Editing Mutation (section)

== Causes ==
{{main|Mutagenesis}}
Four classes of mutations are (1) {{vanchor|spontaneous}} mutations (molecular decay), (2) mutations due to error-prone replication bypass of [[DNA damage (naturally occurring)|naturally occurring DNA damage]] (also called error-prone translesion synthesis), (3) errors introduced during DNA repair, and (4) induced mutations caused by [[mutagen]]s. Scientists may sometimes deliberately introduce mutations into cells or research organisms for the sake of scientific experimentation.<ref>{{Cite web |last=Alberts |first=B |date=2002 |title=Molecular Biology of the Cell: Studying Gene Expression and Function |url=https://www.ncbi.nlm.nih.gov/books/NBK26818/ |access-date=29 October 2024 |website=National Library of Medicine}}</ref>

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 [[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>
* [[Tautomer]]ism – A base is changed by the repositioning of a [[hydrogen]] atom, altering the hydrogen bonding pattern of that base, resulting in incorrect [[base pair]]ing during replication.<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 [[proton tunnelling]] is an important factor in the spontaneous creation of GC [[tautomer]]s.<ref>{{Cite journal | vauthors = Slocombe L, Sacchi M, Al-Khalili J |date=5 May 2022 |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>
* [[Depurination]] – Loss of a [[purine]] base (A or G) to form an apurinic site ([[AP site]]).
* [[Deamination]] – [[Hydrolysis]] changes a normal base to an atypical base containing a [[Ketone|keto]] group in place of the original [[amine]] group. Examples include C → U and A → HX ([[hypoxanthine]]), which can be corrected by DNA repair mechanisms; and 5MeC ([[5-methylcytosine]]) → T, which is less likely to be detected as a mutation because [[thymine]] is a normal DNA base.
* [[Slipped strand mispairing]] – Denaturation of the new strand from the template during replication, followed by renaturation in a different spot ("slipping"). This can lead to insertions or deletions.

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

=== Induced mutation ===

Induced mutations are alterations in the gene after it has come in contact with mutagens and environmental causes.

''Induced mutations'' on the molecular level can be caused by:
* Chemicals
** [[Hydroxylamine]]
** [[Base analogue]]s (e.g., [[Bromodeoxyuridine]] (BrdU))
** [[Alkylation|Alkylating agent]]s (e.g., [[ENU|''N''-ethyl-''N''-nitrosourea]] (ENU). These agents can mutate both replicating and non-replicating DNA. In contrast, a base analogue can mutate the DNA only when the analogue is incorporated in replicating the DNA. Each of these classes of chemical mutagens has certain effects that then lead to [[transition (genetics)|transition]]s, [[transversion]]s, or deletions.
** Agents that form [[DNA adduct]]s (e.g., [[ochratoxin A]])<ref>{{cite journal | vauthors = Pfohl-Leszkowicz A, Manderville RA | title = Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans | journal = Molecular Nutrition & Food Research | volume = 51 | issue = 1 | pages = 61–99 | date = January 2007 | pmid = 17195275 | doi = 10.1002/mnfr.200600137 }}</ref>
** DNA [[Intercalation (biochemistry)|intercalating]] agents (e.g., [[ethidium bromide]])
** [[Crosslinking of DNA|DNA crosslinkers]]
** [[Oxidative stress|Oxidative damage]]
** [[Nitrous acid]] converts amine groups on A and C to [[diazo]] groups, altering their hydrogen bonding patterns, which leads to incorrect base pairing during replication.
* Radiation
** [[Ultraviolet]] light (UV) (including [[non-ionizing radiation]]). Two nucleotide bases in DNA—[[cytosine]] and thymine—are most vulnerable to radiation that can change their properties. UV light can induce adjacent [[pyrimidine]] bases in a DNA strand to become covalently joined as a [[pyrimidine dimer]]. UV radiation, in particular longer-wave UVA, can also cause [[DNA oxidation|oxidative damage to DNA]].<ref name="Kozmin">{{cite journal | vauthors = Kozmin S, Slezak G, Reynaud-Angelin A, Elie C, de Rycke Y, Boiteux S, Sage E | title = UVA radiation is highly mutagenic in cells that are unable to repair 7,8-dihydro-8-oxoguanine in Saccharomyces cerevisiae | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 38 | pages = 13538–43 | date = September 2005 | pmid = 16157879 | pmc = 1224634 | doi = 10.1073/pnas.0504497102 | bibcode = 2005PNAS..10213538K | doi-access = free }}</ref>
** [[Ionizing radiation]]. Exposure to ionizing radiation, such as [[Gamma ray|gamma radiation]], can result in mutation, possibly resulting in cancer or death.

Whereas in former times mutations were assumed to occur by chance, or induced by mutagens, molecular mechanisms of mutation have been discovered in bacteria and across the tree of life. As S. Rosenberg states, "These mechanisms reveal a picture of highly regulated mutagenesis, up-regulated temporally by stress responses and activated when cells/organisms are maladapted to their environments—when stressed—potentially accelerating adaptation."<ref name="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" />