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mutation
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{{other uses}}{{short description|A permanent change of the nucleotide sequence of the genome of an organism}}{{Evolutionary biology|expanded=Process}}{{Genetics sidebar}}
missing image!
- Darwin Hybrid Tulip Mutation 2014-05-01.jpg -
A tulip flower exhibiting a partially yellow petal because of a mutation in its genes.
In biology, a mutation is the alteration of the nucleotide sequence of the genome of an organism, virus, or extrachromosomal DNA.WEB,weblink mutation {{!, Learn Science at Scitable|website=www.nature.com|language=en|access-date=2018-09-24}}Mutations result from errors during DNA replication (especially during meiosis) or other types of damage to DNA (such as may be caused by exposure to radiation or carcinogens), which then may undergo error-prone repair (especially microhomology-mediated end joiningJOURNAL, Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC, Homology and enzymatic requirements of microhomology-dependent alternative end joining, Cell Death & Disease, 6, 3, e1697, March 2015, 25789972, 4385936, 10.1038/cddis.2015.58, ), or cause an error during other forms of repair,JOURNAL, Chen J, Miller BF, Furano AV, Repair of naturally occurring mismatches can induce mutations in flanking DNA, eLife, 3, e02001, April 2014, 24843013, 3999860, 10.7554/elife.02001, JOURNAL, Rodgers K, McVey M, Error-Prone Repair of DNA Double-Strand Breaks, Journal of Cellular Physiology, 231, 1, 15–24, January 2016, 26033759, 4586358, 10.1002/jcp.25053, or else may cause an error during replication (translesion synthesis). Mutations may also result from insertion or deletion of segments of DNA due to mobile genetic elements.JOURNAL, Bertram JS, The molecular biology of cancer, Molecular Aspects of Medicine, 21, 6, 167–223, December 2000, 11173079, 10.1016/S0098-2997(00)00007-8, JOURNAL, Aminetzach YT, Macpherson JM, Petrov DA, Pesticide resistance via transposition-mediated adaptive gene truncation in Drosophila, Science, 309, 5735, 764–7, July 2005, 16051794, 10.1126/science.1112699, 2005Sci...309..764A, JOURNAL, Burrus V, Waldor MK, Shaping bacterial genomes with integrative and conjugative elements, Research in Microbiology, 155, 5, 376–86, June 2004, 15207870, 10.1016/j.resmic.2004.01.012, Mutations may or may not produce discernible changes in the observable characteristics (phenotype) of an organism. Mutations play a part in both normal and abnormal biological processes including: evolution, cancer, and the development of the immune system, including junctional diversity.The genomes of RNA viruses are based on RNA rather than DNA. The RNA viral genome can be double-stranded (as in DNA) or single-stranded. In some of these viruses (such as the single-stranded human immunodeficiency virus) replication occurs quickly and there are no mechanisms to check the genome for accuracy. This error-prone process often results in mutations.Mutation can result in many different types of change in sequences. Mutations in genes can either have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely. Mutations can also occur in nongenic regions. One study on genetic variations between different species of Drosophila suggests that, if a mutation changes a protein produced by a gene, the result is likely to be harmful, with an estimated 70 percent of amino acid polymorphisms that have damaging effects, and the remainder being either neutral or marginally beneficial.JOURNAL, Sawyer SA, Parsch J, Zhang Z, Hartl DL, Prevalence of positive selection among nearly neutral amino acid replacements in Drosophila, Proceedings of the National Academy of Sciences of the United States of America, 104, 16, 6504–10, April 2007, 17409186, 1871816, 10.1073/pnas.0701572104, 2007PNAS..104.6504S, Zhi Zhang, Due to the damaging effects that mutations can have on genes, organisms have mechanisms such as DNA repair to prevent or correct mutations by reverting the mutated sequence back to its original state.

Description

Mutations can involve the duplication of large sections of DNA, usually through genetic recombination.JOURNAL, Hastings PJ, Lupski JR, Rosenberg SM, Ira G, Mechanisms of change in gene copy number, Nature Reviews. Genetics, 10, 8, 551–64, August 2009, 19597530, 2864001, 10.1038/nrg2593, James R. Lupski, 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.BOOK, Carroll, Sean B., Sean B. Carroll, Grenier, Jennifer K., Weatherbee, Scott D., vanc, 2005, From DNA to Diversity: Molecular Genetics and the Evolution of Animal Design, 2nd, Malden, MA, Wiley-Blackwell, Blackwell Publishing, 978-1-4051-1950-4, 2003027991, 53972564, Most genes belong to larger gene families of shared ancestry, detectable by their sequence homology.JOURNAL, Harrison PM, Gerstein M, Studying genomes through the aeons: protein families, pseudogenes and proteome evolution, Journal of Molecular Biology, 318, 5, 1155–74, May 2002, 12083509, 10.1016/S0022-2836(02)00109-2, Mark Bender Gerstein, 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.JOURNAL, Orengo CA, Thornton JM, Protein families and their evolution-a structural perspective, Annual Review of Biochemistry, 74, 867–900, July 2005, 15954844, 10.1146/annurev.biochem.74.082803.133029, Janet Thornton, JOURNAL, Long M, Betrán E, Thornton K, Wang W, The origin of new genes: glimpses from the young and old, Nature Reviews. Genetics, 4, 11, 865–75, November 2003, 14634634, 10.1038/nrg1204, Wen Wang, Here, protein domains act as modules, each with a particular and independent function, that can be mixed together to produce genes encoding new proteins with novel properties.JOURNAL, Wang M, Caetano-Anollés G, The evolutionary mechanics of domain organization in proteomes and the rise of modularity in the protein world, Structure, 17, 1, 66–78, January 2009, 19141283, 10.1016/j.str.2008.11.008, Gustavo Caetano-Anolles, For example, the human eye uses four genes to make structures that sense light: three for cone cell or color vision and one for rod cell or night vision; all four arose from a single ancestral gene.JOURNAL, Bowmaker JK, Evolution of colour vision in vertebrates, Eye, 12, Pt 3b, 541–7, May 1998, 9775215, 10.1038/eye.1998.143, Another advantage of duplicating a gene (or even an entire genome) is that this increases engineering redundancy; this allows one gene in the pair to acquire a new function while the other copy performs the original function.JOURNAL, Gregory TR, Hebert PD, The modulation of DNA content: proximate causes and ultimate consequences, Genome Research, 9, 4, 317–24, April 1999, 10207154, 10.1101/gr.9.4.317, T. Ryan Gregory, Paul D. N. Hebert, 2019-09-03, JOURNAL, Hurles M, Gene duplication: the genomic trade in spare parts, PLoS Biology, 2, 7, E206, July 2004, 15252449, 449868, 10.1371/journal.pbio.0020206, Other types of mutation occasionally create new genes from previously noncoding DNA.JOURNAL, Liu N, Okamura K, Tyler DM, Phillips MD, Chung WJ, Lai EC, The evolution and functional diversification of animal microRNA genes, Cell Research, 18, 10, 985–96, October 2008, 18711447, 2712117, 10.1038/cr.2008.278, JOURNAL, Siepel A, Darwinian alchemy: Human genes from noncoding DNA, Genome Research, 19, 10, 1693–5, October 2009, 19797681, 2765273, 10.1101/gr.098376.109, Adam C. Siepel, Changes in chromosome number may involve even larger mutations, where segments of the DNA within chromosomes break and then rearrange. For example, in the Homininae, two chromosomes fused to produce human chromosome 2; this fusion did not occur in the lineage of the other apes, and they retain these separate chromosomes.JOURNAL, Zhang J, Wang X, Podlaha O, Testing the chromosomal speciation hypothesis for humans and chimpanzees, Genome Research, 14, 5, 845–51, May 2004, 15123584, 479111, 10.1101/gr.1891104, In evolution, the most important role of such chromosomal rearrangements may be to accelerate the divergence of a population into new species by making populations less likely to interbreed, thereby preserving genetic differences between these populations.JOURNAL, Ayala FJ, Coluzzi M, Chromosome speciation: humans, Drosophila, and mosquitoes, Proceedings of the National Academy of Sciences of the United States of America, 102 Suppl 1, Suppl 1, 6535–42, May 2005, 15851677, 1131864, 10.1073/pnas.0501847102, 2005PNAS..102.6535A, Francisco J. Ayala, Sequences of DNA that can move about the genome, such as transposons, make up a major fraction of the genetic material of plants and animals, and may have been important in the evolution of genomes.JOURNAL, Hurst GD, Werren JH, The role of selfish genetic elements in eukaryotic evolution, Nature Reviews Genetics, 2, 8, 597–606, August 2001, 11483984, 10.1038/35084545, For example, more than a million copies of the Alu sequence are present in the human genome, and these sequences have now been recruited to perform functions such as regulating gene expression.JOURNAL, Häsler J, Strub K, Alu elements as regulators of gene expression, Nucleic Acids Research, 34, 19, 5491–7, November 2006, 17020921, 1636486, 10.1093/nar/gkl706, Another effect of these mobile DNA sequences is that when they move within a genome, they can mutate or delete existing genes and thereby produce genetic diversity.Nonlethal mutations accumulate within the gene pool and increase the amount of genetic variation.JOURNAL, Eyre-Walker A, Keightley PD, The distribution of fitness effects of new mutations, Nature Reviews Genetics, 8, 8, 610–8, August 2007, 17637733, 10.1038/nrg2146,weblink Peter Keightley, live,weblink" title="web.archive.org/web/20160304195010weblink">weblink 4 March 2016, dmy-all, The abundance of some genetic changes within the gene pool can be reduced by natural selection, while other "more favorable" mutations may accumulate and result in adaptive changes.File:Prodryas.png|thumb|right|199px|Prodryas persephone, a Late EoceneEoceneFor example, a butterfly may produce offspring with new mutations. The majority of these mutations will have no effect; but one might change the color of one of the butterfly's offspring, making it harder (or easier) for predators to see. If this color change is advantageous, the chances of this butterfly's surviving and producing its own offspring are a little better, and over time the number of butterflies with this mutation may form a larger percentage of the population.Neutral mutations are defined as mutations whose effects do not influence the fitness of an individual. These can increase in frequency over time due to genetic drift. It is believed that the overwhelming majority of mutations have no significant effect on an organism's fitness.BOOK,weblink's+fitness.#v=onepage&q=t%20is%20believed%20that%20the%20overwhelming%20majority%20of%20mutations%20have%20no%20significant%20effect%20on%20an%20organism's%20fitness.&f=false, Fundamentals of Polymer Physics and Molecular Biophysics, Bohidar, Himadri B., vanc, January 2015, Cambridge University Press, 978-1-316-09302-3, {{better source|note=Preferably a biology review paper or textbook|date=January 2017}} Also, DNA repair mechanisms are able to mend most changes before they become permanent mutations, and many organisms have mechanisms for eliminating otherwise-permanently mutated somatic cells.Beneficial mutations can improve reproductive success.BOOK,weblink Dear Mr. Darwin: Letters on the Evolution of Life and Human Nature, Dover, Gabriel A., Darwin, Charles, vanc, 2000, University of California Press, 9780520227903, en, BOOK,weblink Genetics and Evolution of Infectious Diseases, Tibayrenc, Michel, 2017-01-12, Elsevier, 9780128001530, en,

History

File:Hugo de Vries (1848-1935), by Thérèse Schwartze (1851-1918).jpg|thumb|Hugo de Vries, making a painting of an evening primrose, the plant which had apparently produced new forms by large mutations in his experiments, by Thérèse SchwartzeThérèse SchwartzeMutationism is one of several alternatives to evolution by natural selection that have existed both before and after the publication of Charles Darwin's 1859 book, On the Origin of Species. In the theory, mutation was the source of novelty, creating new forms and new species, potentially instantaneously,BOOK, Bowler, Peter J., Peter J. Bowler, The Eclipse of Darwinism, 1992, 1983, 198, in a sudden jump.BOOK, Smocovitis, Vassiliki Betty, 1996, Unifying Biology: The Evolutionary Synthesis and Evolutionary Biology, Princeton, NJ, Princeton University Press, 978-0-691-03343-3, 96005605, 34411399, 56, This was envisaged as driving evolution, which was limited by the supply of mutations.Before Darwin, biologists commonly believed in saltationism, the possibility of large evolutionary jumps, including immediate speciation. For example, in 1822 Étienne Geoffroy Saint-Hilaire argued that species could be formed by sudden transformations, or what would later be called macromutation.BOOK, Hallgrímsson, Benedikt, Hall, Brian K., 2011, Variation: A Central Concept in Biology, Academic Press, 18, Darwin opposed saltation, insisting on gradualism in evolution as in geology. In 1864, Albert von Kölliker revived Geoffroy's theory.Sewall Wright. (1984). Evolution and the Genetics of Populations: Genetics and Biometric Foundations Volume 1. University of Chicago Press. p. 10 In 1901 the geneticist Hugo de Vries gave the name "mutation" to seemingly new forms that suddenly arose in his experiments on the evening primrose Oenothera lamarckiana, and in the first decade of the 20th century, mutationism, or as de Vries named it mutationstheorie,BOOK, De Vries, Hugo, Hugo de Vries, 1905, Species and Varieties: Their Origin by Mutation, became a rival to Darwinism supported for a while by geneticists including William Bateson,BOOK, Bateson, William, William Bateson, 1894, Materials for the Study of Variation, Treated with Especial Regard to Discontinuity in the Origin of Species, Thomas Hunt Morgan, and Reginald Punnett.BOOK, Punnett, Reginald C., Reginald Punnett, Mimicry in Butterflies, 1915, Cambridge University Press, Understanding of mutationism is clouded by the mid-20th century portrayal of the early mutationists by supporters of the modern synthesis as opponents of Darwinian evolution and rivals of the biometrics school who argued that selection operated on continuous variation. In this portrayal, mutationism was defeated by a synthesis of genetics and natural selection that supposedly started later, around 1918, with work by the mathematician Ronald Fisher.BOOK, Ernst Mayr, Mayr, Ernst, 2007, What Makes Biology Unique?: Considerations on the Autonomy of a Scientific Discipline, Cambridge University Press, BOOK, Provine, W. B., 2001, The Origins of Theoretical Population Genetics, with a new afterword, University of Chicago Press, Chicago, 56–107, However, the alignment of Mendelian genetics and natural selection began as early as 1902 with a paper by Udny Yule,JOURNAL, Yule, G. Udny, Udny Yule, Mendel's Laws and their probable relations to inter-racial heredity, New Phytologist, 1, 10, 226–227, 1902, 10.1111/j.1469-8137.1902.tb07336.x, and built up with theoretical and experimental work in Europe and America. Despite the controversy, the early mutationists had by 1918 already accepted natural selection and explained continuous variation as the result of multiple genes acting on the same characteristic, such as height.JOURNAL, Stoltzfus, A., Cable, K., 2014, Mendelian-Mutationism: The Forgotten Evolutionary Synthesis, J Hist Biol, 47, 4, 501–546, 10.1007/s10739-014-9383-2, 24811736, Mutationism, along with other alternatives to Darwinism like Lamarckism and orthogenesis, was discarded by most biologists as they came to see that Mendelian genetics and natural selection could readily work together; mutation took its place as a source of the genetic variation essential for natural selection to work on. However, mutationism did not entirely vanish. In 1940, Richard Goldschmidt again argued for single-step speciation by macromutation, describing the organisms thus produced as "hopeful monsters", earning widespread ridicule.Gould, S. J. (1982). "The uses of heresey; an introduction to Richard Goldschmidt's The Material Basis of Evolution." pp. xiii-xlii. Yale University Press.BOOK, Ruse, Michael, Michael Ruse, 1996, Monad to man: the Concept of Progress in Evolutionary Biology, Harvard University Press, 978-0-674-03248-4, 412–413, In 1987, Masatoshi Nei argued controversially that evolution was often mutation-limited.JOURNAL, A. Stoltzfus, 2014, In search of mutation-driven evolution, Evolution & Development, 16, 57–59, 10.1111/ede.12062, Modern biologists such as Douglas J. Futuyma conclude that essentially all claims of evolution driven by large mutations can be explained by Darwinian evolution.BOOK, Futuyma, Douglas J., Douglas J. Futuyma, Macroevolution, Serrelli, E., Gontier, N., Can Modern Evolutionary Theory Explain Macroevolution?, 2015, Springer, 29–85,weblink

Causes

Four classes of mutations are (1) spontaneous mutations (molecular decay), (2) mutations due to error-prone replication bypass of naturally occurring DNA damage (also called error-prone translesion synthesis), (3) errors introduced during DNA repair, and (4) induced mutations caused by mutagens. Scientists may also deliberately introduce mutant sequences through DNA manipulation for the sake of 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.WEB,weblink Cancer Is Partly Caused By Bad Luck, Study Finds, live,weblink" title="web.archive.org/web/20170713114206weblink">weblink 13 July 2017, dmy-all, 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.WEB,weblink Older fathers pass on more genetic mutations, study shows, Alok, Jha, 22 August 2012, the Guardian,

Spontaneous mutation

Spontaneous mutations occur with non-zero probability even given a healthy, uncontaminated cell. They can be characterized by the specific change:WEB,weblink Mutation, Mutagens, and DNA Repair, Montelone, Beth A., vanc, 1998, www-personal.ksu.edu, 2015-10-02, live,weblink" title="web.archive.org/web/20150926115801weblink">weblink 26 September 2015, dmy-all,
  • Tautomerism — A base is changed by the repositioning of a hydrogen atom, altering the hydrogen bonding pattern of that base, resulting in incorrect base pairing during replication.
  • Depurination — Loss of a purine base (A or G) to form an apurinic site (AP site).
  • Deamination — Hydrolysis changes a normal base to an atypical base containing a keto group in place of the original amine group. Examples include C → U and A → HX (hypoxanthine), which can be corrected by DNA repair mechanisms; and 5MeC (5-methylcytosine) → T, which is less likely to be detected as a mutation because thymine is a normal DNA base.
  • Slipped strand mispairing — Denaturation of the new strand from the template during replication, followed by renaturation in a different spot ("slipping"). This can lead to insertions or deletions.
  • Replication slippage

Error-prone replication bypass

There is increasing evidence that the majority of spontaneously arising mutations are due to error-prone replication (translesion synthesis) past DNA damage in the template strand. Naturally occurring oxidative DNA damages arise at least 10,000 times per cell per day in humans and 50,000 times or more per cell per day in rats.BOOK, Bernstein C, Prasad AR, Nfonsam V, Bernstein H, 2013, DNA Damage, DNA Repair and Cancer, New Research Directions in DNA Repair, Prof. Clark Chen (Ed.), 978-953-51-1114-6, intechopen.com,weblink live,weblink" title="web.archive.org/web/20150924035948weblink">weblink 24 September 2015, dmy-all, In mice, the majority of mutations are caused by translesion synthesis.JOURNAL, Stuart GR, Oda Y, de Boer JG, Glickman BW, Mutation frequency and specificity with age in liver, bladder and brain of lacI transgenic mice, Genetics, 154, 3, 1291–300, March 2000, 10757770, 1460990, Likewise, in yeast, Kunz et al.JOURNAL, Kunz BA, Ramachandran K, Vonarx EJ, DNA sequence analysis of spontaneous mutagenesis in Saccharomyces cerevisiae, Genetics, 148, 4, 1491–505, April 1998, 9560369, 1460101, found that more than 60% of the spontaneous single base pair substitutions and deletions were caused by translation 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 nucleotides to allow somewhat inaccurate alignment of the two ends for rejoining followed by addition of nucleotides to fill in gaps. As a consequence, NHEJ often introduces mutations.JOURNAL, Lieber MR, The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway, Annual Review of Biochemistry, 79, 181–211, July 2010, 20192759, 3079308, 10.1146/annurev.biochem.052308.093131, File:Benzopyrene DNA adduct 1JDG.png|thumb|right|250px|A covalent adduct between the metabolite of benzo[a]pyrene, the major mutagen in (tobacco smoking|tobacco smoke]], and DNACreated from PDB 1JDG {{webarchive|url=https://web.archive.org/web/20151231235020weblink |date=31 December 2015 }})

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 analogs (e.g., Bromodeoxyuridine (BrdU))
    • Alkylating agents (e.g., N-ethyl-N-nitrosourea (ENU). These agents can mutate both replicating and non-replicating DNA. In contrast, a base analog can mutate the DNA only when the analog is incorporated in replicating the DNA. Each of these classes of chemical mutagens has certain effects that then lead to transitions, transversions, or deletions.
    • Agents that form DNA adducts (e.g., ochratoxin A)JOURNAL, Pfohl-Leszkowicz A, Manderville RA, Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans, Molecular Nutrition & Food Research, 51, 1, 61–99, January 2007, 17195275, 10.1002/mnfr.200600137,
    • DNA intercalating agents (e.g., ethidium bromide)
    • DNA crosslinkers
    • (File:Gene structure eukaryote 2 annotated.svg|thumb|242x242px|This figure depicts the following processes of transcription, splicing, and translation of a eukaryotic gene.)Oxidative damage
    • Nitrous acid converts amine groups on A and C to diazo groups, altering their hydrogen bonding patterns, which leads to incorrect base pairing during replication.
  • Radiation
    • Ultraviolet light (UV) (non-ionizing radiation). Two nucleotide bases in DNA—cytosine and thymine—are most vulnerable to radiation that can change their properties. UV light can induce adjacent pyrimidine bases in a DNA strand to become covalently joined as a pyrimidine dimer. UV radiation, in particular longer-wave UVA, can also cause oxidative damage to DNA.JOURNAL, Kozmin S, Slezak G, Reynaud-Angelin A, Elie C, de Rycke Y, Boiteux S, Sage E, UVA radiation is highly mutagenic in cells that are unable to repair 7,8-dihydro-8-oxoguanine in Saccharomyces cerevisiae, Proceedings of the National Academy of Sciences of the United States of America, 102, 38, 13538–43, September 2005, 16157879, 1224634, 10.1073/pnas.0504497102, 2005PNAS..10213538K,
    • Ionizing radiation. Exposure to ionizing radiation, such as 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." JOURNAL, Fitzgerald DM, Rosenberg SM, What is mutation? A chapter in the series: How microbes "jeopardize" the modern synthesis, PLoS Genetics, 15, 4, e1007995, April 2019, 30933985, 10.1371/journal.pgen.1007995, 6443146, 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,JOURNAL, Galhardo RS, Hastings PJ, Rosenberg SM, Mutation as a stress response and the regulation of evolvability, Critical Reviews in Biochemistry and Molecular Biology, 42, 5, 399–435, 2007-01-01, 17917874, 3319127, 10.1080/10409230701648502, ectopic intrachromosomal recombination JOURNAL, Quinto-Alemany D, Canerina-Amaro A, Hernández-Abad LG, Machín F, Romesberg FE, Gil-Lamaignere C, Yeasts acquire resistance secondary to antifungal drug treatment by adaptive mutagenesis, PLOS ONE, 7, 7, e42279, 2012-07-31, 22860105, 10.1371/journal.pone.0042279, Joy, Sturtevant, 3409178, 2012PLoSO...742279Q, and other chromosomal events such as duplications.

Classification of types

{{See also|Chromosome abnormality}}

By effect on structure

(File:Chromosomes mutations-en.svg|thumb|right|301px|Five types of chromosomal mutations.)File:Notable mutations.svg|301px|thumb|right|Selection of disease-causing mutations, in a standard table of the genetic code of amino acids.References for the image are found in Wikimedia Commons page at: (Commons:File:Notable mutations.svg#References).]]The sequence of a gene can be altered in a number of ways.WEB, Rahman, Nazneen, The clinical impact of DNA sequence changes,weblink Transforming Genetic Medicine Initiative, June 27, 2017, live,weblink" title="web.archive.org/web/20170804060005weblink">weblink 4 August 2017, dmy-all, Gene mutations have varying effects on health depending on where they occur and whether they alter the function of essential proteins.Mutations in the structure of genes can be classified into several types.

Small-scale mutations

Small-scale mutations affect a gene in one or a few nucleotides. (If only a single nucleotide is affected, they are called point mutations.) Small-scale mutations include:
  • Insertions add one or more extra nucleotides into the DNA. They are usually caused by transposable elements, or errors during replication of repeating elements. Insertions in the coding region of a gene may alter splicing of the mRNA (splice site mutation), or cause a shift in the reading frame (frameshift), both of which can significantly alter the gene product. Insertions can be reversed by excision of the transposable element.
  • Deletionsor/Deficency 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.
  • Substitution mutations, often caused by chemicals or malfunction of DNA replication, exchange a single nucleotide for another.JOURNAL, Freese E, Proceedings of the National Academy of Sciences of the United States of America, 45, 4, 622–33, April 1959, 16590424, 222607, 10.1073/pnas.45.4.622, Ernst Freese, 1959PNAS...45..622F, The Difference Between Spontaneous and Base-Analogue Induced Mutations of Phage T4, These changes are classified as transitions or transversions.JOURNAL, Freese, Ernst, vanc, June 1959, The specific mutagenic effect of base analogues on Phage T4, Journal of Molecular Biology, 1, 2, 87–105, 10.1016/S0022-2836(59)80038-3, Most common is the transition that exchanges a purine for a purine (A ↔ G) or a pyrimidine for a pyrimidine, (C ↔ T). A transition can be caused by nitrous acid, base mispairing, or mutagenic base analogs such as BrdU. Less common is a transversion, which exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T ↔ A/G). An example of a transversion is the conversion of adenine (A) into a cytosine (C). Point mutations are modifications of single base pairs of DNA or other small base pairs within a gene. A point mutation can be reversed by another point mutation, in which the nucleotide is changed back to its original state (true reversion) or by second-site reversion (a complementary mutation elsewhere that results in regained gene functionality). As discussed below, point mutations that occur within the protein coding region of a gene may be classified as synonymous or nonsynonymous substitutions, the latter of which in turn can be divided into missense or nonsense mutations.

Large-scale mutations

Large-scale mutations in chromosomal structure include:
  • Amplifications (or gene duplications)or/ repetition of a chromosomal segment or presence of extra piece of a chromosome broken piece of a chromosome may become attached to a Homologous or non Homologous chromosome so that some of the genes are present in more than two doses leading to multiple copies of all chromosomal regions, increasing the dosage of the genes located within them.
  • Deletions of large chromosomal regions, leading to loss of the genes within those regions.
  • Mutations whose effect is to juxtapose previously separate pieces of DNA, potentially bringing together separate genes to form functionally distinct fusion genes (e.g., bcr-abl).
  • Large scale changes to the structure of chromosomes called chromosomal rearrangement that can lead to a decrease of fitness but also to speciation in isolated, inbred populations. These include:
    • Chromosomal translocations: interchange of genetic parts from nonhomologous chromosomes.
    • Chromosomal inversions: reversing the orientation of a chromosomal segment.
    • Non-homologous chromosomal crossover.
    • Interstitial deletions: an intra-chromosomal deletion that removes a segment of DNA from a single chromosome, thereby apposing previously distant genes. For example, cells isolated from a human astrocytoma, a type of brain tumor, were found to have a chromosomal deletion removing sequences between the Fused in Glioblastoma (FIG) gene and the receptor tyrosine kinase (ROS), producing a fusion protein (FIG-ROS). The abnormal FIG-ROS fusion protein has constitutively active kinase activity that causes oncogenic transformation (a transformation from normal cells to cancer cells).
  • Loss of heterozygosity: loss of one allele, either by a deletion or a genetic recombination event, in an organism that previously had two different alleles.

By effect on function

  • Loss-of-function mutations, also called inactivating mutations, result in the gene product having less or no function (being partially or wholly inactivated). When the allele has a complete loss of function (null allele), it is often called an amorph or amorphic mutation in the Muller's morphs schema. Phenotypes associated with such mutations are most often recessive. Exceptions are when the organism is haploid, or when the reduced dosage of a normal gene product is not enough for a normal phenotype (this is called haploinsufficiency).
  • Gain-of-function mutations, also called activating mutations, change the gene product such that its effect gets stronger (enhanced activation) or even is superseded by a different and abnormal function. When the new allele is created, a heterozygote containing the newly created allele as well as the original will express the new allele; genetically this defines the mutations as dominant phenotypes. Several of Muller's morphs correspond to gain of function, including hypermorph and neomorph. In December 2017, the U.S. government lifted a temporary ban implemented in 2014 that banned federal funding for any new "gain-of-function" experiments that enhance pathogens "such as Avian influenza, SARS and the Middle East Respiratory Syndrome or MERS viruses."NEWS,weblink U.S. Lifts Funding Ban on Studies That Enhance Dangerous Germs, Steenhuysen, Julie, 2017-12-19, U.S. News & World Report, 2018-01-15,
  • Dominant negative mutations (also called antimorphic mutations) have an altered gene product that acts antagonistically to the wild-type allele. These mutations usually result in an altered molecular function (often inactive) and are characterized by a dominant or semi-dominant phenotype. In humans, dominant negative mutations have been implicated in cancer (e.g., mutations in genes p53,JOURNAL, Goh AM, Coffill CR, Lane DP, The role of mutant p53 in human cancer, The Journal of Pathology, 223, 2, 116–26, January 2011, 21125670, 10.1002/path.2784, David Lane (oncologist), ATM,JOURNAL, Chenevix-Trench G, Spurdle AB, Gatei M, Kelly H, Marsh A, Chen X, Donn K, Cummings M, Nyholt D, Jenkins MA, Scott C, Pupo GM, Dörk T, Bendix R, Kirk J, Tucker K, McCredie MR, Hopper JL, Sambrook J, Mann GJ, Khanna KK, Dominant negative ATM mutations in breast cancer families, Journal of the National Cancer Institute, 94, 3, 205–15, February 2002, 11830610, 10.1093/jnci/94.3.205, Georgia Chenevix-Trench, 10.1.1.557.6394, CEBPAJOURNAL, Paz-Priel I, Friedman A, C/EBPα dysregulation in AML and ALL, Critical Reviews in Oncogenesis, 16, 1–2, 93–102, 2011, 22150310, 3243939, 10.1615/critrevoncog.v16.i1-2.90, and PPARgammaJOURNAL, Capaccio D, Ciccodicola A, Sabatino L, Casamassimi A, Pancione M, Fucci A, Febbraro A, Merlino A, Graziano G, Colantuoni V, A novel germline mutation in peroxisome proliferator-activated receptor gamma gene associated with large intestine polyp formation and dyslipidemia, Biochimica et Biophysica Acta, 1802, 6, 572–81, June 2010, 20123124, 10.1016/j.bbadis.2010.01.012, ). Marfan syndrome is caused by mutations in the FBN1 gene, located on chromosome 15, which encodes fibrillin-1, a glycoprotein component of the extracellular matrix.JOURNAL, McKusick VA, The defect in Marfan syndrome, Nature, 352, 6333, 279–81, July 1991, 1852198, 10.1038/352279a0, 1991Natur.352..279M, Victor A. McKusick, Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency.JOURNAL, Judge DP, Biery NJ, Keene DR, Geubtner J, Myers L, Huso DL, Sakai LY, Dietz HC, Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome, The Journal of Clinical Investigation, 114, 2, 172–81, July 2004, 15254584, 449744, 10.1172/JCI20641, JOURNAL, Judge DP, Dietz HC, Marfan's syndrome, Lancet, 366, 9501, 1965–76, December 2005, 16325700, 1513064, 10.1016/S0140-6736(05)67789-6,
  • Hypomorphs, after Mullerian classification, are characterized by altered gene products that acts with decreased gene expression compared to the wild type allele.
  • Neomorphs are characterized by the control of new protein product synthesis.
  • Lethal mutations are mutations that lead to the death of the organisms that carry the mutations.
  • A back mutation or reversion is a point mutation that restores the original sequence and hence the original phenotype.JOURNAL, Ellis NA, Ciocci S, German J, Back mutation can produce phenotype reversion in Bloom syndrome somatic cells, Human Genetics, 108, 2, 167–73, February 2001, 11281456, 10.1007/s004390000447,

By effect on fitness

{{See also|Fitness (biology)}}In applied genetics, it is usual to speak of mutations as either harmful or beneficial.
  • A harmful, or deleterious, mutation decreases the fitness of the organism.
  • A beneficial, or advantageous mutation increases the fitness of the organism.
  • A neutral mutation has no harmful or beneficial effect on the organism. Such mutations occur at a steady rate, forming the basis for the molecular clock. In the neutral theory of molecular evolution, neutral mutations provide genetic drift as the basis for most variation at the molecular level.
  • A nearly neutral mutation is a mutation that may be slightly deleterious or advantageous, although most nearly neutral mutations are slightly deleterious.

Distribution of fitness effects

Attempts have been made to infer the distribution of fitness effects (DFE) using mutagenesis experiments and theoretical models applied to molecular sequence data. DFE, as used to determine the relative abundance of different types of mutations (i.e., strongly deleterious, nearly neutral or advantageous), is relevant to many evolutionary questions, such as the maintenance of genetic variation,JOURNAL, Charlesworth D, Charlesworth B, Morgan MT, The pattern of neutral molecular variation under the background selection model, Genetics, 141, 4, 1619–32, December 1995, 8601499, 1206892, Deborah Charlesworth, Brian Charlesworth, the rate of genomic decay,JOURNAL, Loewe L, Quantifying the genomic decay paradox due to Muller's ratchet in human mitochondrial DNA, Genetical Research, 87, 2, 133–59, April 2006, 16709275, 10.1017/S0016672306008123, the maintenance of outcrossing sexual reproduction as opposed to inbreedingBOOK, Bernstein H, Hopf FA, Michod RE, The molecular basis of the evolution of sex, Advances in Genetics, 24, 323–70, 1987, 3324702, 10.1016/s0065-2660(08)60012-7, 9780120176243, and the evolution of sex and genetic recombination.JOURNAL, Peck JR, Barreau G, Heath SC, Imperfect genes, Fisherian mutation and the evolution of sex, Genetics, 145, 4, 1171–99, April 1997, 9093868, 1207886, In summary, the DFE plays an important role in predicting evolutionary dynamics.JOURNAL, Keightley PD, Lynch M, Toward a realistic model of mutations affecting fitness, Evolution; International Journal of Organic Evolution, 57, 3, 683–5; discussion 686–9, March 2003, 12703958, 10.1554/0014-3820(2003)057[0683:tarmom]2.0.co;2, 3094781, Michael Lynch (geneticist), JOURNAL, Barton NH, Keightley PD, Understanding quantitative genetic variation, Nature Reviews Genetics, 3, 1, 11–21, January 2002, 11823787, 10.1038/nrg700, Nick Barton, A variety of approaches have been used to study the DFE, including theoretical, experimental and analytical methods.
  • Mutagenesis experiment: The direct method to investigate the DFE is to induce mutations and then measure the mutational fitness effects, which has already been done in viruses, bacteria, yeast, and Drosophila. For example, most studies of the DFE in viruses used site-directed mutagenesis to create point mutations and measure relative fitness of each mutant.JOURNAL, Sanjuán R, Moya A, Elena SF, The distribution of fitness effects caused by single-nucleotide substitutions in an RNA virus, Proceedings of the National Academy of Sciences of the United States of America, 101, 22, 8396–401, June 2004, 15159545, 420405, 10.1073/pnas.0400146101, 2004PNAS..101.8396S, JOURNAL, Carrasco P, de la Iglesia F, Elena SF, Distribution of fitness and virulence effects caused by single-nucleotide substitutions in Tobacco Etch virus, Journal of Virology, 81, 23, 12979–84, December 2007, 17898073, 2169111, 10.1128/JVI.00524-07, JOURNAL, Sanjuán R, Mutational fitness effects in RNA and single-stranded DNA viruses: common patterns revealed by site-directed mutagenesis studies, Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 365, 1548, 1975–82, June 2010, 20478892, 2880115, 10.1098/rstb.2010.0063, JOURNAL, Peris JB, Davis P, Cuevas JM, Nebot MR, Sanjuán R, Distribution of fitness effects caused by single-nucleotide substitutions in bacteriophage f1, Genetics, 185, 2, 603–9, June 2010, 20382832, 2881140, 10.1534/genetics.110.115162, In Escherichia coli, one study used transposon mutagenesis to directly measure the fitness of a random insertion of a derivative of Tn10.JOURNAL, Elena SF, Ekunwe L, Hajela N, Oden SA, Lenski RE, Distribution of fitness effects caused by random insertion mutations in Escherichia coli, Genetica, 102–103, 1–6, 349–58, March 1998, 9720287, 10.1023/A:1017031008316, Richard Lenski, 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.JOURNAL, Hietpas RT, Jensen JD, Bolon DN, Experimental illumination of a fitness landscape, Proceedings of the National Academy of Sciences of the United States of America, 108, 19, 7896–901, May 2011, 21464309, 3093508, 10.1073/pnas.1016024108, 2011PNAS..108.7896H, However, given that many mutations have effects too small to be detectedJOURNAL, Davies EK, Peters AD, Keightley PD, High frequency of cryptic deleterious mutations in Caenorhabditis elegans, Science, 285, 5434, 1748–51, September 1999, 10481013, 10.1126/science.285.5434.1748, and that mutagenesis experiments can detect only mutations of moderately large effect; DNA sequence data analysis can provide valuable information about these mutations.
File:DFE in VSV.png|thumb|right|360px|The distribution of fitness effects (DFE) of mutations in vesicular stomatitis virus. In this experiment, random mutations were introduced into the virus by site-directed mutagenesis, and the fitness of each mutant was compared with the ancestral type. A fitness of zero, less than one, one, more than one, respectively, indicates that mutations are lethal, deleterious, neutral, and advantageous.]]
  • Molecular sequence analysis: With rapid development of 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.JOURNAL, Loewe L, Charlesworth B, Inferring the distribution of mutational effects on fitness in Drosophila, Biology Letters, 2, 3, 426–30, September 2006, 17148422, 1686194, 10.1098/rsbl.2006.0481, JOURNAL, Eyre-Walker A, Woolfit M, Phelps T, The distribution of fitness effects of new deleterious amino acid mutations in humans, Genetics, 173, 2, 891–900, June 2006, 16547091, 1526495, 10.1534/genetics.106.057570, JOURNAL, Sawyer SA, Kulathinal RJ, Bustamante CD, Hartl DL, Bayesian analysis suggests that most amino acid replacements in Drosophila are driven by positive selection, Journal of Molecular Evolution, 57 Suppl 1, 1, S154–64, August 2003, 15008412, 10.1007/s00239-003-0022-3, Carlos D. Bustamante, 10.1.1.78.65, 2003JMolE..57S.154S, JOURNAL, Piganeau G, Eyre-Walker A, Estimating the distribution of fitness effects from DNA sequence data: implications for the molecular clock, Proceedings of the National Academy of Sciences of the United States of America, 100, 18, 10335–40, September 2003, 12925735, 193562, 10.1073/pnas.1833064100, 2003PNAS..10010335P, 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. To be specific, the DNA sequence analysis approach allows us to estimate the effects of mutations with very small effects, which are hardly detectable through mutagenesis experiments.
One of the earliest theoretical studies of the distribution of fitness effects was done by Motoo Kimura, an influential theoretical population geneticist. His neutral theory of molecular evolution proposes that most novel mutations will be highly deleterious, with a small fraction being neutral.JOURNAL, Kimura M, Evolutionary rate at the molecular level, Nature, 217, 5129, 624–6, February 1968, 5637732, 10.1038/217624a0, Motoo Kimura, 1968Natur.217..624K, BOOK, Kimura, Motoo, Motoo Kimura, vanc, 1983, The Neutral Theory of Molecular Evolution, Cambridge, UK; New York, Cambridge University Press, 978-0-521-23109-1, 82022225, 9081989, harv, The Neutral Theory of Molecular Evolution, Hiroshi Akashi more recently proposed a bimodal model for the DFE, with modes centered around highly deleterious and neutral mutations.JOURNAL, Akashi H, Within- and between-species DNA sequence variation and the 'footprint' of natural selection, Gene, 238, 1, 39–51, September 1999, 10570982, 10.1016/S0378-1119(99)00294-2, Both theories agree that the vast majority of novel mutations are neutral or deleterious and that advantageous mutations are rare, which has been supported by experimental results. One example is a study done on the DFE of random mutations in vesicular stomatitis virus. Out of all mutations, 39.6% were lethal, 31.2% were non-lethal deleterious, and 27.1% were neutral. Another example comes from a high throughput mutagenesis experiment with yeast. In this experiment it was shown that the overall DFE is bimodal, with a cluster of neutral mutations, and a broad distribution of deleterious mutations.Though relatively few mutations are advantageous, those that are play an important role in evolutionary changes.JOURNAL, Eyre-Walker A, The genomic rate of adaptive evolution, Trends in Ecology & Evolution, 21, 10, 569–75, October 2006, 16820244, 10.1016/j.tree.2006.06.015, Like neutral mutations, weakly selected advantageous mutations can be lost due to random genetic drift, but strongly selected advantageous mutations are more likely to be fixed. Knowing the DFE of advantageous mutations may lead to increased ability to predict the evolutionary dynamics. Theoretical work on the DFE for advantageous mutations has been done by John H. GillespieJOURNAL, Gillespie, John H., vanc, John H. Gillespie, September 1984, Molecular Evolution Over the Mutational Landscape, Evolution, 38, 5, 1116–1129, 10.2307/2408444, 28555784, 2408444, and H. Allen Orr.JOURNAL, Orr HA, The distribution of fitness effects among beneficial mutations, Genetics, 163, 4, 1519–26, April 2003, 12702694, 1462510, H. Allen Orr, They proposed that the distribution for advantageous mutations should be exponential under a wide range of conditions, which, in general, has been supported by experimental studies, at least for strongly selected advantageous mutations.JOURNAL, Kassen R, Bataillon T, Distribution of fitness effects among beneficial mutations before selection in experimental populations of bacteria, Nature Genetics, 38, 4, 484–8, April 2006, 16550173, 10.1038/ng1751, JOURNAL, Rokyta DR, Joyce P, Caudle SB, Wichman HA, An empirical test of the mutational landscape model of adaptation using a single-stranded DNA virus, Nature Genetics, 37, 4, 441–4, April 2005, 15778707, 10.1038/ng1535, JOURNAL, Imhof M, Schlotterer C, Fitness effects of advantageous mutations in evolving Escherichia coli populations, Proceedings of the National Academy of Sciences of the United States of America, 98, 3, 1113–7, January 2001, 11158603, 14717, 10.1073/pnas.98.3.1113, 2001PNAS...98.1113I, In general, it is accepted that the majority of mutations are neutral or deleterious, with advantageous mutations being rare; however, the proportion of types of mutations varies between species. This indicates two important points: first, the proportion of effectively neutral mutations is likely to vary between species, resulting from dependence on effective population size; second, the average effect of deleterious mutations varies dramatically between species. In addition, the DFE also differs between coding regions and noncoding regions, with the DFE of noncoding DNA containing more weakly selected mutations.

By impact on protein sequence

  • A frameshift mutation is a mutation caused by insertion or deletion of a number of nucleotides that is not evenly divisible by three from a DNA sequence. Due to the triplet nature of gene expression by codons, the insertion or deletion can disrupt the reading frame, or the grouping of the codons, resulting in a completely different translation from the original.ENCYCLOPEDIA, Hogan, C. Michael, Monosson, Emily, Encyclopedia of Earth, Mutation,weblink 2015-10-08, October 12, 2010, Environmental Information Coalition, National Council for Science and the Environment, Washington, D.C., 72808636, live,weblink" title="web.archive.org/web/20151114055631weblink">weblink 14 November 2015, dmy-all, The earlier in the sequence the deletion or insertion occurs, the more altered the protein produced is. (For example, the code CCU GAC UAC CUA codes for the amino acids proline, aspartic acid, tyrosine, and leucine. If the U in CCU was deleted, the resulting sequence would be CCG ACU ACC UAx, which would instead code for proline, threonine, threonine, and part of another amino acid or perhaps a stop codon (where the x stands for the following nucleotide).) By contrast, any insertion or deletion that is evenly divisible by three is termed an in-frame mutation.
  • A point substitution mutation results in a change in a single nucleotide and can be either synonymous or nonsynonymous.
    • A synonymous substitution replaces a codon with another codon that codes for the same amino acid, so that the produced amino acid sequence is not modified. Synonymous mutations occur due to the degenerate nature of the genetic code. If this mutation does not result in any phenotypic effects, then it is called silent, but not all synonymous substitutions are silent. (There can also be silent mutations in nucleotides outside of the coding regions, such as the introns, because the exact nucleotide sequence is not as crucial as it is in the coding regions, but these are not considered synonymous substitutions.)
    • A nonsynonymous substitution replaces a codon with another codon that codes for a different amino acid, so that the produced amino acid sequence is modified. Nonsynonymous substitutions can be classified as nonsense or missense mutations:
      • A missense mutation changes a nucleotide to cause substitution of a different amino acid. This in turn can render the resulting protein nonfunctional. Such mutations are responsible for diseases such as Epidermolysis bullosa, sickle-cell disease, and SOD1-mediated ALS.JOURNAL, Boillée S, Vande Velde C, Cleveland DW, ALS: a disease of motor neurons and their nonneuronal neighbors, Neuron, 52, 1, 39–59, October 2006, 17015226, 10.1016/j.neuron.2006.09.018, 10.1.1.325.7514, On the other hand, if a missense mutation occurs in an amino acid codon that results in the use of a different, but chemically similar, amino acid, then sometimes little or no change is rendered in the protein. For example, a change from AAA to AGA will encode arginine, a chemically similar molecule to the intended lysine. In this latter case the mutation will have little or no effect on phenotype and therefore be neutral.
      • A nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and possibly a truncated, and often nonfunctional protein product. This sort of mutation has been linked to different mutations, such as congenital adrenal hyperplasia. (See Stop codon.)

By inheritance

File:Portulaca grandiflora mutant1.jpg|thumb|right|A mutation has caused this moss rose plant to produce flowers of different colors. This is a somatic mutation that may also be passed on in the germlinegermlineIn multicellular organisms with dedicated reproductive cells, mutations can be subdivided into germline mutations, which can be passed on to descendants through their reproductive cells, and somatic mutations (also called acquired mutations),ENCYCLOPEDIA, Genome Dictionary, Somatic cell genetic mutation,weblink 2010-06-06, June 30, 2007, Information Technology Associates, Athens, Greece, live,weblink" title="web.archive.org/web/20100224074045weblink">weblink 24 February 2010, dmy-all, which involve cells outside the dedicated reproductive group and which are not usually transmitted to descendants.A germline mutation gives rise to a constitutional mutation in the offspring, that is, a mutation that is present in every cell. A constitutional mutation can also occur very soon after fertilisation, or continue from a previous constitutional mutation in a parent.WEB,weblink RB1 Genetics, Daisy's Eye Cancer Fund, Oxford, UK,weblink" title="web.archive.org/web/20111126004753weblink">weblink 2011-11-26, 2015-10-09, 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 budding, because the cells that give rise to the daughter organisms also give rise to that organism's germline.A new germline mutation not inherited from either parent is called a (wiktionary:de novo|de novo) mutation.Diploid organisms (e.g., humans) contain two copies of each gene—a paternal and a maternal allele. Based on the occurrence of mutation on each chromosome, we may classify mutations into three types.
  • A heterozygous mutation is a mutation of only one allele.
  • A homozygous mutation is an identical mutation of both the paternal and maternal alleles.
  • Compound heterozygous mutations or a genetic compound consists of two different mutations in the paternal and maternal alleles.ENCYCLOPEDIA, MedTerms, Compound heterozygote,weblink 2015-10-09, June 14, 2012, WebMD, New York, live,weblink" title="web.archive.org/web/20160304123903weblink">weblink 4 March 2016, dmy-all,
A wild type or homozygous non-mutated organism is one in which neither allele is mutated.

Special classes

  • Conditional mutation is a mutation that has wild-type (or less severe) phenotype under certain "permissive" environmental conditions and a mutant phenotype under certain "restrictive" conditions. For example, a temperature-sensitive mutation can cause cell death at high temperature (restrictive condition), but might have no deleterious consequences at a lower temperature (permissive condition).BOOK, Molecular Biology of the Cell, Alberts, Garland Science, 2014, 9780815344322, 6, 487, These mutations are non-autonomous, as their manifestation depends upon presence of certain conditions, as opposed to other mutations which appear autonomously.JOURNAL, Chadov BF, Fedorova NB, Chadova EV, Conditional mutations in Drosophila melanogaster: On the occasion of the 150th anniversary of G. Mendel's report in Brünn, Mutation Research/Reviews in Mutation Research, 765, 40–55, 2015-07-01, 26281767, 10.1016/j.mrrev.2015.06.001, The permissive conditions may be temperature,JOURNAL, Landis G, Bhole D, Lu L, Tower J, High-frequency generation of conditional mutations affecting Drosophila melanogaster development and life span, Genetics, 158, 3, 1167–76, July 2001, 11454765,weblink 1461716, live,weblink" title="web.archive.org/web/20170322014758weblink">weblink 22 March 2017, dmy-all, certain chemicals,JOURNAL, Gierut JJ, Jacks TE, Haigis KM, Strategies to achieve conditional gene mutation in mice, Cold Spring Harbor Protocols, 2014, 4, 339–49, April 2014, 24692485, 10.1101/pdb.top069807, 4142476, light or mutations in other parts of the genome. In vivo mechanisms like transcriptional switches can create conditional mutations. For instance, association of Steroid Binding Domain can create a transcriptional switch that can change the expression of a gene based on the presence of a steroid ligand.JOURNAL, Spencer DM, Creating conditional mutations in mammals, Trends in Genetics, 12, 5, 181–7, May 1996, 8984733, 10.1016/0168-9525(96)10013-5, Conditional mutations have applications in research as they allow control over gene expression. This is especially useful studying diseases in adults by allowing expression after a certain period of growth, thus eliminating the deleterious effect of gene expression seen during stages of development in model organisms. DNA Recombinase systems like Cre-Lox Recombination used in association with promoters that are activated under certain conditions can generate conditional mutations. Dual Recombinase technology can be used to induce multiple conditional mutations to study the diseases which manifest as a result of simultaneous mutations in multiple genes. Certain inteins have been identified which splice only at certain permissive temperatures, leading to improper protein synthesis and thus, loss of function mutations at other temperatures.JOURNAL, Tan G, Chen M, Foote C, Tan C, Temperature-sensitive mutations made easy: generating conditional mutations by using temperature-sensitive inteins that function within different temperature ranges, Genetics, 183, 1, 13–22, September 2009, 19596904, 10.1534/genetics.109.104794, 2746138, Conditional mutations may also be used in genetic studies associated with ageing, as the expression can be changed after a certain time period in the organism's lifespan.
  • '''Replication timing quantitative trait loci affects 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 biologists, who have the responsibility of establishing the standard or so-called "consensus" sequence. This step requires a tremendous scientific effort. Once the consensus sequence is known, the mutations in a genome can be pinpointed, described, and classified. The committee of the Human Genome Variation Society (HGVS) has developed the standard human sequence variant nomenclature,JOURNAL, den Dunnen JT, Antonarakis SE, Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion, Human Mutation, 15, 1, 7–12, January 2000, 10612815, 10.1002/(SICI)1098-1004(200001)15:13.0.CO;2-N, Stylianos Antonarakis, which should be used by researchers and DNA diagnostic centers to generate unambiguous mutation descriptions. In principle, this nomenclature can also be used to describe mutations in other organisms. The nomenclature specifies the type of mutation and base or amino acid changes.
  • Nucleotide substitution (e.g., 76A>T) — The number is the position of the nucleotide from the 5' end; the first letter represents the wild-type nucleotide, and the second letter represents the nucleotide that replaced the wild type. In the given example, the adenine at the 76th position was replaced by a thymine.
    • If it becomes necessary to differentiate between mutations in genomic DNA, mitochondrial DNA, and RNA, a simple convention is used. For example, if the 100th base of a nucleotide sequence mutated from G to C, then it would be written as g.100G>C if the mutation occurred in genomic DNA, m.100G>C if the mutation occurred in mitochondrial DNA, or r.100g>c if the mutation occurred in RNA. Note that, for mutations in RNA, the nucleotide code is written in lower case.
  • Amino acid substitution (e.g., D111E) — The first letter is the one letter code of the wild-type amino acid, the number is the position of the amino acid from the N-terminus, and the second letter is the one letter code of the amino acid present in the mutation. Nonsense mutations are represented with an X for the second amino acid (e.g. 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

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

Harmful mutations

Changes in DNA caused by mutation can cause errors in protein sequence, creating partially or completely non-functional proteins. Each cell, in order to function correctly, depends on thousands of proteins to function in the right places at the right times. When a mutation alters a protein that plays a critical role in the body, a medical condition can result. Some mutations alter a gene's DNA base sequence but do not change the function of the protein made by the gene. One study on the comparison of genes between different species of Drosophila suggests that if a mutation does change a protein, this will probably be harmful, with an estimated 70 percent of amino acid polymorphisms having damaging effects, and the remainder being either neutral or weakly beneficial. Studies have shown that only 7% of point mutations in noncoding DNA of yeast are deleterious and 12% in coding DNA are deleterious. The rest of the mutations are either neutral or slightly beneficial.JOURNAL, Doniger SW, Kim HS, Swain D, Corcuera D, Williams M, Yang SP, Fay JC, A catalog of neutral and deleterious polymorphism in yeast, PLoS Genetics, 4, 8, e1000183, August 2008, 18769710, 2515631, 10.1371/journal.pgen.1000183, Jonathan K., Fay, Jonathan K. Pritchard, Shiaw-Pyng Yang, Justin C., Pritchard, vanc, If a mutation is present in a germ cell, it can give rise to offspring that carries the mutation in all of its cells. This is the case in hereditary diseases. In particular, if there is a mutation in a DNA repair gene within a germ cell, humans carrying such germline mutations may have an increased risk of cancer. A list of 34 such germline mutations is given in the article DNA repair-deficiency disorder. An example of one is albinism, a mutation that occurs in the OCA1 or OCA2 gene. Individuals with this disorder are more prone to many types of cancers, other disorders and have impaired vision. On the other hand, a mutation may occur in a somatic cell of an organism. Such mutations will be present in all descendants of this cell within the same organism, and certain mutations can cause the cell to become malignant, and, thus, cause cancer.JOURNAL, Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M, Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis, Nature, 363, 6429, 558–61, June 1993, 8505985, 10.1038/363558a0, 1993Natur.363..558I, A DNA damage can cause an error when the DNA is replicated, and this error of replication can cause a gene mutation that, in turn, could cause a genetic disorder. DNA damages are repaired by the DNA repair system of the cell. Each cell has a number of pathways through which enzymes recognize and repair damages in DNA. Because DNA can be damaged in many ways, the process of DNA repair is an important way in which the body protects itself from disease. Once DNA damage has given rise to a mutation, the mutation cannot be repaired.

Beneficial mutations

Although mutations that cause changes in protein sequences can be harmful to an organism, on occasions the effect may be positive in a given environment. In this case, the mutation may enable the mutant organism to withstand particular environmental stresses better than wild-type organisms, or reproduce more quickly. In these cases a mutation will tend to become more common in a population through natural selection. Examples include the following:HIV resistance: a specific 32 base pair deletion in human CCR5 (CCR5-Δ32) confers HIV resistance to homozygotes and delays AIDS onset in heterozygotes.JOURNAL, Sullivan AD, Wigginton J, Kirschner D, The coreceptor mutation CCR5Delta32 influences the dynamics of HIV epidemics and is selected for by HIV, Proceedings of the National Academy of Sciences of the United States of America, 98, 18, 10214–9, August 2001, 11517319, 56941, 10.1073/pnas.181325198, 2001PNAS...9810214S, One possible explanation of the etiology of the relatively high frequency of CCR5-Δ32 in the European population is that it conferred resistance to the bubonic plague in mid-14th century Europe. People with this mutation were more likely to survive infection; thus its frequency in the population increased.EPISODE, Mystery of the Black Death,weblink 2015-10-10, Secrets of the Dead, PBS, October 30, 2002, 3, 2, live,weblink" title="web.archive.org/web/20151012175528weblink">weblink 12 October 2015, dmy-all, Episode background. This theory could explain why this mutation is not found in Southern Africa, which remained untouched by bubonic plague. A newer theory suggests that the selective pressure on the CCR5 Delta 32 mutation was caused by smallpox instead of the bubonic plague.JOURNAL, Galvani AP, Slatkin M, Evaluating plague and smallpox as historical selective pressures for the CCR5-Delta 32 HIV-resistance allele, Proceedings of the National Academy of Sciences of the United States of America, 100, 25, 15276–9, December 2003, 14645720, 299980, 10.1073/pnas.2435085100, 2003PNAS..10015276G, Montgomery Slatkin, Malaria resistance: An example of a harmful mutation is sickle-cell disease, a blood disorder in which the body produces an abnormal type of the oxygen-carrying substance hemoglobin in the red blood cells. One-third of all indigenous inhabitants of Sub-Saharan Africa carry the allele, because, in areas where malaria is common, there is a survival value in carrying only a single sickle-cell allele (sickle cell trait).WEB,weblink Frequently Asked Questions [FAQ's], Konotey-Ahulu, Felix, sicklecell.md, live,weblink" title="web.archive.org/web/20110430031852weblink">weblink 30 April 2011, dmy-all, Those with only one of the two alleles of the sickle-cell disease are more resistant to malaria, since the infestation of the malaria Plasmodium is halted by the sickling of the cells that it infests.Antibiotic resistance: Practically all bacteria develop antibiotic resistance when exposed to antibiotics. In fact, bacterial populations already have such mutations that get selected under antibiotic selection.JOURNAL, Hughes D, Andersson DI, Evolutionary Trajectories to Antibiotic Resistance, Annual Review of Microbiology, 71, 579–596, September 2017, 28697667, 10.1146/annurev-micro-090816-093813, Obviously, such mutations are only beneficial for the bacteria but not for those infected.Lactase persistence. A mutation allowed humans to express the enzyme lactase after they are naturally weaned from breast milk, allowing adults to digest lactose, which is probably one of the most beneficial mutations in recent human evolution.JOURNAL, Ségurel L, Bon C, On the Evolution of Lactase Persistence in Humans, Annual Review of Genomics and Human Genetics, 18, 297–319, August 2017, 28426286, 10.1146/annurev-genom-091416-035340,

Prion mutations

Prions are proteins and do not contain genetic material. However, prion replication has been shown to be subject to mutation and natural selection just like other forms of replication.NEWS, 'Lifeless' prion proteins are 'capable of evolution',weblink Health, BBC News Online, London, January 1, 2010, 2015-10-10, live,weblink" title="web.archive.org/web/20150925132138weblink">weblink 25 September 2015, dmy-all, The human gene PRNP codes for the major prion protein, PrP, and is subject to mutations that can give rise to disease-causing prions.

Somatic mutation

{{see also|Carcinogenesis|Loss of heterozygosity}}A change in the genetic structure that is not inherited from a parent, and also not passed to offspring, is called a somatic mutation. Somatic mutations are not inherited because they do not affect the germline. These types of mutations are usually prompted by environmental causes, such as ultraviolet radiation or any exposure to certain harmful chemicals, and can cause diseases including cancer.NEWS,weblink somatic mutation {{!, genetics |work=Encyclopedia Britannica |access-date=2017-03-31 |url-status=live |archiveurl=https://web.archive.org/web/20170331122201weblink |archivedate=31 March 2017|df=dmy-all}}With plants, some somatic mutations can be propagated without the need for seed production, for example, by grafting and stem cuttings. These type of mutation have led to new types of fruits, such as the "Delicious" apple and the "Washington" navel orange.BOOK, Genetics Principles and Analysis, Hartl, Jones, Daniel L., Elizabeth W., Jones and Bartlett Publishers, 1998, 978-0-7637-0489-6, Sudbury, Massachusetts, 556, registration,weblink Human and mouse somatic cells have a mutation rate more than ten times higher than the germline mutation rate for both species; mice have a higher rate of both somatic and germline mutations per cell division than humans. The disparity in mutation rate between the germline and somatic tissues likely reflects the greater importance of genome maintenance in the germline than in the soma.JOURNAL, Milholland B, Dong X, Zhang L, Hao X, Suh Y, Vijg J, Differences between germline and somatic mutation rates in humans and mice, Nat Commun, 8, 15183, 2017, 28485371, 5436103, 10.1038/ncomms15183, 2017NatCo...815183M,

Amorphic mutations

An amorph, a term utilized by Muller in 1932, is a mutated allele, which has lost the ability of the parent (whether wild type or any other type) allele to encode any functional protein. An amorphic mutation may be caused by the replacement of an amino acid that deactivates an enzyme or by the deletion of part of a gene that produces the enzyme.Cells with heterozygous mutations (one good copy of gene and one mutated copy) may function normally with the unmutated copy until the good copy has been spontaneously somatically mutated. This kind of mutation happens all the time in living organisms, but it is difficult to measure the rate. Measuring this rate is important in predicting the rate at which people may develop cancer.JOURNAL, Araten DJ, Golde DW, Zhang RH, Thaler HT, Gargiulo L, Notaro R, Luzzatto L, A quantitative measurement of the human somatic mutation rate, Cancer Research, 65, 18, 8111–7, September 2005, 16166284, 10.1158/0008-5472.CAN-04-1198, Rong H. Zhang, Point mutations may arise from spontaneous mutations that occur during DNA replication. The rate of mutation may be increased by mutagens. Mutagens can be physical, such as radiation from UV rays, X-rays or extreme heat, or chemical (molecules that misplace base pairs or disrupt the helical shape of DNA). Mutagens associated with cancers are often studied to learn about cancer and its prevention.

Hypomorphic and hypermorphic mutations

{{See also|Muller's morphs}}A hypomorphic mutation is a mutation which results in lowered gene expression. Usually, hypomorphic mutations are recessive, but haploinsufficiency causes some alleles to be dominant.A hypermorphic mutation results in increased gene expression.

See also

{hide}Columns-list|* Aneuploidy

References

{{Reflist|30em}}

External links

{{Mutation}}{{Chromosomal abnormalities}}{{Evolution}}{{Use dmy dates|date=July 2011}}

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