Genetic mutation

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In [[biology]], '''mutations''' are changes to the [[nucleotide]] sequence of the [[genetic material]] of an organism. Mutations can be caused by copying errors in the genetic material during [[cell division]], by exposure to [[ultraviolet]] or [[ionizing radiation]], chemical [[mutagens]], or [[virus (biology)|viruses]], or can occur deliberately under cellular control during processes such as [[hypermutation]]. In multicellular organisms, mutations can be subdivided into '''[[germline mutation|germ line mutation]]s''', which can be passed on to descendants, and '''somatic mutations''', which are not transmitted to descendants in animals. Plants sometimes can transmit somatic mutations to their descendants asexually or sexually (in case when flower buds develop in somatically mutated part of plant). A new mutation that was not inherited from either parent is called a ''de novo'' mutation. The source of the mutation is unrelated to the consequence, although the consequences are related to which cells are affected.

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Mutations create variations in the [[gene pool]]. Less favorable (or ''deleterious'') mutations can be reduced in frequency in the gene pool by [[natural selection]], while more favorable (''beneficial'' or ''advantageous'') mutations may accumulate and result in adaptive [[evolution]]ary changes. For example, a butterfly may produce offspring with new mutations. The majority of these mutations will have no effect; but one might change the color of one of the butterfly's offspring, making it harder (or easier) for predators to see. If this color change is advantageous, the chance of this butterfly 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.

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[[Neutral theory of molecular evolution|Neutral mutations]] are defined as mutations whose effects do not influence the [[Fitness (biology)|fitness]] of an individual. These can accumulate over time due to [[genetic drift]]. It is believed that the overwhelming majority of mutations have no significant effect on an organism's fitness. Also, [[DNA repair]] mechanisms are able to mend most changes before they become permanent mutations, and many organisms have mechanisms for eliminating otherwise permanently mutated [[somatic cell]]s.

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Mutation is generally accepted by the scientific community as the mechanism upon which natural selection acts, providing the advantageous new traits that survive and multiply in offspring or disadvantageous traits that die out with weaker organisms.

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==Classification==

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===By effect on structure===

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[[Image:Types-of-mutation.png|thumb|Illustrations of five types of chromosomal mutations.]]

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The sequence of a gene can be altered in a number of ways. Gene mutations have varying effects on health depending on where they occur and whether they alter the function of essential proteins. Structurally, mutations can be classified as:

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* Small-scale mutations, such those as affecting a small gene in one or a few nucleotides, including:

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** '''[[Point mutation]]s''', often caused by chemicals or malfunction of DNA replication, exchange a single [[nucleotide]] for another<ref>{{cite journal | author=Freese, Ernst | title=The Difference between Spontaneous and Base-Analogue Induced Mutations of Phage T4 | journal=Proc of NAS | year=1959 | pages=622-633 | volume=45 | issue=4 }} [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=222607]</ref>. Most common is the [[transition (genetics)|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 mis-pairing, or mutagenic base analogs such as [[BrdU|5-bromo-2-deoxyuridine (BrdU)]]. Less common is a [[transversion]], which exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T ↔ A/G). 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). These changes are classified as transitions or transversions<ref>{{cite journal | author=Freese, Ernst | title=The Specific Mutagenic Effect of Base Analogues on Phage T4 | journal=J. Mol. Biol. | year=1959 | pages=87-105 | volume=1 }}</ref>. An example of a transversion is [[adenine]] (A) being converted into a [[cytosine]] (C). There are also many other examples that can be found. Point mutations that occur within the [[protein]] coding region of a gene may be classified into three kinds, depending upon what the erroneous [[codon]] codes for:

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*** [[Silent mutation]]s: which code for the same [[amino acid]].

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*** [[Missense mutation]]s: which code for a different amino acid.

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*** [[Nonsense mutation]]s: which code for a stop and can truncate the [[protein]].

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** '''[[insertion (genetics)|Insertions]]''' add one or more extra nucleotides into the DNA. They are usually caused by [[transposable element]]s, or errors during replication of repeating elements (e.g. AT repeats). Insertions in the coding region of a gene may alter [[splicing (genetics)|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 reverted by excision of the [[transposable element]].

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** '''[[Genetic deletion|Deletions]]''' remove one or more nucleotides from the DNA. Like insertions, these mutations can alter the [[reading frame]] of the gene. They are generally irreversible: though exactly the same sequence might theoretically be restored by an insertion, transposable elements able to revert a very short deletion (say 1-2 bases) in ''any'' location are either highly unlikely to exist or do not exist at all. Note that a deletion is not the exact opposite of an insertion: the former is quite random while the latter consists of a specific sequence inserting at locations that are not entirely random or even quite narrowly defined.

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* Large-scale mutations in [[chromosome|chromosomal]] structure, including:

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** '''Amplifications''' (or [[gene duplication]]s) leading to multiple copies of all chromosomal regions, increasing the dosage of the genes located within them.

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** '''[[Genetic deletion|Deletions]]''' of large chromosomal regions, leading to loss of the genes within those regions.

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** Mutations whose effect is to juxtapose previously separate pieces of DNA, potentially bringing together separate genes to form functionally distinct [[fusion gene]]s (e.g. [[bcr-abl]]). These include:

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*** '''[[Chromosomal translocation]]s''': interchange of genetic parts from nonhomologous chromosomes.

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*** '''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).

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*** '''[[Chromosomal inversion]]s''': reversing the orientation of a chromosomal segment.

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**'''[[Loss of heterozygosity]]''': loss of one [[allele]], either by a deletion or [[recombination]] event, in an organism that previously had two different alleles.

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===By effect on function===

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* '''Loss-of-function mutations''' are the result of gene product having less or no function. When the allele has a complete loss of function ([[null allele]]) it is often called an '''[[Muller's morphs|amorphic]] mutation'''. Phenotypes associated with such mutations are most often [[recessive allele|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]]).

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* '''Gain-of-function mutations''' change the gene product such that it gains a new and abnormal function. These mutations usually have [[dominant gene|dominant]] phenotypes. Often called a [[Muller's morphs|neo-morphic]] mutation.

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* '''Dominant negative mutations''' (also called '''[[Muller's morphs|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 characterised by a [[Dominant gene|dominant]] or [[incomplete dominance|semi-dominant]] phenotype. In humans, [[Marfan syndrome]] is an example of a dominant negative mutation occurring in an [[autosomal dominant]] disease. In this condition, the defective glycoprotein product of the fibrillin gene (FBN1) antagonizes the product of the normal allele.

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*'''Lethal mutations''' are mutations that lead the death of the organisms which carry the mutations.

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===By aspect of phenotype affected===

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* '''Morphological mutations''' usually affect the outward appearance of an individual. Mutations can change the height of a plant or change it from smooth to rough seeds.

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* '''Biochemical mutations''' result in lesions stopping the enzymatic pathway. Often, morphological mutants are the direct result of a mutation due to the enzymatic pathway.

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===By inheritance===

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The human genome contains two copies of each gene- a paternal and a maternal allele.

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*'''Wildtype''' or '''Homozygous non-mutated''' is when neither allele is mutated.

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*A '''Heterozygous mutation''' is when only one allele is mutated.

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*A '''Homozygous mutation''' is when both the paternal and maternal alleles have an identical mutation.

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*'''Compound heterozygous''' mutations or a '''Genetic compound''' is when the paternal and maternal alleles have two different mutations. <ref>Medterms.com [http://www.medterms.com/script/main/art.asp?articlekey=33675]</ref>

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===Special classes===

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*'''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).

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===Causes of mutation===

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Two classes of mutations are spontaneous mutations (molecular decay) and induced mutations caused by [[mutagen]]s.

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'''Spontaneous mutations''' on the molecular level include:

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* [[Tautomerism]] - A base is changed by the repositioning of a hydrogen atom.

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* [[Depurination]] - Loss of a purine base (A or G).

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* [[Deamination]] - Changes a normal base to an atypical base; C → U, (which can be corrected by DNA repair mechanisms), or spontaneous deamination of 5-methycytosine (irreparable), or A → HX (hypoxanthine).

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* Transition - A purine changes to another purine, or a pyrimidine to a pyrimidine.

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* Transversion - A purine becomes a pyrimidine, or vice versa.

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'''Induced mutations''' on the molecular level can be caused by:

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* Chemicals

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** Nitrosoguanidine (NTG)

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** [[Hydroxylamine]] NH<sub>2</sub>OH

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** [[Base analog]]s (e.g. [[BrdU]])

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** Simple chemicals (e.g. [[acid]]s)

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** Alkylating agents (e.g. [[ENU|''N''-ethyl-''N''-nitrosourea (ENU)]]) These agents can mutate both replicating and non-replicating DNA. In contrast, a base analog can only mutate the DNA 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.

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** Methylating agents (e.g. [[ethyl methanesulfonate]] (EMS))

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** Polycyclic [[hydrocarbons]] (e.g. [[benzopyrene]]s found in [[internal combustion engine]] [[Exhaust gas|exhaust]])

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** DNA intercalating agents (e.g. [[ethidium bromide]])

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** [[DNA crosslinker]] (e.g. [[platinum]])

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** Oxidative damage caused by [[oxygen]](O) [[Radical (chemistry)|radicals]]

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* Radiation

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** [[Ultraviolet]] radiation (nonionizing radiation) excites electrons to a higher energy level. DNA molecules are good absorbers of ultraviolet light, especially that with [[wavelength|wavelengths]] in the 260 to 280 [[nanometre|nm]] range.{{Fact|date=March 2008}} Two nucleotide bases in DNA - cytosine and thymine-are most vulnerable to excitation that can change base-pairing properties. UV light can induce adjacent thymine bases in a DNA strand to pair with each other, as a bulky dimer.

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** [[Ionizing radiation]]

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DNA has so-called hotspots, where mutations occur up to 100 times more frequently than the normal [[mutation rate]]. A hotspot can be at an unusual base, e.g., [[5-methylcytosine]].

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[[Mutation rate]]s also vary across species. Evolutionary biologists have theorized that higher mutation rates are beneficial in some situations, because they allow organisms to evolve and therefore adapt more quickly to their environments. For example, repeated exposure of bacteria to antibiotics, and selection of resistant mutants, can result in the selection of bacteria that have a much higher mutation rate than the original population ([[mutator genotype|mutator strains]]).

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===Nomenclature===

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Nomenclature of mutations specify the type of mutation and base or amino acid changes.

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*Amino acid substitution - (e.g. D111E) The first letter is the one letter code of the wildtype 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. If the second letter is 'X', any amino acid may replace the wildtype.

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*Amino acid deletion - (e.g. ΔF508) The Greek symbol Δ or '[[delta]]' indicates a deletion. The letter refers to the amino acid present in the wildtype and the number is the position from the N terminus of the amino acid were it to be present as in the wildtype.

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==Types of mutations==

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===Adaptive mutation===

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In mainstream biological thought it is held that while mutagenesis is non-random in many ways, the utility of a genetic mutation to the organism in which it occurs does not affect the rate at which it occurs. However experimental evidence exists that in some instances the rate of specific mutations arising is greater when they are advantageous to the organism than when they are not.

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===Back mutation===

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''Back mutation'' is a change in a [[nucleotide pair]] of a [[point mutation|point-mutated]] [[DNA sequence]] that restores the original sequence and hence the original [[phenotype]].<ref>{{cite journal | author=Ellis NA, Ciocci S, German J | title=Back mutation can produce phenotype reversion in Bloom syndrome somatic cells | journal=Hum Genet | year=2001 | pages=167-73 | volume=108 | issue=2 }} PMID 11281456</ref>

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===Frameshift mutation===

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A ''frameshift mutation'' is a mutation caused by indels, ie. [[gene insertion|inserts]] or [[genetic deletion|deletes]] a number of [[nucleotide]]s that is not evenly divisible by three from a [[DNA]] sequence. Due to the triplet nature of [[gene expression]] by [[codon]]s, the insertion or [[genetic deletion|deletion]] can disrupt the [[reading frame]], or the grouping of the codons, resulting in a completely different [[Translation (genetics)|translation]] from the original. The earlier in the sequence the deletion or [[gene insertion|insertion]] occurs, the more altered the protein produced is.

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===Missense mutation===

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''Missense mutations'' or ''nonsynonymous mutations'' are types of [[point mutation]]s where a single nucleotide is changed to cause substitution of a different [[amino acid]]. This in turn can render the resulting [[protein]] nonfunctional. Such mutations are responsible for diseases such as [[Epidermolysis bullosa]], [[sickle-cell disease]], and [[Superoxide dismutase|SOD1]] mediated [[Amyotrophic lateral sclerosis|ALS]]{{Harv | Boillée | 2006 | p=39}}.

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===Neutral mutation===

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A ''neutral mutation'' is a mutation that occurs in an amino acid [[codon]] (presumably within an [[mRNA]] molecule) which results in the use of a different, but chemically similar, [[amino acid]]. This is similar to a [[silent mutation]], where a codon mutation may encode the same amino acid (see [[Wobble Hypothesis]]); for example, a change from AUU to AUC will still encode [[leucine]], so no discernable change occurs (a [[silent mutation]]).

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===Nonsense mutation===

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A '''nonsense mutation''' is a [[frameshift mutation]] in a [[DNA sequence|sequence]] of [[DNA]] that results in a premature [[stop codon]], or a ''nonsense codon'' in the [[transcription (genetics)|transcribed]] [[mRNA]], and possibly a [[truncation|truncated]], and often nonfunctional [[protein]] product.

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===Point mutation===

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A ''point mutation'', or ''substitution'', is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide. Often the term ''point mutation'' also includes [[insertion (genetics)|insertions]] or deletions of a single base pair (which have more of an adverse effect on the synthesized protein due to nucleotides still being read in triplets, but in different frames- a mutation called a [[frameshift mutation]]).

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===Silent mutation===

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''Silent mutations'' are [[DNA]] mutations that do not result in a change to the [[amino acid]] sequence of a [[protein]]. They may occur in a [[non-coding region]] (outside of a [[gene]] or within an [[intron]]), or they may occur within an [[exon]] in a manner that does not alter the final [[amino acid]] sequence. The phrase '''silent mutation''' is often used interchangeably with the phrase [[Single Nucleotide Polymorphism|synonymous mutation]]; however, synonymous mutations are a subcategory of the former, occurring only within exons.

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==Harmful mutations==

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Changes in DNA caused by mutation can cause errors in [[protein]] sequence, creating partially or completely non-functional proteins. To function correctly, each cell 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. A condition caused by mutations in one or more genes is called a [[genetic disorder]]. However, only a small percentage of mutations cause genetic disorders; most have no impact on health. For example, some mutations alter a gene's DNA base sequence but don’t change the function of the protein made by the gene. Studies in the fly ''[[Drosophila melanogaster]]'' suggest that if a mutation does change a protein, this will probably be harmful, with about 70 percent of these mutations having damaging effects, and the remainder being either neutral or weakly beneficial.<ref>{{cite journal |author=Sawyer SA, Parsch J, Zhang Z, Hartl DL |title=Prevalence of positive selection among nearly neutral amino acid replacements in Drosophila |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=104 |issue=16 |pages=6504-10 |year=2007 |pmid=17409186 |url=http://www.pnas.org/cgi/content/full/104/16/6504}}</ref>

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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 disease]]s. On the other hand, a mutation can occur in a [[somatic cell]] of an organism. Such mutations will be present in all descendants of this cell, and certain mutations can cause the cell to become malignant, and thus cause [[cancer]]<ref>{{cite journal |author=Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M|title=Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis|journal=Nature|volume=363|issue=6429|pages=558-61|year=1993|url=http://dx.doi.org/10.1038/363558a0|pmid=8505985}}</ref>.

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Often, gene mutations that could cause a genetic disorder are repaired by the [[DNA repair]] system of the cell. Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA. Because DNA can be damaged or mutated in many ways, the process of DNA repair is an important way in which the body protects itself from disease.

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==Beneficial mutations==

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A very small percentage of all mutations actually have a positive effect. These mutations lead to new versions of proteins that help an organism and its future generations better adapt to changes in their environment. For example, a specific 32 [[base pair]] deletion in human [[CCR5]] ([[CCR5#CCR5-.CE.9432|CCR5-Δ32]]) confers [[HIV]] resistance to [[Zygosity|homozygotes]] and delays [[AIDS]] onset in [[Zygosity|heterozygotes]].<ref>{{cite web|url=http://www.cdc.gov/genomics/hugenet/factsheets/FS_CCR5.htm|title=CCR5 receptor gene and HIV infection, Antonio Pacheco.}}</ref> The CCR5 mutation is more common in those of European descent. One theory for 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 who had this mutation were able to survive infection; thus, its frequency in the population increased.<ref>{{cite web|url=http://www.pbs.org/wnet/secrets/case_plague/clues.html|title= PBS:Secrets of the Dead. Case File: Mystery of the Black Death}}</ref> It could also explain why this mutation is not found in Africa where the bubonic plague never reached. Newer theory says the [[selective pressure]] on the CCR5 Delta 32 mutation has been caused by [[smallpox]] instead of the bubonic plague.<ref>{{cite journal |author=Galvani A, Slatkin M |title=Evaluating plague and smallpox as historical selective pressures for the CCR5-Δ32 HIV-resistance allele |journal=Proc Natl Acad Sci U S A |volume=100 |issue=25 |pages=15276-9 |year=2003 |pmid=14645720 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=299980 }}</ref>

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==See also==

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* [[Aneuploidy]]

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* [[Antioxidant]]

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* [[Budgerigar colour genetics]]

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* [[Homeobox]]

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* [[Macromutation]]

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* [[Muller's morphs]]

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* [[Mutant]]

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* [[Polyploidy]]

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* [[Robertsonian translocation]]

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* [[Signature tagged mutagenesis]]

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* [[Site-directed mutagenesis]]

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</div>

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==References==

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* Leroi A. 2003. ''Mutants: On the form, varieties & errors of the human body''. 1:16-17. Harper Collins 2003

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* Maki H. 2002. ''Origins of spontaneous mutations: specificity and directionality of base-substitution, frameshift, and sequence-substitution mutageneses''. Annual Review of Genetics 36:279-303.

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* Taggart R. Starr C. ''Biology The Unity and Diversity of Life: Mutated Genes and Their Protein Products''. 14.4:227. Thompson Brooks/Cole 2006.

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===Online books===

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* Chapter 7, [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=mutation+AND+mga%5Bbook%5D+AND+110363%5Buid%5D&rid=mga.section.996 The Molecular Basis of Mutation] in ''Modern Genetic Analysis'' by Anthony J. F. Griffiths, William M. Gelbart, Jeffrey H. Miller and [[Richard Lewontin|Richard C. Lewontin]] (1999) published by W. H. Freeman and Company ISBN 0-7167-3597-0.

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* Chapter 9, [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hmg.section.1050 Instability of the human genome: mutation and DNA repair] in ''Human Molecular Genetics 2'' by Tom Strachan and Andrew P. Read (1999) published by John Wiley & Sons, Inc.

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* ''[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.preface.91 Genes and Disease]'' from the [[National Library of Medicine]] provides descriptions of mutations that cause human diseases. For example, a common mutation associated with [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=mutation+AND+gnd%5Bbook%5D+AND+138070%5Buid%5D&rid=gnd.section.207 Huntington disease] is an increased number of copies of repeated CGA triplets in the [[Huntingtin]] gene.

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* ''[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gene GeneReviews]'' by Roberta A. Pagon, Editor-in-chief is made available by the [[University of Washington]] and contains peer-reviewed descriptions of heritable diseases written by experts. For example, [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gene.chapter.brca1 BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer] describes mutations in [[BRCA1]] and [[BRCA2]] that are associated with predispositions to cancer.

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==External links==

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* [http://miracle.igib.res.in/variationcentral Central Locus Specific Variation Database at the Institute of Genomics and Integrative Biology ]

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* [http://en.wikibooks.org/wiki/General_Biology/Genetics/Mutation#Mutation The mutations chapter of the WikiBooks General Biology textbook]

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* [http://www.gate.net/~rwms/EvoMutations.html Examples of Beneficial Mutations]

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* [http://www.genetherapynet.com Gene Therapy Net]

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[[Category:Mutation| ]]

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[[Category:Evolutionary biology]]

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[[Category:Genetics]]

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[[Category:Radiation health effects]]

Changes: Genetic mutation

Revision as of 15:48, 6 October 2008

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-In [[biology]], '''mutations''' are changes to the [[nucleotide]] sequence of the [[genetic material]] of an organism. Mutations can be caused by copying errors in the genetic material during [[cell division]], by exposure to [[ultraviolet]] or [[ionizing radiation]], chemical [[mutagens]], or [[virus (biology)|viruses]], or can occur deliberately under cellular control during processes such as [[hypermutation]]. In multicellular organisms, mutations can be subdivided into '''[[germline mutation|germ line mutation]]s''', which can be passed on to descendants, and '''somatic mutations''', which are not transmitted to descendants in animals. Plants sometimes can transmit somatic mutations to their descendants asexually or sexually (in case when flower buds develop in somatically mutated part of plant). A new mutation that was not inherited from either parent is called a ''de novo'' mutation.  The source of the mutation is unrelated to the consequence, although the consequences are related to which cells are affected.
-Mutations create variations in the [[gene pool]].  Less favorable (or ''deleterious'') mutations can be reduced in frequency in the gene pool by [[natural selection]], while more favorable (''beneficial'' or ''advantageous'') mutations may accumulate and result in adaptive [[evolution]]ary changes. For example, a butterfly may produce offspring with new mutations.  The majority of these mutations will have no effect; but one might change the color of one of the butterfly's offspring, making it harder (or easier) for predators to see.  If this color change is advantageous, the chance of this butterfly 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 theory of molecular evolution|Neutral mutations]] are defined as mutations whose effects do not influence the [[Fitness (biology)|fitness]] of an individual. These can accumulate over time due to [[genetic drift]]. It is believed that the overwhelming majority of mutations have no significant effect on an organism's fitness. Also, [[DNA repair]] mechanisms are able to mend most changes before they become permanent mutations, and many organisms have mechanisms for eliminating otherwise permanently mutated [[somatic cell]]s.
-Mutation is generally accepted by the scientific community as the mechanism upon which natural selection acts, providing the advantageous new traits that survive and multiply in offspring or disadvantageous traits that die out with weaker organisms.
-==Classification==
-===By effect on structure===
-[[Image:Types-of-mutation.png|thumb|Illustrations of five types of chromosomal mutations.]]
-The sequence of a gene can be altered in a number of ways. Gene mutations have varying effects on health depending on where they occur and whether they alter the function of essential proteins. Structurally, mutations can be classified as:
-* Small-scale mutations, such those as affecting a small gene in one or a few nucleotides, including:
-** '''[[Point mutation]]s''', often caused by chemicals or malfunction of DNA replication, exchange a single [[nucleotide]] for another<ref>{{cite journal | author=Freese, Ernst | title=The Difference between Spontaneous and Base-Analogue Induced Mutations of Phage T4 | journal=Proc of NAS | year=1959 | pages=622-633 | volume=45 | issue=4 }} [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=222607]</ref>. Most common is the [[transition (genetics)|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 mis-pairing, or mutagenic base analogs such as [[BrdU|5-bromo-2-deoxyuridine (BrdU)]]. Less common is a [[transversion]], which exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T ↔ A/G). 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). These changes are classified as transitions or transversions<ref>{{cite journal | author=Freese, Ernst | title=The Specific Mutagenic Effect of Base Analogues on Phage T4 | journal=J. Mol. Biol. | year=1959 | pages=87-105 | volume=1 }}</ref>. An example of a transversion is [[adenine]] (A) being converted into a [[cytosine]] (C). There are also many other examples that can be found. Point mutations that occur within the [[protein]] coding region of a gene may be classified into three kinds, depending upon what the erroneous [[codon]] codes for:
-*** [[Silent mutation]]s: which code for the same [[amino acid]].
-*** [[Missense mutation]]s: which code for a different amino acid.
-*** [[Nonsense mutation]]s: which code for a stop and can truncate the [[protein]].
-** '''[[insertion (genetics)|Insertions]]''' add one or more extra nucleotides into the DNA. They are usually caused by [[transposable element]]s, or errors during replication of repeating elements (e.g. AT repeats). Insertions in the coding region of a gene may alter [[splicing (genetics)|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 reverted by excision of the [[transposable element]].
-** '''[[Genetic deletion|Deletions]]''' remove one or more nucleotides from the DNA. Like insertions, these mutations can alter the [[reading frame]] of the gene. They are generally irreversible: though exactly the same sequence might theoretically be restored by an insertion, transposable elements able to revert a very short deletion (say 1-2 bases) in ''any'' location are either highly unlikely to exist or do not exist at all. Note that a deletion is not the exact opposite of an insertion: the former is quite random while the latter consists of a specific sequence inserting at locations that are not entirely random or even quite narrowly defined.
-* Large-scale mutations in [[chromosome|chromosomal]] structure, including:
-** '''Amplifications''' (or [[gene duplication]]s) leading to multiple copies of all chromosomal regions, increasing the dosage of the genes located within them.
-** '''[[Genetic deletion|Deletions]]''' of large chromosomal regions, leading to loss of the genes within those regions.
-** Mutations whose effect is to juxtapose previously separate pieces of DNA, potentially bringing together separate genes to form functionally distinct [[fusion gene]]s (e.g. [[bcr-abl]]). These include:
-*** '''[[Chromosomal translocation]]s''': interchange of genetic parts from nonhomologous chromosomes.
-*** '''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).
-*** '''[[Chromosomal inversion]]s''': reversing the orientation of a chromosomal segment.
-**'''[[Loss of heterozygosity]]''': loss of one [[allele]], either by a deletion or [[recombination]] event, in an organism that previously had two different alleles.
-===By effect on function===
-* '''Loss-of-function mutations''' are the result of gene product having less or no function. When the allele has a complete loss of function ([[null allele]]) it is often called an '''[[Muller's morphs|amorphic]] mutation'''. Phenotypes associated with such mutations are most often [[recessive allele|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''' change the gene product such that it gains a new and abnormal function. These mutations usually have [[dominant gene|dominant]] phenotypes. Often called a [[Muller's morphs|neo-morphic]] mutation.
-* '''Dominant negative mutations''' (also called '''[[Muller's morphs|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 characterised by a [[Dominant gene|dominant]] or [[incomplete dominance|semi-dominant]] phenotype. In humans, [[Marfan syndrome]] is an example of a dominant negative mutation occurring in an [[autosomal dominant]] disease. In this condition, the defective glycoprotein product of the fibrillin gene (FBN1) antagonizes the product of the normal allele.
-*'''Lethal mutations''' are mutations that lead the death of the organisms which carry the mutations.
-===By aspect of phenotype affected===
-* '''Morphological mutations''' usually affect the outward appearance of an individual. Mutations can change the height of a plant or change it from smooth to rough seeds.
-* '''Biochemical mutations''' result in lesions stopping the enzymatic pathway. Often, morphological mutants are the direct result of a mutation due to the enzymatic pathway.
-===By inheritance===
-The human genome contains two copies of each gene- a paternal and a maternal allele.
-*'''Wildtype''' or '''Homozygous non-mutated''' is when neither allele is mutated.
-*A '''Heterozygous mutation''' is when only one allele is mutated.
-*A '''Homozygous mutation''' is when both the paternal and maternal alleles have an identical mutation.
-*'''Compound heterozygous''' mutations or a '''Genetic compound''' is when the paternal and maternal alleles have two different mutations. <ref>Medterms.com [http://www.medterms.com/script/main/art.asp?articlekey=33675]</ref>
-===Special classes===<!-- This section is linked from [[Cat]] -->
-*'''Conditional mutation''' is a mutation that has wild-type (or less severe) phenotype under certain "permissive" environmental conditions and a mutant phenotype under certain "restrictive" conditions. For example, a temperature-sensitive mutation can cause cell death at high temperature (restrictive condition), but might have no deleterious consequences at a lower temperature (permissive condition).
-===Causes of mutation===
-Two classes of mutations are spontaneous mutations (molecular decay) and induced mutations caused by [[mutagen]]s.
-'''Spontaneous mutations''' on the molecular level include:
-* [[Tautomerism]] - A base is changed by the repositioning of a hydrogen atom.
-* [[Depurination]] - Loss of a purine base (A or G).
-* [[Deamination]] - Changes a normal base to an atypical base; C → U, (which can be corrected by DNA repair mechanisms), or spontaneous deamination of 5-methycytosine (irreparable), or A → HX (hypoxanthine).
-* Transition - A purine changes to another purine, or a pyrimidine to a pyrimidine.
-* Transversion - A purine becomes a pyrimidine, or vice versa.
-[[Image:Pyrene adduct.jpg|thumb|right|250px|[[Benzopyrene]], the major mutagen in [[Tobacco smoking|tobacco smoke]], in an adduct to DNA. Produced from [http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1JDG PDB 1JDG].]]
-'''Induced mutations''' on the molecular level can be caused by:
-* Chemicals
-** Nitrosoguanidine (NTG)
-** [[Hydroxylamine]] NH<sub>2</sub>OH
-** [[Base analog]]s (e.g. [[BrdU]])
-** Simple chemicals (e.g. [[acid]]s)
-** Alkylating agents (e.g. [[ENU|''N''-ethyl-''N''-nitrosourea (ENU)]]) These agents can mutate both replicating and non-replicating DNA. In contrast, a base analog can only mutate the DNA 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.
-** Methylating agents (e.g. [[ethyl methanesulfonate]] (EMS))
-** Polycyclic [[hydrocarbons]] (e.g. [[benzopyrene]]s found in [[internal combustion engine]] [[Exhaust gas|exhaust]])
-** DNA intercalating agents (e.g. [[ethidium bromide]])
-** [[DNA crosslinker]] (e.g. [[platinum]])
-** Oxidative damage caused by [[oxygen]](O) [[Radical (chemistry)|radicals]]
-* Radiation
-** [[Ultraviolet]] radiation (nonionizing radiation) excites electrons to a higher energy level. DNA molecules are good absorbers of ultraviolet light, especially that with [[wavelength|wavelengths]] in the 260 to 280 [[nanometre|nm]] range.{{Fact|date=March 2008}} Two nucleotide bases in DNA - cytosine and thymine-are most vulnerable to excitation that can change base-pairing properties. UV light can induce adjacent thymine bases in a DNA strand to pair with each other, as a bulky dimer.
-** [[Ionizing radiation]]
-DNA has so-called hotspots, where mutations occur up to 100 times more frequently than the normal [[mutation rate]]. A hotspot can be at an unusual base, e.g., [[5-methylcytosine]].
-[[Mutation rate]]s also vary across species. Evolutionary biologists have theorized that higher mutation rates are beneficial in some situations, because they allow organisms to evolve and therefore adapt more quickly to their environments. For example, repeated exposure of bacteria to antibiotics, and selection of resistant mutants, can result in the selection of bacteria that have a much higher mutation rate than the original population ([[mutator genotype|mutator strains]]).
-===Nomenclature===
-Nomenclature of mutations specify the type of mutation and base or amino acid changes.
-*Amino acid substitution - (e.g. D111E) The first letter is the one letter code of the wildtype 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. If the second letter is 'X', any amino acid may replace the wildtype.
-*Amino acid deletion - (e.g. ΔF508) The Greek symbol Δ or '[[delta]]' indicates a deletion. The letter refers to the amino acid present in the wildtype and the number is the position from the N terminus of the amino acid were it to be present as in the wildtype.
-==Types of mutations==
-===Adaptive mutation===
-{{main|Adaptive mutation}}
-In mainstream biological thought it is held that while mutagenesis is non-random in many ways, the utility of a genetic mutation to the organism in which it occurs does not affect the rate at which it occurs. However experimental evidence exists that in some instances the rate of specific mutations arising is greater when they are advantageous to the organism than when they are not.
-===Back mutation===
-''Back mutation'' is a change in a [[nucleotide pair]] of a [[point mutation|point-mutated]] [[DNA sequence]] that restores the original sequence and hence the original [[phenotype]].<ref>{{cite journal | author=Ellis NA, Ciocci S, German J | title=Back mutation can produce phenotype reversion in Bloom syndrome somatic cells | journal=Hum Genet | year=2001 | pages=167-73 | volume=108 | issue=2 }} PMID 11281456</ref>
-===Frameshift mutation===
-{{main|Frameshift mutation}}
-A ''frameshift mutation'' is a mutation caused by indels, ie. [[gene insertion|inserts]] or [[genetic deletion|deletes]] a number of [[nucleotide]]s that is not evenly divisible by three from a [[DNA]] sequence. Due to the triplet nature of [[gene expression]] by [[codon]]s, the insertion or [[genetic deletion|deletion]] can disrupt the [[reading frame]], or the grouping of the codons, resulting in a completely different [[Translation (genetics)|translation]] from the original.  The earlier in the sequence the deletion or [[gene insertion|insertion]] occurs, the more altered the protein produced is.
-===Missense mutation===
-{{main|Missense mutation}}
-''Missense mutations'' or ''nonsynonymous mutations'' are types of [[point mutation]]s where a single nucleotide is changed to cause substitution of a different [[amino acid]].  This in turn can render the resulting [[protein]] nonfunctional.  Such mutations are responsible for diseases such as [[Epidermolysis bullosa]], [[sickle-cell disease]], and [[Superoxide dismutase|SOD1]] mediated [[Amyotrophic lateral sclerosis|ALS]]{{Harv | Boillée | 2006 | p=39}}.
-===Neutral mutation===
-{{main|Neutral mutation}}
-A ''neutral mutation'' is a mutation that occurs in an amino acid [[codon]] (presumably within an [[mRNA]] molecule) which results in the use of a different, but chemically similar, [[amino acid]]. This is similar to a [[silent mutation]], where a codon mutation may encode the same amino acid (see [[Wobble Hypothesis]]); for example, a change from AUU to AUC will still encode [[leucine]], so no discernable change occurs (a [[silent mutation]]).
-===Nonsense mutation===
-{{main|Nonsense mutation}}
-A '''nonsense mutation''' is a [[frameshift mutation]] in a [[DNA sequence|sequence]] of [[DNA]] that results in a premature [[stop codon]], or a ''nonsense codon'' in the [[transcription (genetics)|transcribed]] [[mRNA]], and possibly a [[truncation|truncated]], and often nonfunctional [[protein]] product.
-===Point mutation===
-{{main|Point mutation}}
-A ''point mutation'', or ''substitution'', is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide. Often the term ''point mutation'' also includes [[insertion (genetics)|insertions]] or deletions of a single base pair (which have more of an adverse effect on the synthesized protein due to nucleotides still being read in triplets, but in different frames- a mutation called a [[frameshift mutation]]).
-===Silent mutation===
-{{main|Silent mutation}}
-''Silent mutations'' are [[DNA]] mutations that do not result in a change to the [[amino acid]] sequence of a [[protein]]. They may occur in a [[non-coding region]] (outside of a [[gene]] or within an [[intron]]), or they may occur within an [[exon]] in a manner that does not alter the final [[amino acid]] sequence. The phrase '''silent mutation''' is often used interchangeably with the phrase [[Single Nucleotide Polymorphism|synonymous mutation]]; however, synonymous mutations are a subcategory of the former, occurring only within exons.
-==Harmful mutations==
-Changes in DNA caused by mutation can cause errors in [[protein]] sequence, creating partially or completely non-functional proteins. To function correctly, each cell 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. A condition caused by mutations in one or more genes is called a [[genetic disorder]]. However, only a small percentage of mutations cause genetic disorders; most have no impact on health. For example, some mutations alter a gene's DNA base sequence but don’t change the function of the protein made by the gene. Studies in the fly ''[[Drosophila melanogaster]]'' suggest that if a mutation does change a protein, this will probably be harmful, with about 70 percent of these mutations having damaging effects, and the remainder being either neutral or weakly beneficial.<ref>{{cite journal |author=Sawyer SA, Parsch J, Zhang Z, Hartl DL |title=Prevalence of positive selection among nearly neutral amino acid replacements in Drosophila |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=104 |issue=16 |pages=6504-10 |year=2007 |pmid=17409186 |url=http://www.pnas.org/cgi/content/full/104/16/6504}}</ref>
-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 disease]]s. On the other hand, a mutation can occur in a [[somatic cell]] of an organism. Such mutations will be present in all descendants of this cell, and certain mutations can cause the cell to become malignant, and thus cause [[cancer]]<ref>{{cite journal |author=Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M|title=Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis|journal=Nature|volume=363|issue=6429|pages=558-61|year=1993|url=http://dx.doi.org/10.1038/363558a0|pmid=8505985}}</ref>.
-Often, gene mutations that could cause a genetic disorder are repaired by the [[DNA repair]] system of the cell. Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA. Because DNA can be damaged or mutated in many ways, the process of DNA repair is an important way in which the body protects itself from disease.
-==Beneficial mutations==
-A very small percentage of all mutations actually have a positive effect. These mutations lead to new versions of proteins that help an organism and its future generations better adapt to changes in their environment. For example, a specific 32 [[base pair]] deletion in human [[CCR5]] ([[CCR5#CCR5-.CE.9432|CCR5-Δ32]]) confers [[HIV]] resistance to [[Zygosity|homozygotes]] and delays [[AIDS]] onset in [[Zygosity|heterozygotes]].<ref>{{cite web|url=http://www.cdc.gov/genomics/hugenet/factsheets/FS_CCR5.htm|title=CCR5 receptor gene and HIV infection, Antonio Pacheco.}}</ref> The CCR5 mutation is more common in those of European descent. One theory for 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 who had this mutation were able to survive infection; thus, its frequency in the population increased.<ref>{{cite web|url=http://www.pbs.org/wnet/secrets/case_plague/clues.html|title= PBS:Secrets of the Dead. Case File: Mystery of the Black Death}}</ref> It could also explain why this mutation is not found in Africa where the bubonic plague never reached. Newer theory says the [[selective pressure]] on the CCR5 Delta 32 mutation has been caused by [[smallpox]] instead of the bubonic plague.<ref>{{cite journal |author=Galvani A, Slatkin M |title=Evaluating plague and smallpox as historical selective pressures for the CCR5-Δ32 HIV-resistance allele |journal=Proc Natl Acad Sci U S A |volume=100 |issue=25 |pages=15276-9 |year=2003 |pmid=14645720 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=299980 }}</ref>
-==See also==
-<div style="-moz-column-count:3; column-count:3;">
-* [[Aneuploidy]]
-* [[Antioxidant]]
-* [[Budgerigar colour genetics]]
-* [[Homeobox]]
-* [[Macromutation]]
-* [[Muller's morphs]]
-* [[Mutant]]
-* [[Polyploidy]]
-* [[Robertsonian translocation]]
-* [[Signature tagged mutagenesis]]
-* [[Site-directed mutagenesis]]
-</div>
-==References==
-{{reflist}}
-* Leroi A. 2003. ''Mutants: On the form, varieties & errors of the human body''. 1:16-17. Harper Collins 2003
-* Maki H. 2002. ''Origins of spontaneous mutations: specificity and directionality of base-substitution, frameshift, and sequence-substitution mutageneses''. Annual Review of Genetics 36:279-303.
-* Taggart R. Starr C. ''Biology The Unity and Diversity of Life: Mutated Genes and Their Protein Products''. 14.4:227. Thompson Brooks/Cole 2006.
-===Online books===
-* Chapter 7, [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=mutation+AND+mga%5Bbook%5D+AND+110363%5Buid%5D&rid=mga.section.996 The Molecular Basis of Mutation] in ''Modern Genetic Analysis'' by Anthony J. F. Griffiths, William M. Gelbart, Jeffrey H. Miller and [[Richard Lewontin|Richard C. Lewontin]] (1999) published by W. H. Freeman and Company ISBN 0-7167-3597-0.
-* Chapter 9, [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hmg.section.1050 Instability of the human genome: mutation and DNA repair] in ''Human Molecular Genetics 2'' by Tom Strachan and Andrew P. Read (1999) published by John Wiley & Sons, Inc.
-* ''[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.preface.91 Genes and Disease]'' from the [[National Library of Medicine]] provides descriptions of mutations that cause human diseases. For example, a common mutation associated with [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=mutation+AND+gnd%5Bbook%5D+AND+138070%5Buid%5D&rid=gnd.section.207 Huntington disease] is an increased number of copies of repeated CGA triplets in the [[Huntingtin]] gene.
-* ''[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gene GeneReviews]'' by Roberta A. Pagon, Editor-in-chief is made available by the [[University of Washington]] and contains peer-reviewed descriptions of heritable diseases written by experts. For example, [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gene.chapter.brca1 BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer] describes mutations in [[BRCA1]] and [[BRCA2]] that are associated with predispositions to cancer.
-==External links==
-* [http://miracle.igib.res.in/variationcentral Central Locus Specific Variation Database at the Institute of Genomics and Integrative Biology ]
-* [http://en.wikibooks.org/wiki/General_Biology/Genetics/Mutation#Mutation The mutations chapter of the WikiBooks General Biology textbook]
-* [http://www.gate.net/~rwms/EvoMutations.html Examples of Beneficial Mutations]
-* [http://www.genetherapynet.com Gene Therapy Net]
-{{evolution}}
-[[Category:Mutation| ]]
-[[Category:Evolutionary biology]]
-[[Category:Genetics]]
-[[Category:Radiation health effects]]