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biology Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of cells that process hereditar ...
, a mutation is an alteration in the
nucleic acid sequence A nucleic acid sequence is a succession of Nucleobase, bases signified by a series of a set of five different letters that indicate the order of nucleotides forming alleles within a DNA (using GACT) or RNA (GACU) molecule. By convention, sequence ...
of the
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ...
of an
organism In biology, an organism () is any life, living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy (biology), taxonomy into groups such as Multicellular o ...
,
virus A virus is a wikt:submicroscopic, submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and ...
, or
extrachromosomal DNA Extrachromosomal DNA (abbreviated ecDNA) is any DNA that is found off the chromosomes, either inside or outside the nucleus of a cell. Most DNA in an individual genome is found in chromosomes contained in the nucleus. Multiple forms of extrachromo ...
. Viral genomes contain either DNA or
RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
. Mutations result from errors during DNA or
viral replication Viral replication is the formation of biological viruses during the infection process in the target host cells. Viruses must first get into the cell before viral replication can occur. Through the generation of abundant copies of its genome a ...
,
mitosis In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is maint ...
, or
meiosis Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately ...
or other types of damage to DNA (such as pyrimidine dimers caused by exposure to
ultraviolet Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30  PHz) to 400 nm (750  THz), shorter than that of visible light, but longer than X-rays. UV radiati ...
radiation), which then may undergo error-prone repair (especially microhomology-mediated end joining), cause an error during other forms of repair, or cause an error during replication ( translesion synthesis). Mutations may also result from
insertion Insertion may refer to: *Insertion (anatomy), the point of a tendon or ligament onto the skeleton or other part of the body *Insertion (genetics), the addition of DNA into a genetic sequence *Insertion, several meanings in medicine, see ICD-10-PCS ...
or
deletion Deletion or delete may refer to: Computing * File deletion, a way of removing a file from a computer's file system * Code cleanup, a way of removing unnecessary variables, data structures, cookies, and temporary files in a programming language * ...
of segments of DNA due to
mobile genetic elements Mobile genetic elements (MGEs) sometimes called selfish genetic elements are a type of genetic material that can move around within a genome, or that can be transferred from one species or replicon to another. MGEs are found in all organisms. In ...
. Mutations may or may not produce detectable changes in the observable characteristics (
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological prop ...
) of an organism. Mutations play a part in both normal and abnormal biological processes including:
evolution Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
,
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
, and the development of the
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as Tumor immunology, cancer cells and objects such ...
, including junctional diversity. Mutation is the ultimate source of all
genetic variation Genetic variation is the difference in DNA among individuals or the differences between populations. The multiple sources of genetic variation include mutation and genetic recombination. Mutations are the ultimate sources of genetic variation, b ...
, providing the raw material on which evolutionary forces such as
natural selection Natural selection is the differential survival and reproduction of individuals due to differences in phenotype. It is a key mechanism of evolution, the change in the heritable traits characteristic of a population over generations. Cha ...
can act. Mutation can result in many different types of change in sequences. Mutations in
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s can have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely. Mutations can also occur in non-genic regions. A 2007 study on
genetic variation Genetic variation is the difference in DNA among individuals or the differences between populations. The multiple sources of genetic variation include mutation and genetic recombination. Mutations are the ultimate sources of genetic variation, b ...
s between different
species In biology, a species is the basic unit of Taxonomy (biology), classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A species is often defined as the largest group of organisms in which any two individuals of ...
of ''
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many s ...
'' suggested that, if a mutation changes a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
produced by a gene, the result is likely to be harmful, with an estimated 70% of
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
polymorphism Polymorphism, polymorphic, polymorph, polymorphous, or polymorphy may refer to: Computing * Polymorphism (computer science), the ability in programming to present the same programming interface for differing underlying forms * Ad hoc polymorphis ...
s that have damaging effects, and the remainder being either neutral or marginally beneficial. Due to the damaging effects that mutations can have on genes, organisms have mechanisms such as
DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
to prevent or correct mutations by reverting the mutated sequence back to its original state.


Overview

Mutations can involve the duplication of large sections of DNA, usually through
genetic recombination Genetic recombination (also known as genetic reshuffling) is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukary ...
. 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 gene families of shared ancestry, detectable by their
sequence homology Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a sp ...
. 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. Here,
protein domain In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist o ...
s 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 human eye uses four genes to make structures that sense light: three for
cone cell Cone cells, or cones, are photoreceptor cells in the retinas of vertebrate eyes including the human eye. They respond differently to light of different wavelengths, and the combination of their responses is responsible for color vision. Con ...
or
color vision Color vision, a feature of visual perception, is an ability to perceive differences between light composed of different wavelengths (i.e., different spectral power distributions) independently of light intensity. Color perception is a part of ...
and one for
rod cell Rod cells are photoreceptor cells in the retina of the eye that can function in lower light better than the other type of visual photoreceptor, cone cells. Rods are usually found concentrated at the outer edges of the retina and are used in p ...
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
engineering redundancy In engineering, redundancy is the intentional duplication of critical components or functions of a system with the goal of increasing reliability of the system, usually in the form of a backup or fail-safe, or to improve actual system perfo ...
; 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 noncoding DNA. Changes in
chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins ar ...
number may involve even larger mutations, where segments of the DNA within chromosomes break and then rearrange. For example, in the
Homininae Homininae (), also called "African hominids" or "African apes", is a subfamily of Hominidae. It includes two tribes, with their extant as well as extinct species: 1) the tribe Hominini (with the genus ''Homo'' including modern humans and numer ...
, 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. In evolution, the most important role of such chromosomal rearrangements may be to accelerate the divergence of a population into
new species A species description is a formal description of a newly discovered species, usually in the form of a scientific paper. Its purpose is to give a clear description of a new species of organism and explain how it differs from species that have be ...
by making populations less likely to interbreed, thereby preserving genetic differences between these populations. Sequences of DNA that can move about the genome, such as
transposon A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transp ...
s, 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 Alu sequence are present in the
human genome The human genome is a complete set of nucleic acid sequences for humans, encoded as DNA within the 23 chromosome pairs in cell nuclei and in a small DNA molecule found within individual mitochondria. These are usually treated separately as the ...
, and these sequences have now been recruited to perform functions such as regulating
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. ...
. Another effect of these mobile DNA sequences is that when they move within a genome, they can mutate or delete existing genes and thereby produce genetic diversity. Nonlethal mutations accumulate within the
gene pool The gene pool is the set of all genes, or genetic information, in any population, usually of a particular species. Description A large gene pool indicates extensive genetic diversity, which is associated with robust populations that can surv ...
and increase the amount of genetic variation. The abundance of some genetic changes within the gene pool can be reduced by
natural selection Natural selection is the differential survival and reproduction of individuals due to differences in phenotype. It is a key mechanism of evolution, the change in the heritable traits characteristic of a population over generations. Cha ...
, while other "more favorable" mutations may accumulate and result in adaptive changes. For example, a
butterfly Butterflies are insects in the macrolepidopteran clade Rhopalocera from the order Lepidoptera, which also includes moths. Adult butterflies have large, often brightly coloured wings, and conspicuous, fluttering flight. The group comprises ...
may produce offspring with new mutations. The majority of these mutations will have no effect; but one might change the
color Color (American English) or colour (British English) is the visual perceptual property deriving from the spectrum of light interacting with the photoreceptor cells of the eyes. Color categories and physical specifications of color are assoc ...
of one of the butterfly's offspring, making it harder (or easier) for predators to see. If this color change is advantageous, the chances of this butterfly's surviving and producing its own offspring are a little better, and over time the number of butterflies with this mutation may form a larger percentage of the population. Neutral mutations are defined as mutations whose effects do not influence the fitness of an individual. These can increase in frequency over time due to
genetic drift Genetic drift, also known as allelic drift or the Wright effect, is the change in the frequency of an existing gene variant (allele) in a population due to random chance. Genetic drift may cause gene variants to disappear completely and there ...
. 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. Beneficial mutations can improve reproductive success.


Causes

Four classes of mutations are (1) spontaneous mutations (molecular decay), (2) mutations due to error-prone replication bypass of naturally occurring DNA damage (also called error-prone translesion synthesis), (3) errors introduced during DNA repair, and (4) induced mutations caused by mutagens. Scientists may also deliberately introduce
mutant In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It ...
sequences through DNA manipulation for the sake of scientific experimentation. One 2017 study claimed that 66% of cancer-causing mutations are random, 29% are due to the environment (the studied population spanned 69 countries), and 5% are inherited. 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.


Spontaneous mutation

''Spontaneous mutations'' 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
rat Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include ''Neotoma'' ( pack rats), ''Bandicota'' (bandicoot ...
s. Spontaneous mutations can be characterized by the specific change: *
Tautomer Tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hyd ...
ism – A base is changed by the repositioning of a
hydrogen Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic ...
atom, altering the hydrogen bonding pattern of that base, resulting in incorrect base pairing during replication. Theoretical results suggest that proton tunneling is an important factor in the spontaneous creation of GC
tautomer Tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hyd ...
s. * Depurination – Loss of a
purine Purine is a heterocyclic aromatic organic compound that consists of two rings ( pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purin ...
base (A or G) to form an apurinic site ( AP site). *
Deamination Deamination is the removal of an amino group from a molecule. Enzymes that catalyse this reaction are called deaminases. In the human body, deamination takes place primarily in the liver, however it can also occur in the kidney. In situations o ...
Hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...
changes a normal base to an atypical base containing a keto group in place of the original
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent su ...
group. Examples include C → U and A → HX (
hypoxanthine Hypoxanthine is a naturally occurring purine derivative. It is occasionally found as a constituent of nucleic acids, where it is present in the anticodon of tRNA in the form of its nucleoside inosine. It has a tautomer known as 6-hydroxypurine. H ...
), 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.


Error-prone replication bypass

There is increasing evidence that the majority of spontaneously arising mutations are due to error-prone replication ( translesion synthesis) past DNA damage in the template strand. In mice, the majority of mutations are caused by translesion synthesis. Likewise, in
yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to consti ...
, Kunz et al. found that more than 60% of the spontaneous single base pair substitutions and deletions were caused by translesion synthesis.


Errors introduced during DNA repair

Although naturally occurring double-strand breaks occur at a relatively low frequency in DNA, their repair often causes mutation.
Non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direct ...
(NHEJ) is a major pathway for repairing double-strand breaks. NHEJ involves removal of a few
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecul ...
s 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.


Induced mutation

Induced mutations are alterations in the gene after it has come in contact with mutagens and environmental causes. ''Induced mutations'' on the molecular level can be caused by: * Chemicals ** Hydroxylamine ** Base analogs (e.g., Bromodeoxyuridine (BrdU)) ** Alkylating agents (e.g., ''N''-ethyl-''N''-nitrosourea (ENU). These agents can mutate both replicating and non-replicating DNA. In contrast, a base analog can mutate the DNA only when the analog is incorporated in replicating the DNA. Each of these classes of chemical mutagens has certain effects that then lead to transitions, transversions, or deletions. ** Agents that form DNA adducts (e.g., ochratoxin A) ** DNA intercalating agents (e.g.,
ethidium bromide Ethidium bromide (or homidium bromide, chloride salt homidium chloride) is an intercalating agent commonly used as a fluorescent tag ( nucleic acid stain) in molecular biology laboratories for techniques such as agarose gel electrophoresis. I ...
) ** 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 Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30  PHz) to 400 nm (750  THz), shorter than that of visible light, but longer than X-rays. UV radiati ...
light (UV) (including non-ionizing radiation). Two nucleotide bases in DNA—
cytosine Cytosine () (symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached ...
and thymine—are most vulnerable to radiation that can change their properties. UV light can induce adjacent pyrimidine bases in a DNA strand to become covalently joined as a pyrimidine dimer. UV radiation, in particular longer-wave UVA, can also cause oxidative damage to DNA. ** Ionizing radiation. Exposure to ionizing radiation, such as
gamma radiation A gamma ray, also known as gamma radiation (symbol γ or \gamma), is a penetrating form of electromagnetic radiation arising from the radioactive decay of atomic nuclei. It consists of the shortest wavelength electromagnetic waves, typically s ...
, can result in mutation, possibly resulting in cancer or death. Whereas in former times mutations were assumed to occur by chance, or induced by mutagens, molecular mechanisms of mutation have been discovered in bacteria and across the tree of life. As S. Rosenberg states, "These mechanisms reveal a picture of highly regulated mutagenesis, up-regulated temporally by stress responses and activated when cells/organisms are maladapted to their environments—when stressed—potentially accelerating adaptation." 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.


Classification of types


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 into several types.


Large-scale mutations

Large-scale mutations in
chromosomal A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
structure include: * Amplifications (or
gene duplication Gene duplication (or chromosomal duplication or gene amplification) is a major mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene ...
s) 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. *
Polyploidy Polyploidy is a condition in which the cells of an organism have more than one pair of (homologous) chromosomes. Most species whose cells have nuclei (eukaryotes) are diploid, meaning they have two sets of chromosomes, where each set contains ...
, duplication of entire sets of chromosomes, potentially resulting in a separate breeding population and
speciation Speciation is the evolutionary process by which populations evolve to become distinct species. The biologist Orator F. Cook coined the term in 1906 for cladogenesis, the splitting of lineages, as opposed to anagenesis, phyletic evolution withi ...
. * Deletions of large chromosomal regions, leading to loss of the genes within those regions. * Mutations whose effect is to juxtapose previously separate pieces of DNA, potentially bringing together separate genes to form functionally distinct fusion genes (e.g., bcr-abl). * Large scale changes to the structure of
chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins ar ...
s called
chromosomal rearrangement In genetics, a chromosomal rearrangement is a mutation that is a type of chromosome abnormality involving a change in the structure of the native chromosome. Such changes may involve several different classes of events, like deletions, duplicatio ...
that can lead to a decrease of fitness but also to speciation in isolated, inbred populations. These include: **
Chromosomal translocation In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes balanced and unbalanced translocation, with two main types: reciprocal-, and Robertsonian translocation. Reciprocal translo ...
s: interchange of genetic parts from nonhomologous chromosomes. ** Chromosomal inversions: reversing the orientation of a chromosomal segment. ** Non-homologous chromosomal crossover. ** Interstitial deletions: an intra-chromosomal deletion that removes a segment of DNA from a single chromosome, thereby apposing previously distant genes. For example, cells isolated from a human astrocytoma, a type of brain tumor, were found to have a chromosomal deletion removing sequences between the Fused in Glioblastoma (FIG) gene and the receptor tyrosine kinase (ROS), producing a fusion protein (FIG-ROS). The abnormal FIG-ROS fusion protein has constitutively active kinase activity that causes
oncogenic Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
transformation (a transformation from normal cells to cancer cells). * Loss of heterozygosity: loss of one
allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chro ...
, either by a deletion or a genetic recombination event, in an organism that previously had two different alleles.


Small-scale mutations

Small-scale mutations affect a gene in one or a few nucleotides. (If only a single nucleotide is affected, they are called point mutations.) Small-scale mutations include: * Insertions add one or more extra nucleotides into the DNA. They are usually caused by
transposable element A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Trans ...
s, or errors during replication of repeating elements. Insertions in the coding region of a gene may alter splicing of the
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...
( splice site mutation), or cause a shift in the
reading frame In molecular biology, a reading frame is a way of dividing the sequence of nucleotides in a nucleic acid ( DNA or RNA) molecule into a set of consecutive, non-overlapping triplets. Where these triplets equate to amino acids or stop signals during ...
(
frameshift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation that results in the production of multiple, unique proteins from a single mRNA. The process c ...
), both of which can significantly alter the gene product. Insertions can be reversed 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. In general, they are irreversible: Though exactly the same sequence might, in theory, be restored by an insertion, transposable elements able to revert a very short deletion (say 1–2 bases) in ''any'' location either are highly unlikely to exist or do not exist at all. * Substitution mutations, often caused by chemicals or malfunction of DNA replication, exchange a single nucleotide for another. These changes are classified as transitions or transversions. Most common is the transition that exchanges a purine for a purine (A ↔ G) or a pyrimidine for a pyrimidine, (C ↔ T). A transition can be caused by nitrous acid, base mispairing, or mutagenic base analogs such as BrdU. Less common is a transversion, which exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T ↔ A/G). An example of a transversion is the conversion of adenine (A) into a cytosine (C). Point mutations are modifications of single base pairs of DNA or other small base pairs within a gene. A point mutation can be reversed by another point mutation, in which the nucleotide is changed back to its original state (true reversion) or by second-site reversion (a complementary mutation elsewhere that results in regained gene functionality). As discussed
below Below may refer to: *Earth * Ground (disambiguation) * Soil * Floor * Bottom (disambiguation) * Less than *Temperatures below freezing * Hell or underworld People with the surname * Ernst von Below (1863–1955), German World War I general * Fr ...
, point mutations that occur within the protein coding region of a gene may be classified as synonymous or nonsynonymous substitutions, the latter of which in turn can be divided into
missense In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense ...
or nonsense mutations.


By impact on protein sequence

The effect of a mutation on protein sequence depends in part on where in the genome it occurs, especially whether it is in a Coding region, coding or Non-coding DNA, non-coding region. Mutations in the non-coding regulatory sequences 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 introns and in regions with no known biological function (e.g. pseudogenes, retrotransposons) are generally Neutral mutation, neutral, having no effect on phenotype – though intron mutations could alter the protein product if they affect mRNA splicing. 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: * A frameshift mutation 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 Translation (biology), translation 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 ACU ACC UAx, which would instead code for proline, threonine, threonine, and part of another amino acid or perhaps a stop codon (where the x stands for the following nucleotide).) By contrast, any insertion or deletion that is evenly divisible by three is termed an ''in-frame mutation''. * A point substitution mutation results in a change in a single nucleotide and can be either synonymous or nonsynonymous. ** A synonymous substitution replaces a codon with another codon that codes for the same amino acid, so that the produced amino acid sequence is not modified. Synonymous mutations occur due to the Degeneracy (biology), degenerate nature of the genetic code. If this mutation does not result in any phenotypic effects, then it is called Silent mutation, silent, but not all synonymous substitutions are silent. (There can also be silent mutations in nucleotides outside of the coding regions, such as the introns, because the exact nucleotide sequence is not as crucial as it is in the coding regions, but these are not considered synonymous substitutions.) ** A nonsynonymous substitution replaces a codon with another codon that codes for a different amino acid, so that the produced amino acid sequence is modified. Nonsynonymous substitutions can be classified as nonsense or missense mutations: *** A missense mutation changes a nucleotide to cause substitution of a different amino acid. This in turn can render the resulting protein nonfunctional. Such mutations are responsible for diseases such as Epidermolysis bullosa, sickle-cell disease, and Superoxide dismutase, SOD1-mediated Amyotrophic lateral sclerosis, ALS. On the other hand, if a missense mutation occurs in an amino acid codon that results in the use of a different, but chemically similar, amino acid, then sometimes little or no change is rendered in the protein. For example, a change from AAA to AGA will encode arginine, a chemically similar molecule to the intended lysine. In this latter case the mutation will have little or no effect on phenotype and therefore be neutral mutation, neutral. *** A nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the transcribed mRNA, and possibly a truncated, and often nonfunctional protein product. This sort of mutation has been linked to different diseases, such as congenital adrenal hyperplasia. (See Stop codon.)


By effect on function

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 function, but depending on the specificity of the change the mutations listed below will occur. * Loss-of-function mutations, also called inactivating mutations, result in the gene product having less or no function (being partially or wholly inactivated). When the allele has a complete loss of function (null allele), it is often called an Amorph (gene), amorph or amorphic mutation in Muller's morphs schema. Phenotypes associated with such mutations are most often Dominance (genetics), recessive. Exceptions are when the organism is Ploidy#Haploid and monoploid, haploid, or when the reduced dosage of a normal gene product is not enough for a normal phenotype (this is called haploinsufficiency). A disease that is caused by a loss-of-function mutation is Gitelman syndrome and cystic fibrosis. * Gain-of-function research, 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 Zygosity#Heterozygous, heterozygote containing the newly created allele as well as the original will express the new allele; genetically this defines the mutations as Dominance (genetics), dominant phenotypes. Several of Muller's morphs correspond to the gain of function, including hypermorph (increased gene expression) and neomorph (novel function). In December 2017, the U.S. government lifted a temporary ban implemented in 2014 that banned federal funding for any new "gain-of-function" experiments that enhance pathogens "such as Avian influenza, SARS, and the Middle East Respiratory Syndrome or MERS viruses. Many diseases are caused by this mutation including systemic mastocytosis and STAT3 disease. * 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 Dominance (genetics)#Incomplete dominance, semi-dominant phenotype. In humans, dominant negative mutations have been implicated in cancer (e.g., mutations in genes p53, Ataxia telangiectasia mutated, ATM, CEBPA, and Peroxisome proliferator-activated receptor gamma, PPARgamma]). Marfan syndrome is caused by mutations in the FBN1 gene, located on Chromosome 15 (human), chromosome 15, which encodes fibrillin-1, a glycoprotein component of the extracellular matrix. Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency. * Lethal mutations result in the instant death of the developing organism. Lethal mutations can also lead to a substantial loss in the life expectancy of the organism. An example of a disease that is caused by a dominant lethal mutation is Huntington's disease, Huntington’s disease. * 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. Atopic dermatitis, Atopic eczema and dermatitis syndrome are common diseases caused by a null mutation of the gene that activates filaggrin. * 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 Epistasis, intragenic 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 Alzheimer's disease. * 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 occurs has a complete change in function. * A back mutation or reversion is a point mutation that restores the original sequence and hence the original phenotype.


By effect on fitness (harmful, beneficial, neutral mutations)

In genetics, it is sometimes useful to classify mutations as either harmful or beneficial (or neutral): * A harmful, or deleterious, mutation decreases the fitness of the organism. Many, but not all mutations in essential genes are harmful (if a mutation does not change the amino acid sequence in an essential protein, it is harmless in most cases). * A beneficial, or advantageous mutation increases the fitness of the organism. Examples are mutations that lead to Antimicrobial resistance, antibiotic resistance in bacteria (which are beneficial for bacteria but usually not for humans). * A neutral mutation has no harmful or beneficial effect on the organism. Such mutations occur at a steady rate, forming the basis for the molecular clock. In the neutral theory of molecular evolution, neutral mutations provide genetic drift as the basis for most variation at the molecular level. 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 ("Non-coding DNA, junk DNA"). Large-scale quantitative mutagenesis screens, in which thousands of millions of mutations are tested, invariably find that a larger fraction of mutations has harmful effects but always returns a number of beneficial mutations as well. For instance, in a screen of all gene deletions in ''Escherichia coli, E. coli'', 80% of mutations were negative, but 20% were positive, even though many had a very small effect on growth (depending on condition). Note that gene ''deletions'' involve removal of whole genes, so that point mutations almost always have a much smaller effect. In a similar screen in ''Streptococcus pneumoniae'', but this time with
transposon A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transp ...
insertions, 76% of insertion mutants were classified as neutral, 16% had a significantly reduced fitness, but 6% were advantageous. 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 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 nutrition. Height (or size) itself may be more or less beneficial as the huge range of sizes in animal or plant groups shows.


Distribution of fitness effects (DFE)

Attempts have been made to infer the distribution of fitness effects (DFE) using mutagenesis experiments and theoretical models applied to molecular sequence data. DFE, as used to determine the relative abundance of different types of mutations (i.e., strongly deleterious, nearly neutral or advantageous), is relevant to many evolutionary questions, such as the maintenance of
genetic variation Genetic variation is the difference in DNA among individuals or the differences between populations. The multiple sources of genetic variation include mutation and genetic recombination. Mutations are the ultimate sources of genetic variation, b ...
, the rate of Pathogenomics#Gene Loss / Genome Decay, genomic decay, the maintenance of outcrossing sexual reproduction as opposed to inbreeding and the evolution of sex and
genetic recombination Genetic recombination (also known as genetic reshuffling) is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukary ...
. 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 evolutionary dynamics. A variety of approaches have been used to study the DFE, including theoretical, experimental and analytical methods. * Mutagenesis experiment: The direct method to investigate the DFE is to induce mutations and then measure the mutational fitness effects, which has already been done in viruses, bacteria, yeast, and ''Drosophila''. For example, most studies of the DFE in viruses used site-directed mutagenesis to create point mutations and measure relative fitness of each mutant. In ''Escherichia coli'', one study used transposon mutagenesis to directly measure the fitness of a random insertion of a derivative of Tn10. In yeast, a combined mutagenesis and deep sequencing approach has been developed to generate high-quality systematic mutant libraries and measure fitness in high throughput. 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 sequence analysis can provide valuable information about these mutations. * Molecular sequence analysis: With rapid development of DNA sequencing technology, an enormous amount of DNA sequence data is available and even more is forthcoming in the future. Various methods have been developed to infer the DFE from DNA sequence data. By examining DNA sequence differences within and between species, we are able to infer various characteristics of the DFE for neutral, deleterious and advantageous mutations. To be specific, the DNA sequence analysis approach allows us to estimate the effects of mutations with very small effects, which are hardly detectable through mutagenesis experiments. One of the earliest theoretical studies of the distribution of fitness effects was done by Motoo Kimura, an influential theoretical population geneticist. His neutral theory of molecular evolution proposes that most novel mutations will be highly deleterious, with a small fraction being neutral. A later proposal by Hiroshi Akashi proposed a Multimodal distribution, bimodal 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 the DFE of random mutations in vesicular stomatitis virus. Out of all mutations, 39.6% were lethal, 31.2% were non-lethal deleterious, and 27.1% were neutral. Another example comes from a high throughput mutagenesis experiment with yeast. In this experiment it was shown that the overall DFE is bimodal, with a cluster of neutral mutations, and a broad distribution of deleterious mutations. Though relatively few mutations are advantageous, those that are play an important role in evolutionary changes. Like neutral mutations, weakly selected advantageous mutations can be lost due to random genetic drift, but strongly selected advantageous mutations are more likely to be fixed. Knowing the DFE of advantageous mutations may lead to increased ability to predict the evolutionary dynamics. Theoretical work on the DFE for advantageous mutations has been done by John H. Gillespie and H. Allen Orr. They proposed that the distribution for advantageous mutations should be exponential decay, exponential under a wide range of conditions, which, in general, has been supported by experimental studies, at least for strongly selected advantageous mutations. In general, it is accepted that the majority of mutations are neutral or deleterious, with advantageous mutations being rare; however, the proportion of types of mutations varies between species. This indicates two important points: first, the proportion of effectively neutral mutations is likely to vary between species, resulting from dependence on effective population size; second, the average effect of deleterious mutations varies dramatically between species. In addition, the DFE also differs between coding regions and Noncoding DNA, noncoding regions, with the DFE of noncoding DNA containing more weakly selected mutations.


By inheritance

In multicellular organisms with dedicated Gamete, reproductive cells, mutations can be subdivided into germline mutations, which can be passed on to descendants through their reproductive cells, and Somatic (biology), somatic mutations (also called acquired mutations), which involve cells outside the dedicated reproductive group and which are not usually transmitted to descendants. 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 wild type or homozygous non-mutated organism is one in which neither allele is mutated. * 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 heterozygosity, Compound heterozygous mutations or a genetic compound consists of two different mutations in the paternal and maternal alleles.


Germline mutation

A germline mutation in the reproductive cells of an individual 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. A germline mutation can be passed down through subsequent generations of organisms. The distinction between germline and somatic mutations is important in animals that have a dedicated germline to produce reproductive cells. However, it is of little value in understanding the effects of mutations in plants, which lack a dedicated germline. The distinction is also blurred in those animals that asexual reproduction, reproduce asexually through mechanisms such as budding, because the cells that give rise to the daughter organisms also give rise to that organism's germline. A new germline mutation not inherited from either parent is called a ''wikt:de novo, de novo'' mutation.


Somatic mutation

GENE MUTATIONS: Gene mutations include either the replacement of one of the nucleotides with the nucleotide by the other nucleotide or may be by the addition or the deletion of the nucleotide. This would be explained as the sudden change or the alteration in nucleotide sequence of the DNA molecule, which would affect one pair of nucleotide or the bigger art of the gene on chromosome. These gene mutations can be further classified as: 1.      Point mutations: This results when there is difference in only one base pair of nucleotide which can also be called as base pair substitution and this is also one of the common type among the gene mutations. Point mutations can be again divided into three types of mutations namely Silent mutations, Nonsense mutations, Missense mutations. a)      Silent Mutations: This occurs when there is a change in codon for one amino acid molecule is swapped or is into the other codon of the same amino acid molecule and is also referred as “synonymous mutations” b)      Missense Mutations: This occurs when the codon of one amino acid is interchanged with the codon of another amino acid and can also be referred as non-synonymous mutations. c)      Nonsense Mutations: This occurs when the codon of the amino acid changes to the stop codon. 2.      Frameshift Mutations: This kind of mutation results when there is addition or deletion of DNA base molecules changes the reading frame of the gene. This mutations would be insertions or deletions. a)     Insertion: This type of mutation differs the DNA base number in the gene by adding the part of the DNA. b)    Deletion: This type of mutation occurs when there is a difference in the number of DNA bases by eliminating a piece of DNA. 3.     Base substitution Mutations: This type of mutations occur when there is replacement of one base pair by the other base pair. This mutations are further classified as Transition mutation and transversion mutation, a)      Transition mutation:  This occurs when the base of one chemical is replaced by the other base of the same chemical molecule (4). It mainly happens when there is the transposing of the purine molecules i.e., A is transposed by G or by the transposing of pyrimidine molecules i.e., C by T in the DNA molecule. b)      Tranvsersion Mutation: This occurs when there is an opposite replacement of a category base chemical by another base of the other category . This is mainly due to the incorrect replacement of the DNA bases i.e., when a pyrimidine is replaced with purine molecule. A change in the genetic structure that is not inherited from a parent, and also not passed to offspring, is called a somatic cell, somatic mutation''.'' Somatic mutations are not inherited by an organism's offspring because they do not affect the germline. 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.' With plants, some somatic mutations can be propagated without the need for seed production, for example, by grafting and stem cuttings. These type of mutation have led to new types of fruits, such as the "Delicious" apple and the "Washington" navel Orange (fruit), orange. Human and mouse somatic cells have a mutation rate more than ten times higher than the germline mutation rate for both species; mice have a higher rate of both somatic and germline mutations per cell division than humans. The disparity in mutation rate between the germline and somatic tissues likely reflects the greater importance of
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ...
maintenance in the germline than in the soma.


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). 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 Permissive temperature, temperature, certain chemicals, light or mutations in other parts of the
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ...
. In vivo, ''In'' ''vivo'' mechanisms like transcriptional switches can create conditional mutations. For instance, association of Steroid Binding Domain can create a transcriptional switch that can change the expression of a gene based on the presence of a steroid ligand. Conditional mutations have applications in research as they allow control over gene expression. This is especially useful studying diseases in adults by allowing expression after a certain period of growth, thus eliminating the deleterious effect of gene expression seen during stages of development in model organisms. DNA Recombinase systems like Cre-Lox recombination used in association with Promoter (genetics), promoters that are activated under certain conditions can generate conditional mutations. Dual Recombinase technology can be used to induce multiple conditional mutations to study the diseases which manifest as a result of simultaneous mutations in multiple genes. Certain inteins have been identified which splice only at certain permissive temperatures, leading to improper protein synthesis and thus, loss-of-function mutations at other temperatures. Conditional mutations may also be used in genetic studies associated with ageing, as the expression can be changed after a certain time period in the organism's lifespan. * Replication timing quantitative trait loci affects DNA replication.


Nomenclature

In order to categorize a mutation as such, the "normal" sequence must be obtained from the DNA of a "normal" or "healthy" organism (as opposed to a "mutant" or "sick" one), it should be identified and reported; ideally, it should be made publicly available for a straightforward nucleotide-by-nucleotide comparison, and agreed upon by the scientific community or by a group of expert geneticists and biologists, who have the responsibility of establishing the ''standard'' or so-called "consensus" sequence. This step requires a tremendous scientific effort. Once the consensus sequence is known, the mutations in a genome can be pinpointed, described, and classified. The committee of the Human Genome Variation Society (HGVS) has developed the standard human sequence variant nomenclature, which should be used by researchers and Genetic testing, DNA diagnostic centers to generate unambiguous mutation descriptions. In principle, this nomenclature can also be used to describe mutations in other organisms. The nomenclature specifies the type of mutation and base or amino acid changes. * Nucleotide substitution (e.g., 76A>T) – The number is the position of the nucleotide from the 5' end; the first letter represents the wild-type nucleotide, and the second letter represents the nucleotide that replaced the wild type. In the given example, the adenine at the 76th position was replaced by a thymine. ** If it becomes necessary to differentiate between mutations in genomic DNA, mitochondrial DNA, and
RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
, 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 Amino acid#Table of standard amino acid abbreviations and properties, 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 (letter), delta) indicates a deletion. The letter refers to the amino acid present in the wild type and the number is the position from the N terminus of the amino acid were it to be present as in the wild type.


Mutation rates

Mutation rates vary substantially across species, and the evolutionary forces that generally determine mutation are the subject of ongoing investigation. In humans, the mutation rate is about 50-90 ''de novo'' 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 DNA sequencing, sequencing thousands of human trios, that is, two parents and at least one child. The genomes of RNA viruses are based on
RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
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 HIV, human immunodeficiency virus), replication occurs quickly, and there are no mechanisms to check the genome for accuracy. This error-prone process often results in mutations.


Randomness of mutations

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
DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
- and mutation-biases being associated with various factors. For instance, biologically important regions were found to be protected from mutations and mutations beneficial to the studied plant were found to be more likely – i.e. mutation is "non-random in a way that benefits the plant".


Disease causation

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 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 ''Drosophila'' 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 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.


Inherited disorders

If a mutation is present in a germ cell, it can give rise to offspring that carries the mutation in all of its cells. This is the case in hereditary diseases. In particular, if there is a mutation in a DNA repair gene within a germ cell, humans carrying such germline mutations may have an increased risk of cancer. A list of 34 such germline mutations is given in the article DNA repair-deficiency disorder. An example of one is albinism, a mutation that occurs in the OCA1 or OCA2 gene. Individuals with this disorder are more prone to many types of cancers, other disorders and have impaired vision. DNA damage can cause an error when the DNA is replicated, and this error of replication can cause a gene mutation that, in turn, could cause a genetic disorder. DNA damages are repaired by the DNA repair system of the cell. Each cell has a number of pathways through which enzymes recognize and repair damages in DNA. Because DNA can be damaged in many ways, the process of DNA repair is an important way in which the body protects itself from disease. Once DNA damage has given rise to a mutation, the mutation cannot be repaired.


Role in carcinogenesis

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 malignant transformation, from normal cell to cancer cell. 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 rate. Measuring this rate is important in predicting the rate at which people may develop cancer. 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 ultraviolet light, 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.


Prion mutations

Prions are proteins and do not contain genetic material. However, prion replication has been shown to be subject to mutation and natural selection just like other forms of replication. The human gene PRNP codes for the major prion protein, PrP, and is subject to mutations that can give rise to disease-causing prions.


Beneficial mutations

Although mutations that cause changes in protein sequences can be harmful to an organism, on occasions the effect may be positive in a given environment. In this case, the mutation may enable the mutant organism to withstand particular environmental stresses better than wild-type organisms, or reproduce more quickly. In these cases a mutation will tend to become more common in a population through natural selection. Examples include the following: HIV resistance: a specific 32 base pair deletion in human CCR5 (CCR5#CCR5-Δ32, CCR5-Δ32) confers HIV resistance to Zygosity, homozygotes and delays AIDS onset in heterozygotes. One possible explanation of the etiology of the relatively high frequency of CCR5-Δ32 in the Ethnic groups in Europe, 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. This theory could explain why this mutation is not found in Southern Africa, which remained untouched by bubonic plague. A newer theory suggests that the Evolutionary pressure, selective pressure on the CCR5 Delta 32 mutation was caused by smallpox instead of the bubonic plague. Malaria resistance: An example of a harmful mutation is sickle-cell disease, a blood disorder in which the body produces an abnormal type of the oxygen-carrying substance hemoglobin in the red blood cells. One-third of all Indigenous peoples, indigenous inhabitants of Sub-Saharan Africa carry the allele, because, in areas where malaria is common, there is a Evolution, survival value in carrying only a single sickle-cell allele (sickle cell trait). Those with only one of the two alleles of the sickle-cell disease are more resistant to malaria, since the infestation of the malaria ''Plasmodium'' is halted by the sickling of the cells that it infests. Antibiotic resistance: Practically all bacteria develop antibiotic resistance when exposed to antibiotics. In fact, bacterial populations already have such mutations that get selected under antibiotic selection. Obviously, such mutations are only beneficial for the bacteria but not for those infected. Lactase persistence. A mutation allowed humans to express the enzyme lactase after they are naturally weaned from breast milk, allowing adults to digest lactose, which is likely one of the most beneficial mutations in recent human evolution.


Compensated pathogenic deviations

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 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.    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 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.


Compensatory mutations in RNA

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 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.


Evolutionary mechanism of compensation

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 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 a 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.  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 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.


Experimental evidence of compensatory mutations


Experiment in bacteria

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 ''Escherichia coli'' IMDH that are wild type residues in IMDH ''Pseudomonas aeruginosa''. They found that over one third of these substitutions compromised IMDH enzymatic activity in the ''Escherichia coli'' 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 staphylococcus aureus 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 normal cell growth. 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 M. tuberculosis 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 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 Escherichia coli. Results obtained from this study demonstrate that drug resistance is linked to bacterial fitness as higher fitness costs are linked to greater transcription errors.


Experiment in virus

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 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 Fisher's geometric model of adaptive evolution by testing whether bacteriophage φ6 evolves by small steps. Their results showed that bacteriophage 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.


History

Mutationism is one of several alternatives to Darwinian evolution that have existed both before and after the publication of Charles Darwin's 1859 book, ''On the Origin of Species''. In the theory, mutation was the source of novelty, creating new forms and speciation, new species, potentially instantaneously, in a sudden jump. This was envisaged as driving evolution, which was limited by the supply of mutations. Before Darwin, biologists commonly believed in saltationism, the possibility of large evolutionary jumps, including immediate
speciation Speciation is the evolutionary process by which populations evolve to become distinct species. The biologist Orator F. Cook coined the term in 1906 for cladogenesis, the splitting of lineages, as opposed to anagenesis, phyletic evolution withi ...
. For example, in 1822 Étienne Geoffroy Saint-Hilaire argued that species could be formed by sudden transformations, or what would later be called macromutation. Darwin opposed saltation, insisting on phyletic gradualism, gradualism in evolution as uniformitarianism, in geology. In 1864, Albert von Kölliker revived Geoffroy's theory. In 1901 the geneticist Hugo de Vries gave the name "mutation" to seemingly new forms that suddenly arose in his experiments on the evening primrose ''Oenothera lamarckiana'', and in the first decade of the 20th century, mutationism, or as de Vries named it ''mutationstheorie'', became a rival to Darwinism supported for a while by geneticists including William Bateson, Thomas Hunt Morgan, and Reginald Punnett. Understanding of mutationism is clouded by the mid-20th century portrayal of the early mutationists by supporters of the Modern synthesis (20th century), modern synthesis as opponents of Darwinian evolution and rivals of the biometrics school who argued that selection operated on continuous variation. In this portrayal, mutationism was defeated by a synthesis of genetics and natural selection that supposedly started later, around 1918, with work by the mathematician Ronald Fisher. However, the alignment of Mendelian genetics and natural selection began as early as 1902 with a paper by Udny Yule, and built up with theoretical and experimental work in Europe and America. Despite the controversy, the early mutationists had by 1918 already accepted natural selection and explained continuous variation as the result of multiple genes acting on the same characteristic, such as height. Mutationism, along with other alternatives to Darwinism like Lamarckism and orthogenesis, was discarded by most biologists as they came to see that Mendelian genetics and natural selection could readily work together; mutation took its place as a source of the genetic variation essential for natural selection to work on. However, mutationism did not entirely vanish. In 1940, Richard Goldschmidt again argued for single-step speciation by macromutation, describing the organisms thus produced as "hopeful monsters", earning widespread ridicule. In 1987, Masatoshi Nei argued controversially that evolution was often mutation-limited. Modern biologists such as Douglas J. Futuyma conclude that essentially all claims of evolution driven by large mutations can be explained by Darwinian evolution.


See also


References


External links

* * * * – The Mutalyzer website. {{Authority control Mutation, Evolutionary biology Radiation health effects Molecular evolution