HOME

TheInfoList




In
biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanisms, Development ...

biology
, a mutation is an alteration in the
nucleotide sequence A nucleic acid sequence is a succession of bases signified by a series of a set of five different letters that indicate the order of nucleotides Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monom ...
of the
genome In the fields of molecular biology and genetics, a genome is all genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The genome includes both the genes (the coding regions) and the noncodin ...

genome
of an
organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological me ...

organism
,
virus A virus is a that only inside the living of an . Viruses infect all , from animals and plants to s, including and . Since 's 1892 article describing a non-bacterial infecting tobacco plants and the discovery of the by in 1898, more ...

virus
, or
extrachromosomal DNA Extrachromosomal DNA (abbreviated ecDNA) is any DNA that is found off the chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. Most eukaryotic chromosomes include packaging proteins calle ...
. Viral genomes contain either
DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically neutral gro ...

DNA
or
RNA Ribonucleic acid (RNA) is a polymer A polymer (; Greek ''wikt:poly-, poly-'', "many" + ''wikt:-mer, -mer'', "part") is a Chemical substance, substance or material consisting of very large molecules, or macromolecules, composed of many Repe ...

RNA
. Mutations result from errors during
DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically neutral gro ...

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 and ...

viral replication
,
mitosis In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical proce ...

mitosis
, or
meiosis Meiosis (; , because it is a reductional division) is a special type of of in organisms used to produce the , such as or . It involves two rounds of division that ultimately result in four cells with only one copy of each (). Additionall ...

meiosis
or other types of
damage Damage is any change Change or Changing may refer to: Alteration * Impermanence Impermanence, also known as the philosophical problem This is a list of the major unsolved problems in philosophy Philosophy (from , ) is the study ...
to DNA (such as
pyrimidine dimer Pyrimidine dimers are molecular lesions formed from thymine or cytosine bases in DNA via photochemical reactions. Ultraviolet, Ultraviolet light (UV) induces the formation of covalent bond, covalent linkages between consecutive bases along the nucl ...
s caused by exposure to
ultraviolet Ultraviolet (UV) is a form of electromagnetic radiation In physics Physics (from grc, φυσική (ἐπιστήμη), physikḗ (epistḗmē), knowledge of nature, from ''phýsis'' 'nature'), , is the natural science that stud ...

ultraviolet
radiation), which then may undergo error-prone repair (especially
microhomology-mediated end joining Microhomology-mediated end joining (MMEJ), also known as alternative nonhomologous end-joining (Alt-NHEJ) is one of the pathways for repairing double-strand break DNA repair is a collection of processes by which a cell Cell most often refers ...
), cause an error during other forms of repair, or cause an error during replication (
translesion synthesis DNA repair is a collection of processes by which a cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or reli ...
). Mutations may also result from insertion or deletion 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 h ...
. Mutations may or may not produce detectable changes in the observable characteristics (
phenotype In genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular inter ...

phenotype
) of an organism. Mutations play a part in both normal and abnormal biological processes including:
evolution Evolution is change in the heritable Heredity, also called inheritance or biological inheritance, is the passing on of Phenotypic trait, traits from parents to their offspring; either through asexual reproduction or sexual reproduction, ...

evolution
,
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 tumor A benign tumor is a mass of cells Cell most often refers to: * Cell (biolo ...

cancer
, 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 frame, Generation of junctional diversity through recombination illustrated between two gene segments: D (blue) and J (green). Sections highlighted in red show nucleotides added at each stage. Junctional diversity describes the DNA The struct ...
. Mutation is the ultimate source of all
genetic variation thumb File:Genetic Variation and Inheritance.svg, Parents have similar gene coding in this specific situation where they reproduce and variation in the offspring is seen. Offspring containing the variation also reproduce and passes down traits t ...

genetic variation
, 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 right , Here the relation between genotype and phenotype is illustrated, using a Punnett square, for the character of peta ...
can act. Mutation can result in many different types of change in sequences. Mutations in
gene In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mecha ...

gene
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 nongenic regions. A 2007 study on
genetic variation thumb File:Genetic Variation and Inheritance.svg, Parents have similar gene coding in this specific situation where they reproduce and variation in the offspring is seen. Offspring containing the variation also reproduce and passes down traits t ...

genetic variation
s between different
species In biology, a species is the basic unit of biological classification, 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 individu ...

species
of ''
Drosophila ''Drosophila'' () is a genus of fly, flies, belonging to the family (biology), family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the character ...

Drosophila
'' suggested that, if a mutation changes a
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
produced by a gene, the result is likely to be harmful, with an estimated 70% of
amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acid
polymorphisms 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 Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene mol ...

DNA repair
to prevent or correct mutations by reverting the mutated sequence back to its original state.


Overview

Mutations can involve the
duplication Duplication, duplicate, and duplicator may refer to: Biology and genetics * Gene duplication, a process which can result in free mutation * Chromosomal duplication, which can cause Bloom and Rett syndrome * Polyploidy, a phenomenon also known a ...
of large sections of DNA, usually through
genetic recombination Genetic recombination (also known as genetic reshuffling) is the exchange of genetic material between different organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, ph ...
. 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 homology (biology), biological homology between DNA sequence, DNA, RNA sequence, RNA, or Protein primary structure, protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments o ...
. 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 A protein domain is a region of the protein's Peptide, polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact protein folding, folded three-dimensional structure. Many proteins consist ...
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 Humans (''Homo sapiens'') are the most abundant and widespread species In biology, a species is the basic unit of biological classification, classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A speci ...

human
eye uses four genes to make structures that sense light: three for
cone cell Cone cells, or cones, are photoreceptor cells A photoreceptor cell is a specialized type of neuroepithelial cell found in the retina The retina (from la, rete) is the innermost, light-sensitive layer of tissue of the eye of most ve ...

cone cell
or
color vision Color vision, a feature of visual perception Visual perception is the ability to interpret the surrounding environment (biophysical), environment through photopic vision (daytime vision), color vision, scotopic vision (night vision), and ...

color vision
and one for
rod cell Rod cells are photoreceptor cells in the retina of the eye that can function in lower light Light or visible light is electromagnetic radiation within the portion of the electromagnetic spectrum that can be visual perception, perceived by ...
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; 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 Non-coding DNA sequences are components of an organism's DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of ...
. Changes in
chromosome A chromosome is a long DNA molecule with part or all of the genome, genetic material of an organism. Most eukaryotic chromosomes include packaging proteins called histones which, aided by Chaperone (protein), chaperone proteins, bind to and ...

chromosome
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 The Hominidae (), whose members are known as great apes or hominids (), are a taxonomic family of primates that includes eight extant species in f ...

Homininae
, two chromosomes fused to produce human
chromosome 2 Fusion of ancestral chromosomes left distinctive remnants of telomeres, and a vestigial centromere Chromosome 2 is one of the twenty-three pairs of chromosome A chromosome is a long DNA molecule with part or all of the genetic material of ...
; this fusion did not occur in the lineage of the other
ape Apes (Hominoidea ) are a branch The branches and leaves of a tree. A branch ( or , ) or tree branch (sometimes referred to in botany Botany, also called , plant biology or phytology, is the science of plant life and a branch of bi ...

ape
s, 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 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 DNA sequence DNA sequencing is the process of determining the nucleic acid sequence A nucleic acid sequence is a succession of bases signified by a series of a set of five diff ...
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 An Alu element is a short stretch of DNA originally characterized by the action of the '' Arthrobacter luteus (Alu)'' restriction endonuclease. ''Alu'' elements are the most abundant transposable elements, containing over one million copies disp ...
are present in the
human genome The human genome is a complete set of nucleic acid sequence A nucleic acid sequence is a succession of bases signified by a series of a set of five different letters that indicate the order of nucleotides Nucleotides are organic molecules c ...

human genome
, 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. The ...

gene expression
. 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 surviv ...
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 right , Here the relation between genotype and phenotype is illustrated, using a Punnett square, for the character of peta ...
, while other "more favorable" mutations may accumulate and result in adaptive changes. For example, a
butterfly Butterflies are insect Insects (from Latin ') are pancrustacean Hexapoda, hexapod invertebrates of the class (biology), class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three ...

butterfly
may produce
offspring In biology, offspring are the young creation of living organisms, produced either by a Asexual reproduction, single organism or, in the case of sexual reproduction, two organisms. Collective offspring may be known as a brood or progeny in a more ...

offspring
with new mutations. The majority of these mutations will have no effect; but one might change the
color Color (American English American English (AmE, AE, AmEng, USEng, en-US), sometimes called United States English or U.S. English, is the set of varieties of the English language native to the United States. Currently, American Engli ...

color
of one of the butterfly's offspring, making it harder (or easier) for predators to see. If this color change is advantageous, the chances of this butterfly's surviving and producing its own offspring are a little better, and over time the number of butterflies with this mutation may form a larger percentage of the population.
Neutral mutationNeutral mutations are changes in DNA The structure of part of a DNA double helix Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist o ...
s 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 (allelic drift or the Sewall Wright effect) is the change in the frequency of an existing gene In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical stru ...

genetic drift
. It is believed that the overwhelming majority of mutations have no significant effect on an organism's fitness. Also, DNA repair mechanisms are able to mend most changes before they become permanent mutations, and many organisms have mechanisms for eliminating otherwise-permanently mutated
somatic cell A somatic cell (from Ancient Greek Ancient Greek includes the forms of the Greek language used in ancient Greece and the classical antiquity, ancient world from around 1500 BC to 300 BC. It is often roughly divided into the following period ...
s. 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
mutagen In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of penta ...
s. Scientists may also deliberately introduce
mutant In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechan ...

mutant
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 rodent Rodents (from Latin Latin (, or , ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originally spoken in the area a ...

rat
s. Spontaneous mutations can be characterized by the specific change: *
Tautomer Tautomers () are structural isomer In chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemical compound, compounds composed of atoms, molecules and ions: their composition, structure, properties, ...

Tautomer
ism – A base is changed by the repositioning of a
hydrogen Hydrogen is the chemical element with the Symbol (chemistry), symbol H and atomic number 1. Hydrogen is the lightest element. At standard temperature and pressure, standard conditions hydrogen is a gas of diatomic molecules having the che ...

hydrogen
atom, altering the hydrogen bonding pattern of that base, resulting in incorrect
base pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids Nucleic acids are biopolymer Biopolymers are natural polymers produced by the cells of Organism, living organisms. Biopolymers consist of monomeric units that are Covalent_ ...
ing during replication. *
DepurinationDepurination is a chemical reaction of purine Purine is a heterocyclic compound, heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole). It is water-soluble. Purine also gives its name to the wider class of mo ...

Depurination
– Loss of a
purine Purine is a heterocyclic 125px, Pyridine, a heterocyclic compound A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different chemical element, elements as members of its ring(s). Heterocyclic chemi ...

purine
base (A or G) to form an apurinic site ( AP site). *
Deamination Deamination is the removal of an amino group from a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically n ...
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 Substitution may refer to: Arts and media *Chord substitution, in music, swapping one chord fo ...

Hydrolysis
changes a normal base to an atypical base containing a keto group in place of the original
amine In organic chemistry Organic chemistry is a branch of chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, ...

amine
group. Examples include C → U and A → HX (
hypoxanthine Hypoxanthine is a naturally occurring purine Purine is a heterocyclic compound, heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole). It is water-soluble. Purine also gives its name to the wider class of mo ...

hypoxanthine
), which can be corrected by DNA repair mechanisms; and 5MeC () → T, which is less likely to be detected as a mutation because
thymine Thymine () (symbol A symbol is a mark, sign, or word In linguistics, a word of a spoken language can be defined as the smallest sequence of phonemes that can be uttered in isolation with semantic, objective or pragmatics, practical m ...

thymine
is a normal DNA base. *
Slipped strand mispairing Slipped strand mispairing (SSM), (also known as replication slippage), is a mutation process which occurs during DNA replication is un'zipped' and unwound, then each separated strand (turquoise) acts as a template for replicating a new partner st ...
– Denaturation of the new strand from the template during replication, followed by renaturation in a different spot ("slipping"). This can lead to insertions or deletions. *
Replication slippage Replication may refer to: Science * Replication (scientific method)Reproducibility is a major principle of the scientific method The scientific method is an Empirical evidence, empirical method of acquiring knowledge that has characterized t ...


Error-prone replication bypass

There is increasing evidence that the majority of spontaneously arising mutations are due to error-prone replication (
translesion synthesis DNA repair is a collection of processes by which a cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or reli ...
) past DNA damage in the template strand. In
mice A mouse, plural mice, is a small mammal Mammals (from Latin Latin (, or , ) is a classical language A classical language is a language A language is a structured system of communication Communication (from Latin ...

mice
, the majority of mutations are caused by translesion synthesis. Likewise, in
yeast Yeasts are eukaryotic Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular ...

yeast
, 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 directe ...
(NHEJ) is a major pathway for repairing double-strand breaks. NHEJ involves removal of a few
nucleotide Nucleotides are organic molecules , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, ...

nucleotide
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 Hydroxylamine is an inorganic compound with the formula NH2OH. The pure material is a white, unstable crystal A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a hig ...
**
Base analog Nucleic acid analogues are compounds which are Analog (chemistry), analogous (structurally similar) to naturally occurring RNA and DNA, used in medicine and in molecular biology research. Nucleic acids are chains of nucleotides, which are compo ...
s (e.g.,
Bromodeoxyuridine Bromodeoxyuridine (5-bromo-2'-deoxyuridine, BrdU, BUdR, BrdUrd, broxuridine) is a synthetic nucleoside analogue Nucleoside analogues are nucleosides which contain a nucleic acid analogue and a sugar. Nucleotide analogs are nucleotide Nucle ...

Bromodeoxyuridine
(BrdU)) **
Alkylating agent Alkylation is the transfer of an alkyl In organic chemistry, an alkyl substituent A substituent is one or a group of atom An atom is the smallest unit of ordinary matter In classical physics and general chemistry, matter is any sub ...

Alkylating agent
s (e.g., (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,
transversion 300px, Illustration of a transversion: each of the 8 nucleotide changes between a purine and a pyrimidine (in red). The 4 other changes are transitions (in blue). Transversion, in molecular biology, refers to a point mutation 350px, Schematic ...
s, or deletions. ** Agents that form
DNA adduct In molecular genetics, a DNA adduct is a segment of DNA bound to a Carcinogen, cancer-causing chemical. This process could lead to the development of cancerous cells, or carcinogenesis. DNA adducts in scientific experiments are used as Biomarker, ...
s (e.g.,
ochratoxin A Ochratoxin A—a toxin A toxin is a harmful substance produced within living cells or organisms; synthetic toxicants created by artificial processes are thus excluded. The term was first used by organic chemist Ludwig Brieger (1849–1919), der ...

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 In molecular biology and biotechnology, a fluorescent tag, also known as a fluorescent label or fluorescent pr ...

ethidium bromide
) ** DNA crosslinkers **
Oxidative damage (mild reducing agent) are added to powdered potassium permanganate Potassium permanganate is an inorganic compound with the chemical formula KMnO4 and composed of potassium ion, K+ and permanganate, . It is a purplish-black crystalline salt, th ...
**
Nitrous acid Nitrous acid (molecular formula ) is a weak and monoprotic acid An acid is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings ...

Nitrous acid
converts amine groups on A and C to
diazo The diazo group is an organic moiety Moiety may refer to: * Moiety (chemistry), a part or functional group of a molecule * Moiety (kinship), either of two groups into which a society is divided * A division of society in the Iroquois government ...
groups, altering their hydrogen bonding patterns, which leads to incorrect base pairing during replication. * Radiation **
Ultraviolet Ultraviolet (UV) is a form of electromagnetic radiation In physics Physics is the natural science that studies matter, its Elementary particle, fundamental constituents, its Motion (physics), motion and behavior through Spacetime, ...

Ultraviolet
light (UV) (including
non-ionizing radiation Non-ionizing (or non-ionising) radiation refers to any type of electromagnetic radiation In physics Physics is the natural science that studies matter, its Elementary particle, fundamental constituents, its Motion (physics), motion an ...
). Two nucleotide bases in DNA—
cytosine Cytosine () (symbol A symbol is a mark, sign, or word In linguistics, a word of a spoken language can be defined as the smallest sequence of phonemes that can be uttered in isolation with semantic, objective or pragmatics, practical ...

cytosine
and thymine—are most vulnerable to radiation that can change their properties. UV light can induce adjacent
pyrimidine Pyrimidine is an aromatic In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts ...

pyrimidine
bases in a DNA strand to become covalently joined as a
pyrimidine dimer Pyrimidine dimers are molecular lesions formed from thymine or cytosine bases in DNA via photochemical reactions. Ultraviolet, Ultraviolet light (UV) induces the formation of covalent bond, covalent linkages between consecutive bases along the nucl ...
. UV radiation, in particular longer-wave UVA, can also cause oxidative damage to DNA. **
Ionizing radiation Ionizing radiation (or ionising radiation), including nuclear radiation, consists of s or s that have sufficient to s or s by detaching s from them. The particles generally travel at a speed that is greater than 1% of , and the electromagnetic w ...
. Exposure to ionizing radiation, such as
gamma radiation A gamma ray, or gamma radiation (symbol γ or \gamma), is a penetrating form of electromagnetic radiation arising from the radioactive decay Radioactive decay (also known as nuclear decay, radioactivity, radioactive disintegration or nuc ...
, 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 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 Molecular evolution is the process of change in the sequence composition of c ...
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. * Deletions of large chromosomal regions, leading to loss of the genes within those regions. * Mutations whose effect is to juxtapose previously separate pieces of DNA, potentially bringing together separate genes to form functionally distinct
fusion gene A fusion gene is a hybrid gene formed from two previously independent genes. It can occur as a result of translocation, interstitial deletion, or chromosomal inversion preparations Image:a_arm_inversion.jpg, 250px, An inversion loop in the A arm ...
s (e.g.,
bcr-abl The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in Chromosome 22 (human), chromosome 22 of Leukemia, leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defec ...

bcr-abl
). * Large scale changes to the structure of
chromosome A chromosome is a long DNA molecule with part or all of the genome, genetic material of an organism. Most eukaryotic chromosomes include packaging proteins called histones which, aided by Chaperone (protein), chaperone proteins, bind to and ...

chromosome
s called
chromosomal rearrangementIn genetics Genetics is a branch of biology concerned with the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) Though heredity had been observed for millennia, Gregor Mendel, Moravia, Moravian scientist and ...
that can lead to a decrease of fitness but also to
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 within ...

speciation
in isolated, inbred populations. These include: **
Chromosomal translocation In genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions ...
s: interchange of genetic parts from nonhomologous chromosomes. **
Chromosomal inversion preparations Image:a_arm_inversion.jpg, 250px, An inversion loop in the A arm of a chromosome from an ''Axarus'' species midge An inversion is a chromosome rearrangement in which a segment of a chromosome is reversed end to end. An inversion occur ...
s: reversing the orientation of a chromosomal segment. ** Non-homologous
chromosomal crossover Chromosomal crossover, or crossing over, is the exchange of genetic material during sexual reproduction between two homologous chromosomes' sister chromatids, non-sister chromatids that results in recombinant chromosomes. It is one of the final ...
. ** 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 Astrocytomas are a type of brain tumor. They originate in a particular kind of glia Glia, also called glial cells or neuroglia, are non-neuron A neuron or nerve cell is an electrically excitable cell that communicates with other cells ...

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 cell (biology), cells are malignant transformation, transformed into cancer cells. The process is characterized by changes at the cellular, Gen ...
transformation (a transformation from normal cells to cancer cells). *
Loss of heterozygosity Loss of heterozygosity (LOH) is a cross chromosomal event that results in loss of the entire gene and the surrounding chromosomal region. All diploid cells, for example most human somatic cell A somatic cell (from Ancient Greek Ancient Gre ...
: loss of one
allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is one of two, or more, forms of a given gene In biology, a gene (from ''genos'' "...Wilhelm Johannsen coined the word gene to describe the Mendelian_inheritance ...
, 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 mutation A point mutation or substitution is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product ...

point mutation
s.) 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 DNA sequence that can change its position within a genome In the fields of molecular biology and genetics Genetics is a branch of biology concerned with the study of gen ...
s, or errors during replication of repeating elements. Insertions in the coding region of a gene may alter 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 Protein biosynthesis, synthesizing a protein. mRNA i ...
(
splice site mutation A splice site mutation is a Genetics, genetic mutation that Insertion (genetics), inserts, Deletion (genetics), deletes or changes a number of nucleotides in the specific site at which RNA splicing, splicing takes place during the processing of prec ...

splice site mutation
), or cause a shift in the
reading frame In molecular biology Molecular biology is the branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, mol ...

reading frame
(
frameshift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during Translation (biology), translation that results in the production of multiple, unique proteins from a single ...

frameshift
), both of which can significantly alter the
gene product A gene product is the biochemical material, either RNA Ribonucleic acid (RNA) is a polymer A polymer (; Greek '' poly-'', "many" + '' -mer'', "part") is a substance or material consisting of very large molecule File:Pentacene on Ni( ...
. 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. * , 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 Pyrimidine is an aromatic In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts ...

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 Adenine (A, Ade) is a nucleobase 230px, Pyrimidine nucleobases are simple ring molecules. Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides Nucleos ...

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 *Fred Below (1926–1988), American blues drummer *Fritz von Below (1853 ...
, point mutations that occur within the protein
coding region The coding region of a gene, also known as the CDS (from ''coding sequence''), is the portion of a gene's DNA or RNA that codes for protein. Studying the length, composition, regulation, splicing, structures, and functions of coding regions compare ...
of a gene may be classified as
synonymous A synonym is a word, morpheme, or phrase that means exactly or nearly the same as another word, morpheme, or phrase in a given language. For example, in the English language, the words ''begin'', ''start'', ''commence'', and ''initiate'' are al ...
or
nonsynonymous substitution A nonsynonymous substitution is a 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 ...
s, 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 mut ...
or
nonsense mutations Nonsense is a Linguistics, communication, via speech, writing, or any other symbolic system, that lacks any coherent meaning. Sometimes in ordinary usage, nonsense is synonymous with absurdity or the ridiculous. Many poets, novelists and songwrit ...
.


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 Coding may refer to: Computer science * Computer programming, the process of creating and maintaining the source code of computer programs * Line coding, in data storage * Source coding, compression used in data transmission * Coding theory * Chann ...
or
non-coding region Non-coding DNA sequences are components of an organism's DNA The structure of part of a DNA double helix Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene m ...
. Mutations in the non-coding
regulatory sequence A regulatory sequence is a segment of a nucleic acid Nucleic acids are biopolymers, macromolecules, essential to all Organism, known forms of life. They are composed of nucleotides, which are the monomers made of three components: a pentose, 5-car ...
s 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
intron An intron (for ''intragenic region'') is any Nucleic acid sequence, nucleotide sequence within a gene that is removed by RNA splicing during Post-transcriptional modification, maturation of the final RNA product. In other words, introns are non-c ...

intron
s 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 A nonsynonymous substitution is a 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 ...
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

* 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 the 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). * 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 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." * Dominant negative mutations (also called Muller's morphs#Antimorph, antimorphic mutations) have an altered gene product that acts antagonistically to the wild-type allele. These mutations usually result in an altered molecular function (often inactive) and are characterized by a dominant or 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. * Hypomorphs, after Mullerian classification, are characterized by altered gene products that acts with decreased
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. The ...

gene expression
compared to the wild type allele. Usually, hypomorphic mutations are recessive, but haploinsufficiency causes some alleles to be dominant. * Neomorphs are characterized by the control of new
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
product synthesis. * Lethal allele, Lethal mutations are mutations that lead to the death of the organisms that carry the mutations. * A back mutation or reversion is a point mutation that restores the original sequence and hence the original phenotype.


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 DNA sequence DNA sequencing is the process of determining the nucleic acid sequence A nucleic acid sequence is a succession of bases signified by a series of a set of five diff ...
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 thumb File:Genetic Variation and Inheritance.svg, Parents have similar gene coding in this specific situation where they reproduce and variation in the offspring is seen. Offspring containing the variation also reproduce and passes down traits t ...

genetic variation
, 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 organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, ph ...
. 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, sequence data 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. Hiroshi Akashi more recently 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

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 cell A somatic cell (from Ancient Greek Ancient Greek includes the forms of the Greek language used in ancient Greece and the classical antiquity, ancient world from around 1500 BC to 300 BC. It is often roughly divided into the following period ...
s 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 genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The genome includes both the genes (the coding regions) and the noncodin ...

genome
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 genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The genome includes both the genes (the coding regions) and the noncodin ...

genome
. 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 polymer A polymer (; Greek ''wikt:poly-, poly-'', "many" + ''wikt:-mer, -mer'', "part") is a Chemical substance, substance or material consisting of very large molecules, or macromolecules, composed of many Repe ...

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 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 polymer A polymer (; Greek ''wikt:poly-, poly-'', "many" + ''wikt:-mer, -mer'', "part") is a Chemical substance, substance or material consisting of very large molecules, or macromolecules, composed of many Repe ...

RNA
rather than DNA. The RNA viral genome can be double-stranded (as in DNA) or single-stranded. In some of these viruses (such as the single-stranded 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.


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.


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 within ...

speciation
. For example, in 1822 Étienne Geoffroy Saint-Hilaire argued that species could be formed by sudden transformations, or what would later be called macromutation. 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