naturally weaned from breast milk, allowing adults to digest [[Chemistry:Lactose|lactose]], which is likely one of the most beneficial mutations in recent [[Biology:Human evolution|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===

[[Medicine:Prion|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.-->|url=http://news.bbc.co.uk/2/hi/health/8435320.stm|title='Lifeless' prion proteins are 'capable of evolution'|date=1 January 2010|work=BBC News|access-date=10 October 2015|url-status=live|archive-url=https://web.archive.org/web/20150925132138/http://news.bbc.co.uk/2/hi/health/8435320.stm|archive-date=25 September 2015|department=Health|location=London}}</ref> The human gene [[Biology:PRNP|PRNP]] codes for the major prion protein, PrP, and is subject to mutations that can give rise to disease-causing prions.

==Role in evolution==
By introducing novel genetic qualities to a population of organisms, de novo mutations play a critical role in the combined forces of evolutionary change. However, the weight of genetic diversity generated by mutational change is often considered a generally "weak" evolutionary force.<ref name="The population genetics of mutation"/> Although the random emergence of mutations alone provides the basis for genetic variation across all organic life, this force must be taken in consideration alongside all evolutionary forces at play. Spontaneous de novo mutations as cataclysmic events of speciation depend on factors introduced by [[Biology:Natural selection|natural selection]], genetic flow, and [[Biology:Genetic drift|genetic drift]]. For example, smaller populations with heavy mutational input (high rates of mutation) are prone to increases of genetic variation which lead to speciation in future generations. In contrast, larger populations tend to see lesser effects of newly introduced mutated traits. In these conditions, selective forces diminish the frequency of mutated alleles, which are most often deleterious, over time.<ref>{{cite journal |last1=Amicone |first1=Massimo |last2=Gordo |first2=Isabel |title=Molecular signatures of resource competition: Clonal interference favors ecological diversification and can lead to incipient speciation |journal=Evolution; International Journal of Organic Evolution |date=2021 |volume=75 |issue=11 |pages=2641–2657 |publisher=International Journal of Organic Evolution |doi=10.1111/evo.14315 |pmid=34341983 |pmc=9292366 }}</ref>

== Compensated pathogenic deviations ==
Compensated pathogenic deviations refer to amino acid residues in a protein sequence that are pathogenic in one species but are wild type residues in the functionally equivalent protein in another species. Although the amino acid residue is pathogenic in the first species, it is not so in the second species because its pathogenicity is compensated by one or more amino acid substitutions in the second species. The compensatory mutation can occur in the same protein or in another protein with which it interacts.<ref name="Barešić-2011">{{Cite journal |last1=Barešić |first1=Anja |last2=Martin |first2=Andrew C.R. |date=2011-08-01 |title=Compensated pathogenic deviations |journal=BioMolecular Concepts |volume=2 |issue=4 |pages=281–292 |doi=10.1515/bmc.2011.025 |pmid=25962036 |s2cid=6540447 |issn=1868-503X|doi-access=free }}</ref>   

It is critical to understand the effects of compensatory mutations in the context of fixed deleterious mutations due to the population fitness decreasing because of fixation.<ref name="Whitlock-2003">{{Cite journal |last1=Whitlock |first1=Michael C. |last2=Griswold |first2=Cortland K. |last3=Peters |first3=Andrew D. |date=2003 |title=Compensating for the meltdown: The critical effective size of a population with deleterious and compensatory mutations |url=https://www.jstor.org/stable/23736523 |journal=Annales Zoologici Fennici |volume=40 |issue=2 |pages=169–183 |jstor=23736523 |issn=0003-455X}}</ref> Effective population size refers to a population that is reproducing.<ref name="Lanfear-2014">{{Cite journal |last1=Lanfear |first1=Robert |last2=Kokko |first2=Hanna |last3=Eyre-Walker |first3=Adam |date=2014-01-01 |title=Population size and the rate of evolution |url=https://www.sciencedirect.com/science/article/pii/S0169534713002322 |journal=Trends in Ecology & Evolution |language=en |volume=29 |issue=1 |pages=33–41 |doi=10.1016/j.tree.2013.09.009 |pmid=24148292 |issn=0169-5347}}</ref> An increase in this population size has been correlated with a decreased rate of genetic diversity.<ref name="Lanfear-2014" /> The position of a population relative to the critical effect population size is essential to determine the effect deleterious alleles will have on fitness.<ref name="Whitlock-2003" /> If the population is below the critical effective size fitness will decrease drastically, however if the population is above the critical effect size, fitness can increase regardless of deleterious mutations due to compensatory alleles.<ref name="Whitlock-2003" />

=== Compensatory mutations in RNA ===
As the function of a RNA molecule is dependent on its structure,<ref>{{Cite journal |last=Doudna |first=Jennifer A. |title=Structural genomics of RNA |date=2000-11-01 |url=http://www.nature.com/doifinder/10.1038/80729 |journal=Nature Structural Biology |volume=7 |pages=954–956 |doi=10.1038/80729|pmid=11103998 |s2cid=998448 }}</ref> the structure of RNA molecules is evolutionarily conserved. Therefore, any mutation that alters the stable structure of RNA molecules must be compensated by other compensatory mutations. In the context of RNA, the sequence of the RNA can be considered as ' genotype' and the structure of the RNA can be considered as its 'phenotype'. Since RNAs have relatively simpler composition than proteins, the structure of RNA molecules can be computationally predicted with high degree of accuracy. Because of this convenience, compensatory mutations have been studied in computational simulations using RNA folding algorithms.<ref>{{Cite journal |last1=Cowperthwaite |first1=Matthew C. |last2=Bull |first2=J. J. |last3=Meyers |first3=Lauren Ancel |date=2006-10-20 |title=From Bad to Good: Fitness Reversals and the Ascent of Deleterious Mutations |journal=PLOS Computational Biology |language=en |volume=2 |issue=10 |pages=e141 |doi=10.1371/journal.pcbi.0020141 |issn=1553-7358 |pmc=1617134 |pmid=17054393|bibcode=2006PLSCB...2..141C |doi-access=free }}</ref><ref>{{Cite journal |last1=Cowperthwaite |first1=Matthew C. |last2=Meyers |first2=Lauren Ancel |date=2007-12-01 |title=How Mutational Networks Shape Evolution: Lessons from RNA Models |url=https://www.annualreviews.org/doi/10.1146/annurev.ecolsys.38.091206.095507 |journal=Annual Review of Ecology, Evolution, and Systematics |language=en |volume=38 |issue=1 |pages=203–230 |doi=10.1146/annurev.ecolsys.38.091206.095507 |issn=1543-592X}}</ref>

=== Evolutionary mechanism of compensation ===
Compensatory mutations can be explained by the genetic phenomenon epistasis whereby the phenotypic effect of one mutation is dependent upon mutation(s) at other loci. While epistasis was originally conceived in the context of interaction between different genes, intragenic epistasis has also been studied recently.<ref name="Azbukina-2022">{{Cite journal |last1=Azbukina |first1=Nadezhda |last2=Zharikova |first2=Anastasia |last3=Ramensky |first3=Vasily |date=2022-10-01 |title=Intragenic compensation through the lens of deep mutational scanning |url=https://doi.org/10.1007/s12551-022-01005-w |journal=Biophysical Reviews |language=en |volume=14 |issue=5 |pages=1161–1182 |doi=10.1007/s12551-022-01005-w |pmid=36345285 |pmc=9636336 |issn=1867-2469}}</ref> Existence of compensated pathogenic deviations can be explained by 'sign epistasis', in which the effects of a deleterious mutation can be compensated by the presence of an epistatic mutation in another loci. For a given protein, a deleterious mutation (D) and a compensatory mutation (C) can be considered, where C can be in the same protein as D or in a different interacting protein depending on the context. The fitness effect of C itself could be neutral or somewhat deleterious such that it can still exist in the population, and the effect of D is deleterious to the extent that it cannot exist in the population. However, when C and D co-occur together, the combined fitness effect becomes neutral or positive.<ref name="Barešić-2011"/> Thus, compensatory mutations can bring novelty to proteins by forging new pathways of protein evolution : it allows individuals to travel from one fitness peak to another through the valleys of lower fitness.<ref name="Azbukina-2022" /> 

DePristo et al. 2005 outlined two models to explain the dynamics of compensatory pathogenic deviations (CPD).<ref name="DePristo-2005">{{Cite journal |last1=DePristo |first1=Mark A. |last2=Weinreich |first2=Daniel M. |last3=Hartl |first3=Daniel L. |date=September 2005 |title=Missense meanderings in sequence space: a biophysical view of protein evolution |url=https://pubmed.ncbi.nlm.nih.gov/16074985/ |journal=Nature Reviews. Genetics |volume=6 |issue=9 |pages=678–687 |doi=10.1038/nrg1672 |issn=1471-0056 |pmid=16074985|s2cid=13236893 }}</ref> In the first hypothesis P is a pathogenic amino acid mutation that and C is a neutral compensatory mutation.<ref name="DePristo-2005" /> Under these conditions, if the pathogenic mutation arises after a compensatory mutation, then P can become fixed in the population.<ref name="DePristo-2005" /> The second model of CPDs states that P and C are both deleterious mutations resulting in fitness valleys when mutations occur simultaneously.<ref name="DePristo-2005" /> Using publicly available, Ferrer-Costa et al. 2007 obtained compensatory mutations and human pathogenic mutation datasets that were characterized to determine what causes CPDs.<ref name="Ferrer-Costa-2007">{{Cite journal |last1=Ferrer-Costa |first1=Carles |last2=Orozco |first2=Modesto |last3=Cruz |first3=Xavier de la |date=2007-01-05 |title=Characterization of Compensated Mutations in Terms of Structural and Physico-Chemical Properties |url=https://www.sciencedirect.com/science/article/pii/S0022283606012770 |journal=Journal of Molecular Biology |language=en |volume=365 |issue=1 |pages=249–256 |doi=10.1016/j.jmb.2006.09.053 |pmid=17059831 |issn=0022-2836}}</ref> Results indicate that the structural constraints and the location in protein structure determine whether compensated mutations will occur.<ref name="Ferrer-Costa-2007" />

=== Experimental evidence of compensatory mutations ===

==== Experiment in bacteria ====
Lunzer et al.<ref>{{Cite journal |last1=Lunzer |first1=Mark |last2=Golding |first2=G. Brian |last3=Dean |first3=Antony M. |date=2010-10-21 |title=Pervasive Cryptic Epistasis in Molecular Evolution |journal=PLOS Genetics |language=en |volume=6 |issue=10 |pages=e1001162 |doi=10.1371/journal.pgen.1001162 |issn=1553-7404 |pmc=2958800 |pmid=20975933 |doi-access=free }}</ref> tested the outcome of swapping divergent amino acids between two orthologous proteins of isopropymalate dehydrogenase (IMDH). They substituted 168 amino acids in ''Escherichia coli'' IMDH that are wild type residues in IMDH ''Pseudomonas aeruginosa''. They found that over one third of these substitutions compromised IMDH enzymatic activity in the ''Escherichia coli'' genetic background. This demonstrated that identical amino acid states can result in different phenotypic states depending on the genetic background. Corrigan et al. 2011 demonstrated how staphylococcus aureus was able to grow normally without the presence of lipoteichoic acid due to compensatory mutations.<ref name="Corrigan-2011">{{Cite journal |last1=Corrigan |first1=Rebecca M. |last2=Abbott |first2=James C. |last3=Burhenne |first3=Heike |last4=Kaever |first4=Volkhard |last5=Gründling |first5=Angelika |date=2011-09-01 |title=c-di-AMP Is a New Second Messenger in Staphylococcus aureus with a Role in Controlling Cell Size and Envelope Stress |journal=PLOS Pathogens |volume=7 |issue=9 |pages=e1002217 |doi=10.1371/journal.ppat.1002217 |issn=1553-7366 |pmc=3164647 |pmid=21909268 |doi-access=free }}</ref> Whole genome sequencing results revealed that when Cyclic-di-AMP phosphodiesterase (GdpP) was disrupted in this bacterium, it compensated for the disappearance of the cell wall polymer, resulting in normal cell growth.<ref name="Corrigan-2011" />

Research has shown that bacteria can gain drug resistance through compensatory mutations that do not impede or having little effect on fitness.<ref name="Comas-2012">{{Cite journal |last1=Comas |first1=Iñaki |last2=Borrell |first2=Sonia |last3=Roetzer |first3=Andreas |last4=Rose |first4=Graham |last5=Malla |first5=Bijaya |last6=Kato-Maeda |first6=Midori |last7=Galagan |first7=James |last8=Niemann |first8=Stefan |last9=Gagneux |first9=Sebastien |date=January 2012 |title=Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes |journal=Nature Genetics |language=en |volume=44 |issue=1 |pages=106–110 |doi=10.1038/ng.1038 |pmid=22179134 |pmc=3246538 |issn=1546-1718}}</ref> Previous research from Gagneux et al. 2006 has found that laboratory grown M. tuberculosis strains with rifampicin resistance have reduced fitness, however drug resistant clinical strains of this pathogenic bacteria do not have reduced fitness.<ref name="Gagneux-2006">{{Cite journal |last1=Gagneux |first1=Sebastien |last2=Long |first2=Clara Davis |last3=Small |first3=Peter M. |last4=Van |first4=Tran |last5=Schoolnik |first5=Gary K. |last6=Bohannan |first6=Brendan J. M. |date=2006-06-30 |title=The competitive cost of antibiotic resistance in Mycobacterium tuberculosis |url=https://pubmed.ncbi.nlm.nih.gov/16809538/ |journal=Science |volume=312 |issue=5782 |pages=1944–1946 |doi=10.1126/science.1124410 |issn=1095-9203 |pmid=16809538|bibcode=2006Sci...312.1944G |s2cid=7454895 }}</ref> Comas et al. 2012 used whole genome comparisons between clinical strains and lab derived mutants to determine the role and contribution of compensatory mutations in drug resistance to rifampicin.<ref name="Comas-2012" /> Genome analysis reveal rifampicin resistant strains have a mutation in rpoA and rpoC.<ref name="Comas-2012" /> A similar study investigated the bacterial fitness associated with compensatory mutations in rifampin resistant Escherichia coli.<ref name="Reynolds-2000">{{Cite journal |last=Reynolds |first=M. G. |date=December 2000 |title=Compensatory evolution in rifampin-resistant Escherichia coli |journal=Genetics |volume=156 |issue=4 |pages=1471–1481 |doi=10.1093/genetics/156.4.1471 |issn=0016-6731 |pmc=1461348 |pmid=11102350}}</ref> Results obtained from this study demonstrate that drug resistance is linked to bacterial fitness as higher fitness costs are linked to greater transcription errors.<ref name="Reynolds-2000" />

==== Experiment in virus ====
Gong et al.<ref>{{Cite journal |last1=Gong |first1=Lizhi Ian |last2=Suchard |first2=Marc A |last3=Bloom |first3=Jesse D |date=2013-05-14 |editor-last=Pascual |editor-first=Mercedes |title=Stability-mediated epistasis constrains the evolution of an influenza protein |journal=eLife |volume=2 |pages=e00631 |doi=10.7554/eLife.00631 |issn=2050-084X |pmc=3654441 |pmid=23682315 |doi-access=free }}</ref> collected obtained genotype data of influenza nucleoprotein from different timelines and temporally ordered them according to their time of origin. Then they isolated 39 amino acid substitutions that occurred in different timelines and substituted them in a genetic background that approximated the ancestral genotype. They found that 3 of the 39 substitutions significantly reduced the fitness of the ancestral background. Compensatory mutations are new mutations that arise and have a positive or neutral impact on a populations fitness.<ref name="Davis-2009">{{Cite journal |last1=Davis |first1=Brad H. |last2=Poon |first2=Art F.Y. |last3=Whitlock |first3=Michael C. |date=2009-05-22 |title=Compensatory mutations are repeatable and clustered within proteins |journal=Proceedings of the Royal Society B: Biological Sciences |volume=276 |issue=1663 |pages=1823–1827 |doi=10.1098/rspb.2008.1846 |issn=0962-8452 |pmc=2674493 |pmid=19324785}}</ref> Previous research has shown that populations have can compensate detrimental mutations.<ref name="Barešić-2011"/><ref name="Davis-2009" /><ref>{{Cite journal |last1=Azbukina |first1=Nadezhda |last2=Zharikova |first2=Anastasia |last3=Ramensky |first3=Vasily |date=2022-10-01 |title=Intragenic compensation through the lens of deep mutational scanning |url=https://doi.org/10.1007/s12551-022-01005-w |journal=Biophysical Reviews |language=en |volume=14 |issue=5 |pages=1161–1182 |doi=10.1007/s12551-022-01005-w |issn=1867-2469 |pmc=9636336 |pmid=36345285}}</ref> Burch and Chao tested [[Biology:Fisher's geometric model|Fisher's geometric model]] of adaptive evolution by testing whether bacteriophage φ6 evolves by small steps.<ref name="Burch-1999">{{Cite journal |last1=Burch |first1=Christina L |last2=Chao |first2=Lin |date=1999-03-01 |title=Evolution by Small Steps and Rugged Landscapes in the RNA Virus ϕ6 |url=https://academic.oup.com/genetics/article/151/3/921/6034699 |journal=Genetics |language=en |volume=151 |issue=3 |pages=921–927 |doi=10.1093/genetics/151.3.921 |issn=1943-2631 |pmc=1460516 |pmid=10049911}}</ref> Their results showed that [[Biology:Bacteriophage|bacteriophage]] φ6 fitness declined rapidly and recovered in small steps .<ref name="Burch-1999" /> Viral nucleoproteins have been shown to avoid cytotoxic T lymphocytes (CTLs) through arginine-to glycine substitutions.<ref name="Rimmelzwaan-2005">{{Cite journal |last1=Rimmelzwaan |first1=G. F. |last2=Berkhoff |first2=E. G. M. |last3=Nieuwkoop |first3=N. J. |last4=Smith |first4=D. J. |last5=Fouchier |first5=R. A. M. |last6=Osterhaus |first6=A. D. M. E.YR 2005 |title=Full restoration of viral fitness by multiple compensatory co-mutations in the nucleoprotein of influenza A virus cytotoxic T-lymphocyte escape mutants |journal=Journal of General Virology |year=2005 |volume=86 |issue=6 |pages=1801–1805 |doi=10.1099/vir.0.80867-0 |pmid=15914859 |issn=1465-2099|doi-access=free |hdl=1765/8466 |hdl-access=free }}</ref> This substitution mutations impacts the fitness of viral nucleoproteins, however compensatory co-mutations impede fitness declines and aid the virus to avoid recognition from CTLs.<ref name="Rimmelzwaan-2005" /> Mutations can have three different effects; mutations can have deleterious effects, some increase fitness through compensatory mutations, and lastly mutations can be counterbalancing resulting in compensatory neutral mutations.<ref>{{Cite journal |last=Kimura |first=Motoo |date=1985-07-01 |title=The role of compensatory neutral mutations in molecular evolution |url=https://doi.org/10.1007/BF02923549 |journal=Journal of Genetics |language=en |volume=64 |issue=1 |pages=7–19 |doi=10.1007/BF02923549 |s2cid=129866 |issn=0973-7731}}</ref><ref name="Reynolds-2000" /><ref name="Gagneux-2006" />

==Application in human evolution and disease==
In the human genome, the frequency and characteristics of de novo mutations have been studied as important contextual factors to our evolution. Compared to the human reference genome, a typical human genome varies at approximately 4.1 to 5.0 million loci, and the majority of this genetic diversity is shared by nearly 0.5% of the population.<ref>{{cite journal |last1=1000 Genomes Project Consortium |display-authors=0 |title=A global reference for human genetic variation |date=2015 |volume=526 |issue=7571 |pages=68–74 |journal=Nature |doi=10.1038/nature15393 |pmid=26432245 |pmc=4750478 |bibcode=2015Natur.526...68T }}</ref> The typical human genome also contains 40,000 to 200,000 rare variants observed in less than 0.5% of the population that can only have occurred from at least one de novo germline mutation in the history of human evolution.<ref>{{cite journal |last1=Lupski |first1=James R. |last2=Belmont |first2=John W. |last3=Boerwinkle |first3=Eric |last4=Gibbs |first4=Richard A. |title=Clan Genomics and the Complex Architecture of Human Disease |date=2011 |volume=147 |issue=1 |pages=32–43 |journal=Cell |doi=10.1016/j.cell.2011.09.008 |pmid=21962505 |pmc=3656718 }}</ref> De novo mutations have also been researched as playing a crucial role in the persistence of genetic disease in humans. With recents advancements in next-generation sequencing (NGS), all types of de novo mutations within the genome can be directly studied, the detection of which provides a magnitude of insight toward the causes of both rare and common genetic disorders. Currently, the best estimate of the average human germline SNV mutation rate is 1.18 x 10^-8, with an approximate ~78 novel mutations per generation. The ability to conduct whole genome sequencing of parents and offspring allows for the comparison of mutation rates between generations, narrowing down the origin possibilities of certain genetic disorders.<ref>{{cite journal |last1=Veltman |first1=Joris A. |last2=Brunner |first2=Han G. |title=De novo mutations in human genetic Disease |date=2012 |url=https://www.nature.com/articles/nrg3241#citeas |journal=Nature Reviews Genetics |volume=13 |issue=8 |pages=565–575 |doi=10.1038/nrg3241 |pmid=22805709 |s2cid=21702926 |access-date=9 December 2023}}</ref>

==See also==
{{Columns-list|
* [[Medicine:Aneuploidy|Aneuploidy]]
* [[Biology:Antioxidant|Antioxidant]]
* [[Biology:Behavior mutation|Behavior mutation]]
* Budgerigar colour genetics
* [[Biology:DbDNV|DbDNV]] (2010)
* [[Biology:Deletion (genetics)|Deletion (genetics)]]
* [[Biology:Ecogenetics|Ecogenetics]]
* [[Biology:Embryology|Embryology]]
* [[Biology:Homeobox|Homeobox]]
* [[Biology:Human somatic variation|Human somatic variation]]
* [[Biology:Polyploidy|Polyploidy]]
* [[Biology:Robertsonian translocation|Robertsonian translocation]]
* [[Biology:Signature-tagged mutagenesis|Signature-tagged mutagenesis]]
* [[Biology:Somatic hypermutation|Somatic hypermutation]]
* [[Biology:TILLING (molecular biology)|TILLING (molecular biology)]]
* [[Biology:Trinucleotide repeat expansion|Trinucleotide repeat expansion]]
|colwidth=30em}}

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

==External links==
* {{cite episode |title=Genetic Mutation |url=http://www.bbc.co.uk/programmes/b008drvm |access-date=18 October 2015 |series=In Our Time| vauthors = Jones S, Woolfson A, Partridge L | author-link3=Linda Partridge |network=BBC Radio 4 |date=6 December 2007}}
* {{cite web |url=https://web.stanford.edu/group/hopes/cgi-bin/hopes_test/all-about-mutations/ |title=All About Mutations | vauthors = Liou S |date=5 February 2011 |website=HOPES |publisher=Huntington's Disease Outreach Project for Education at Stanford |access-date=18 October 2015}}
* {{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 |access-date=18 October 2015}}
* {{cite web |url=https://mutalyzer.nl/ |title=Welcome to the Mutalyzer website |publisher=Leiden University Medical Center |location=Leiden, the Netherlands |access-date=18 October 2015}} – The [[Medicine:Mutalyzer|Mutalyzer]] website.

{{Mutation}}
{{Chromosomal abnormalities}}
{{Evolution}}

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

{{Sourceattribution|Mutation}}