Mutation - Knowledge

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studied recently. Existence of compensated pathogenic deviations can be explained by 'sign epistasis', in which the effects of a deleterious mutation can be compensated by the presence of an epistatic mutation in another loci. For a given protein, a deleterious mutation (D) and a compensatory mutation (C) can be considered, where C can be in the same protein as D or in a different interacting protein depending on the context. The fitness effect of C itself could be neutral or somewhat deleterious such that it can still exist in the population, and the effect of D is deleterious to the extent that it cannot exist in the population. However, when C and D co-occur together, the combined fitness effect becomes neutral or positive. Thus, compensatory mutations can bring novelty to proteins by forging new pathways of protein evolution : it allows individuals to travel from one fitness peak to another through the valleys of lower fitness.

1468: 2795:φ6 fitness declined rapidly and recovered in small steps . Viral nucleoproteins have been shown to avoid cytotoxic T lymphocytes (CTLs) through arginine-to glycine substitutions. This substitution mutations impacts the fitness of viral nucleoproteins, however compensatory co-mutations impede fitness declines and aid the virus to avoid recognition from CTLs. Mutations can have three different effects; mutations can have deleterious effects, some increase fitness through compensatory mutations, and lastly mutations can be counterbalancing resulting in compensatory neutral mutations. 591: 178: 2808:(NGS), all types of de novo mutations within the genome can be directly studied, the detection of which provides a magnitude of insight toward the causes of both rare and common genetic disorders. Currently, the best estimate of the average human germline SNV mutation rate is 1.18 x 10^-8, with an approximate ~78 novel mutations per generation. The ability to conduct whole genome sequencing of parents and offspring allows for the comparison of mutation rates between generations, narrowing down the origin possibilities of certain genetic disorders. 1245: 700:

cellular level, mutations can alter protein function and regulation. Unlike DNA damages, mutations are replicated when the cell replicates. At the level of cell populations, cells with mutations will increase or decrease in frequency according to the effects of the mutations on the ability of the cell to survive and reproduce. Although distinctly different from each other, DNA damages and mutations are related because DNA damages often cause errors of DNA synthesis during replication or repair and these errors are a major source of mutation.

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mutation, then P can become fixed in the population. The second model of CPDs states that P and C are both deleterious mutations resulting in fitness valleys when mutations occur simultaneously. Using publicly available, Ferrer-Costa et al. 2007 obtained compensatory mutations and human pathogenic mutation datasets that were characterized to determine what causes CPDs. Results indicate that the structural constraints and the location in protein structure determine whether compensated mutations will occur.

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by stress responses and activated when cells/organisms are maladapted to their environments—when stressed—potentially accelerating adaptation." Since they are self-induced mutagenic mechanisms that increase the adaptation rate of organisms, they have some times been named as adaptive mutagenesis mechanisms, and include the SOS response in bacteria, ectopic intrachromosomal recombination and other chromosomal events such as duplications.

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with a decreased rate of genetic diversity. The position of a population relative to the critical effect population size is essential to determine the effect deleterious alleles will have on fitness. If the population is below the critical effective size fitness will decrease drastically, however if the population is above the critical effect size, fitness can increase regardless of deleterious mutations due to compensatory alleles.

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shared by nearly 0.5% of the population. The typical human genome also contains 40,000 to 200,000 rare variants observed in less than 0.5% of the population that can only have occurred from at least one de novo germline mutation in the history of human evolution. De novo mutations have also been researched as playing a crucial role in the persistence of genetic disease in humans. With recents advancements in

2003: 2700:. For example, smaller populations with heavy mutational input (high rates of mutation) are prone to increases of genetic variation which lead to speciation in future generations. In contrast, larger populations tend to see lesser effects of newly introduced mutated traits. In these conditions, selective forces diminish the frequency of mutated alleles, which are most often deleterious, over time. 1985: 12185: 1434:(A) into a cytosine (C). Point mutations are modifications of single base pairs of DNA or other small base pairs within a gene. A point mutation can be reversed by another point mutation, in which the nucleotide is changed back to its original state (true reversion) or by second-site reversion (a complementary mutation elsewhere that results in regained gene functionality). As discussed 2418:. Many observations of de novo mutation rates have associated higher rates of mutation correlated to paternal age. In sexually reproducing organisms, the comparatively higher frequency of cell divisions in the parental sperm donor germline drive conclusions that rates of de novo mutation can be tracked along a common basis. The frequency of error during the DNA replication process of 2722:

can be considered as ' genotype' and the structure of the RNA can be considered as its 'phenotype'. Since RNAs have relatively simpler composition than proteins, the structure of RNA molecules can be computationally predicted with high degree of accuracy. Because of this convenience, compensatory mutations have been studied in computational simulations using RNA folding algorithms.

816: 2334:, 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. 2204:. However, they are passed down to all the progeny of a mutated cell within the same organism during mitosis. A major section of an organism therefore might carry the same mutation. These types of mutations are usually prompted by environmental causes, such as ultraviolet radiation or any exposure to certain harmful chemicals, and can cause diseases including cancer. 2787:

approximated the ancestral genotype. They found that 3 of the 39 substitutions significantly reduced the fitness of the ancestral background. Compensatory mutations are new mutations that arise and have a positive or neutral impact on a populations fitness. Previous research has shown that populations have can compensate detrimental mutations. Burch and Chao tested

1279:) or repetition of a chromosomal segment or presence of extra piece of a chromosome broken piece of a chromosome may become attached to a homologous or non-homologous chromosome so that some of the genes are present in more than two doses leading to multiple copies of all chromosomal regions, increasing the dosage of the genes located within them. 2492:, 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 2039:. Out of all mutations, 39.6% were lethal, 31.2% were non-lethal deleterious, and 27.1% were neutral. Another example comes from a high throughput mutagenesis experiment with yeast. In this experiment it was shown that the overall DFE is bimodal, with a cluster of neutral mutations, and a broad distribution of deleterious mutations. 1893:

conditions will become relevant. Also, many traits are determined by hundreds of genes (or loci), so that each locus has only a minor effect. For instance, human height is determined by hundreds of genetic variants ("mutations") but each of them has a very minor effect on height, apart from the impact of

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In the human genome, the frequency and characteristics of de novo mutations have been studied as important contextual factors to our evolution. Compared to the human reference genome, a typical human genome varies at approximately 4.1 to 5.0 million loci, and the majority of this genetic diversity is

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DNA damage can cause an error when the DNA is replicated, and this error of replication can cause a gene mutation that, in turn, could cause a genetic disorder. DNA damages are repaired by the DNA repair system of the cell. Each cell has a number of pathways through which enzymes recognize and repair

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suggests that if a mutation does change a protein, the mutation will most likely be harmful, with an estimated 70 percent of amino acid polymorphisms having damaging effects, and the remainder being either neutral or weakly beneficial. Some mutations alter a gene's DNA base sequence but do not change

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with short periods of time between cellular divisions that limit the efficiency of repair machinery. Rates of de novo mutations that affect an organism during its development can also increase with certain environmental factors. For example, certain intensities of exposure to radioactive elements can

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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. Conditional mutations have applications in research as

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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

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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

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Whereas in former times mutations were assumed to occur by chance, or induced by mutagens, molecular mechanisms of mutation have been discovered in bacteria and across the tree of life. As S. Rosenberg states, "These mechanisms reveal a picture of highly regulated mutagenesis, up-regulated temporally

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It is critical to understand the effects of compensatory mutations in the context of fixed deleterious mutations due to the population fitness decreasing because of fixation. Effective population size refers to a population that is reproducing. An increase in this population size has been correlated

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Compensated pathogenic deviations refer to amino acid residues in a protein sequence that are pathogenic in one species but are wild type residues in the functionally equivalent protein in another species. Although the amino acid residue is pathogenic in the first species, it is not so in the second

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In general, it is accepted that the majority of mutations are neutral or deleterious, with advantageous mutations being rare; however, the proportion of types of mutations varies between species. This indicates two important points: first, the proportion of effectively neutral mutations is likely to

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is caused by insertion or deletion of a number of nucleotides that is not evenly divisible by three from a DNA sequence. Due to the triplet nature of gene expression by codons, the insertion or deletion can disrupt the reading frame, or the grouping of the codons, resulting in a completely different

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may also be blocked and/or the cell may die. In contrast to a DNA damage, a mutation is an alteration of the base sequence of the DNA. Ordinarily, a mutation cannot be recognized by enzymes once the base change is present in both DNA strands, and thus a mutation is not ordinarily repaired. At the

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Changes in DNA caused by mutation in a coding region of DNA can cause errors in protein sequence that may result in partially or completely non-functional proteins. Each cell, in order to function correctly, depends on thousands of proteins to function in the right places at the right times. When a

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model for the DFE, with modes centered around highly deleterious and neutral mutations. 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

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technology, an enormous amount of DNA sequence data is available and even more is forthcoming in the future. Various methods have been developed to infer the DFE from DNA sequence data. By examining DNA sequence differences within and between species, we are able to infer various characteristics of

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from the original. 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

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As the function of a RNA molecule is dependent on its structure, the structure of RNA molecules is evolutionarily conserved. Therefore, any mutation that alters the stable structure of RNA molecules must be compensated by other compensatory mutations. In the context of RNA, the sequence of the RNA

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By introducing novel genetic qualities to a population of organisms, de novo mutations play a critical role in the combined forces of evolutionary change. However, the weight of genetic diversity generated by mutational change is often considered a generally "weak" evolutionary force. Although the

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The distinction between germline and somatic mutations is important in animals that have a dedicated germline to produce reproductive cells. However, it is of little value in understanding the effects of mutations in plants, which lack a dedicated germline. The distinction is also blurred in those

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Though relatively few mutations are advantageous, those that are play an important role in evolutionary changes. 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

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This classification is obviously relative and somewhat artificial: a harmful mutation can quickly turn into a beneficial mutations when conditions change. Also, there is a gradient from harmful/beneficial to neutral, as many mutations may have small and mostly neglectable effects but under certain

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was able to grow normally without the presence of lipoteichoic acid due to compensatory mutations. Whole genome sequencing results revealed that when Cyclic-di-AMP phosphodiesterase (GdpP) was disrupted in this bacterium, it compensated for the disappearance of the cell wall polymer, resulting in

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DePristo et al. 2005 outlined two models to explain the dynamics of compensatory pathogenic deviations (CPD). In the first hypothesis P is a pathogenic amino acid mutation that and C is a neutral compensatory mutation. Under these conditions, if the pathogenic mutation arises after a compensatory

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Compensatory mutations can be explained by the genetic phenomenon epistasis whereby the phenotypic effect of one mutation is dependent upon mutation(s) at other loci. While epistasis was originally conceived in the context of interaction between different genes, intragenic epistasis has also been

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Cells with heterozygous loss-of-function mutations (one good copy of gene and one mutated copy) may function normally with the unmutated copy until the good copy has been spontaneously somatically mutated. This kind of mutation happens often in living organisms, but it is difficult to measure the

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Neomorphic mutations are a part of the gain-of-function mutations and are characterized by the control of new protein product synthesis. The newly synthesized gene normally contains a novel gene expression or molecular function. The result of the neomorphic mutation is the gene where the mutation

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Suppressor mutations are a type of mutation that causes the double mutation to appear normally. In suppressor mutations the phenotypic activity of a different mutation is completely suppressed, thus causing the double mutation to look normal. There are two types of suppressor mutations, there are

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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

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or so-called "consensus" sequence. This step requires a tremendous scientific effort. Once the consensus sequence is known, the mutations in a genome can be pinpointed, described, and classified. The committee of the Human Genome Variation Society (HGVS) has developed the standard human sequence

1597:, but not all synonymous substitutions are silent. (There can also be silent mutations in nucleotides outside of the coding regions, such as the introns, because the exact nucleotide sequence is not as crucial as it is in the coding regions, but these are not considered synonymous substitutions.) 2281:

have been identified which splice only at certain permissive temperatures, leading to improper protein synthesis and thus, loss-of-function mutations at other temperatures. Conditional mutations may also be used in genetic studies associated with ageing, as the expression can be changed after a

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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

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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

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Gong et al. collected obtained genotype data of influenza nucleoprotein from different timelines and temporally ordered them according to their time of origin. Then they isolated 39 amino acid substitutions that occurred in different timelines and substituted them in a genetic background that

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they allow control over gene expression. This is especially useful studying diseases in adults by allowing expression after a certain period of growth, thus eliminating the deleterious effect of gene expression seen during stages of development in model organisms. DNA Recombinase systems like

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strains with rifampicin resistance have reduced fitness, however drug resistant clinical strains of this pathogenic bacteria do not have reduced fitness. Comas et al. 2012 used whole genome comparisons between clinical strains and lab derived mutants to determine the role and contribution of

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A mutation becomes an effect on function mutation when the exactitude of functions between a mutated protein and its direct interactor undergoes change. The interactors can be other proteins, molecules, nucleic acids, etc. There are many mutations that fall under the category of by effect on

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for a pyrimidine, (C ↔ T). A transition can be caused by nitrous acid, base mispairing, or mutagenic base analogs such as BrdU. Less common is a transversion, which exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T ↔ A/G). An example of a transversion is the conversion of

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The rate of de novo mutations, whether germline or somatic, vary among organisms. Individuals within the same species can even express varying rates of mutation. Overall, rates of de novo mutations are low compared to those of inherited mutations, which categorizes them as rare forms of

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random emergence of mutations alone provides the basis for genetic variation across all organic life, this force must be taken in consideration alongside all evolutionary forces at play. Spontaneous de novo mutations as cataclysmic events of speciation depend on factors introduced by

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approach has been developed to generate high-quality systematic mutant libraries and measure fitness in high throughput. However, given that many mutations have effects too small to be detected and that mutagenesis experiments can detect only mutations of moderately large effect; DNA

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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

1858:, neutral mutations provide genetic drift as the basis for most variation at the molecular level. In animals or plants, most mutations are neutral, given that the vast majority of their genomes is either non-coding or consists of repetitive sequences that have no obvious function (" 2663:: Practically all bacteria develop antibiotic resistance when exposed to antibiotics. In fact, bacterial populations already have such mutations that get selected under antibiotic selection. Obviously, such mutations are only beneficial for the bacteria but not for those infected. 2452:)—more important genes mutate less frequently than less important ones. They demonstrated that mutation is "non-random in a way that benefits the plant". Additionally, previous experiments typically used to demonstrate mutations being random with respect to fitness (such as the 2299:

In order to categorize a mutation as such, the "normal" sequence must be obtained from the DNA of a "normal" or "healthy" organism (as opposed to a "mutant" or "sick" one), it should be identified and reported; ideally, it should be made publicly available for a straightforward

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no deleterious consequences at a lower temperature (permissive condition). These mutations are non-autonomous, as their manifestation depends upon presence of certain conditions, as opposed to other mutations which appear autonomously. The permissive conditions may be

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and extragenic suppressor mutations. Intragenic mutations occur in the gene where the first mutation occurs, while extragenic mutations occur in the gene that interacts with the product of the first mutation. A common disease that results from this type of mutation is

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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. Mutations in the structure of genes can be classified into several types.

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Dominant negative mutations (also called anti-morphic mutations) have an altered gene product that acts antagonistically to the wild-type allele. These mutations usually result in an altered molecular function (often inactive) and are characterized by a dominant or

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reproduce more quickly. In these cases a mutation will tend to become more common in a population through natural selection. That said, the same mutation can be beneficial in one condition and disadvantageous in another condition. Examples include the following:

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that are activated under certain conditions can generate conditional mutations. Dual Recombinase technology can be used to induce multiple conditional mutations to study the diseases which manifest as a result of simultaneous mutations in multiple genes. Certain

1628:. On the other hand, if a missense mutation occurs in an amino acid codon that results in the use of a different, but chemically similar, amino acid, then sometimes little or no change is rendered in the protein. For example, a change from AAA to AGA will encode 1125:(ENU). These agents can mutate both replicating and non-replicating DNA. In contrast, a base analog can mutate the DNA only when the analog is incorporated in replicating the DNA. Each of these classes of chemical mutagens has certain effects that then lead to 690:

adduct. DNA damages can be recognized by enzymes, and therefore can be correctly repaired using the complementary undamaged strand in DNA as a template or an undamaged sequence in a homologous chromosome if it is available. If DNA damage remains in a cell,

1937:. DFE can also be tracked by tracking the skewness of the distribution of mutations with putatively severe effects as compared to the distribution of mutations with putatively mild or absent effect. In summary, the DFE plays an important role in predicting 1769:

Null mutations, also known as Amorphic mutations, are a form of loss-of-function mutations that completely prohibit the gene's function. The mutation leads to a complete loss of operation at the phenotypic level, also causing no gene product to be formed.

859:. 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, such as 2774:

compensatory mutations in drug resistance to rifampicin. Genome analysis reveal rifampicin resistant strains have a mutation in rpoA and rpoC. A similar study investigated the bacterial fitness associated with compensatory mutations in rifampin resistant

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On the other hand, a mutation may occur in a somatic cell of an organism. Such mutations will be present in all descendants of this cell within the same organism. The accumulation of certain mutations over generations of somatic cells is part of cause of

2422:, especially amplified in the rapid production of sperm cells, can promote more opportunities for de novo mutations to replicate unregulated by DNA repair machinery. This claim combines the observed effects of increased probability for mutation in rapid 1425:, often caused by chemicals or malfunction of DNA replication, exchange a single nucleotide for another. These changes are classified as transitions or transversions. Most common is the transition that exchanges a purine for a purine (A ↔ G) or a 2014:

the DFE for neutral, deleterious and advantageous mutations. To be specific, the DNA sequence analysis approach allows us to estimate the effects of mutations with very small effects, which are hardly detectable through mutagenesis experiments.

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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

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are the two major types of errors that occur in DNA, but they are fundamentally different. DNA damage is a physical alteration in the DNA structure, such as a single or double strand break, a modified guanosine residue in DNA such as

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Lethal mutations result in rapid organismal death when occurring during development and cause significant reductions of life expectancy for developed organisms. An example of a disease that is caused by a dominant lethal mutation is

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the protein made by the gene. Studies have shown that only 7% of point mutations in noncoding DNA of yeast are deleterious and 12% in coding DNA are deleterious. The rest of the mutations are either neutral or slightly beneficial.

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There is a widespread assumption that mutations are (entirely) "random" with respect to their consequences (in terms of probability). This was shown to be wrong as mutation frequency can vary across regions of the genome, with such

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damages in DNA. Because DNA can be damaged in many ways, the process of DNA repair is an important way in which the body protects itself from disease. Once DNA damage has given rise to a mutation, the mutation cannot be repaired.

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species because its pathogenicity is compensated by one or more amino acid substitutions in the second species. The compensatory mutation can occur in the same protein or in another protein with which it interacts.

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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.

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Research has shown that bacteria can gain drug resistance through compensatory mutations that do not impede or having little effect on fitness. Previous research from Gagneux et al. 2006 has found that laboratory grown

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occur with non-zero probability even given a healthy, uncontaminated cell. Naturally occurring oxidative DNA damage is estimated to occur 10,000 times per cell per day in humans and 100,000 times per cell per day in

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replaces a codon with another codon that codes for a different amino acid, so that the produced amino acid sequence is modified. Nonsynonymous substitutions can be classified as nonsense or missense mutations:

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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

724:. 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. 2114:

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

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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.

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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.

2354:) 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. 1336:

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

716:. 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. Most genes belong to larger 2760:

genetic background. This demonstrated that identical amino acid states can result in different phenotypic states depending on the genetic background. Corrigan et al. 2011 demonstrated how

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Point mutations may arise from spontaneous mutations that occur during DNA replication. The rate of mutation may be increased by mutagens. Mutagens can be physical, such as radiation from

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Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, et al. (September 2017). "Parental influence on human germline de novo mutations in 1,548 trios from Iceland".

751:; this allows one gene in the pair to acquire a new function while the other copy performs the original function. Other types of mutation occasionally create new genes from previously 9795: 1612:

changes a nucleotide to cause substitution of a different amino acid. This in turn can render the resulting protein nonfunctional. Such mutations are responsible for diseases such as

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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".

1344:(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 2391:

mutations per genome per generation, that is, each human accumulates about 50–90 novel mutations that were not present in his or her parents. This number has been established by

789:, make up a major fraction of the genetic material of plants and animals, and may have been important in the evolution of genomes. For example, more than a million copies of the 1945:

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,

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Lunzer et al. tested the outcome of swapping divergent amino acids between two orthologous proteins of isopropymalate dehydrogenase (IMDH). They substituted 168 amino acids in

778:, and they retain these separate chromosomes. In evolution, the most important role of such chromosomal rearrangements may be to accelerate the divergence of a population into 7185:

Chadov BF, Fedorova NB, Chadova EV (1 July 2015). "Conditional mutations in Drosophila melanogaster: On the occasion of the 150th anniversary of G. Mendel's report in Brünn".

2601:. People with this mutation were more likely to survive infection; thus its frequency in the population increased. This theory could explain why this mutation is not found in 2347:, 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). 2043:

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

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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.

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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.

10105: 997:– 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. 731:

act as modules, each with a particular and independent function, that can be mixed together to produce genes encoding new proteins with novel properties. For example, the

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replaces a codon with another codon that codes for the same amino acid, so that the produced amino acid sequence is not modified. Synonymous mutations occur due to the

2778:. Results obtained from this study demonstrate that drug resistance is linked to bacterial fitness as higher fitness costs are linked to greater transcription errors. 801:. Another effect of these mobile DNA sequences is that when they move within a genome, they can mutate or delete existing genes and thereby produce genetic diversity. 7377:"Temperature-sensitive mutations made easy: generating conditional mutations by using temperature-sensitive inteins that function within different temperature ranges" 908:

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.

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Comas, Iñaki; Borrell, Sonia; Roetzer, Andreas; Rose, Graham; Malla, Bijaya; Kato-Maeda, Midori; Galagan, James; Niemann, Stefan; Gagneux, Sebastien (January 2012).

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mutation alters a protein that plays a critical role in the body, a medical condition can result. One study on the comparison of genes between different species of

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Mutations that occur in coding regions of the genome are more likely to alter the protein product, and can be categorized by their effect on amino acid sequence:

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in the transcribed mRNA, and possibly a truncated, and often nonfunctional protein product. This sort of mutation has been linked to different diseases, such as

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of a gene, such as promoters, enhancers, and silencers, can alter levels of gene expression, but are less likely to alter the protein sequence. Mutations within

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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 virus".

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mutations (also called acquired mutations), which involve cells outside the dedicated reproductive group and which are not usually transmitted to descendants.

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Kassen R, Bataillon T (April 2006). "Distribution of fitness effects among beneficial mutations before selection in experimental populations of bacteria".

2460:) have been shown to only support the weaker claim that those mutations are random with respect to external selective constraints, not fitness as a whole. 1714:

phenotypes. Several of Muller's morphs correspond to the gain of function, including hypermorph (increased gene expression) and neomorph (novel function).

10829: 10825: 10063: 9458:"Full restoration of viral fitness by multiple compensatory co-mutations in the nucleoprotein of influenza A virus cytotoxic T-lymphocyte escape mutants" 2063:; second, the average effect of deleterious mutations varies dramatically between species. In addition, the DFE also differs between coding regions and 2055:

under a wide range of conditions, which, in general, has been supported by experimental studies, at least for strongly selected advantageous mutations.

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or night vision; all four arose from a single ancestral gene. Another advantage of duplicating a gene (or even an entire genome) is that this increases

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Mutations whose effect is to juxtapose previously separate pieces of DNA, potentially bringing together separate genes to form functionally distinct

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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

1735: 1059: 8183: 2410:), replication occurs quickly, and there are no mechanisms to check the genome for accuracy. This error-prone process often results in mutations. 2030:

proposes that most novel mutations will be highly deleterious, with a small fraction being neutral. A later proposal by Hiroshi Akashi proposed a

9633: 9515: 4292: 3135:

Aminetzach YT, Macpherson JM, Petrov DA (July 2005). "Pesticide resistance via transposition-mediated adaptive gene truncation in Drosophila".

9034:"Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes" 6969: 1018:, Kunz et al. found that more than 60% of the spontaneous single base pair substitutions and deletions were caused by translesion synthesis. 11618: 10918: 2376:

vary substantially across species, and the evolutionary forces that generally determine mutation are the subject of ongoing investigation.

1875:, 80% of mutations were negative, but 20% were positive, even though many had a very small effect on growth (depending on condition). Gene 8378:"Molecular signatures of resource competition: Clonal interference favors ecological diversification and can lead to incipient speciation" 6939: 1571:(where the x stands for the following nucleotide).) By contrast, any insertion or deletion that is evenly divisible by three is termed an 10632: 6449:, Hartl DL (August 2003). "Bayesian analysis suggests that most amino acid replacements in Drosophila are driven by positive selection". 2651:). Those with only one of the two alleles of the sickle-cell disease are more resistant to malaria, since the infestation of the malaria 2448:- and mutation-biases being associated with various factors. For instance, Monroe and colleagues demonstrated that—in the studied plant ( 2006:

This figure shows a simplified version of loss-of-function, switch-of-function, gain-of-function, and conservation-of-function mutations.

1850:

A neutral mutation has no harmful or beneficial effect on the organism. Such mutations occur at a steady rate, forming the basis for the

4393: 2286: 1479:(red) can result in a change in the amino acid sequence. Mutations in other areas of the gene can have diverse effects. Changes within 490: 4719:

Pfohl-Leszkowicz A, Manderville RA (January 2007). "Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans".

4139: 762:

number may involve even larger mutations, where segments of the DNA within chromosomes break and then rearrange. For example, in the

7446: 7429: 4916:

Quinto-Alemany D, Canerina-Amaro A, Hernández-Abad LG, Machín F, Romesberg FE, Gil-Lamaignere C (31 July 2012). Sturtevant J (ed.).

1889:

insertions, 76% of insertion mutants were classified as neutral, 16% had a significantly reduced fitness, but 6% were advantageous.

12122: 11577: 4703: 1710:

containing the newly created allele as well as the original will express the new allele; genetically this defines the mutations as

9456:

Rimmelzwaan, G. F.; Berkhoff, E. G. M.; Nieuwkoop, N. J.; Smith, D. J.; Fouchier, R. A. M.; Osterhaus, A. D. M. E.YR 2005 (2005).

6312:

Davies EK, Peters AD, Keightley PD (September 1999). "High frequency of cryptic deleterious mutations in Caenorhabditis elegans".

6111:"Mutational fitness effects in RNA and single-stranded DNA viruses: common patterns revealed by site-directed mutagenesis studies" 5095: 1036:

Although naturally occurring double-strand breaks occur at a relatively low frequency in DNA, their repair often causes mutation.

10056: 7045: 2340: 10928: 9092:

Gagneux, Sebastien; Long, Clara Davis; Small, Peter M.; Van, Tran; Schoolnik, Gary K.; Bohannan, Brendan J. M. (30 June 2006).

5402:

Ellis NA, Ciocci S, German J (February 2001). "Back mutation can produce phenotype reversion in Bloom syndrome somatic cells".

4107: 2236:

than humans. The disparity in mutation rate between the germline and somatic tissues likely reflects the greater importance of

2150:

in the offspring, that is, a mutation that is present in every cell. A constitutional mutation can also occur very soon after

894:(also called error-prone translesion synthesis), (3) errors introduced during DNA repair, and (4) induced mutations caused by 11885: 11645: 7084: 7003: 4196: 4153: 3393: 1855: 1522:

The effect of a mutation on protein sequence depends in part on where in the genome it occurs, especially whether it is in a

7920:

Bartlett, J. (2023). "Random with Respect to Fitness or External Selection? An Important but Often Overlooked Distinction".

11242: 4756:"UVA radiation is highly mutagenic in cells that are unable to repair 7,8-dihydro-8-oxoguanine in Saccharomyces cerevisiae" 4315: 1369:

Small-scale mutations affect a gene in one or a few nucleotides. (If only a single nucleotide is affected, they are called

808:

and increase the amount of genetic variation. The abundance of some genetic changes within the gene pool can be reduced by

17: 6623:

Akashi H (September 1999). "Within- and between-species DNA sequence variation and the 'footprint' of natural selection".

5153:

Boillée S, Vande Velde C, Cleveland DW (October 2006). "ALS: a disease of motor neurons and their nonneuronal neighbors".

1840:

are harmful (if a mutation does not change the amino acid sequence in an essential protein, it is harmless in most cases).

11968: 10888: 10745: 5840:"Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases" 5131: 2300:

nucleotide-by-nucleotide comparison, and agreed upon by the scientific community or by a group of expert geneticists and

1879:

involve removal of whole genes, so that point mutations almost always have a much smaller effect. In a similar screen in

8494:"Compensating for the meltdown: The critical effective size of a population with deleterious and compensatory mutations" 7224: 2512:

gene. Individuals with this disorder are more prone to many types of cancers, other disorders and have impaired vision.

1578:

A point substitution mutation results in a change in a single nucleotide and can be either synonymous or nonsynonymous.

1550:, having no effect on phenotype – though intron mutations could alter the protein product if they affect mRNA splicing. 11630: 11290: 10049: 9871: 1941:. A variety of approaches have been used to study the DFE, including theoretical, experimental and analytical methods. 568: 107: 8970:"c-di-AMP Is a New Second Messenger in Staphylococcus aureus with a Role in Controlling Cell Size and Envelope Stress" 1794:

A back mutation or reversion is a point mutation that restores the original sequence and hence the original phenotype.

1006:

There is increasing evidence that the majority of spontaneously arising mutations are due to error-prone replication (

12227: 10735: 7166: 5765: 4276: 4249: 2192:

A change in the genetic structure that is not inherited from a parent, and also not passed to offspring, is called a

1897:. Height (or size) itself may be more or less beneficial as the huge range of sizes in animal or plant groups shows. 1567:

ACU ACC UAx, which would instead code for proline, threonine, threonine, and part of another amino acid or perhaps a

126: 79: 11697: 11702: 11300: 10318: 9814: 8968:

Corrigan, Rebecca M.; Abbott, James C.; Burhenne, Heike; Kaever, Volkhard; Gründling, Angelika (1 September 2011).

3289:

Bernstein H, Byerly HC, Hopf FA, Michod RE (September 1985). "Genetic damage, mutation, and the evolution of sex".

1083:

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

1027: 891: 782:

by making populations less likely to interbreed, thereby preserving genetic differences between these populations.

678: 3503:

Long M, Betrán E, Thornton K, Wang W (November 2003). "The origin of new genes: glimpses from the young and old".

1843:

A beneficial, or advantageous mutation increases the fitness of the organism. Examples are mutations that lead to

1360:, either by a deletion or a genetic recombination event, in an organism that previously had two different alleles. 11947: 11937: 11861: 11136: 10717: 10660: 10250: 7863:

Monroe JG, Srikant T, Carbonell-Bejerano P, Becker C, Lensink M, Exposito-Alonso M, et al. (February 2022).

687: 7225:"High-frequency generation of conditional mutations affecting Drosophila melanogaster development and life span" 5912: 3552:"The evolutionary mechanics of domain organization in proteomes and the rise of modularity in the protein world" 1719: 86: 12075: 11942: 11722: 11466: 11264: 11168: 11057: 10711: 10650: 10588: 9787: 6062:"Distribution of fitness and virulence effects caused by single-nucleotide substitutions in Tobacco Etch virus" 2894: 2502: 2493: 1652: 483: 64: 8212:"Evaluating plague and smallpox as historical selective pressures for the CCR5-Delta 32 HIV-resistance allele" 7836: 1314:

that can lead to a decrease of fitness but also to speciation in isolated, inbred populations. These include:

363: 12222: 12140: 11727: 11471: 11210: 10205: 8696: 6512:"Estimating the distribution of fitness effects from DNA sequence data: implications for the molecular clock" 1727: 1625: 11672: 2791:

of adaptive evolution by testing whether bacteriophage φ6 evolves by small steps. Their results showed that

2209:

With plants, some somatic mutations can be propagated without the need for seed production, for example, by

1992:. In this experiment, random mutations were introduced into the virus by site-directed mutagenesis, and the 1194:

and thymine—are most vulnerable to radiation that can change their properties. UV light can induce adjacent

12232: 12080: 11582: 10654: 10646: 10602: 10294: 10234: 10169: 10147: 5547:"Tn-seq: high-throughput parallel sequencing for fitness and genetic interaction studies in microorganisms" 2879: 1774:

and dermatitis syndrome are common diseases caused by a null mutation of the gene that activates filaggrin.

1722:

phenotype. In humans, dominant negative mutations have been implicated in cancer (e.g., mutations in genes

1698:, or when the reduced dosage of a normal gene product is not enough for a normal phenotype (this is called 1340:, a type of brain tumor, were found to have a chromosomal deletion removing sequences between the Fused in 1175:

groups, altering their hydrogen bonding patterns, which leads to incorrect base pairing during replication.

1148: 8270: 6211:(March 1998). "Distribution of fitness effects caused by random insertion mutations in Escherichia coli". 1384:, or errors during replication of repeating elements. Insertions in the coding region of a gene may alter 93: 12201: 12150: 11744: 10845: 10833: 10213: 10100: 8112:"The coreceptor mutation CCR5Delta32 influences the dynamics of HIV epidemics and is selected for by HIV" 2889: 2788: 2166:, because the cells that give rise to the daughter organisms also give rise to that organism's germline. 2131:

mutations or a genetic compound consists of two different mutations in the paternal and maternal alleles.

1285:, duplication of entire sets of chromosomes, potentially resulting in a separate breeding population and 8169: 4984: 4425:"Quantum and classical effects in DNA point mutations: Watson-Crick tautomerism in AT and GC base pairs" 3429:(May 2002). "Studying genomes through the aeons: protein families, pseudogenes and proteome evolution". 12163: 11846: 11020: 10592: 10290: 10286: 10030: 9766: 5896: 4145: 2874: 2833: 2805: 2036: 1989: 1601: 1447: 1037: 252: 8860: 8535: 1915: 11640: 11437: 11247: 11015: 10908: 10759: 10721: 10520: 10355: 9980: 2060: 1954: 1317: 1311: 994: 476: 75: 60: 31: 11769: 5255:

Housden BE, Muhar M, Gemberling M, Gersbach CA, Stainier DY, Seydoux G, et al. (January 2017).

5167: 2427:

inflict damage to an organism's genome, heightening rates of mutation. In humans, the appearance of

1702:). A disease that is caused by a loss-of-function mutation is Gitelman syndrome and cystic fibrosis. 610:) of an organism. Mutations play a part in both normal and abnormal biological processes including: 12063: 11927: 11899: 11874: 11831: 11734: 11667: 11542: 11415: 11383: 11356: 11346: 10209: 3961:

Hurst GD, Werren JH (August 2001). "The role of selfish genetic elements in eukaryotic evolution".

2756:. They found that over one third of these substitutions compromised IMDH enzymatic activity in the 2532: 2232:

mutation rate for both species; mice have a higher rate of both somatic and germline mutations per

2213:

and stem cuttings. These type of mutation have led to new types of fruits, such as the "Delicious"

1881: 1844: 1484: 748: 270: 11547: 8861:"Characterization of Compensated Mutations in Terms of Structural and Physico-Chemical Properties" 6981: 2539:

rate. Measuring this rate is important in predicting the rate at which people may develop cancer.

840:

with new mutations. The majority of these mutations will have no effect; but one might change the

12068: 11998: 11907: 11635: 11517: 11285: 10881: 10775: 10767: 10753: 10739: 10697: 10618: 10330: 10025: 9753: 6471: 4555:"Mutation frequency and specificity with age in liver, bladder and brain of lacI transgenic mice" 3547: 2864: 2590: 2128: 2031: 1763: 1582: 1443: 1300: 692: 683: 584: 53: 5594:

Allen HL, Estrada K, Lettre G, Berndt SI, Weedon MN, Rivadeneira F, et al. (October 2010).

5257:"Loss-of-function genetic tools for animal models: cross-species and cross-platform differences" 2623:, a blood disorder in which the body produces an abnormal type of the oxygen-carrying substance 1673:

function, but depending on the specificity of the change the mutations listed below will occur.

12107: 11756: 11625: 11587: 11488: 11459: 11432: 11427: 11025: 10221: 10072: 9864: 6466: 6160:"Distribution of fitness effects caused by single-nucleotide substitutions in bacteriophage f1" 6003:"The distribution of fitness effects caused by single-nucleotide substitutions in an RNA virus" 5162: 4754:

Kozmin S, Slezak G, Reynaud-Angelin A, Elie C, de Rycke Y, Boiteux S, Sage E (September 2005).

2368: 2254: 2096: 1964: 1784: 1636:. In this latter case the mutation will have little or no effect on phenotype and therefore be 1353: 1262: 1187: 671: 11613: 9397: 7430:"Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion" 7076: 7069: 4653:"The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway" 4266: 4239: 2200:

Somatic mutations are not inherited by an organism's offspring because they do not affect the

674:

that have damaging effects, and the remainder being either neutral or marginally beneficial.

12048: 11922: 11841: 11836: 11821: 11806: 11796: 11712: 11687: 11522: 11478: 11442: 11410: 11351: 11329: 11310: 11173: 11126: 11077: 11072: 11030: 9985: 9949: 9912: 9627: 9509: 8712: 8069:

Araten DJ, Golde DW, Zhang RH, Thaler HT, Gargiulo L, Notaro R, Luzzatto L (September 2005).

7964: 7425: 5114: 3481: 3232:"Prevalence of positive selection among nearly neutral amino acid replacements in Drosophila" 2884: 2606: 2269: 2080: 1938: 1934: 1747: 1613: 1563: 1488: 1476: 1330: 1323: 1126: 1040:(NHEJ) is a major pathway for repairing double-strand breaks. NHEJ involves removal of a few 1007: 713: 572: 512: 443: 423: 388: 300: 295: 154: 6947: 5596:"Hundreds of variants clustered in genomic loci and biological pathways affect human height" 4401: 12022: 11917: 11851: 11652: 11567: 11483: 11395: 11378: 11305: 11295: 11005: 10913: 10897: 10576: 10501: 10440: 10246: 9894: 9589: 9105: 8641: 8223: 8123: 8027: 7876: 7795: 7486: 7113: 6890: 6581: 6523: 6458: 6446: 6266: 6014: 5851: 5651: 5607: 5022: 4929: 4818:"What is mutation? A chapter in the series: How microbes "jeopardize" the modern synthesis" 4767: 4511: 4436: 4346: 3915: 3426: 3243: 3144: 2159: 2018:

One of the earliest theoretical studies of the distribution of fitness effects was done by

1886: 1755: 1711: 1691: 1621: 1586: 1393: 1381: 1377: 786: 767: 645:, or prevent the gene from functioning properly or completely. Mutations can also occur in 623: 576: 528: 11657: 11527: 5709:"Quantifying the genomic decay paradox due to Muller's ratchet in human mitochondrial DNA" 4918:"Yeasts acquire resistance secondary to antifungal drug treatment by adaptive mutagenesis" 4668: 1758:. Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency. 1292:

Deletions of large chromosomal regions, leading to loss of the genes within those regions.

590: 8: 12085: 12043: 11993: 11912: 11760: 11752: 11682: 11662: 11608: 11452: 11205: 11148: 11010: 10993: 10971: 10749: 10562: 10196: 9959: 9899: 9217:

Gong, Lizhi Ian; Suchard, Marc A; Bloom, Jesse D (14 May 2013). Pascual, Mercedes (ed.).

8174: 2844: 2667: 2620: 2273: 2125:

A homozygous mutation is an identical mutation of both the paternal and maternal alleles.

2027: 1922: 1617: 1558: 1531: 1480: 1411: 1401: 1158: 820: 771: 580: 418: 398: 333: 290: 284: 275: 247: 146: 11363: 9593: 9109: 8645: 8354: 8318: 8301: 8227: 8127: 8031: 7880: 7799: 7586:

Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences

7490: 7117: 6894: 6585: 6527: 6462: 6270: 6115:

Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences

6018: 5855: 5611: 5026: 4933: 4771: 4700: 4515: 4440: 4350: 3919: 3247: 3148: 2942:"Microhomology-Mediated End Joining: A Back-up Survival Mechanism or Dedicated Pathway?" 2914: 812:, while other "more favorable" mutations may accumulate and result in adaptive changes. 177: 12058: 12010: 12003: 11600: 11512: 11373: 11334: 11158: 11102: 11092: 11052: 10966: 10961: 10956: 10874: 10853: 10841: 10837: 10801: 10796: 10731: 10345: 10125: 9725: 9673: 9648: 9610: 9577: 9558: 9430: 9370: 9313: 9280: 9253: 9218: 9194: 9161: 9137: 9066: 9033: 9004: 8969: 8942: 8907: 8838: 8771: 8672: 8629: 8610: 8513: 8469: 8402: 8377: 8207: 8051: 7995: 7968: 7945: 7897: 7864: 7759: 7732: 7708: 7681: 7657: 7630: 7606: 7581: 7554: 7529: 7510: 7459: 7401: 7376: 7317: 7292: 7249: 7134: 7101: 6859: 6816: 6768: 6743: 6713: 6605: 6492: 6422: 6398:"The distribution of fitness effects of new deleterious amino acid mutations in humans" 6397: 6373: 6348: 6289: 6254: 6232: 6184: 6159: 6135: 6110: 6086: 6061: 5978: 5932: 5916: 5872: 5839: 5815: 5790: 5748:

Bernstein H, Hopf FA, Michod RE (1987). "The molecular basis of the evolution of sex".

5684: 5659: 5655: 5628: 5595: 5571: 5546: 5522: 5497: 5473: 5446: 5427: 5379: 5354: 5330: 5305: 5281: 5256: 5232: 5208:"Predicting the functional impact of protein mutations: application to cancer genomics" 5207: 5188: 4952: 4917: 4893: 4868: 4844: 4817: 4790: 4755: 4677: 4652: 4628: 4603: 4579: 4554: 4535: 4501: 4470: 4099: 4030: 4005: 3986: 3938: 3903: 3899: 3827: 3802: 3775: 3750: 3680: 3622: 3528: 3354: 3329: 3266: 3231: 3168: 3114: 3066: 3041: 3017: 2990: 2966: 2941: 2636: 2632: 1699: 1687: 1467: 1455: 1209: 606:

Mutations may or may not produce detectable changes in the observable characteristics (

413: 408: 383: 305: 8246: 8211: 7733:"New insights into the generation and role of de novo mutations in health and disease" 7037: 6636: 6546: 6511: 6037: 6002: 5757: 5496:

Nichols RJ, Sen S, Choo YJ, Beltrao P, Zietek M, Chaba R, et al. (January 2011).

5081: 5045: 5010: 3876: 3851: 3726: 3699: 3442: 3102: 1647:

is a point mutation in a sequence of DNA that results in a premature stop codon, or a

797:, and these sequences have now been recruited to perform functions such as regulating 571:), cause an error during other forms of repair, or cause an error during replication ( 100: 12217: 12146: 12100: 11826: 11774: 11552: 11368: 11269: 11232: 11227: 11183: 11178: 11131: 11097: 10815: 10432: 10351: 10306: 10274: 10262: 9944: 9939: 9857: 9717: 9678: 9615: 9550: 9497: 9489: 9435: 9417: 9375: 9357: 9318: 9300: 9258: 9240: 9199: 9181: 9129: 9121: 9071: 9053: 9009: 8991: 8947: 8929: 8888: 8880: 8830: 8822: 8776: 8758: 8716: 8677: 8659: 8602: 8563: 8555: 8505: 8461: 8453: 8407: 8358: 8341:

Ségurel L, Bon C (August 2017). "On the Evolution of Lactase Persistence in Humans".

8323: 8251: 8151: 8146: 8111: 8092: 8043: 8000: 7949: 7937: 7902: 7811: 7764: 7713: 7662: 7611: 7559: 7514: 7502: 7451: 7406: 7357: 7353: 7322: 7254: 7202: 7162: 7139: 7080: 6918: 6913: 6878: 6851: 6808: 6773: 6721: 6693: 6675: 6640: 6597: 6551: 6484: 6427: 6378: 6329: 6294: 6224: 6189: 6140: 6091: 6042: 5970: 5936: 5924: 5877: 5820: 5771: 5761: 5730: 5689: 5633: 5576: 5527: 5478: 5419: 5384: 5335: 5286: 5237: 5180: 5123: 5068:

Freese E (June 1959). "The specific mutagenic effect of base analogues on Phage T4".

5050: 4957: 4898: 4849: 4795: 4736: 4682: 4633: 4584: 4539: 4527: 4489: 4474: 4462: 4454: 4374: 4369: 4334: 4272: 4245: 4192: 4167: 4159: 4149: 4091: 4035: 3978: 3943: 3881: 3832: 3780: 3731: 3672: 3644: 3614: 3573: 3520: 3485: 3446: 3407: 3399: 3389: 3359: 3306: 3271: 3209: 3160: 3106: 3071: 3022: 2971: 2828: 2693: 2648: 2543: 2415: 2327: 2141: 2108: 2104: 2084: 2052: 2044: 1993: 1977: 1911: 1804: 1771: 1695: 1644: 1609: 1451: 1244: 1105: 852: 809: 721: 695:

of a gene may be prevented and thus translation into a protein may also be blocked.

650: 631: 627: 544: 463: 348: 227: 9729: 8842: 7963:

Doniger SW, Kim HS, Swain D, Corcuera D, Williams M, Yang SP, Fay JC (August 2008).

7463: 6879:"Fitness effects of advantageous mutations in evolving Escherichia coli populations" 6863: 6496: 5431: 5192: 5011:"The Difference Between Spontaneous and Base-Analogue Induced Mutations of Phage T4" 4103: 3684: 3626: 3532: 3172: 3118: 890:

mutations (molecular decay), (2) mutations due to error-prone replication bypass of

11692: 11259: 11237: 11045: 10810: 10806: 10703: 10580: 10548: 10179: 10015: 9964: 9709: 9668: 9660: 9605: 9597: 9542: 9479: 9469: 9425: 9409: 9365: 9349: 9308: 9292: 9248: 9230: 9189: 9173: 9141: 9113: 9061: 9045: 8999: 8981: 8937: 8919: 8872: 8814: 8766: 8750: 8708: 8667: 8649: 8594: 8547: 8473: 8443: 8397: 8389: 8350: 8313: 8241: 8231: 8141: 8131: 8082: 8055: 8035: 7990: 7980: 7929: 7892: 7884: 7803: 7754: 7744: 7703: 7693: 7652: 7642: 7601: 7593: 7549: 7541: 7494: 7441: 7396: 7388: 7349: 7312: 7304: 7244: 7236: 7194: 7129: 7121: 6908: 6898: 6843: 6820: 6800: 6763: 6755: 6705: 6667: 6632: 6609: 6589: 6541: 6531: 6476: 6417: 6409: 6368: 6360: 6321: 6284: 6274: 6236: 6216: 6179: 6171: 6130: 6122: 6081: 6073: 6032: 6022: 5982: 5962: 5908: 5867: 5859: 5810: 5802: 5753: 5720: 5679: 5671: 5623: 5615: 5566: 5558: 5517: 5509: 5468: 5458: 5411: 5374: 5366: 5325: 5317: 5276: 5268: 5227: 5219: 5172: 5077: 5040: 5030: 4947: 4937: 4888: 4880: 4839: 4829: 4785: 4775: 4728: 4672: 4664: 4623: 4615: 4574: 4566: 4519: 4444: 4364: 4354: 4083: 4060: 4025: 4017: 3990: 3970: 3933: 3923: 3871: 3863: 3822: 3814: 3770: 3762: 3721: 3711: 3662: 3604: 3563: 3512: 3477: 3438: 3349: 3341: 3298: 3261: 3251: 3199: 3152: 3098: 3061: 3053: 3012: 3002: 2961: 2953: 2483: 2453: 2343:

of the wild-type amino acid, the number is the position of the amino acid from the

2187: 1959: 1871: 1637: 1547: 1276: 1199: 1163: 1152: 984: 940: 848: 709: 599: 560: 355: 150: 11537: 9562: 9177: 8614: 8087: 8070: 7240: 7015: 6759: 6325: 5806: 5675: 5306:"Map positions and specificities of suppressor mutations in Escherichia coli K-12" 4619: 4570: 556: 12189: 12053: 11677: 11504: 11493: 11447: 11390: 11339: 11119: 10923: 10820: 10409: 9954: 9757: 9697: 9413: 8986: 8924: 8803:"Missense meanderings in sequence space: a biophysical view of protein evolution" 8654: 7985: 6946:. Athens, Greece: Information Technology Associates. 30 June 2007. Archived from 5660:"The pattern of neutral molecular variation under the background selection model" 5176: 4942: 4834: 4707: 4064: 3716: 3653: 3640: 3385: 3377: 3325: 3204: 3187: 2680: 2602: 2457: 2423: 2310: 1972: 1905:

Attempts have been made to infer the distribution of fitness effects (DFE) using

1851: 1836:, mutation decreases the fitness of the organism. Many, but not all mutations in 1739: 1594: 1543: 1492: 1071: 935:

atom, altering the hydrogen bonding pattern of that base, resulting in incorrect

798: 696: 667:

produced by a gene, the result is likely to be harmful, with an estimated 70% of

637:

Mutation can result in many different types of change in sequences. Mutations in

540: 9647:

Lupski, James R.; Belmont, John W.; Boerwinkle, Eric; Gibbs, Richard A. (2011).

8628:

Cowperthwaite, Matthew C.; Bull, J. J.; Meyers, Lauren Ancel (20 October 2006).

8582: 7392: 7198: 6413: 6175: 5321: 4915: 2075: 1798: 1707: 1593:. If this mutation does not result in any phenotypic effects, then it is called 12177: 11893: 11765: 11707: 11067: 11062: 11000: 10978: 10494: 10460: 10455: 10130: 9931: 9664: 9353: 9219:"Stability-mediated epistasis constrains the evolution of an influenza protein" 8754: 8551: 8216: