mutation

(myū-tā'shən)

1. The act or process of being altered or changed.
2. An alteration or change, as in nature, form, or quality.
3. Genetics.
   1. A change of the DNA sequence within a gene or chromosome of an organism resulting in the creation of a new character or trait not found in the parental type.
   2. The process by which such a change occurs in a chromosome, either through an alteration in the nucleotide sequence of the DNA coding for a gene or through a change in the physical arrangement of a chromosome.
   3. A mutant.
4. Linguistics. The change that is caused in a sound by its assimilation to another sound, such as umlaut.

[Middle English mutacioun, from Old French mutacion, from Latin mūtātiō, mūtātiōn-, from past participle of mūtāre, to change. See mutate.]

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Concept

A word familiar to all fans of science fiction, mutation refers to any sudden change in DNA—deoxyribonucleic acid, the genetic blueprint for an organism—that creates a change in an organism's appearance, behavior, or health. Unlike in the sci-fi movies, however, scientists typically use the word mutant as an adjective rather than as a noun, as, for example, in the phrase "a mutant strain." Mutation is a phenomenon significant to many aspects of life on Earth and is one of the principal means by which evolutionary change takes place. It is also the cause of numerous conditions, ranging from albinism to cystic fibrosis to dwarfism. Mutation indicates a response to an outside factor, and the nature of that factor can vary greatly, from environmental influences to drugsto high-energy radiation.

How It Works

Dna, Chromosomes, and Mutations

Deoxyribonucleic acid, or DNA, is a molecule in the cells of all life-forms that contains genetic codes for inheritance. DNA, discussed elsewhere in this book, is as complex in structure as it is critically important in shaping the characteristics of the organism to which it belongs, and therefore it is not surprising that a subtle alteration in DNA can produce significant results. Alterations to DNA are called mutations, and they can result in the formation of new characteristics that are heritable, or capable of being inherited.

Every cell in the body of every living organism contains DNA in threadlike structures called chromosomes. Stretches of DNA that hold coded instructions for the manufacture of specific proteins are known as genes, of which the human race has approximately 40,000 varieties. If the DNA of a particular gene is altered, that gene may become defective, and the protein for which it codes also may be missing or defective. Just one missing or abnormal protein can have an enormous effect on the entire body: albinism, for instance, is the result of one missing protein.

Mutations also can be errors in all or part of a chromosome. Humans normally have 23 pairs of chromosomes, and an extra chromosome can have a tremendous negative impact. For example, there should be two of chromosome 21, as with all other chromosomes, but if there are three, the result is Down syndrome. People with Down syndrome have a unique physical appearance and are developmentally disabled. Nor is an extra chromosome the only chromosomal abnormality that causes problems: if chromosomes 9 and 22 exchange materials, a phenomenon known as translocation, the result can be a certain type of leukemia. Down syndrome also results from translocation.

Germinal mutations are those that occur in the egg or sperm cells and therefore can be passed on to the organism's offspring. Somatic mutations are those that happen in cells other than the sex cells, and they cannot be transmitted to the next generation. This is an important distinction to keep in mind in terms of both the causes and the effects of mutation. If only the somatic cells of the organism are affected, the mutation will not appear in the next generation; on the other hand, if a germinal mutation is involved, what was once an abnormality may become so common in certain populations that it emerges as the norm.

The Role of Mutation in Evolution

Most of the forms of mutation we discuss in this essay appear suddenly (i.e., in a single generation) and affect just a few generations. Yet even such seemingly "normal" characteristics as our ten fingers and ten toes or our two eyes or our relatively hairless skin (compared with that of apes) are ultimately the product of mutations that took shape over the many hundreds of millions of years during which animal life has been evolving. Evolution, in fact, is driven by mutation, along with natural selection (see Evolution).

Over the eons, advantageous mutations, examples of which we look at later, have allowed life to develop and diversify from primitive cells into the multitude of species—including Homo sapiens—that exist on Earth today. If DNA replicated perfectly every time, without errors, the only life-forms existing now would be those that existed about three billion years ago: single-cell organisms. Mutations, therefore, are critical to the development of diverse life-forms, a phenomenon known as speciation (see Speciation). Mutations that allow an organism to survive and reproduce better than other members of its species are always beneficial, though a mutation that may be beneficial in some circumstances can be harmful in others. Mutations become especially important when an organism's environment is changing—something that has happened often over the course of evolutionary history. And though we cannot watch evolution taking place, we can see how mutations are used among domesticated plants and animals, as discussed later.

Real-Life Applications

Ethnicity and Mutation

Every single human trait—blue eyes, red hair, cystic fibrosis, a second toe longer than the big toe, and so on—is the result of some genetic mutation somewhere back down the line. Traits that are shared by all people must have arisen long ago, while other traits occur only in certain populations of people. Traits may be as innocuous as eye color or hair texture or as grave as a shared tendency toward a particular disease. Cystic fibrosis, for instance, is most common in people of northern European descent, while sickle cell anemia (see Amino Acids) occurs frequently in those of African and Mediterranean ancestry. A fatal disorder known as Tay-Sachs is found primarily in Jewish people whose ancestors came from Eastern Europe. In many cases, the particular mutation, while harmful in one regard, proved to be a useful one for that population. We know, for example, that while two copies of the mutant sickle cell anemia gene cause illness, one copy confers resistance to malaria—a very useful trait to people living in the tropics, where malaria is common.

The Pima "fat-Storage Mutation."

Researchers have noted a high incidence of obesity among the Pima, a Native American tribe whose ancestral homeland is along the Gila and Salt rivers in Arizona. The Pima tend to eat a diet that is no more fatty than that of the average American—which, of course, means that it is plenty fatty, complete with chips, bologna, ice cream, and all the other high-calorie, low-nutrient foods that most Americans consume. But whereas the average American is over-weight, the average Pima is more dramatically so. This suggests that long ago, when the ancestors of the Pima had to face repeated periods of famine in the dry lands of the American Southwest, survival favored the individual or individuals who had a mutation for fat storage. It so happens that today, there is more than enough food at the local supermarket, but by now the Pima as a group has the fat-storage gene. Therefore, many members of the tribe have to undergo strict dietary and exercise regimens so as not to become grossly overweight and susceptible to heart disease and other ailments.

Favorable Mutations

As with other mutations relating to ethnic groups, scientists have hypothesized that some advantage must be conferred upon people with single copies of the cystic fibrosis gene or the Tay-Sachs disease gene. Though many mutations are harmful, others prove to be beneficial to a species by helping it adapt to a particular environmental influence. Useful mutations, in fact, are the driving force behind evolution.

The processes of evolution are usually much too slow for people to discern, but it is possible to observe the effects of selective breeding when applied to domesticated animals and plants. The artificial selection of pigeons by breeders, in fact, provided the English naturalist Charles Darwin (1809-1882) with a model for his theory of natural selection, discussed in Evolution. Likewise, animal and plant breeders use mutations to produce new or improved strains of crops and livestock. Careful breeding in this manner has spawned the many different breeds of dogs, cats, and horses—each with their characteristic coloring, size, temperament, and so on—that we know today. It also has resulted in crops that are resistant to drought or insects or which have a high yield per acre. Likewise, goldfish, yellow roses, and Concord grapes are all descendants of ancestors with specific mutations.

Diseases and Mutation

The majority of mutations, however, are less than favorable, and this is illustrated by the relationship between mutation and certain hereditary diseases. An example is Huntington disease, a condition that strikes people in their forties or fifties and slowly disables their nervous systems. It produces shaking and a range of other symptoms, including depression, irritability, and apathy, and is usually fatal. The gene associated with Huntington's is dominant.

The horrible degenerative brain condition known as Creutzfeldt-Jakob disease, discussed in Diseases, is usually caused by another mutation. (Though it can be caused by infection, most cases of the disease are the result of heredity.) As with some of the other conditions we have mentioned, this one seems to affect particular groups more than others. Whereas the worldwide incidence of this rare condition is about one in one million, among Libyan Jews the rate is higher. The disease is a type of spongiform encephalopathy, so named because it produces characteristic spongelike patterns on the surface of the brain. Spongiform encephalopathies are caused by the appearance of a prion, a deviant form of protein whose production typically is caused by a mutation.

Most hereditary diseases are, by definition, linked with a mutation. Such is the case with hemophilia, for instance (see Noninfectious Diseases), and with cystic fibrosis, a lethal disorder that clogs the lungs with mucus and typically kills the patient before the age of 30 years. Cystic fibrosis, like Huntington, occurs when a person inherits two copies of a mutated gene. In 1989 researchers found the source of cystic fibrosis on chromosome 7, where an infinitesimal change in the DNA sequence leads to the production of an aberrant protein.

Congenital Disorders

In the past, all manner of superstitions arose to explain why a child was born, for instance, with a cleft palate, a situation in which the two sides of the roof of the mouth fail to meet, causing a speech disorder that may be mild or severe. Once known as a harelip, the cleft palate was said to have formed as a result of the mother's being frightened by a hare while she was carrying the child. In fact, it is just one example of a congenital disorder, an abnormality of structure or function or a disease that is present at birth. Congenital disorders, which also are called birth defects, may be the result of several different factors, mutation being one of the most significant. Among the many examples of congenital disorder are the hereditary diseases we have already mentioned, as well as dwarfism, Down syndrome, albinism, and numerous other conditions.

Dwarves and Midgets

The term dwarf has many associations from fairy tales—an example of the combined fascination and revulsion with which people with congenital disorders have long been treated—but it also is used to describe persons of abnormally short stature. A dwarf is distinguished from a midget in a number of ways, all of which indicate that the features of a midget are less removed from the norm. Midgets, while small, have bodies with proportions in the ordinary range. Likewise, the intelligence and sexual development of an adult midget are similar to those of other adults, and a midget or midget couple typically produces children of ordinary size. Pygmies, a group of people in southern Africa, appear to be midgets through a germinal mutation, but in many populations the mutation is somatic, occurring only occasionally in families whose other members are of ordinary size.

Dwarfs, by contrast, have several different disorders. One variety of dwarfism, known in the past as cretinism, is characterized by a small, abnormally proportioned body and an impaired mind. On the other hand, several forms of hereditary dwarfism carry with them no ill effect on the mental capacity. For example, people with the type of dwarfism known as achondroplasia have short limbs and unusually large heads, but the life span and intelligence of someone with this condition are quite normal. In the case of diastrophic dwarfism, the brain is fine, but the skeleton is deformed, and the risk of death from respiratory failure is high in infancy. Persons with diastrophic dwarfism who survive early childhood, however, are likely to enjoy a normal life span.

Down Syndrome

Like people with many other congenital disorders, those with Down syndrome used to be called by a name that now is considered crude and insensitive: mongoloid. The term, when used with a capital M, refers to people of east Asian descent and is analogous to other broad racial groupings: Caucasoid, Negroid, and Australoid. In the case of people with Down syndrome, mongoloid referred to the unusual facial features that mark someone with that condition.

A person with Down syndrome (caused by an extra chromosome in the 21st chromosomal pair) is likely to have a wide, flat face and eyes that are slanted, sometimes with what is known as an inner epicanthal fold—all facial characteristics common among people who are racially Mongoloid. Numerous other facial features identify a person with Down syndrome as someone who suffers from a specific congenital disorder, including a short neck, ears that are set low, a small nose, large tongue and lips, and a chin that slopes. People with Down syndrome are apt to have poor muscle tone and possess abnormal ridge patterns on their palms and fingers and the soles of their feet. Heart and kidney problems are common with Down syndrome as well, but one feature is most common of all: mental retardation. The condition occurs in about one of 1,000 live births among women under age 40 but about one in 40 live births to older women. Overall, the incidence is about one in 800 live births. As noted earlier, the cause of Down syndrome is translocation, but the reason translocation occurs is not known.

Albinism

Compared with dwarfism or Down syndrome, albinism is not nearly as severe in terms of its effect on a person's functioning. A condition that results from an inherited defect in melanin metabolism (melanin is responsible for the coloring of skin), albinism is marked by an absence of pigment from the hair, skin, and eyes. The hair of an albino tends to be whitish blond, the skin an extremely pale white, and the eyes pinkish. Albinism occurs among other animals: hence the white rats, rabbits, and mice almost everyone has seen. Domestic white chickens, geese, and horses are partial albinos that retain pigment in their eyes, legs, and feet. As was once true of people with other congenital disorders, human albinos once inspired fear and awe. Sometimes they were killed at birth, and in the mid-nineteenth century, albinos were exhibited in carnival sideshows. In these cruel spectacles, sometimes whole families were put on display, touted as a unique race of "night people" who lived underground and came out only when the light was dim enough not to hurt their eyes.

On the other hand, some ethnic groups experience enough albino births that another one causes no excitement. For example, among the San Blas Indians of Panama, one in approximately 130 births is an albino, compared with one in 17,000 for humans as a whole. Albinism comes about when melanocytes (melanin-producing cells) fail to produce melanin. In tyrosinase-negative albinism, the most common form, the enzyme tyrosinase (a catalyst in the conversion of tyrosine to melanin) is missing from the melanocytes. When the enzyme is missing, nomelanin is produced. In tyrosinase-positivealbinism, a defect in the body's tyrosine transportsystem impairs melanin production. One inevery 34,000 persons in the United States has tyrosinase-negative albinism. It is equally common among blacks and whites, while more blacksthan whites are affected by tyrosinase-positivealbinism. Native Americans have a particularlyhigh incidence of both forms of albinism.

Mutagens and Other Causes

As might be expected, cells that divide many, many times in a lifetime are more at risk of errors and mutations than cells that divide less frequently. In a human female, egg cells are fully formed at birth, and they never divide thereafter. By contrast, sperm cells are being produced constantly, and the older a man is, the more frequently his sperm-producing cells have divided. By age 20 they will have divided 200 times and by age 45 about 770 times. This has led scientists to hypothesize that when a baby is born with a congenital disorder caused by an error in cell division, the father is the parent more likely to have contributed the gene with the mutation.

This is just one example of why mutation occurs. Many mutations are caused by mutagens—chemical or physical factors that increase the rate of mutation. Some mutagens occur naturally, and some are synthetic. Cosmic rays from space, for instance, are natural, but they are mutagenic. Some naturally occurring viruses are considered mutagenic, since they can insert themselves into host DNA. Hydrogen and atomic bombs are man-made, and they emit harmful radiation, which is a mutagen. Recreational drugs, tobacco, and alcohol also can be mutagens in the bodies of pregnant women. The first mutagens to be identified were carcinogens, or cancer-causing substances. Carcinogens in chimney soot were linked with the chimney sweep's cancer of late eighteenth-century England, discussed in Noninfectious Diseases. In fact, cancer itself is a kind of mutation, involving uncontrolled cell growth. Other environmental factors that are known to bring about mutations include exposure to pesticides, asbestos, and some food additives, many of which have been banned.

Where to Learn More

"Are Mutations Harmful?" Talk. Origins (Web site). <http://www.talkorigins.org/faqs/mutations.html>.

Human Gene Mutation Database, Institute of Medical Genetics, University of Wales College of Medicine (Web site). <http://archive.uwcm.ac.uk/uwcm/mg/hgmd0.html>.

Kimball, Jim. Mutations. Kimball's Biology Pages (Web site). <http://www.ultranet.com/~jkimball/Biology-Pages/M/Mutations.html>.

"Mutations." Brooklyn College, City University of New York (Web site). <http://www.brooklyn.cuny.edu/bc/ahp/BioInfo/SD.Mut.HP.html>.

Patterson, Colin. Evolution. Ithaca: Comstock Publishing Associates, 1999.

Reilly, Philip. Abraham Lincoln's DNA and Other Adventures in Genetics. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2000.

Twyman, Richard M. Advanced Molecular Biology: A Concise Reference. Oxford, UK: Bios Scientific Publishers, 1998.

Weinberg, Robert A. One Renegade Cell: How Cancer Begins. New York: Basic Books, 1998.

Any alteration capable of being replicated in the genetic material of an organism. When the alteration is in the nucleotide sequence of a single gene, it is referred to as gene mutation; when it involves the structures or number of the chromosomes, it is referred to as chromosome mutation, or rearrangement. Mutations may be recognizable by their effects on the phenotype of the organism (mutant).

Gene mutations

Two classes of gene mutations are recognized: point mutations and intragenic deletions. Two different types of point mutation have been described. In the first of these, one nucleic acid base is substituted for another. The second type of change results from the insertion of a base into, or its deletion from, the polynucleotide sequence. These mutations are all called sign mutations or frame-shift mutations because of their effect on the translation of the information of the gene. See also Nucleic acid.

More extensive deletions can occur within the gene which are sometimes difficult to distinguish from mutants which involve only one or two bases. In the most extreme case, all the informational material of the gene is lost.

A single-base alteration, whether a transition or a transversion, affects only the codon or triplet in which it occurs. Because of code redundancy, the altered triplet may still insert the same amino acid as before into the polypeptide chain, which in many cases is the product specified by the gene. Such DNA changes pass undetected. However, many base substitutions do lead to the insertion of a different amino acid, and the effect of this on the function of the gene product depends upon the amino acid and its importance in controlling the folding and shape of the enzyme molecule. Some substitutions have little or no effect, while others destroy the function of the molecule completely.

Single-base substitutions may sometimes lead not to a triplet which codes for a different amino acid but to the creation of a chain termination signal. Premature termination of translation at this point will lead to an incomplete and generally inactive polypeptide.

Sign mutations (adding or subtracting one or two bases to the nucleic acid base sequence of the gene) have a uniformly drastic effect on gene function. Because the bases of each triplet encode the information for each amino acid in the polypeptide product, and because they are read in sequence from one end of the gene to the other without any punctuation between triplets, insertion of an extra base or two bases will lead to translation out of register of the whole sequence distal to the insertion or deletion point. The polypeptide formed is at best drastically modified and usually fails to function at all. This sometimes is hard to distinguish from the effects of intragenic deletions. However, whereas extensive intragenic deletions cannot revert, the deletion of a single base can be compensated for by the insertion of another base at, or near, the site of the original change. See also Gene; Genetic code.

Chromosomal changes

Some chromosomal changes involve alterations in the quantity of geneticmaterial in the cell nuclei, while others simply lead to the rearrangement ofchromosomal material without altering its total amount. See also Chromosome.

Origins of mutations

Mutations can be induced by various physical and chemical agents or can occur spontaneously without any artificial treatment with known mutagenic agents.

Until the discovery of x-rays as mutagens, all the mutants studied were spontaneous in origin; that is, they were obtained without the deliberate application of any mutagen. Spontaneous mutations occur unpredictably, and among the possible factors responsible for them are tautomeric changes occurring in the DNA bases which alter their pairing characteristics, ionizing radiation from various natural sources, naturally occurring chemical mutagens, and errors in the action of the DNA-polymerizing and correcting enzymes.

Spontaneous chromosomal aberrations are also found infrequently. One way in which deficiencies and duplications may be generated is by way of the breakage-fusion-bridge cycle. During a cell division one divided chromosome suffers a break near its tip, and the sticky ends of the daughter chromatids fuse. When the centromere divides and the halves begin to move to opposite poles, a chromosome bridge is formed, and breakage may occur again along this strand. Since new broken ends are produced, this sequence of events can be repeated. Unequal crossing over is sometimes cited as a source of duplications and deficiencies, but it is probably less important than often suggested.

In the absence of mutagenic treatment, mutations are very rare. In 1927 H. J. Muller discovered that x-rays significantly increased the frequency of mutation in Drosophila. Subsequently, other forms of ionizing radiation, for example, gamma rays, beta particles, fast and thermal neutrons, and alpha particles, were also found to be effective. Ultraviolet light is also an effective mutagen. The wavelength most employed experimentally is 253.7 nm, which corresponds to the peak of absorption of nucleic acids.

Some of the chemicals which have been found to be effective as mutagens are the alkylating agents which attack guanine principally although not exclusively. The N7 portion appears to be a major target in the guanine molecule, although the O⁶ alkylation product is probably more important mutagenically. Base analogs are incorporated into DNA in place of normal bases and produce mutations probably because there is a higher chance that they will mispair at replication. Nitrous acid, on the other hand, alters DNA bases in place. Adenine becomes hypoxanthine and cytosine becomes uracil. In both cases the deaminated base pairs differently from the parent base. A third deamination product, xanthine, produced by the deamination of guanine, appears to be lethal in its effect and not mutagenic. Chemicals which react with DNA to generate mutations produce a range of chemical reaction products not all of which have significance for mutagenesis.

Significance of mutations

Mutations are the source of genetic variability, upon which natural selection has worked to produce organisms adapted to their present environments. It is likely, therefore, that most new mutations will now be disadvantageous, reducing the degree of adaptation. Harmful mutations will be eliminated after being made homozygous or because the heterozygous effects reduce the fitness of carriers. This may take some generations, depending on the severity of their effects. Chromosome alterations may also have great significance in evolutionary advance. Duplications are, for example, believed to permit the accumulation of new mutational changes, some of which may prove useful at a later stage in an altered environment.

Rarely, mutations may occur which are beneficial: Drug yields may beenhanced in microorganisms; the characteristics of cereals can be improved.However, for the few mutations which are beneficial, many deleterious mutationsmust be discarded. Evidence suggests that the metabolic conditions in thetreated cell and the specific activities of repair enzymes may sometimespromote the expression of some types of mutation rather than others. See also Deoxyribonucleic acid (DNA).

Mutation is a change in the structure of the genome by alteration of the DNA. Alterations in the DNA sequence can arise when mistakes made during replication (copying of the DNA) cause the insertion or omission of a base (point mutation) or the removal or inversion of larger segments of DNA. Mutations can also be caused by radiation or by some chemicals (mutagens). The consequences of mutations are variable; if a mutation occurs within a gene then the composition of the gene product (a protein) will be altered and may affect its function. The evolutionary process depends on mutations in DNA.

— Alan W. Cuthbert

noun

1. The process or result of making or becoming different: alteration, change, modification, permutation, variation. See change/persist.
2. The process or result of changing from one appearance, state, or phase to another: change, changeover, conversion, metamorphosis, shift, transfiguration, transformation, translation, transmogrification, transmutation, transubstantiation. See change/persist.

Definition: metamorphosis
Antonyms: inaction, stagnation

A mutation is any heritable change in the genome of an organism. For a population, heritable mutations provide the source of genetic variation, without which evolution could not occur: If all individuals of a species were genetically identical, every subsequent generation would be identical regardless of which members of the species reproduced successfully. For an individual organism, mutations are rarely beneficial, and many cause genetic diseases, including cancer. For researchers, mutations (either spontaneous or introduced) provide important clues about gene location and function.

Phenotypic Effects and Evolution

Mutations in the germ-line cells are heritable and provide the raw material upon which natural selection operates to produce evolution. Mutations in somatic cells, which are cells that are not germ line, are not heritable but may lead to disease in the organism possessing them.

Most mutations do not cause disease and are said to be "silent" mutations. This is for at least two reasons. First, most DNA does not code for genes, so changes in the sequence do not affect the types or amounts of protein made and there is no change in the phenotype of the organism. Second, most sexually reproducing organisms are diploid, meaning they possess two copies of every gene. Many types of mutation simply disable one copy, leaving the other intact and functional. Therefore these mutations display a recessive inheritance pattern, with no effect on phenotype unless an individual inherits two copies of the mutation. Diploid species can accumulate a large pool of such recessive mutations, which are mostly disadvantageous and thus contribute to the burden of genetic disease.

Some mutations lead to detrimental alterations of the normal pheno-type and are, therefore, selected against. Very occasionally, the mutant phenotype is superior and provides a selective advantage, which leads to an increase in the frequency of this mutant allele and, thus, to evolution of the population. Alternatively, a disadvantageous mutation in one environment may become advantageous in another, again leading to increased frequency of this allele.

Molecular Basis of Mutations

DNA is composed of a double helix, each side of which is a long string of four types of nucleotides. Each nucleotide possesses identical sugar-phosphate groups that contribute to the DNA backbone but differs in the structure of the base suspended between the two backbones. The bases are adenine, thymine, cytosine, and guanine (A, T, C, G). Because of their structure, A pairs only with T across the double helix, and C only with G.

Within genes, the sequence of DNA encodes a sequence of amino acids used to build a protein. The DNA is read in triplets of bases, with each triplet coding for an amino acid. With the recognition that the genetic information lies in the sequence of bases in the DNA, it became possible to understand the chemical nature of gene mutations and how these could be as stable as the original allele of the gene.

Consideration of the genetic code linking DNA and amino acids reveals how mutations can either alter a protein, have no effect, or prevent it from being produced entirely. Mutations fall into four broad categories (point mutations, structural chromosomal aberrations, numerical chromosomal aberrations, and transposon-induced mutations), each of which may be subdivided further.

Point Mutations

"Point mutations" are small changes in the sequence of DNAbases within a gene. These are what are most commonly meant by the word "mutation." Point mutations include substitutions, insertions, and deletions of one or more bases.

If one base is replaced by another, the mutation is called a base substitution. Because the DNA is double-stranded, a change on one strand is always accompanied by a change on the other (this change may occur spontaneously during DNA replication, or it can be created by errors during DNA repair. Consequently, it is often difficult to know which base of the pair was mutated and which was simply the result of repairing the mismatch at the mutation.

For example, the most common mutation in mammalian cells is the substitution of a G-C pair with an A-T pair. This could arise if G is replaced by A and subsequently the A is replicated to give T on the other strand. Alternatively, the C could be replaced by a T and the T could then be replicated to give an A on the complementary strand, the final result being the same. It is believed that the G-C to A-T conversion most commonly begins with a C-to-T mutation. This is because most of these mutations occur at DNA sequences in which C is methylated (i.e., chemically modified by the addition of a-CH₃ group). The methylated form of C can be converted to a base that resembles T (and thus pairs with A) by removal of an-NH₂ group (deamination)—a relatively common event.

Base substitution mutations are classified as transitions or transversions. Transitions are mutations in which one pyrimidine (C or T) is substituted by the other and one purine (G or A) is substituted on the complementary strand. The G-C to A-T conversion is a transition mutation, since C becomes T.

Transversions are mutations in which a purine is replaced by a pyrimidine or vice versa. Sickle cell anemia is caused by a transversion: T is substituted for A in the gene for a hemoglobin subunit. This mutation has arisen numerous times in human evolution. It causes a single amino acid change, from glutamic acid to valine, in the β subunit of hemoglobin. Sickle cell anemia was the first genetic condition for which the change in the protein was demonstrated in 1954 by Linus Pauling (a Nobel laureate from the California Institute of Technology) and subsequently shown to be a single amino acid difference by Vernon Ingram (a Nobel laureate from the Massachusetts Institute of Technology).

Base substitutions are sometimes silent mutations—mutations that do not change the amino acid sequence in the protein encoded by the gene. Silent mutations are possible because the original and mutated sequences can code for the same amino acid, given the redundancy of the genetic code. In the divergence between sea urchins and humans, for example, one of the histone proteins has only two amino acid substitutions, although the gene has many base pair substitutions. Histones are proteins around which DNA is wrapped in chromosomes. The very close similarity in sequence between such distantly related organisms is an indication of how critical the structure is for the function: Most mutations that change it are very disadvantageous.

One type of substitution mutation that almost always inactivates the gene is mutation to a stop codon. A stop codon ends the assembly of the protein, and a truncated protein is usually not active biochemically. Many recessive genetic diseases occur when a mutation converts a coding triplet to a stop codon.

Other mutations involve the insertion or deletion of one or more base pairs in the DNA. When they occur in genes, such mutations typically inactivate the encoded protein, because they change the "reading frame" of the gene. The DNA sequence is translated in groups of three nucleotides. Insertion or deletion of a nucleotide changes the sets of triplets, and thus every subsequent amino acid is altered, changing the protein completely, as shown in Figure 2. Stop codons also frequently arise from insertions or deletions.

Naturally occurring trinucleotide repeat sequences (e.g., CAGCAG CAGCAG) are hot spots for certain important human mutations that involve the insertion of more copies of the repeated sequence. For example at the locus for Huntington's disease, a sequence of 10-29 copies of CAG is normal and stable, but if there are 30-38, there is a high rate of mutation to increased numbers of copies, and if there are 39 or more copies, middle-age dementia called Huntington's disease results.

Functional Consequences and Inheritance Patterns

Mutations can be classified by their functional consequences. Mutations that inactivate the resulting protein, or prevent it from being made at all, are called loss-of-function mutations. These are usually recessive, since the organism still retains one functional copy on the other chromosome. Loss-of-function mutations may be dominant if the organism cannot compensate for the loss by using the other gene copy. Gain-of-function mutations are those in which the protein takes on a new function, or loses the ability to be regulated by other proteins. These mutations are typically dominant, since the new function may be deleterious even in the presence of a normal protein, encoded by the other gene copy.

Chromosomal Aberrations and Transposons

"Structural chromosomal aberrations," the second category of mutations, arise when DNA in chromosomes is broken. The broken ends may remain unrepaired or may be joined with those of another break, to form new combinations of genes, such as translocations. A translocation between chromosomes 8 and 21 in humans causes acute myeloid leukemia by increasing the activity of c-myc, a gene involved in cell replication.

Translocations often cause human infertility, because they interfere with the normal distribution of chromosomes during meiosis. Chromosomes pair up before separating, as eggs or sperm are formed, and the correct pairing depends on matching sequences between them. Structural aberrations also include inversions and duplications of pieces of chromosomes.

Most chromosomal aberrations lead to the formation of chromosomal fragments without centromeres. Centromeres are crucial for proper chromosomal division, during both mitosis and meiosis. Therefore a chromosomal fragment is likely to be lost from one of the daughter cells formed after cell division.

Structural aberrations are nonetheless common in evolutionary history. As a result, although the chromosomes of mouse and man are quite different in appearance, most genes have the same neighbors in the two species, representing the ancestral mammalian arrangement, even if they have been moved to another chromosome as shown in Figure 3.

"Numerical chromosomal aberrations," the third category of mutations, are changes in the number of chromosomes. In some cases, the whole genome has been duplicated (called polyploidy) and the mutant has, for example, four of each chromosome (and is thus tetraploid) rather than the usual two (diploid, as in humans). These are much more common in the evolution of plants than animals. In other cases, only one or a few of the chromosomes are involved, which is referred to as aneuploidy. Down syndrome, in which a person has an extra chromosome 21, is an example of such a mutation. Aneuploidy may also involve the loss of a chromosome. The absence of one of the sex chromosomes, X or Y, is a mutation in humans that results in Turner's syndrome, in which there is only one X.

"Transposon-induced mutations" are the fourth category of mutations. Transposable genetic elements (transposons) are pieces of DNA that can copy themselves and insert into a new location in the genome. They were first discovered by Barbara McClintock, a U.S. geneticist and Nobel laureate in 1950. When transposons jump into a new position, the insertion may disrupt a gene and thus mutate it, usually inactivating it. Sometimes the transposon jumps again, and the activity of the gene it leaves is restored. Often, however, the transposon stays in the original position, permanently disrupting the gene. Some forms of hemophilia are due to transposon insertion. Transposon mutations have been extremely common in human evolution, and such mutations are still occurring.

Mutations in Research and Medicine

Early geneticists treasured mutations in the organisms they studied, since no characteristic can be studied genetically unless heritable variants exist. If, for example, everyone had brown eyes, nothing could be learned about the inheritance of eye color, as all generations would have the same color of eyes. For this reason, geneticists collected and propagated all the mutants they could find, and methods were developed to deliberately induce mutations, a process called mutagenesis. Such techniques include exposing their experimental organisms to X rays and chemicals.

Transposons can also be deliberately used to introduce mutations in model organisms. In the plant Arabidopsis thaliana and in the fruit fly Drosophila melanogaster, transposon mutagenesis is often used to induce mutations, as the mutation can be very rapidly cloned and mapped with the transposon's DNA sequence as starting point.

Comparing existing mutations can help determine the evolutionary relatedness of two organisms. During evolution, there has been a relatively constant rate of accumulation of mutations in genes for a number of proteins, so the number of changes can be used to estimate the time since two species had a common ancestor. This is called the molecular clock and is illustrated in Figure 1. Each gene has evolved at a characteristic rate—the result of mutation rates, selection, and chance changes in the gene pool.

Advances in genetics have only intensified the search for mutations, especially in complex traits such as behavior and cancer, as the key to finding the genes involved and then unraveling the underlying mechanisms. This involves mapping the mutations, cloning the genes, and studying the mutants to discover what biochemical processes are changed in the mutants.

Mutations are believed to underlie most, if not all cancers. Cancer-causing mutations found so far include genes involved in communication between cells (signal transduction) and in the control of cell division. Many of these genes have been categorized into two broad classes: oncogenes and tumor suppressor genes. The mutation that has been found most often, in a tumor suppressor gene called p53, usually arises as a somatic mutation but can also be inherited as Li Fraumeni syndrome.

Xeroderma pigmentosum is an autosomal recessive condition in which the ability to repair DNA damage induced by UV light is defective. Many mutations are produced, and the affected people have large numbers of skin cancers.

Bibliography

Drake, John W. "Spontaneous Mutation." Annual Review of Genetics 25 (1991): 125-46.

Hartwell, Leland H., et al. Genetics: From Genes to Genomes. Boston: McGraw-Hill,2000.

Lewis, Ricki. Human Genetics: Concepts and Applications, 4th ed. Boston: McGraw-Hill,2001.

Pauling, Linus, et al. "Sickle Cell Anemia, a Molecular Disease." Science 110 (1949):543-548.

Internet Resource

International Agency for Research on Cancer. http://www.iarc.fr/.

—John Heddle

A mutation is an alteration in the DNA sequence of a gene. Mutations are a source of variation to a population, but they can have detrimental effects in that they may cause diseases and disorders. One example of a disease caused by a mutation is sickle cell disease, in which there is a change in the amino acid sequence (valine is substituted for glutamic acid) of two of the four polypeptide chains that make up the oxygen-carrying protein known as hemoglobin.

LearnThatWord.com is a free vocabulary and spelling program where you only pay for results!

• 1941 R.A. Heinlein Universe Astounding S-F (May) № 16/2: Our present wise rule of inspecting each infant for the mark of sin and returning to the Converter any who are found to be mutations was not in force.
• 1946 A.E. van Vogt Hand of Gods Astounding SF (Dec.) № 144/1: It would be impossible for a despised mutation ever to become Lord Leader.
• 1989 O. Butler Imago (1991) № 112: It was well cooked, steaming hot, spicy, and sweet. It had not existed before the Humans had their war. Lilith said it was one of the few good-tasting mutations she had eaten.

Changes in chromosomes or genes that cause offspring to have characteristics different from those of their parents. Mutations can be caused by the effects of chemicals, radiation, or even ordinary heat on DNA. Mutations produce some of the differences between members of a species on which natural selection acts.

1. the process by which genetic material undergoes a detectable and heritable structural change, or the result of such a change. Three categories are recognized: genome mutations, in which addition or subtraction of one or more whole chromosomes occurs; chromosome mutations, in which the structure of one or more chromosomes is affected; and gene mutations, in which the structure of a gene is altered at the molecular level.
2. any modified gene arising from a mutation (def. 1).
3. a mutant (def. 1). See also deletion, inversion (def. 4), point mutation, translocation (def. 2).

1. a nucleotide change, including base substitutions, insertions or deletions in DNA, or RNA in the case of some viruses, that gives rise to the mutant phenotype.
2. an animal exhibiting such change. Called also a sport.

• back m. — see reverse mutation (below).
• base substitution m. — may be a transition in which a purine–pyrimidine pair is substituted by the other purine–pyrimidine pair, or transversion in which a purine–pyrimidine pair is replaced by one of the two pyrimidine pairs.
• chain termination m. — one in which the new base sequence introduces a stop codon and thereby prematurely terminates synthesis of the polypeptide; the three mutations are also called amber (UAG), ochre (UAA) and opal (UGA).
• deletion m. — one produced by loss of nucleotides from a DNA sequence.
• frame shift m. — occur as a result of either the insertion of a new base pair or the deletion of a base pair or a block of base pairs from the DNA base sequence; these, unless they occur in 3 or multiples of 3, are most serious in that the message to the right of the frame shift is garbled.
• leaky m. — one in which the amino acid substitution only partially disrupts the function of the protein; in bacteria this is usually manifested by reduced growth rate.
• mis-sense m. — one causing an amino acid substitution in the protein.
• nonsense m. — one in which a stop codon is substituted for a codon that specifies an amino acid.
• operator constitutive m. — one or more base changes in the operator region (originally defined for the lactose operon) which stop the repressor protein from tightly binding to sequence such that it is less effective in preventing RNA polymerase from inhibiting transcription.
• point m. — a single changed base pair in the DNA of an organism which may be a base substitution, base insertion or base deletion.
• m. rate — the frequency of mutations in the population over time.
• repressor-constitutive m. — in regulation of gene expression, a mutation in the repressor protein that decreases the binding affinity of the repressor protein for the operator which leaves the gene permanently turned on.
• reverse m. — one in which the wild-type phenotype is restored; such organisms are called revertants. Called also back mutation, reversion mutation.
• second-site m. — see suppressor mutation.
• silent m. — one in which there is a base change but because of the redundancy of the genetic code the same amino acid is coded, or one in which there is an amino acid substitution in the protein which has no detectable effect on the phenotype.
• somatic m. — a change in the DNA sequence that occurs in somatic cells, i.e. not gametes. The mechanism underlying the generation of diversity of antigen recognition by immunoglobulins and T cell receptor molecules. The fundamental cause of cancer, in which the mutation occurs spontaneously or is induced by carcinogens, such as sunlight, chemicals or viruses.
• suppressor m. — a particular type of reversion mutation in which a mutation at a second site restores the original phenotype; most simply a mutation produced by a base deletion may be restored to wild type by a proximate but independent base substitution. Called also second-site mutation.
• temperature-sensitive (ts) m. — one in which there is an altered protein that is active at one temperature, typically 86°F (30°C) and inactive at a higher temperature, usually 104 to 108°F (40 to 42°C), e.g. ts mutant virus and bacteria.
• transdominant m. — occur in genes producing diffusible products, in contrast to cis-dominant mutation in which mutations occur in regulatory sequences that are recognized by other proteins.
• transition m. — one in which the base change does not change the pyrimidine–purine orientation. See also base substitution mutation (above).
• transposition m. — one produced by the insertion of a transposable genetic element.
• transversion m. — one in which the purine–pyrimidine orientation is changed to pyrimidine–purine or vice versa. See also base substitution mutation (above).

A departure from the parent type, as when an organism differs from its parents in one or more heritable characteristics; caused by genetic change.

• Defects and Disabilities - mutation: altered inherited characteristic due to genetic change
• Genetics, Heredity, and Evolution - mutation: sudden inheritable change to new allelic form of gene
• Phonetics - mutation: phonetic change in initial consonant of a word under certain conditions, as observed in the Celtic languages; umlaut

For other uses, see Mutation (disambiguation).

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In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic chemicals, as well as errors that occur during meiosis or DNA replication.^[1][2][3] They can also be induced by the organism itself, by cellular processes such as hypermutation.

Mutation can result in several different types of change in sequences; these can either have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely. Studies in the fly Drosophila melanogaster suggest that if a mutation changes a protein produced by a gene, this will probably be harmful, with about 70 percent of these mutations having damaging effects, and the remainder being either neutral or weakly beneficial.^[4] Due to the damaging effects that mutations can have on genes, organisms have mechanisms such as DNA repair to prevent mutations.^[1]

Contents 1 Description 2 Causes 2.1 Spontaneous mutation 2.2 Induced mutation 3 Classification of mutation types 3.1 By effect on structure 3.2 By effect on function 3.3 By effect on fitness 3.4 By impact on protein sequence 3.5 By inheritance ability 3.6 Special classes 3.7 Nomenclature 4 Harmful mutations 5 Beneficial mutations 6 Prion mutation 7 Somatic mutation rate 8 See also 9 References 10 External links

Description

Mutations can involve large sections of DNA becoming duplicated, usually through genetic recombination.^[5] 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.^[6] Most genes belong to larger families of genes of shared ancestry.^[7] 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.^[8][9]

Here, 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.^[10] For example, the human eye uses four genes to make structures that sense light: three for color vision and one for night vision; all four arose from a single ancestral gene.^[11] Another advantage of duplicating a gene (or even an entire genome) is that this increases redundancy; this allows one gene in the pair to acquire a new function while the other copy performs the original function.^[12][13] Other types of mutation occasionally create new genes from previously noncoding DNA.^[14][15]

Changes in chromosome number may involve even larger mutations, where segments of the DNA within chromosomes break and then rearrange. For example, in the Homininae, two chromosomes fused to produce human chromosome 2; this fusion did not occur in the lineage of the other apes, and they retain these separate chromosomes.^[16] 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, and thereby preserving genetic differences between these populations.^[17]

Sequences of DNA that can move about the genome, such as transposons, make up a major fraction of the genetic material of plants and animals, and may have been important in the evolution of genomes.^[18] 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.^[19] 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.^[2]

Nonlethal mutations accumulate within the gene pool and increase the amount of genetic variation.^[20] 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.

For example, a butterfly may produce offspring with new mutations. The majority of these mutations will have no effect; but one might change the color of one of the butterfly's offspring, making it harder (or easier) for predators to see. If this color change is advantageous, the chance of this butterfly surviving and producing its own offspring are a little better, and over time the number of butterflies with this mutation may form a larger percentage of the population.

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

Mutation is generally accepted by biologists as the mechanism by which natural selection acts, generating advantageous new traits that survive and multiply in offspring as well as disadvantageous traits, in less fit offspring, that tend to die out.

Causes

Main article: Mutagenesis

Two classes of mutations are spontaneous mutations (molecular decay) and induced mutations caused by mutagens.

Spontaneous mutation

Spontaneous mutations on the molecular level can be caused by:^[21]

• Tautomerism – A base is changed by the repositioning of a hydrogen atom, altering the hydrogen bonding pattern of that base resulting in incorrect base pairing during replication.
• Depurination – Loss of a purine base (A or G) to form an apurinic site (AP site).
• Deamination – Hydrolysis changes a normal base to an atypical base containing a keto group in place of the original amine group. Examples include C → U and A → HX (hypoxanthine), which can be corrected by DNA repair mechanisms; and 5MeC (5-methylcytosine) → T, which is less likely to be detected as a mutation because thymine is a normal DNA base.
• Slipped strand mispairing – Denaturation of the new strand from the template during replication, followed by renaturation in a different spot ("slipping"). This can lead to insertions or deletions.

A covalent adduct between benzo[a]pyrene, the major mutagen in tobacco smoke, and DNA^[22]

Induced mutation

Induced mutations on the molecular level can be caused by:

• Chemicals
  • Hydroxylamine NH₂OH
  • Base analogs (e.g. BrdU)
  • Alkylating agents (e.g. N-ethyl-N-nitrosourea) These agents can mutate both replicating and non-replicating DNA. In contrast, a base analog can only mutate the DNA when the analog is incorporated in replicating the DNA. Each of these classes of chemical mutagens has certain effects that then lead to transitions, transversions, or deletions.
  • Agents that form DNA adducts (e.g. ochratoxin A metabolites)^[23]
  • DNA intercalating agents (e.g. ethidium bromide)
  • DNA crosslinkers
  • Oxidative damage
  • Nitrous acid converts amine groups on A and C to diazo groups, altering their hydrogen bonding patterns which leads to incorrect base pairing during replication.
• Radiation
  • Ultraviolet radiation (nonionizing radiation). Two nucleotide bases in DNA – cytosine and thymine – are most vulnerable to radiation that can change their properties. UV light can induce adjacent pyrimidine bases in a DNA strand to become covalently joined as a pyrimidine dimer. UV radiation, particularly longer-wave UVA, can also cause oxidative damage to DNA.^[24] Mutation rates also vary across species. Evolutionary biologists^{[citation needed]} have theorized that higher mutation rates are beneficial in some situations, because they allow organisms to evolve and therefore adapt more quickly to their environments. For example, repeated exposure of bacteria to antibiotics, and selection of resistant mutants, can result in the selection of bacteria that have a much higher mutation rate than the original population (mutator strains).

Classification of mutation types

Illustrations of five types of chromosomal mutations.

Selection of disease-causing mutations, in a standard table of the genetic code of amino acids.^[25]

By effect on structure

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 as:

• Small-scale mutations, such as those affecting a small gene in one or a few nucleotides, including:
  • Point mutations, often caused by chemicals or malfunction of DNA replication, exchange a single nucleotide for another.^[26] These changes are classified as transitions or transversions.^[27] 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 5-bromo-2-deoxyuridine (BrdU). Less common is a transversion, which exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T ↔ A/G). An example of a transversion is adenine (A) being converted into a cytosine (C). 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 three kinds, depending upon what the erroneous codon codes for:
    • Silent mutations: which code for the same amino acid.
    • Missense mutations: which code for a different amino acid.
    • Nonsense mutations: which code for a stop 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 (e.g. AT repeats^{[citation needed]}). Insertions in the coding region of a gene may alter splicing of the mRNA (splice site mutation), or cause a shift in the reading frame (frameshift), both of which can significantly alter the gene product. Insertions can be reverted by excision of the transposable element.
  • Deletions remove one or more nucleotides from the DNA. Like insertions, these mutations can alter the reading frame of the gene. They are generally irreversible: though exactly the same sequence might theoretically be restored by an insertion, transposable elements able to revert a very short deletion (say 1–2 bases) in any location are either highly unlikely to exist or do not exist at all. Note that a deletion is not the exact opposite of an insertion: the former is quite random while the latter consists of a specific sequence inserting at locations that are not entirely random or even quite narrowly defined.
• Large-scale mutations in chromosomal structure, including:
  • 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). These include:
    • Chromosomal translocations: interchange of genetic parts from nonhomologous chromosomes.
    • Interstitial deletions: an intra-chromosomal deletion that removes a segment of DNA from a single chromosome, thereby apposing previously distant genes. For example, cells isolated from a human astrocytoma, a type of brain tumor, were found to have a chromosomal deletion removing sequences between the "fused in glioblastoma" (fig) gene and the receptor tyrosine kinase "ros", producing a fusion protein (FIG-ROS). The abnormal FIG-ROS fusion protein has constitutively active kinase activity that causes oncogenic transformation (a transformation from normal cells to cancer cells).
    • Chromosomal inversions: reversing the orientation of a chromosomal segment.
  • Loss of heterozygosity: loss of one allele, either by a deletion or recombination event, in an organism that previously had two different alleles.

By effect on function

• Loss-of-function mutations are the result of gene product having less or no function. When the allele has a complete loss of function (null allele) it is often called an amorphic mutation. 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 change the gene product such that it gains a new and abnormal function. These mutations usually have dominant phenotypes. Often called a neomorphic mutation.
• 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 characterised by a dominant or semi-dominant phenotype. In humans, Marfan syndrome is an example of a dominant negative mutation occurring in an autosomal dominant disease. In this condition, the defective glycoprotein product of the fibrillin gene (FBN1) antagonizes the product of the normal allele.
• Lethal mutations are mutations that lead to the death of the organisms which carry the mutations.
• A back mutation or reversion is a point mutation that restores the original sequence and hence the original phenotype.^[28]

See also Behavior mutation.

By effect on fitness

In applied genetics it is usual to speak of mutations as either harmful or beneficial.

• A harmful mutation is a mutation that decreases the fitness of the organism.
• A beneficial mutation is a mutation that increases fitness of the organism, or which promotes traits that are desirable.

In theoretical population genetics, it is more usual to speak of such mutations as deleterious or advantageous. In the neutral theory of molecular evolution, genetic drift is the basis for most variation at the molecular level.

• 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.
• A deleterious mutation has a negative effect on the phenotype, and thus decreases the fitness of the organism.
• An advantageous mutation has a positive effect on the phenotype, and thus increases the fitness of the organism.
• A nearly neutral mutation is a mutation that may be slightly deleterious or advantageous, although most nearly neutral mutations are slightly deleterious.

In reality, viewing the fitness effects of mutations in these discrete categories is an oversimplification. Attempts have been made to infer the distribution of fitness effects using mutagenesis experiments or theoretical models applied to molecular sequence data. However, the current distribution is still uncertain, and some aspects of the distribution likely vary between species.^[20]

By inheritance

• inheritable generic in pro-generic tissue or cells on path to be changed to gametes.
• non inheritable somatic (e.g., carcinogenic mutation)
• non inheritable post mortem aDNA mutation in decaying remains.

By pattern of inheritance The human genome contains two copies of each gene – a paternal and a maternal allele.

• 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 comprises two different mutations in the paternal and maternal alleles.^[29]

A wildtype or homozygous non-mutated organism is one in which neither allele is mutated.

By impact on protein sequence

• A frameshift mutation is a mutation caused by insertion or deletion of a number of nucleotides that is not evenly divisible by three from a DNA sequence. Due to the triplet nature of gene expression by codons, the insertion or deletion can disrupt the reading frame, or the grouping of the codons, resulting in a completely different translation from the original.^[30] The earlier in the sequence the deletion or insertion occurs, the more altered the protein produced is.

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 that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and possibly a truncated, and often nonfunctional protein product.
• 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 (Boillée 2006, p. 39).
• A neutral mutation is a mutation that occurs in an amino acid codon which 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 are mutations that do not result in a change to the amino acid sequence of a protein. 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. 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. The name silent could be a misnomer. For example, a silent mutation in the exon/intron border may lead to alternative splicing by changing the splice site (see Splice site mutation), thereby leading to a changed protein. Silent mutations occur because of the degenerate nature of the genetic code.

By inheritance ability

A mutation has caused this garden moss rose to produce flowers of different colors. This is a somatic mutation that may also be passed on in the germ line.

In multicellular organisms with dedicated reproductive cells, mutations can be subdivided into germ line mutations, which can be passed on to descendants through their reproductive cells, and somatic mutations (also called acquired mutations),^[31] 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.^[32]

If the organism can reproduce asexually through mechanisms such as cuttings or budding the distinction can become blurred. For example, plants can sometimes transmit somatic mutations to their descendants asexually or sexually where flower buds develop in somatically mutated parts of plants. A new mutation that was not inherited from either parent is called a de novo mutation. The source of the mutation is unrelated to the consequence^{[clarification needed]}, although the consequences are related to which cells were mutated.

Special classes

• Conditional mutation is a mutation that has wild-type (or less severe) phenotype under certain "permissive" environmental conditions and a mutant phenotype under certain "restrictive" conditions. For example, a temperature-sensitive mutation can cause cell death at high temperature (restrictive condition), but might have no deleterious consequences at a lower temperature (permissive condition).

Nomenclature

A committee of the Human Genome Variation Society (HGVS) has developed the standard human sequence variant nomenclature,^[33] which should be used by researchers and DNA diagnostic centers to generate unambiguous mutation descriptions. In principle, this nomenclature can also be used to describe mutations in other organisms. The nomenclature specifies the type of mutation and base or amino acid changes.

• Nucleotide substitution (e.g. 76A>T) – The number is the position of the nucleotide from the 5' end, the first letter represents the wild type nucleotide, and the second letter represents the nucleotide which replaced the wild type. In the given example, the adenine at the 76th position was replaced by a thymine.
  • If it becomes necessary to differentiate between mutations in genomic DNA, mitochondrial DNA, and RNA, a simple convention is used. For example, if the 100th base of a nucleotide sequence mutated from G to C, then it would be written as g.100G>C if the mutation occurred in genomic DNA, m.100G>C if the mutation occurred in mitochondrial DNA, or r.100g>c if the mutation occurred in RNA. Note that for mutations in RNA, the nucleotide code is written in lower case.
• Amino acid substitution (e.g. D111E) – The first letter is the one letter code of the wild type amino acid, the number is the position of the amino acid from the N-terminus, and the second letter is the one letter code of the amino acid present in the mutation. Nonsense mutations are represented with an X for the second amino acid (e.g. D111X).
• Amino acid deletion (e.g. ΔF508) – The Greek letter Δ (delta) indicates a deletion. The letter refers to the amino acid present in the wild type and the number is the position from the N terminus of the amino acid were it to be present as in the wild type.

Harmful mutations

Changes in DNA caused by mutation can cause errors in protein sequence, creating partially or completely non-functional proteins. Each cell, in order to function correctly, depends on thousands of proteins to function in the right places at the right times. When a mutation alters a protein that plays a critical role in the body, a medical condition can result. A condition caused by mutations in one or more genes is called a genetic disorder. Some mutations alter a gene's DNA base sequence but do not change the function of the protein made by the gene. Studies of the fly Drosophila melanogaster suggest that if a mutation does change a protein, this will probably be harmful, with about 70 percent of these mutations having damaging effects, and the remainder being either neutral or weakly beneficial.^[4] However, studies in yeast have shown that only 7% of mutations that are not in genes are harmful.^[34]

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. 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.^[35]

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

Beneficial mutations

Although mutations that change 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 resistance to homozygotes and delays AIDS onset in heterozygotes.^[36] The CCR5 mutation is more common in those of European descent. 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.^[37] This theory could explain why this mutation is not found in southern Africa, where the bubonic plague never reached. A newer theory suggests that the selective pressure on the CCR5 Delta 32 mutation was caused by smallpox instead of the bubonic plague.^[38]

Another example is Sickle cell disease, a blood disorder in which the body produces an abnormal type of the oxygen-carrying substance hemoglobin in the red blood cells. One-third of all indigenous inhabitants of Sub-Saharan Africa carry the gene,^[39] because in areas where malaria is common, there is a survival value in carrying only a single sickle-cell gene (sickle cell trait).^[40] Those with only one of the two alleles of the sickle-cell disease are more resistant to malaria, since the infestation of the malaria plasmodium is halted by the sickling of the cells which it infests.

Another research from Denmark concludes that blue-eyes are the mutated character of human eyes which were originally brown for around 6,000 to 1,000 years ago. The benign mutation actually effected the OAC2 gene which colorizes our hair and has other functions related to liver e.t.c. So all blue-eyed people share a common ancestor^[41]

Prion mutation

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.^[42]

Somatic mutation rate

Main article: Loss of heterozygosity

See also: Carcinogenesis

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.^[43]

Point mutations may arise from spontaneous mutations that occur during DNA replication. The rate of mutation may be increased by mutagens. Mutagens can be physical, such as radiation from UV rays, X-rays or extreme heat, or chemical (molecules that misplace base pairs or disrupt the helical shape of DNA). Mutagens associated with cancers are often studied to learn about cancer and its prevention.

See also

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

References

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External links

• "All About Mutations" from the Huntington's Disease Outreach Project for Education at Stanford
• Central Locus Specific Variation Database at the Institute of Genomics and Integrative Biology
• The mutations chapter of the WikiBooks General Biology textbook
• Examples of Beneficial Mutations
• BBC Radio 4 In Our Time – GENETIC MUTATION – with Steve Jones – streaming audio
• HGVS sequence variant nomenclature website
• Mutalyzer website

v d e Basic topics in evolutionary biology Evidence of common descent Processes of evolution Adaptation · Macroevolution · Microevolution · Speciation Population genetic mechanisms Genetic drift · Gene flow · Mutation · Natural selection Evolutionary developmental biology (Evo-devo) concepts Canalisation · Inversion · Modularity · Phenotypic plasticity Evolution of organs and biological processes Aging · Avian flight · Cellular · DNA · Eye · Flagella · Hair · Human intelligence · Mammalian auditory ossicles · Mosaic evolution · Multicellular · Nervous Systems · Sex Taxa evolution Birds · Butterflies · Cats · Cephalopods · Dinosaurs · Dogs · Dolphins and whales · Fish · Fungi · Horses · Humans · Influenza · Insects · Lemur · Life · Mammals · Molluscs · Plants · Reptiles · Sirenians (sea cows) · Spiders · Viruses Modes of speciation Anagenesis · Catagenesis · Cladogenesis History of evolutionary thought Charles Darwin · On the Origin of Species · Modern evolutionary synthesis · Gene-centered view of evolution · Life (classification trees) Other subfields Ecological genetics · Molecular evolution · Phylogenetics · Systematics List of evolutionary biology topics · Timeline of evolution

v d e Mutation Mechanisms of mutation. Insertion  · Deletion  · Substitution (Transversion, Transition) Mutation with respect to structure. Point mutation Nonsense mutation  · Missense mutation  · Silent mutation  · Frameshift mutation · Dynamic mutation Large scale mutation Chromosomal translocations  · Chromosomal inversions Mutation with respect to overall fitness. Deleterious mutation  · Advantageous mutation  · Neutral mutation  · Nearly neutral mutation

This entry is from Wikipedia, the leading user-contributed encyclopedia. It may not have been reviewed by professional editors (see full disclaimer)

Dansk (Danish)
n. - mutation, mutant

Nederlands (Dutch)
mutatie, verandering, umlaut

Français (French)
n. - (gén, Biol) mutation, (Ling) altération

Deutsch (German)
n. - Wandel, Mutation

Ελληνική (Greek)
n. - μεταλλαγή, μετάλλαξη, μεταβολή

Italiano (Italian)
mutazione

Português (Portuguese)
n. - mutação (f)

Русский (Russian)
изменение, превратность, мутация

Español (Spanish)
n. - mutación

Svenska (Swedish)
n. - förändring, mutation, omljud

中文（简体）(Chinese (Simplified))
变化, 元音变化, 转变

中文（繁體）(Chinese (Traditional))
n. - 變化, 母音變化, 轉變

한국어 (Korean)
n. - 환경, 변천, 변종

日本語 (Japanese)
n. - 変化, 突然変異, 母音変異

العربيه (Arabic)
‏(الاسم) تغير‏

עברית (Hebrew)
n. - ‮שינוי, גלגול, מוטציה, צורה שנוצרה מהישתנות, שינוי גנטי שכאשר הוא מועבר לצאצא יוצר שינויים עוברים בתורשה, שינוי לא צפוי בתנועה בהשפעת תנועה בהברה סמוכה‬

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