Mutation

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In biology, a mutation is the permanent alteration of the nucleotide sequence of the genome of an organism, virus, or extrachromosomal DNA or other genetic elements. Mutations result from errors during DNA
DNA replication (especially during Meiosis) or other types of damage to DNA
DNA (such as may be caused by exposure to radiation or carcinogens), which then may undergo error-prone repair (especially microhomology-mediated end joining[1]), or cause an error during other forms of repair,[2][3] or else may cause an error during replication (translesion synthesis). Mutations may also result from insertion or deletion of segments of DNA
DNA due to mobile genetic elements.[4][5][6] 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
RNA viruses are based on RNA
RNA rather than DNA. The RNA viral genome can be double stranded (as in DNA) or single stranded. In some of these viruses (such as the single stranded 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
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
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.[7] Due to the damaging effects that mutations can have on genes, organisms have mechanisms such as DNA
DNA repair to prevent or correct mutations by reverting the mutated sequence back to its original state.[4]

Contents

1 Description 2 History 3 Causes

3.1 Spontaneous mutation 3.2 Error-prone replication bypass 3.3 Errors introduced during DNA
DNA repair 3.4 Induced mutation

4 Classification of types

4.1 By effect on structure

4.1.1 Small-scale mutations 4.1.2 Large-scale mutations

4.2 By effect on function 4.3 By effect on fitness

4.3.1 Distribution of fitness effects

4.4 By impact on protein sequence 4.5 By inheritance 4.6 Special
Special classes 4.7 Nomenclature

5 Mutation
Mutation rates 6 Harmful mutations 7 Beneficial mutations 8 Prion
Prion mutations 9 Somatic mutations 10 Amorphic mutations 11 Hypomorphic and hypermorphic mutations 12 See also 13 References 14 External links

Description[edit] Mutations can involve the duplication of large sections of DNA, usually through genetic recombination.[8] 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.[9] Most genes belong to larger gene families of shared ancestry, known as homology.[10] 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.[11][12] 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.[13] 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.[14] 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.[15][16] Other types of mutation occasionally create new genes from previously noncoding DNA.[17][18] Changes in chromosome number may involve even larger mutations, where segments of the DNA
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.[19] 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.[20] Sequences of DNA
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.[21] 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.[22] Another effect of these mobile DNA
DNA sequences is that when they move within a genome, they can mutate or delete existing genes and thereby produce genetic diversity.[5] Nonlethal mutations accumulate within the gene pool and increase the amount of genetic variation.[23] 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.

Prodryas persephone, a Late Eocene
Eocene butterfly

For example, a butterfly may produce offspring with new mutations. The majority of these mutations will have no effect; but one might change the color of one of the butterfly's offspring, making it harder (or easier) for predators to see. If this color change is advantageous, the chances of this butterfly's surviving and producing its own offspring are a little better, and over time the number of butterflies with this mutation may form a larger percentage of the population. Neutral 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.[24][25][better source needed] 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.[26][27] History[edit] Main article: Mutationism

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 Schwartze, 1918

Mutationism
Mutationism is one of several alternatives to evolution by natural selection that have existed both before and after the publication of Charles Darwin's 1859 book, On the Origin of Species. In the theory, mutation was the source of novelty, creating new forms and new species, potentially instantaneously,[28] in a sudden jump.[29] 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.[30] Darwin opposed saltation, insisting on gradualism in evolution as in geology. In 1864, Albert von Kölliker revived Geoffroy's theory.[31] In 1901 the geneticist Hugo de Vries
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,[32][28] became a rival to Darwinism
Darwinism supported for a while by geneticists including William Bateson,[33] Thomas Hunt Morgan, and Reginald Punnett.[34][28] 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.[35][36][37][38] However, the alignment of Mendelian genetics and natural selection began as early as 1902 with a paper by Udny Yule,[39] and built up with theoretical and experimental work in Europe
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.[36][37] Mutationism, along with other alternatives to Darwinism
Darwinism like Lamarckism
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.[40][41] In 1987, Masatoshi Nei
Masatoshi Nei argued controversially that evolution was often mutation-limited.[42] Modern biologists such as Douglas J. Futuyma conclude that essentially all claims of evolution driven by large mutations can be explained by Darwinian evolution.[43] Causes[edit] Main article: Mutagenesis Four classes of mutations are (1) spontaneous mutations (molecular decay), (2) mutations due to error-prone replication bypass of naturally occurring DNA
DNA damage (also called error-prone translesion synthesis), (3) errors introduced during DNA
DNA repair, and (4) induced mutations caused by mutagens. Scientists may also deliberately introduce mutant sequences through DNA
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.[44] 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.[45] Spontaneous mutation[edit] Spontaneous mutations occur with non-zero probability even given a healthy, uncontaminated cell. They can be characterized by the specific change:[46]

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
Deamination — Hydrolysis
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
DNA repair mechanisms; and 5MeC (5-methylcytosine) → T, which is less likely to be detected as a mutation because thymine is a normal DNA
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[edit] There is increasing evidence that the majority of spontaneously arising mutations are due to error-prone replication (translesion synthesis) past DNA
DNA damage in the template strand. Naturally occurring oxidative DNA
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.[47] In mice, the majority of mutations are caused by translesion synthesis.[48] Likewise, in yeast, Kunz et al.[49] found that more than 60% of the spontaneous single base pair substitutions and deletions were caused by translesion synthesis. Errors introduced during DNA
DNA repair[edit] See also: DNA
DNA damage (naturally occurring) and DNA
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
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.[50]

A covalent adduct between the metabolite of benzo[a]pyrene, the major mutagen in tobacco smoke, and DNA[51]

Induced mutation[edit] 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
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
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
DNA adducts (e.g., ochratoxin A)[52] DNA
DNA intercalating agents (e.g., ethidium bromide) DNA
DNA crosslinkers

This figure depicts the following processes of transcription, splicing, and translation of a eukaryotic gene.

Oxidative damage Nitrous acid
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
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
DNA strand to become covalently joined as a pyrimidine dimer. UV radiation, in particular longer-wave UVA, can also cause oxidative damage to DNA.[53] Ionizing radiation. Exposure to ionizing radiation, such as gamma radiation, can result in mutation, possibly resulting in cancer or death.

Classification of types[edit] See also: Chromosome
Chromosome abnormality By effect on structure[edit]

Five types of chromosomal mutations.

Selection of disease-causing mutations, in a standard table of the genetic code of amino acids.[54]

The sequence of a gene can be altered in a number of ways.[55] 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[edit] Small-scale mutations, affecting a gene in one or a few nucleotides, include:

Substitution mutations, often caused by chemicals or malfunction of DNA
DNA replication, exchange a single nucleotide for another.[56] These changes are classified as transitions or transversions.[57] 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 mis-pairing, 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). A point mutation are modifications of single base pairs of DNA
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).

Point mutations that occur within the protein coding region of a gene may be classified into a few kinds, depending upon what the erroneous codon codes for:

Silent mutations, which code for the same (or a sufficiently similar) amino acid. Missense mutations, which code for a different amino acid. Nonsense mutations, which code for a stop codon and can truncate the protein. 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 m RNA
RNA (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. (Deletion 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. Synonymous substitution Nonsynonymous substitution

Large-scale mutations[edit] Large-scale mutations in chromosomal structure include:

Amplifications (or gene duplications) 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
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[edit]

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."[58] 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,[59] ATM,[60] CEBPA[61] and PPARgamma[62]). Marfan syndrome
Marfan syndrome is caused by mutations in the FBN1
FBN1 gene, located on chromosome 15, which encodes fibrillin-1, a glycoprotein component of the extracellular matrix.[63] Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency.[64][65] 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.[66]

By effect on fitness[edit] 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. Mutations that promotes traits that are desirable, are also called beneficial. In theoretical population genetics, it is more usual to speak of mutations as deleterious or advantageous than harmful or beneficial. 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[edit] 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,[67] the rate of genomic decay,[68] the maintenance of outcrossing sexual reproduction as opposed to inbreeding[69] and the evolution of sex and genetic recombination.[70] In summary, the DFE plays an important role in predicting evolutionary dynamics.[71][72] A variety of approaches have been used to study the DFE, including theoretical, experimental and analytical methods.

Mutagenesis
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.[73][74][75][76] In Escherichia coli, one study used transposon mutagenesis to directly measure the fitness of a random insertion of a derivative of Tn10.[77] 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.[78] However, given that many mutations have effects too small to be detected[79] and that mutagenesis experiments can detect only mutations of moderately large effect; DNA sequence data analysis can provide valuable information about these mutations.

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.[73]

Molecular sequence analysis: With rapid development of DNA
DNA sequencing technology, an enormous amount of DNA
DNA sequence data is available and even more is forthcoming in the future. Various methods have been developed to infer the DFE from DNA
DNA sequence data.[80][81][82][83] By examining DNA
DNA sequence differences within and between species, we are able to infer various characteristics of the DFE for neutral, deleterious and advantageous mutations.[23] 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.[84][85] Hiroshi Akashi more recently proposed a bimodal model for the DFE, with modes centered around highly deleterious and neutral mutations.[86] 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.[73] 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.[78] 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.[87] Like neutral mutations, weakly selected advantageous mutations can be lost due to random genetic drift, but strongly selected advantageous mutations are more likely to be fixed. Knowing the DFE of advantageous mutations may lead to increased ability to predict the evolutionary dynamics. Theoretical work on the DFE for advantageous mutations has been done by John H. Gillespie[88] and H. Allen Orr.[89] 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.[90][91][92] In general, it is accepted that the majority of mutations are neutral or deleterious, with rare mutations being advantageous; 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.[23] In addition, the DFE also differs between coding regions and noncoding regions, with the DFE of noncoding DNA
DNA containing more weakly selected mutations.[23] By impact on protein sequence[edit]

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
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.[93] 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).

In contrast, any insertion or deletion that is evenly divisible by three is termed an in-frame mutation.

A nonsense mutation is a point mutation in a sequence of DNA
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.) Missense mutations or nonsynonymous mutations are types of point mutations 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 SOD1-mediated ALS.[94] A neutral mutation is a mutation that occurs in an amino acid codon that results in the use of a different, but chemically similar, amino acid. The similarity between the two is enough that little or no change is often rendered in the protein. For example, a change from AAA to AGA will encode arginine, a chemically similar molecule to the intended lysine. Silent mutations
Silent mutations are mutations that do not result in a change to the amino acid sequence of a protein but do change the nucleotide sequence, unless the changed amino acid is sufficiently similar to the original. They may occur in a region that does not code for a protein, or they may occur within a codon in a manner that does not alter the final amino acid sequence. Silent mutations
Silent mutations are also called silent substitutions, since they are not palpable changes as the changes in phenotype. The phrase silent mutation is often used interchangeably with the phrase synonymous mutation; however, synonymous mutations are a subcategory of the former, occurring only within exons (and necessarily exactly preserving the amino acid sequence of the protein). Synonymous mutations occur due to the degenerate nature of the genetic code. 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.

By inheritance[edit]

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 germline.

In 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),[95] 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.[96] 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 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 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.[97]

A wild type or homozygous non-mutated organism is one in which neither allele is mutated. Special
Special classes[edit]

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).[98] These mutations are non-autonomous, as their manifestation depends upon presence of certain conditions, as opposed to other mutations which appear autonomously.[99] The permissive conditions may be temperature,[100] certain chemicals,[101] light[101] or mutations in other parts of the genome.[99] 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.[102] 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.[101] DNA
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.[101] 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.[103] 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.[100] Replication timing quantitative trait loci affects DNA
DNA replication.

Nomenclature[edit] In order to categorize a mutation as such, the "normal" sequence must be obtained from the DNA
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
Human Genome
Genome Variation Society (HGVS) has developed the standard human sequence variant nomenclature,[104] which should be used by researchers and DNA
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
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
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
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
Mutation rates[edit] Further information: Mutation
Mutation rate Mutation
Mutation rates vary substantially across species, and the evolutionary forces that generally determine mutation are the subject of ongoing investigation. Harmful mutations[edit] Changes in DNA
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
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
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.[7] Studies have shown that only 7% of point mutations in noncoding DNA
DNA of yeast are deleterious and 12% in coding DNA
DNA are deleterious. The rest of the mutations are either neutral or slightly beneficial.[105] 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
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.[106] A DNA
DNA damage can cause an error when the DNA
DNA is replicated, and this error of replication can cause a gene mutation that, in turn, could cause a genetic disorder. DNA
DNA damages are repaired by the DNA
DNA repair system of the cell. Each cell has a number of pathways through which enzymes recognize and repair damages in DNA. Because DNA
DNA can be damaged in many ways, the process of DNA
DNA repair is an important way in which the body protects itself from disease. Once DNA
DNA damage has given rise to a mutation, the mutation cannot be repaired. DNA
DNA repair pathways can only recognize and act on "abnormal" structures in the DNA. Once a mutation occurs in a gene sequence it then has normal DNA structure and cannot be repaired. Beneficial mutations[edit] 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. For example, a specific 32 base pair deletion in human CCR5 (CCR5-Δ32) confers HIV
HIV resistance to homozygotes and delays AIDS onset in heterozygotes.[107] 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.[108] 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
CCR5 Delta 32 mutation was caused by smallpox instead of the bubonic plague.[109] 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
Sub-Saharan Africa carry the gene, because, in areas where malaria is common, there is a survival value in carrying only a single sickle-cell gene (sickle cell trait).[110] 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
Plasmodium is halted by the sickling of the cells that it infests. Prion
Prion mutations[edit] 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.[111] The human gene PRNP
PRNP codes for the major prion protein, PrP, and is subject to mutations that can give rise to disease-causing prions. Somatic mutations[edit] Main article: Loss of heterozygosity See also: Carcinogenesis A change in the genetic structure that is not inherited from a parent, and also not passed to offspring, is called a somatic mutation.[95] 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.[112] 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.[113] Human
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.[114] Amorphic mutations[edit] 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.[115] Point mutations may arise from spontaneous mutations that occur during DNA
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[edit] A hypomorphic mutation is a replacement of amino acids that would hinder enzyme activity, which would reduce the enzyme level but not to the point of complete loss. Usually, hypomorphic mutations are recessive, but haploinsufficiency causes some alleles to be dominant. A hypermorphic mutation changes the regulation of the gene and causes it to overproduce the gene produce causing a greater than normal enzyme levels. These type of alleles are dominant gain of function type of alleles. See also[edit]

Aneuploidy Antioxidant Budgerigar colour genetics Carcinogenesis Ecogenetics Embryology Frameshift mutation Homeobox Muller's morphs Mutagenesis Mutant Mutation
Mutation rate Polyploidy Robertsonian translocation Saltation (biology) Signature-tagged mutagenesis Site-directed mutagenesis TILLING (molecular biology) Trinucleotide repeat expansion

References[edit]

^ Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC (March 2015). "Homology and enzymatic requirements of microhomology-dependent alternative end joining". Cell Death & Disease. 6 (3): e1697. doi:10.1038/cddis.2015.58. PMC 4385936 . PMID 25789972. ^ Chen J, Miller BF, Furano AV (April 2014). "Repair of naturally occurring mismatches can induce mutations in flanking DNA". eLife. 3: e02001. doi:10.7554/elife.02001. PMC 3999860 . PMID 24843013. ^ Rodgers K, McVey M (January 2016). "Error-Prone Repair of DNA Double-Strand Breaks". Journal of Cellular Physiology. 231 (1): 15–24. doi:10.1002/jcp.25053. PMC 4586358 . PMID 26033759. ^ a b Bertram JS (December 2000). "The molecular biology of cancer". Molecular Aspects of Medicine. Elsevier. 21 (6): 167–223. doi:10.1016/S0098-2997(00)00007-8. PMID 11173079. ^ a b Aminetzach YT, Macpherson JM, Petrov DA (July 2005). "Pesticide resistance via transposition-mediated adaptive gene truncation in Drosophila". Science. American Association for the Advancement of Science. 309 (5735): 764–7. Bibcode:2005Sci...309..764A. doi:10.1126/science.1112699. PMID 16051794. ^ Burrus V, Waldor MK (June 2004). "Shaping bacterial genomes with integrative and conjugative elements". Research in Microbiology. Elsevier. 155 (5): 376–86. doi:10.1016/j.resmic.2004.01.012. PMID 15207870. ^ a b Sawyer SA, Parsch J, Zhang Z, Hartl DL (April 2007). "Prevalence of positive selection among nearly neutral amino acid replacements in Drosophila". Proceedings of the National Academy of Sciences
National Academy of Sciences of the United States of America. National Academy of Sciences. 104 (16): 6504–10. Bibcode:2007PNAS..104.6504S. doi:10.1073/pnas.0701572104. PMC 1871816 . PMID 17409186. ^ Hastings PJ, Lupski JR, Rosenberg SM, Ira G (August 2009). "Mechanisms of change in gene copy number". Nature Reviews Genetics. Nature Publishing Group. 10 (8): 551–64. doi:10.1038/nrg2593. PMC 2864001 . PMID 19597530. ^ Carroll SB, Grenier JK, Weatherbee SD (2005). From DNA
DNA to Diversity: Molecular Genetics
Genetics and the Evolution
Evolution of Animal Design (2nd ed.). Malden, MA: Blackwell Publishing. ISBN 1-4051-1950-0. LCCN 2003027991. OCLC 53972564. ^ Harrison PM, Gerstein M (May 2002). "Studying genomes through the aeons: protein families, pseudogenes and proteome evolution". Journal of Molecular Biology. Elsevier. 318 (5): 1155–74. doi:10.1016/S0022-2836(02)00109-2. PMID 12083509. ^ Orengo CA, Thornton JM (July 2005). " Protein
Protein families and their evolution-a structural perspective". Annual Review of Biochemistry. Annual Reviews. 74: 867–900. doi:10.1146/annurev.biochem.74.082803.133029. PMID 15954844. ^ Long M, Betrán E, Thornton K, Wang W (November 2003). "The origin of new genes: glimpses from the young and old". Nature Reviews Genetics. Nature Publishing Group. 4 (11): 865–75. doi:10.1038/nrg1204. PMID 14634634. ^ Wang M, Caetano-Anollés G (January 2009). "The evolutionary mechanics of domain organization in proteomes and the rise of modularity in the protein world". Structure. Cell Press. 17 (1): 66–78. doi:10.1016/j.str.2008.11.008. PMID 19141283. ^ Bowmaker JK (May 1998). " Evolution
Evolution of colour vision in vertebrates". Eye. Nature Publishing Group. 12 (Pt 3b): 541–7. doi:10.1038/eye.1998.143. PMID 9775215. ^ Gregory TR, Hebert PD (April 1999). "The modulation of DNA
DNA content: proximate causes and ultimate consequences". Genome
Genome Research. Cold Spring Harbor Laboratory Press. 9 (4): 317–24. doi:10.1101/gr.9.4.317 (inactive 2017-08-16). PMID 10207154. ^ Hurles M (July 2004). " Gene
Gene duplication: the genomic trade in spare parts". PLoS Biology. Public Library of Science. 2 (7): E206. doi:10.1371/journal.pbio.0020206. PMC 449868 . PMID 15252449. ^ Liu N, Okamura K, Tyler DM, Phillips MD, Chung WJ, Lai EC (October 2008). "The evolution and functional diversification of animal micro RNA
RNA genes". Cell Research. Nature Publishing Group on behalf of the Shanghai Institutes for Biological Sciences. 18 (10): 985–96. doi:10.1038/cr.2008.278. PMC 2712117 . PMID 18711447. ^ Siepel A (October 2009). "Darwinian alchemy: Human
Human genes from noncoding DNA". Genome
Genome Research. Cold Spring Harbor Laboratory Press. 19 (10): 1693–5. doi:10.1101/gr.098376.109. PMC 2765273 . PMID 19797681. ^ Zhang J, Wang X, Podlaha O (May 2004). "Testing the chromosomal speciation hypothesis for humans and chimpanzees". Genome
Genome Research. Cold Spring Harbor Laboratory Press. 14 (5): 845–51. doi:10.1101/gr.1891104. PMC 479111 . PMID 15123584. ^ Ayala FJ, Coluzzi M (May 2005). " Chromosome
Chromosome speciation: humans, Drosophila, and mosquitoes". Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences. 102 Suppl 1 (Suppl 1): 6535–42. Bibcode:2005PNAS..102.6535A. doi:10.1073/pnas.0501847102. PMC 1131864 . PMID 15851677. ^ Hurst GD, Werren JH (August 2001). "The role of selfish genetic elements in eukaryotic evolution". Nature Reviews Genetics. Nature Publishing Group. 2 (8): 597–606. doi:10.1038/35084545. PMID 11483984. ^ Häsler J, Strub K (November 2006). "Alu elements as regulators of gene expression". Nucleic Acids Research. Oxford University Press. 34 (19): 5491–7. doi:10.1093/nar/gkl706. PMC 1636486 . PMID 17020921. ^ a b c d Eyre-Walker A, Keightley PD (August 2007). "The distribution of fitness effects of new mutations" (PDF). Nature Reviews Genetics. 8 (8): 610–8. doi:10.1038/nrg2146. PMID 17637733. Archived (PDF) from the original on 4 March 2016. ^ Kimura, M. 1983. The neutral theory of molecular evolution. Cambridge University Press, Cambridge. ^ Bohidar HB (January 2015). Fundamentals of Polymer Physics and Molecular Biophysics. Cambridge University Press. ISBN 978-1-316-09302-3. ^ Dover, Gabriel A.; Darwin, Charles (2000). Dear Mr. Darwin: Letters on the Evolution
Evolution of Life and Human
Human Nature. University of California Press. ISBN 9780520227903. ^ Tibayrenc, Michel (2017-01-12). Genetics
Genetics and Evolution
Evolution of Infectious Diseases. Elsevier. ISBN 9780128001530. ^ a b c Bowler, Peter J. (1992) [1983]. The Eclipse of Darwinism. p. 198. ^ Smocovitis, Vassiliki Betty (1996). Unifying Biology: The Evolutionary Synthesis and Evolutionary Biology. Princeton, NJ: Princeton University Press. p. 56. ISBN 0-691-03343-9. LCCN 96005605. OCLC 34411399. ^ Hallgrímsson, Benedikt; Hall, Brian K. (2011). Variation: A Central Concept in Biology. Academic Press. p. 18. CS1 maint: Multiple names: authors list (link) ^ Sewall Wright. (1984). Evolution
Evolution and the Genetics
Genetics of Populations: Genetics
Genetics and Biometric Foundations Volume 1. University of Chicago Press. p. 10 ^ De Vries, Hugo (1905). Species
Species and Varieties: Their Origin by Mutation. ^ Bateson, William (1894). Materials for the Study of Variation, Treated with Especial Regard to Discontinuity in the Origin of Species. ^ Punnett, Reginald C. (1915). Mimicry in Butterflies. Cambridge University Press. ^ Mayr, Ernst (2007). What Makes Biology
Biology Unique?: Considerations on the Autonomy of a Scientific Discipline. Cambridge University Press. ^ a b Provine, W. B. (2001). The Origins of Theoretical Population Genetics, with a new afterword. University of Chicago Press, Chicago. pp. 56–107. ^ a b Stoltzfus, A.; Cable, K. (2014). "Mendelian-Mutationism: The Forgotten Evolutionary Synthesis". J Hist Biol. 47 (4): 501–546. doi:10.1007/s10739-014-9383-2. ^ Hull, D. L. (1985). " Darwinism
Darwinism as an historical entity: A historiographic proposal". In Kohn, D. The Darwinian Heritage. Princeton University Press. pp. 773–812. ^ Yule, G. Udny (1902). "Mendel's Laws and their probable relations to inter-racial heredity". New Phytologist. 1: 226–227. doi:10.1111/j.1469-8137.1902.tb07336.x. ^ 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. ^ Ruse, Michael (1996). Monad to man: the Concept of Progress in Evolutionary Biology. Harvard University Press. pp. 412–413. ISBN 978-0-674-03248-4. ^ A. Stoltzfus (2014). In search of mutation-driven evolution. Evolution
Evolution & Development. 16. Publisher. pp. 57–59. doi:10.1111/ede.12062. ^ Futuyma, Douglas J. (2015). Serrelli, E.; Gontier, N., eds. "Can Modern Evolutionary Theory Explain Macroevolution?" (PDF). Macroevolution. Springer. pp. 29–85. ^ " Cancer
Cancer Is Partly Caused By Bad Luck, Study Finds". Archived from the original on 13 July 2017. ^ https://www.theguardian.com/science/2012/aug/22/older-fathers-genetic-mutations-research ^ Montelone BA (1998). "Mutation, Mutagens, and DNA
DNA Repair". www-personal.ksu.edu. Archived from the original on 26 September 2015. Retrieved 2 October 2015. ^ Bernstein C, Prasad AR, Nfonsam V, Bernstein H. (2013). DNA
DNA Damage, DNA
DNA Repair and Cancer, New Research Directions in DNA
DNA Repair, Prof. Clark Chen (Ed.). intechopen.com. ISBN 978-953-51-1114-6. Archived from the original on 24 September 2015. CS1 maint: Multiple names: authors list (link) ^ Stuart GR, Oda Y, de Boer JG, Glickman BW (March 2000). "Mutation frequency and specificity with age in liver, bladder and brain of lacI transgenic mice". Genetics. Genetics
Genetics Society of America. 154 (3): 1291–300. PMC 1460990 . PMID 10757770. ^ Kunz BA, Ramachandran K, Vonarx EJ (April 1998). " DNA
DNA sequence analysis of spontaneous mutagenesis in Saccharomyces cerevisiae". Genetics. Genetics
Genetics Society of America. 148 (4): 1491–505. PMC 1460101 . PMID 9560369. ^ Lieber MR (July 2010). "The mechanism of double-strand DNA
DNA break repair by the nonhomologous DNA
DNA end-joining pathway". Annual Review of Biochemistry. Annual Reviews. 79: 181–211. doi:10.1146/annurev.biochem.052308.093131. PMC 3079308 . PMID 20192759. ^ Created from PDB 1JDG Archived 31 December 2015 at the Wayback Machine. ^ Pfohl-Leszkowicz A, Manderville RA (January 2007). "Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans". Molecular Nutrition & Food Research. Wiley-Blackwell. 51 (1): 61–99. doi:10.1002/mnfr.200600137. PMID 17195275. ^ Kozmin S, Slezak G, Reynaud-Angelin A, Elie C, de Rycke Y, Boiteux S, Sage E (September 2005). "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. National Academy of Sciences. 102 (38): 13538–43. Bibcode:2005PNAS..10213538K. doi:10.1073/pnas.0504497102. PMC 1224634 . PMID 16157879. ^ References for the image are found in Wikimedia Commons page at: Commons:File:Notable mutations.svg#References. ^ Rahman, Nazneen. "The clinical impact of DNA
DNA sequence changes". Transforming Genetic Medicine Initiative. Archived from the original on 4 August 2017. Retrieved 27 June 2017. ^ Freese E (April 1959). "THE DIFFERENCE BETWEEN SPONTANEOUS AND BASE-ANALOGUE INDUCED MUTATIONS OF PHAGE T4". Proceedings of the National Academy of Sciences
National Academy of Sciences of the United States of America. National Academy of Sciences. 45 (4): 622–33. doi:10.1073/pnas.45.4.622. PMC 222607 . PMID 16590424. ^ Freese E (June 1959). "The specific mutagenic effect of base analogues on Phage T4". Journal of Molecular Biology. Amsterdam, the Netherlands: Elsevier. 1 (2): 87–105. doi:10.1016/S0022-2836(59)80038-3. ^ Steenhuysen, Julie (2017-12-19). "U.S. Lifts Funding Ban on Studies That Enhance Dangerous Germs". U.S. News & World Report. Retrieved 2018-01-15. ^ Goh AM, Coffill CR, Lane DP (January 2011). "The role of mutant p53 in human cancer". The Journal of Pathology. John Wiley & Sons. 223 (2): 116–26. doi:10.1002/path.2784. PMID 21125670. ^ 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 (February 2002). "Dominant negative ATM mutations in breast cancer families". Journal of the National Cancer
Cancer Institute. Oxford University Press. 94 (3): 205–15. CiteSeerX 10.1.1.557.6394 . doi:10.1093/jnci/94.3.205. PMID 11830610. ^ Paz-Priel I, Friedman A (2011). "C/EBPα dysregulation in AML and ALL". Critical Reviews in Oncogenesis. Begell House. 16 (1–2): 93–102. doi:10.1615/critrevoncog.v16.i1-2.90. PMC 3243939 . PMID 22150310. (Subscription required (help)). ^ Capaccio D, Ciccodicola A, Sabatino L, Casamassimi A, Pancione M, Fucci A, Febbraro A, Merlino A, Graziano G, Colantuoni V (June 2010). "A novel germline mutation in peroxisome proliferator-activated receptor gamma gene associated with large intestine polyp formation and dyslipidemia". Biochimica et Biophysica Acta. Elsevier. 1802 (6): 572–81. doi:10.1016/j.bbadis.2010.01.012. PMID 20123124. ^ McKusick VA (July 1991). "The defect in Marfan syndrome". Nature. Nature Publishing Group. 352 (6333): 279–81. Bibcode:1991Natur.352..279M. doi:10.1038/352279a0. PMID 1852198. ^ Judge DP, Biery NJ, Keene DR, Geubtner J, Myers L, Huso DL, Sakai LY, Dietz HC (July 2004). "Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome". The Journal of Clinical Investigation. American Society for Clinical Investigation. 114 (2): 172–81. doi:10.1172/JCI20641. PMC 449744 . PMID 15254584. ^ Judge DP, Dietz HC (December 2005). "Marfan's syndrome". Lancet. Elsevier. 366 (9501): 1965–76. doi:10.1016/S0140-6736(05)67789-6. PMC 1513064 . PMID 16325700. ^ Ellis NA, Ciocci S, German J (February 2001). "Back mutation can produce phenotype reversion in Bloom syndrome somatic cells". Human Genetics. Springer-Verlag. 108 (2): 167–73. doi:10.1007/s004390000447. PMID 11281456. ^ Charlesworth D, Charlesworth B, Morgan MT (December 1995). "The pattern of neutral molecular variation under the background selection model". Genetics. Genetics
Genetics Society of America. 141 (4): 1619–32. PMC 1206892 . PMID 8601499. ^ Loewe L (April 2006). "Quantifying the genomic decay paradox due to Muller's ratchet in human mitochondrial DNA". Genetical Research. Cambridge University Press. 87 (2): 133–59. doi:10.1017/S0016672306008123. PMID 16709275. ^ Bernstein H, Hopf FA, Michod RE (1987). "The molecular basis of the evolution of sex". Advances in Genetics. 24: 323–70. doi:10.1016/s0065-2660(08)60012-7. PMID 3324702. ^ Peck JR, Barreau G, Heath SC (April 1997). "Imperfect genes, Fisherian mutation and the evolution of sex". Genetics. Genetics Society of America. 145 (4): 1171–99. PMC 1207886 . PMID 9093868. ^ Keightley PD, Lynch M (March 2003). "Toward a realistic model of mutations affecting fitness". Evolution; International Journal of Organic Evolution. John Wiley & Sons for the Society for the Study of Evolution. 57 (3): 683–5; discussion 686–9. doi:10.1554/0014-3820(2003)057[0683:tarmom]2.0.co;2. JSTOR 3094781. PMID 12703958. ^ Barton NH, Keightley PD (January 2002). "Understanding quantitative genetic variation". Nature Reviews Genetics. Nature Publishing Group. 3 (1): 11–21. doi:10.1038/nrg700. PMID 11823787. ^ a b c Sanjuán R, Moya A, Elena SF (June 2004). "The distribution of fitness effects caused by single-nucleotide substitutions in an RNA virus". Proceedings of the National Academy of Sciences
National Academy of Sciences of the United States of America. National Academy of Sciences. 101 (22): 8396–401. doi:10.1073/pnas.0400146101. PMC 420405 . PMID 15159545. ^ Carrasco P, de la Iglesia F, Elena SF (December 2007). "Distribution of fitness and virulence effects caused by single-nucleotide substitutions in Tobacco Etch virus". Journal of Virology. American Society for Microbiology. 81 (23): 12979–84. doi:10.1128/JVI.00524-07. PMC 2169111 . PMID 17898073. ^ Sanjuán R (June 2010). "Mutational fitness effects in RNA
RNA and single-stranded DNA
DNA viruses: common patterns revealed by site-directed mutagenesis studies". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. Royal Society. 365 (1548): 1975–82. doi:10.1098/rstb.2010.0063. PMC 2880115 . PMID 20478892. ^ Peris JB, Davis P, Cuevas JM, Nebot MR, Sanjuán R (June 2010). "Distribution of fitness effects caused by single-nucleotide substitutions in bacteriophage f1". Genetics. Genetics
Genetics Society of America. 185 (2): 603–9. doi:10.1534/genetics.110.115162. PMC 2881140 . PMID 20382832. ^ Elena SF, Ekunwe L, Hajela N, Oden SA, Lenski RE (March 1998). "Distribution of fitness effects caused by random insertion mutations in Escherichia coli". Genetica. Kluwer Academic Publishers. 102–103 (1–6): 349–58. doi:10.1023/A:1017031008316. PMID 9720287. ^ a b Hietpas RT, Jensen JD, Bolon DN (May 2011). "Experimental illumination of a fitness landscape". Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences. 108 (19): 7896–901. doi:10.1073/pnas.1016024108. PMC 3093508 . PMID 21464309. ^ Davies EK, Peters AD, Keightley PD (September 1999). "High frequency of cryptic deleterious mutations in Caenorhabditis elegans". Science. American Association for the Advancement of Science. 285 (5434): 1748–51. doi:10.1126/science.285.5434.1748. PMID 10481013. ^ Loewe L, Charlesworth B (September 2006). "Inferring the distribution of mutational effects on fitness in Drosophila". Biology Letters. Royal Society. 2 (3): 426–30. doi:10.1098/rsbl.2006.0481. PMC 1686194 . PMID 17148422. ^ Eyre-Walker A, Woolfit M, Phelps T (June 2006). "The distribution of fitness effects of new deleterious amino acid mutations in humans". Genetics. Genetics
Genetics Society of America. 173 (2): 891–900. doi:10.1534/genetics.106.057570. PMC 1526495 . PMID 16547091. ^ Sawyer SA, Kulathinal RJ, Bustamante CD, Hartl DL (August 2003). "Bayesian analysis suggests that most amino acid replacements in Drosophila
Drosophila are driven by positive selection". Journal of Molecular Evolution. Springer-Verlag. 57 Suppl 1 (1): S154–64. CiteSeerX 10.1.1.78.65 . doi:10.1007/s00239-003-0022-3. PMID 15008412. ^ Piganeau G, Eyre-Walker A (September 2003). "Estimating the distribution of fitness effects from DNA
DNA sequence data: implications for the molecular clock". Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences. 100 (18): 10335–40. doi:10.1073/pnas.1833064100. PMC 193562 . PMID 12925735. ^ Kimura M (February 1968). "Evolutionary rate at the molecular level". Nature. Nature Publishing Group. 217 (5129): 624–6. doi:10.1038/217624a0. PMID 5637732. ^ Kimura M (1983). The Neutral Theory of Molecular Evolution. Cambridge, UK; New York: Cambridge University Press. ISBN 0-521-23109-4. LCCN 82022225. OCLC 9081989. ^ Akashi H (September 1999). "Within- and between-species DNA
DNA sequence variation and the 'footprint' of natural selection". Gene. Elsevier. 238 (1): 39–51. doi:10.1016/S0378-1119(99)00294-2. PMID 10570982. ^ Eyre-Walker A (October 2006). "The genomic rate of adaptive evolution". Trends in Ecology & Evolution. Cell Press. 21 (10): 569–75. doi:10.1016/j.tree.2006.06.015. PMID 16820244. ^ Gillespie JH (September 1984). "Molecular Evolution
Evolution Over the Mutational Landscape". Evolution. Hoboken, NJ: John Wiley & Sons for the Society for the Study of Evolution. 38 (5): 1116–1129. doi:10.2307/2408444. JSTOR 2408444. ^ Orr HA (April 2003). "The distribution of fitness effects among beneficial mutations". Genetics. Genetics
Genetics Society of America. 163 (4): 1519–26. PMC 1462510 . PMID 12702694. ^ Kassen R, Bataillon T (April 2006). "Distribution of fitness effects among beneficial mutations before selection in experimental populations of bacteria". Nature Genetics. Nature Publishing Group. 38 (4): 484–8. doi:10.1038/ng1751. PMID 16550173. ^ Rokyta DR, Joyce P, Caudle SB, Wichman HA (April 2005). "An empirical test of the mutational landscape model of adaptation using a single-stranded DNA
DNA virus". Nature Genetics. Nature Publishing Group. 37 (4): 441–4. doi:10.1038/ng1535. PMID 15778707. ^ Imhof M, Schlotterer C (January 2001). "Fitness effects of advantageous mutations in evolving Escherichia coli
Escherichia coli populations". Proceedings of the National Academy of Sciences
National Academy of Sciences of the United States of America. National Academy of Sciences. 98 (3): 1113–7. doi:10.1073/pnas.98.3.1113. PMC 14717 . PMID 11158603. ^ Hogan, C. Michael (12 October 2010). "Mutation". In Monosson, Emily. Encyclopedia of Earth. Washington, D.C.: Environmental Information Coalition, National Council for Science and the Environment. OCLC 72808636. Archived from the original on 14 November 2015. Retrieved 8 October 2015. ^ Boillée S, Vande Velde C, Cleveland DW (October 2006). "ALS: a disease of motor neurons and their nonneuronal neighbors". Neuron. Cell Press. 52 (1): 39–59. CiteSeerX 10.1.1.325.7514 . doi:10.1016/j.neuron.2006.09.018. PMID 17015226. ^ a b " Somatic cell genetic mutation". Genome
Genome Dictionary. Athens, Greece: Information Technology Associates. 30 June 2007. Archived from the original on 24 February 2010. Retrieved 6 June 2010. ^ "RB1 Genetics". Daisy's Eye Cancer
Cancer Fund. Oxford, UK. Archived from the original on 2011-11-26. Retrieved 2015-10-09. ^ "Compound heterozygote". MedTerms. New York: WebMD. 14 June 2012. Archived from the original on 4 March 2016. Retrieved 9 October 2015. ^ Alberts (2014). Molecular Biology
Biology of the Cell (6 ed.). Garland Science. p. 487. ISBN 9780815344322. ^ a b Chadov BF, Fedorova NB, Chadova EV (2015-07-01). "Conditional mutations in Drosophila
Drosophila melanogaster: On the occasion of the 150th anniversary of G. Mendel's report in Brünn". Mutation
Mutation Research - Reviews in Mutation
Mutation Research. 765: 40–55. doi:10.1016/j.mrrev.2015.06.001. PMID 26281767. ^ a b Landis G, Bhole D, Lu L, Tower J (July 2001). "High-frequency generation of conditional mutations affecting Drosophila
Drosophila melanogaster development and life span". Genetics. 158 (3): 1167–76. PMC 1461716 . PMID 11454765. Archived from the original on 22 March 2017. ^ a b c d Gierut JJ, Jacks TE, Haigis KM (April 2014). "Strategies to achieve conditional gene mutation in mice". Cold Spring Harbor Protocols. 2014 (4): 339–49. doi:10.1101/pdb.top069807. PMC 4142476 . PMID 24692485. ^ Spencer DM (May 1996). "Creating conditional mutations in mammals". Trends in Genetics. 12 (5): 181–7. doi:10.1016/0168-9525(96)10013-5. PMID 8984733. ^ Tan G, Chen M, Foote C, Tan C (September 2009). "Temperature-sensitive mutations made easy: generating conditional mutations by using temperature-sensitive inteins that function within different temperature ranges". Genetics. 183 (1): 13–22. doi:10.1534/genetics.109.104794. PMC 2746138 . PMID 19596904. ^ den Dunnen JT, Antonarakis SE (January 2000). " Mutation
Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion". Human
Human Mutation. Wiley-Liss, Inc. 15 (1): 7–12. doi:10.1002/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N. PMID 10612815. ^ Doniger SW, Kim HS, Swain D, Corcuera D, Williams M, Yang SP, Fay JC (August 2008). Pritchard JK, ed. "A catalog of neutral and deleterious polymorphism in yeast". PLoS Genetics. Public Library of Science. 4 (8): e1000183. doi:10.1371/journal.pgen.1000183. PMC 2515631 . PMID 18769710. ^ Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (June 1993). "Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis". Nature. Nature Publishing Group. 363 (6429): 558–61. Bibcode:1993Natur.363..558I. doi:10.1038/363558a0. PMID 8505985. ^ Sullivan AD, Wigginton J, Kirschner D (August 2001). "The coreceptor mutation CCR5Delta32 influences the dynamics of HIV
HIV epidemics and is selected for by HIV". Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences. 98 (18): 10214–9. Bibcode:2001PNAS...9810214S. doi:10.1073/pnas.181325198. PMC 56941 . PMID 11517319. ^ "Mystery of the Black Death". Secrets of the Dead. Season 3. Episode 2. 30 October 2002. PBS. Archived from the original on 12 October 2015. Retrieved 10 October 2015. Episode background. ^ Galvani AP, Slatkin M (December 2003). "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. National Academy of Sciences. 100 (25): 15276–9. Bibcode:2003PNAS..10015276G. doi:10.1073/pnas.2435085100. PMC 299980 . PMID 14645720. ^ Konotey-Ahulu, Felix. "Frequently Asked Questions [FAQ's]". sicklecell.md. Archived from the original on 30 April 2011. ^ "'Lifeless' prion proteins are 'capable of evolution'". Health. BBC News Online. London. 1 January 2010. Archived from the original on 25 September 2015. Retrieved 10 October 2015. ^ "somatic mutation genetics". Encyclopedia Britannica. Archived from the original on 31 March 2017. Retrieved 31 March 2017. ^ Hartl, Jones, Daniel L., Elizabeth W. (1998). Genetics
Genetics Principles and Analysis. Sudbury, Massachusetts: Jones and Bartlett Publishers. p. 556. ISBN 0-7637-0489-X. ^ Milholland B, Dong X, Zhang L, Hao X, Suh Y, Vijg J (2017). "Differences between germline and somatic mutation rates in humans and mice". Nat Commun. 8: 15183. doi:10.1038/ncomms15183. PMC 5436103 . PMID 28485371. ^ Araten DJ, Golde DW, Zhang RH, Thaler HT, Gargiulo L, Notaro R, Luzzatto L (September 2005). "A quantitative measurement of the human somatic mutation rate". Cancer
Cancer Research. American Association for Cancer
Cancer Research. 65 (18): 8111–7. doi:10.1158/0008-5472.CAN-04-1198. PMID 16166284.

External links[edit]

Wikimedia Commons has media related to Mutations.

Jones, Steve; Woolfson, Adrian; Partridge, Linda (December 6, 2007). "Genetic Mutation". In Our Time. BBC Radio 4. Retrieved 2015-10-18. Liou, Stephanie (February 5, 2011). "All About Mutations". HOPES. Huntington's Disease Outreach Project for Education at Stanford. Retrieved 2015-10-18. "Locus Specific Mutation
Mutation Databases". Leiden, the Netherlands: Leiden University Medical Center. Retrieved 2015-10-18. "Welcome to the Mutalyzer website". Leiden, the Netherlands: Leiden University Medical Center. Retrieved 2015-10-18. — The Mutalyzer website.

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Mutation

Mechanisms of mutation

Insertion Deletion Substitution

Transversion Transition

Mutation
Mutation with respect to structure

Point mutation

Nonsense mutation Missense mutation Conservative mutation Silent mutation Frameshift mutation Dynamic mutation

Large-scale mutation

Chromosomal translocations Chromosomal inversions

Mutation
Mutation with respect to overall fitness

Deleterious mutation Advantageous mutation Neutral mutation Nearly neutral mutation

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Chromosome
Chromosome abnormalities (Q90–Q99, 758)

Autosomal

Trisomies

Down syndrome

Edwards syndrome

Patau syndrome

Trisomy
Trisomy 9 Warkany syndrome 2

Cat eye syndrome/ Trisomy
Trisomy 22

Trisomy
Trisomy 16

Monosomies/deletions

1q21.1 deletion syndrome/1q21.1 duplication syndrome/TAR syndrome

Wolf–Hirschhorn syndrome

Cri du chat/ Chromosome
Chromosome 5q deletion syndrome

Williams syndrome

Jacobsen syndrome

Miller–Dieker syndrome/Smith–Magenis syndrome

DiGeorge syndrome

22q11.2 distal deletion syndrome

22q13 deletion syndrome

genomic imprinting

Angelman syndrome/ Prader–Willi syndrome
Prader–Willi syndrome (15)

Distal 18q-/Proximal 18q-

X/Y linked

Monosomy

Turner syndrome
Turner syndrome (45,X)

Trisomy/tetrasomy, other karyotypes/mosaics

Klinefelter syndrome
Klinefelter syndrome (47,XXY) XXYY syndrome
XXYY syndrome (48,XXYY) XXXY syndrome
XXXY syndrome (48,XXXY) 49,XXXYY 49,XXXXY

Triple X syndrome
Triple X syndrome (47,XXX) Tetrasomy X (48,XXXX) 49,XXXXX

Jacobs syndrome (47,XYY) 48,XYYY 49,XYYYY

45,X/46,XY

Translocations

Leukemia/lymphoma

Lymphoid

Burkitt's lymphoma
Burkitt's lymphoma t(8 MYC;14 IGH) Follicular lymphoma
Follicular lymphoma t(14 IGH;18 BCL2) Mantle cell lymphoma/ Multiple myeloma
Multiple myeloma t(11 CCND1:14 IGH) Anaplastic large-cell lymphoma
Anaplastic large-cell lymphoma t(2 ALK;5 NPM1) Acute lymphoblastic leukemia

Myeloid

Philadelphia chromosome
Philadelphia chromosome t(9 ABL; 22 BCR) Acute myeloblastic leukemia with maturation
Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1) Acute promyelocytic leukemia
Acute promyelocytic leukemia t(15 PML,17 RARA) Acute megakaryoblastic leukemia
Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1)

Other

Ewing's sarcoma
Ewing's sarcoma t(11 FLI1; 22 EWS) Synovial sarcoma
Synovial sarcoma t(x SYT;18 SSX) Dermatofibrosarcoma protuberans
Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB) Myxoid liposarcoma
Myxoid liposarcoma t(12 DDIT3; 16 FUS) Desmoplastic small-round-cell tumor
Desmoplastic small-round-cell tumor t(11 WT1; 22 EWS) Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1)

Other

Fragile X syndrome Uniparental disomy XX male syndrome/46,XX testicular disorders of sex development Marker chromosome Ring chromosome

6; 9; 14; 15; 18; 20; 21, 22

v t e

Evolutionary biology

Evolutionary history of life Index of evolutionary biology articles Introduction Outline of evolution Timeline of evolution

Evolution

Abiogenesis Adaptation Adaptive radiation Cladistics Coevolution Common descent Convergence Divergence Earliest known life forms Evidence of common descent Extinction

Event

Gene-centered view Homology Last universal common ancestor Macroevolution Microevolution Origin of life Panspermia Parallel evolution Prehistoric Autopsy Speciation Taxonomy

Population genetics

Biodiversity Gene
Gene flow Genetic drift Mutation Natural selection Variation

Development

Canalisation Evolutionary developmental biology Inversion Modularity Phenotypic plasticity

Of taxa

Birds

origin

Brachiopods Molluscs

Cephalopods

Dinosaurs Fish Fungi Insects

butterflies

Life Mammals

cats canids

wolves dogs

hyenas dolphins and whales horses primates

humans lemurs

sea cows

Plants Reptiles Spiders Tetrapods Viruses

influenza

Of organs

Cell DNA Flagella Eukaryotes

symbiogenesis chromosome endomembrane system mitochondria nucleus plastids

In animals

eye hair auditory ossicle nervous system brain

Of processes

Aging

Death Programmed cell death

Avian flight Biological complexity Cooperation Color vision

in primates

Emotion Empathy Ethics Eusociality Immune system Metabolism Monogamy Morality Mosaic evolution Multicellularity Sexual reproduction

Gamete
Gamete differentiation/sexes Life cycles/nuclear phases Mating types Sex-determination

Snake venom

Tempo and modes

Gradualism/Punctuated equilibrium/Saltationism Micromutation/Macromutation Uniformitarianism/Catastrophism

Speciation

Allopatric Anagenesis Catagenesis Cladogenesis Cospeciation Ecological Hybrid Parapatric Peripatric Reinforcement Sympatric

History

Renaissance and Enlightenment Transmutation of species Charles Darwin

On the Origin of Species

History of paleontology Transitional fossil Blending inheritance Mendelian inheritance The eclipse of Darwinism Modern synthesis History of molecular evolution Extended evolutionary synthesis

Philosophy

Darwinism Alternatives

Catastrophism Lamarckism Orthogenesis Mutationism Saltationism Structuralism

Spandrel

Theistic Vitalism

Teleology in biology

Biogeography Ecological genetics Molecular evolution Phylogenetics

Tree

Polymorphism Protocell Systematics

Category Commons Portal WikiProject

Biology
Biology portal Medicine portal Evolution