Pari Genetics

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Ingenetics, a mutation is a change of thenucleotidesequenceof thegenomeof anorganism,virus,orextrachromosomal genetic element. Mutations result

from unrepaireddamage to DNAor to RNA genomes(typically caused by radiation or chemicalmutagens),errors in the process ofreplication, or from the insertion ordeletion of segments of DNA bymobile geneticelements.

[1][2][3]Mutations may or may not produce

discernible changes in the observable characteristics(phenotype) of an organism. Mutations play a part in bothnormal and abnormal biological processesincluding:evolution,cancer, and thedevelopment of theimmune system.

Mutation can result in several different types of change insequences. Mutations in genes can either have no effect,alter theproduct of a gene, or prevent the gene fromfunctioning properly or completely. Mutations can alsooccur in nongenic regions. One study on genetic variationsbetween different species ofDrosophilasuggests that if amutation changes aproteinproduced by a gene, the resultis likely to be harmful, with an estimated 70 percent ofamino acidpolymorphismswhich have damaging effects,and the remainder being either neutral or weaklybeneficial.

[4]Due to the damaging effects that mutations

can have on genes, organisms have mechanisms such

asDNA repairto prevent or correct (revert the mutatedsequence back to its original state) mutations.

[

Description[edit]
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Mutations can involve large sections of DNAbecomingduplicated, usually throughgeneticrecombination.

[5]These duplications are a major source of

raw material for evolving new genes, with tens tohundreds of genes duplicated in animal genomes everymillion years.

[6]Most genes belong to largerfamilies of

genesofshared ancestry.[7]

Novel genes are produced byseveral methods, commonly through the duplication andmutation of an ancestral gene, or by recombining parts ofdifferent genes to form new combinations with newfunctions.

[8][9]

Here,domainsact as modules, each with a particular andindependent function, that can be mixed together toproduce genes encoding new proteins with novelproperties.

[10]For example, the human eye uses four

genes to make structures that sense light: three forcolorvisionand one fornight vision; all four arose from a singleancestral gene.

[11]Another advantage of duplicating a

gene (or even anentire genome) is that thisincreasesredundancy; this allows one gene in the pair toacquire a new function while the other copy performs theoriginal function.

[12][13]Other types of mutation occasionally

create new genes from previously noncoding DNA.[14][15]

Changes in chromosome number may involve even largermutations, where segments of the DNA within

chromosomes break and then rearrange. For example, intheHomininae, two chromosomes fused to producehumanchromosome 2; this fusion did not occur inthelineageof the other apes, and they retain theseseparate chromosomes.

[16]In evolution, the most
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important role of such chromosomal rearrangements maybe to accelerate the divergence of a population into newspecies by making populations less likely to interbreed,

and thereby preserving genetic differences between thesepopulations.[17]

Sequences of DNA that can move about the genome,such astransposons, make up a major fraction of thegenetic material of plants and animals, and may havebeen important in the evolution of genomes.

[18]For

example, more than a million copies of theAlusequenceare present in thehuman genome, and thesesequences have now been recruited to perform functionssuch as regulatinggene expression.

[19]Another effect of

these mobile DNA sequences is that when they movewithin a genome, they can mutate or delete existing genesand thereby produce genetic diversity.

[2]

Nonlethalmutations accumulate within thegene poolandincrease the amount of genetic variation.

[20]The

abundance of some genetic changes within the gene poolcan be reduced bynatural selection, while other "morefavorable" mutations may accumulate and result inadaptive changes.

For example, a butterfly may produce offspring with newmutations. The majority of these mutations will have noeffect; but one might change the color of one of thebutterfly's offspring, making it harder (or easier) forpredators to see. If this color change is advantageous, thechance of this butterfly surviving and producing its ownoffspring are a little better, and over time the number of
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butterflies with this mutation may form a larger percentageof the population.

Neutral mutationsare defined as mutations whose effects

do not influence thefitnessof an individual. These canaccumulate over time due togenetic drift. It is believedthat the overwhelming majority of mutations have nosignificant effect on an organism's fitness. Also,DNArepairmechanisms are able to mend most changes beforethey become permanent mutations, and many organismshave mechanisms for eliminating otherwise permanentlymutatedsomatic cells.

Beneficial mutations can improve reproductive success.

Causes[edit]

Main article:Mutagenesis

Four classes of mutations are (1) spontaneous mutations(molecular decay), (2) mutations due to error pronereplication by-pass ofnaturally occurring DNAdamage(also called error pronetranslesion synthesis), (3)errors introduced during DNA repair, and (4) inducedmutations caused bymutagens.

Spontaneous mutation[edit]

Spontaneous mutations on the molecular level can becaused by:

[21]

Tautomerism A base is changed by the repositioningof a hydrogen atom, altering the hydrogen bonding
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pattern of that base resulting in incorrect base pairingduring replication.

Depurination Loss of a purine base (A or G) to form

an apurinic site (AP site). Deamination Hydrolysis changes a normal base to an

atypical base containing a keto group in place of theoriginal amine group. Examples include C U and A HX (hypoxanthine), which can be corrected by DNArepair mechanisms; and 5MeC (5-methylcytosine) T,which is less likely to be detected as a mutationbecause thymine is a normal DNA base.

Slipped strand mispairing Denaturation of the newstrand from the template during replication, followed byrenaturation in a different spot ("slipping"). This can leadto insertions or deletions.

Error prone replication by-pass[edit]

There is increasing evidence that the majority ofspontaneously arising mutations are due to error prone

replication (translesion synthesis) past a DNA damage inthe template strand. As described in the articleDNAdamage (naturally occurring), naturally occurring DNAdamages arise about 10,000 to 100,000 times per day permammalian cell. In mice, the majority of mutations arecaused by translesion synthesis.

[22]Similarly, in yeast,

Kunz et al.[23]

found that more than 60% of the

spontaneous single base pair substitutions and deletionswere caused by translesion synthesis.

Errors introduced during DNA repair[edit]

Although naturally occurring double-strand breaks occur ata relatively low frequency in DNA (seeDNA damage
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(naturally occurring)) their repair often causesmutation.Non-homologous end joining(NHEJ) is a majorpathway for repairing double-strand breaks. NHEJ

involves removal of a few nucleotides to allow somewhatinaccurate alignment of the two ends for rejoining followedby addition of nucleotides to fill in gaps. Consequently,NHEJ often introduces mutations.

[24]

Induced mutation[edit]

Induced mutations on the molecular level can be causedby:-

Chemicals

HydroxylamineNH2OH

Base analogs(e.g.BrdU)

Alkylating agents (e.g.N-ethyl-N-nitrosourea) Theseagents can mutate both replicating and non-

replicating DNA. In contrast, a base analog can onlymutate the DNA when the analog is incorporated inreplicating the DNA. Each of these classes ofchemical mutagens has certain effects that then leadto transitions, transversions, or deletions.

Agents that formDNA adducts (e.g.ochratoxinAmetabolites)

[26]

DNA intercalatingagents (e.g.ethidium bromide) DNA crosslinkers

Oxidative damage

Nitrous acid converts amine groups on A and C todiazo groups, altering their hydrogen bonding
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patterns which leads to incorrect base pairing duringreplication.

Radiation

Ultravioletradiation (nonionizing radiation). Twonucleotide bases in DNA cytosine and thymineare most vulnerable to radiation that can change theirproperties. UV light can induceadjacent pyrimidinebases in a DNA strand to becomecovalently joined as a pyrimidine dimer. UV radiation,particularly longer-wave UVA, can alsocause oxidative damage to DNA.

[27]

Classification of mutation types[edit]
http://en.wikipedia.org/wiki/Ultraviolethttp://en.wikipedia.org/wiki/Ultraviolethttp://en.wikipedia.org/wiki/Pyrimidinehttp://en.wikipedia.org/wiki/Pyrimidinehttp://en.wikipedia.org/wiki/Pyrimidine_dimerhttp://en.wikipedia.org/wiki/Pyrimidine_dimerhttp://en.wikipedia.org/wiki/DNA_oxidationhttp://en.wikipedia.org/wiki/Mutation#cite_note-Kozmin-27http://en.wikipedia.org/wiki/Mutation#cite_note-Kozmin-27http://en.wikipedia.org/w/index.php?title=Mutation&action=edit&section=7http://en.wikipedia.org/w/index.php?title=Mutation&action=edit&section=7http://en.wikipedia.org/w/index.php?title=Mutation&action=edit&section=7http://en.wikipedia.org/w/index.php?title=Mutation&action=edit&section=7http://en.wikipedia.org/wiki/Mutation#cite_note-Kozmin-27http://en.wikipedia.org/wiki/DNA_oxidationhttp://en.wikipedia.org/wiki/Pyrimidine_dimerhttp://en.wikipedia.org/wiki/Pyrimidinehttp://en.wikipedia.org/wiki/Ultraviolet


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Illustrations of five types of chromosomal mutations.
http://en.wikipedia.org/wiki/File:Chromosomes_mutations-en.svghttp://en.wikipedia.org/wiki/File:Notable_mutations.svghttp://en.wikipedia.org/wiki/File:Chromosomes_mutations-en.svghttp://en.wikipedia.org/wiki/File:Chromosomes_mutations-en.svg


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Selection of disease-causing mutations, in a standardtable of thegenetic codeofamino acids.

[28]

By effect on structure[edit]

The sequence of a gene can be altered in a number ofways. Gene mutations have varying effects on healthdepending on where they occur and whether they alter thefunction of essential proteins. Mutations in the structure ofgenes can be classified as:

Small-scale mutations, such as those affecting a smallgene in one or a few nucleotides, including:

Point mutations, often caused by chemicals ormalfunction of DNA replication, exchange asingle nucleotidefor another.

[29]These changes are

classified as transitions or transversions.[30]

Mostcommon is the transitionthat exchanges apurine for

a purine (A G) or apyrimidinefor a pyrimidine, (C T). A transition can be caused bynitrous acid,base mis-pairing, or mutagenic base analogs suchas 5-bromo-2-deoxyuridine (BrdU). Less common isa transversion, which exchanges a purine for apyrimidine or a pyrimidine for a purine (C/T A/G).

An example of a transversion isadenine (A) beingconverted into a cytosine(C). A point mutation can be

reversed by another point mutation, in which thenucleotide is changed back to its original state (truereversion) or by second-site reversion (acomplementary mutation elsewhere that results inregained gene functionality). Point mutations that
http://en.wikipedia.org/wiki/File:Notable_mutations.svghttp://en.wikipedia.org/wiki/Genetic_codehttp://en.wikipedia.org/wiki/Genetic_codehttp://en.wikipedia.org/wiki/Genetic_codehttp://en.wikipedia.org/wiki/Amino_acidshttp://en.wikipedia.org/wiki/Amino_acidshttp://en.wikipedia.org/wiki/Mutation#cite_note-28http://en.wikipedia.org/wiki/Mutation#cite_note-28http://en.wikipedia.org/w/index.php?title=Mutation&action=edit&section=8http://en.wikipedia.org/w/index.php?title=Mutation&action=edit&section=8http://en.wikipedia.org/w/index.php?title=Mutation&action=edit&section=8http://en.wikipedia.org/wiki/Point_mutationhttp://en.wikipedia.org/wiki/Point_mutationhttp://en.wikipedia.org/wiki/Nucleotidehttp://en.wikipedia.org/wiki/Nucleotidehttp://en.wikipedia.org/wiki/Mutation#cite_note-29http://en.wikipedia.org/wiki/Mutation#cite_note-29http://en.wikipedia.org/wiki/Mutation#cite_note-30http://en.wikipedia.org/wiki/Transition_(genetics)http://en.wikipedia.org/wiki/Transition_(genetics)http://en.wikipedia.org/wiki/Purinehttp://en.wikipedia.org/wiki/Purinehttp://en.wikipedia.org/wiki/Pyrimidinehttp://en.wikipedia.org/wiki/Pyrimidinehttp://en.wikipedia.org/wiki/Pyrimidinehttp://en.wikipedia.org/wiki/Nitrous_acidhttp://en.wikipedia.org/wiki/BrdUhttp://en.wikipedia.org/wiki/BrdUhttp://en.wikipedia.org/wiki/Transversionhttp://en.wikipedia.org/wiki/Transversionhttp://en.wikipedia.org/wiki/Adeninehttp://en.wikipedia.org/wiki/Adeninehttp://en.wikipedia.org/wiki/Cytosinehttp://en.wikipedia.org/wiki/Cytosinehttp://en.wikipedia.org/wiki/Adeninehttp://en.wikipedia.org/wiki/Transversionhttp://en.wikipedia.org/wiki/BrdUhttp://en.wikipedia.org/wiki/Nitrous_acidhttp://en.wikipedia.org/wiki/Pyrimidinehttp://en.wikipedia.org/wiki/Purinehttp://en.wikipedia.org/wiki/Transition_(genetics)http://en.wikipedia.org/wiki/Mutation#cite_note-30http://en.wikipedia.org/wiki/Mutation#cite_note-29http://en.wikipedia.org/wiki/Nucleotidehttp://en.wikipedia.org/wiki/Point_mutationhttp://en.wikipedia.org/w/index.php?title=Mutation&action=edit&section=8http://en.wikipedia.org/wiki/Mutation#cite_note-28http://en.wikipedia.org/wiki/Amino_acidshttp://en.wikipedia.org/wiki/Genetic_codehttp://en.wikipedia.org/wiki/File:Notable_mutations.svg


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occur within the proteincoding region of a gene maybe classified into three kinds, depending upon whatthe erroneous codoncodes for:

Silent mutations: which code for the same (or asufficiently similar)amino acid.

Missense mutations: which code for a differentamino acid.

Nonsense mutations: which code for astopandcan truncate theprotein.

Insertionsadd one or more extra nucleotides into theDNA. They are usually caused by transposableelements, or errors during replication of repeatingelements (e.g. AT repeats

[citation needed]). Insertions in

the coding region of a gene may altersplicing ofthemRNA(splice site mutation), or cause a shift inthe reading frame(frameshift), both of which cansignificantly alter the gene product. Insertions can bereversed by excision of thetransposable element.

Deletionsremove one or more nucleotides from theDNA. Like insertions, these mutations can alterthe reading frameof the gene. They are generallyirreversible: though exactly the same sequence mighttheoretically be restored by an insertion, transposableelements able to revert a very short deletion (say 12bases) in anylocation are either highly unlikely to

exist or do not exist at all. Note that a deletion is notthe exact opposite of an insertion: the former is quiterandom while the latter consists of a specificsequence inserting at locations that are not entirelyrandom or even quite narrowly defined.
http://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Codonhttp://en.wikipedia.org/wiki/Codonhttp://en.wikipedia.org/wiki/Silent_mutationhttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Missense_mutationhttp://en.wikipedia.org/wiki/Nonsense_mutationhttp://en.wikipedia.org/wiki/Stop_codonhttp://en.wikipedia.org/wiki/Stop_codonhttp://en.wikipedia.org/wiki/Stop_codonhttp://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Insertion_(genetics)http://en.wikipedia.org/wiki/Insertion_(genetics)http://en.wikipedia.org/wiki/Transposable_elementhttp://en.wikipedia.org/wiki/Transposable_elementhttp://en.wikipedia.org/wiki/Transposable_elementhttp://en.wikipedia.org/wiki/Wikipedia:Citation_neededhttp://en.wikipedia.org/wiki/Wikipedia:Citation_neededhttp://en.wikipedia.org/wiki/Wikipedia:Citation_neededhttp://en.wikipedia.org/wiki/Splicing_(genetics)http://en.wikipedia.org/wiki/Splicing_(genetics)http://en.wikipedia.org/wiki/MRNAhttp://en.wikipedia.org/wiki/MRNAhttp://en.wikipedia.org/wiki/Splice_site_mutationhttp://en.wikipedia.org/wiki/Reading_framehttp://en.wikipedia.org/wiki/Reading_framehttp://en.wikipedia.org/wiki/Frameshift_mutationhttp://en.wikipedia.org/wiki/Transposable_elementhttp://en.wikipedia.org/wiki/Transposable_elementhttp://en.wikipedia.org/wiki/Genetic_deletionhttp://en.wikipedia.org/wiki/Genetic_deletionhttp://en.wikipedia.org/wiki/Reading_framehttp://en.wikipedia.org/wiki/Reading_framehttp://en.wikipedia.org/wiki/Reading_framehttp://en.wikipedia.org/wiki/Genetic_deletionhttp://en.wikipedia.org/wiki/Transposable_elementhttp://en.wikipedia.org/wiki/Frameshift_mutationhttp://en.wikipedia.org/wiki/Reading_framehttp://en.wikipedia.org/wiki/Splice_site_mutationhttp://en.wikipedia.org/wiki/MRNAhttp://en.wikipedia.org/wiki/Splicing_(genetics)http://en.wikipedia.org/wiki/Wikipedia:Citation_neededhttp://en.wikipedia.org/wiki/Transposable_elementhttp://en.wikipedia.org/wiki/Transposable_elementhttp://en.wikipedia.org/wiki/Insertion_(genetics)http://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Stop_codonhttp://en.wikipedia.org/wiki/Nonsense_mutationhttp://en.wikipedia.org/wiki/Missense_mutationhttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Silent_mutationhttp://en.wikipedia.org/wiki/Codonhttp://en.wikipedia.org/wiki/Protein


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Large-scale mutations in chromosomalstructure,including:

Amplifications (orgene duplications) leading to

multiple copies of all chromosomal regions,increasing the dosage of the genes located withinthem.

Deletionsof large chromosomal regions, leading toloss of the genes within those regions.

Mutations whose effect is to juxtapose previouslyseparate pieces of DNA, potentially bringing togetherseparate genes to form functionally distinctfusiongenes(e.g. bcr-abl). These include:

Chromosomal translocations: interchange ofgenetic parts from nonhomologous chromosomes.

Interstitial deletions: an intra-chromosomaldeletion that removes a segment of DNA from asingle chromosome, thereby apposing previouslydistant genes. For example, cells isolated from a

humanastrocytoma, a type of brain tumor, werefound to have a chromosomal deletion removingsequences between the "fused in glioblastoma"(fig) gene and the receptor tyrosine kinase "ros",producing a fusion protein (FIG-ROS). Theabnormal FIG-ROS fusion protein has constitutivelyactive kinase activity that causes oncogenic

transformation (a transformation from normal cellsto cancer cells).

Chromosomal inversions: reversing theorientation of a chromosomal segment.
http://en.wikipedia.org/wiki/Chromosomehttp://en.wikipedia.org/wiki/Chromosomehttp://en.wikipedia.org/wiki/Gene_duplicationhttp://en.wikipedia.org/wiki/Genetic_deletionhttp://en.wikipedia.org/wiki/Genetic_deletionhttp://en.wikipedia.org/wiki/Fusion_genehttp://en.wikipedia.org/wiki/Fusion_genehttp://en.wikipedia.org/wiki/Fusion_genehttp://en.wikipedia.org/wiki/Fusion_genehttp://en.wikipedia.org/wiki/Bcr-ablhttp://en.wikipedia.org/wiki/Chromosomal_translocationhttp://en.wikipedia.org/wiki/Astrocytomahttp://en.wikipedia.org/wiki/Astrocytomahttp://en.wikipedia.org/wiki/Chromosomal_inversionhttp://en.wikipedia.org/wiki/Chromosomal_inversionhttp://en.wikipedia.org/wiki/Astrocytomahttp://en.wikipedia.org/wiki/Chromosomal_translocationhttp://en.wikipedia.org/wiki/Bcr-ablhttp://en.wikipedia.org/wiki/Fusion_genehttp://en.wikipedia.org/wiki/Fusion_genehttp://en.wikipedia.org/wiki/Genetic_deletionhttp://en.wikipedia.org/wiki/Gene_duplicationhttp://en.wikipedia.org/wiki/Chromosome


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Loss of heterozygosity: loss of oneallele, either bya deletion orrecombination event, in an organism thatpreviously had two different alleles.

By effect on function[edit] Loss-of-function mutations result in the gene product

having less or no function. When the allele has acomplete loss of function (null allele) it is often calledanamorphicmutation. Phenotypes associated withsuch mutations are most often recessive. Exceptionsare when the organism is haploid, or when the reduced

dosage of a normal gene product is not enough for anormal phenotype (this is called haploinsufficiency).

Gain-of-function mutations change the gene productsuch that it gains a new and abnormal function. Thesemutations usually have dominantphenotypes. Oftencalled aneomorphicmutation.

Dominant negative mutations (also

calledantimorphicmutations) have an altered geneproduct that acts antagonistically to the wild-type allele.These mutations usually result in an altered molecularfunction (often inactive) and are characterized byadominantorsemi-dominantphenotype. In humans,dominant negative mutations have been implicated incancer (e.g. mutations ingenesp53,

[31]ATM,

[32]CEBPA

[33]andPPARgamma.

[34]I

t was once thought that Marfan syndromeis an exampleof a dominant negative mutation occurring inanautosomal dominantdisease where the defectiveglycoprotein product of the fibrillin gene (FBN1)antagonizes the product of the normal allele. However,
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it may appear this is not that case and that Marfan'smay be a result ofHaploinsufficiencydue to theabsence of one normal allele that causes the disease

not the presence of an abnormal allele (i.e. Dominantnegative).[citation needed]

Lethal mutations are mutations that lead to the deathof the organisms which carry the mutations.

A back mutation orreversion is a point mutation thatrestores the original sequence and hence the originalphenotype.

[35]

See alsoBehavior mutation.By effect on fitness[edit]

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

A harmful, ordeleterious, mutation decreases thefitness of the organism.

A beneficial, oradvantageous mutation increases thefitness of the organism. Mutations which promotes traitsthat are desirable, are also called beneficial. Intheoretical population genetics, it is more usual to speakof mutations as deleterious or advantageous thanharmful or beneficial.

A neutral mutation has no harmful or beneficial effecton the organism. Such mutations occur at a steady rate,

forming the basis for the molecular clock. In the neutraltheory of molecular evolution, neutral mutationsprovidegenetic driftis the basis for most variation at themolecular level.
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A nearly neutral mutation is a mutation that may beslightly deleterious or advantageous, although mostnearly neutral mutations are slightly deleterious.

Distr ibu t ion of f i tness effects[edit]In reality, viewing the fitness effects of mutations in thesediscrete categories is an oversimplification. Attempts havebeen made to infer the distribution of fitness effects (DFE)usingmutagenesisexperiments and theoretical modelsapplied to molecular sequence data. Distribution of fitnesseffects, as used to determine the relative abundance ofdifferent types of mutations (i.e. strongly deleterious,nearly neutral or advantageous), is relevant to manyevolutionary questions, such as the maintenanceofgenetic variation,

[36]the rate of genomic decay,

[37]the

maintenance of outcrossing sexual reproduction asopposed to inbreeding

[38]and the evolution of sex

andrecombination.[39]

In summary, DFE plays animportant role in predictingevolutionary dynamics.

[40][41]A

variety of approaches have been used to study thedistribution of fitness effects, including theoretical,experimental and analytical methods.

Mutagenesis experiment: The direct method toinvestigate DFE is to induce mutations and thenmeasure the mutational fitness effects, which hasalready been done in viruses, bacteria, yeast,and Drosophila. For example, most studies of DFE inviruses used site-directed mutagenesisto create pointmutationsand measure relative fitnessofeachmutant.

[42][43][44][45]InEscherichiacoli, one study

usedtransposonmutagenesis to directly measure the
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fitness of a random insertion of a derivativeofTn10.

[46]In yeast, a combinedmutagenesis anddeep

sequencingapproach has been developed to generate

high-quality systematic mutant libraries and measurefitness in high throughput.[47]

However, given that manymutations have effects too small to be detected

[48]and

that mutagenesis experiments can only detectmutations of moderately large effect, DNA sequencedata analysis can provide valuable information aboutthese mutations.

The distribution of fitness effects of mutations in vesicularstomatitis virus. In this experiment, random mutationswere introduced into the virus by site-directedmutagenesis, and the fitness of each mutant wascompared with the ancestral type. A fitness of zero, lessthan one, one, more than one, respectively, indicates thatmutations are lethal, deleterious, neutral andadvantageous. Data from.[42]

Molecular sequence analysis: With rapid developmentofDNA sequencingtechnology, an enormous amount ofDNA sequence data is available and even more is
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forthcoming in the future. Various methods have beendeveloped to infer DFE from DNA sequencedata.

[49][50][51][52]By examining DNA sequence

differences within and between species, we are able toinfer various characteristics of the DFE for neutral,deleterious and advantageous mutations.

[53]Specifically,

the DNA sequence analysis approach allows us toestimate the effects of mutations with very small effects,which are hardly detectable through mutagenesisexperiments.

One of the earliest theoretical studies of the distribution offitness effects was done byMotoo Kimura, an influentialtheoretical population geneticist. Hisneutral theory ofmolecular evolutionproposes that most novel mutationswill be highly deleterious, with a small fraction beingneutral.

[54][55]Hiroshi Akashi more recently proposed

abimodalmodel for DFE, with modes centered aroundhighly deleterious and neutral mutations.

[56]Both theories

agree that the vast majority of novel mutations are neutralor deleterious and that advantageous mutations are rare,which has been supported by experimental results. Oneexample is a study done on the distribution of fitnesseffects of random mutations invesicular stomatitisvirus.

[42]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 throughputmutagenesis experiment with yeast.[47]

In this experiment itwas shown that the overall distribution of fitness effects isbimodal, with a cluster of neutral mutations, and a broaddistribution of deleterious mutations.
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Though relatively few mutations are advantageous, thosethat are play an important role in evolutionarychanges.

[57]Like neutral mutations, weakly selected

advantageous mutations can be lost due torandomgenetic drift, but strongly selected advantageousmutations are more likely to be fixed. Knowing thedistribution of fitness effects of advantageous mutationsmay lead to increased ability to predict theevolutionarydynamics. Theoretical work on the DFE for advantageousmutations has been done byJohn H. Gillespie

[58]andH.

Allen Orr.[59]

They proposed that the distribution for

advantageous mutations should beexponentialunder awide range of conditions, which has generally beensupported by experimental studies, at least for stronglyselected advantageous mutations.

[60][61][62]

In summary, it is generally accepted that the majority ofmutations are neutral or deleterious, with rare mutationsbeing advantageous; however, the proportion of types of

mutations varies between species. This indicates twoimportant points: first, the proportion of effectively neutralmutations is likely to vary between species, resulting fromdependence oneffective population size; second, theaverage effect of deleterious mutations varies dramaticallybetween species.

[53]In addition, the DFE also differs

betweencoding regionsandnon-coding regions, with the

DFE of non-coding DNA containing more weakly selectedmutations.

[53]

By impact on protein sequence[edit]

Aframeshift mutationis a mutation causedbyinsertionordeletionof a number of nucleotides that
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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 completelydifferenttranslationfrom the original.[63]

The earlier inthe sequence the deletion or insertion occurs, the morealtered the protein produced is.

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

Anonsense mutationis apoint mutationin a

sequence of DNA that results in a prematurestopcodon, or a nonsense codon in the transcribedmRNA, and possibly a truncated, and oftennonfunctional protein product. (SeeStop codon.)

Missense mutationsornonsynonymousmutations are types ofpoint mutationswhere a singlenucleotide is changed to cause substitution of a

different amino acid. This in turn can render theresulting protein nonfunctional. Such mutations areresponsible for diseases such asEpidermolysisbullosa,sickle-cell disease,and SOD1mediatedALS (Boille 2006, p. 39).

Aneutral mutationis a mutation that occurs in anamino acid codon which results in the use of adifferent, but chemically similar, amino acid. The

similarity between the two is enough that little or nochange is often rendered in the protein. For example,a change from AAA to AGA will encodearginine, achemically similar molecule to the intendedlysine.
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Silent mutationsare mutations that do not result in achange to the amino acid sequence of a protein,unless the changed amino acid is sufficiently similar

to the original. They may occur in a region that doesnot code for a protein, or they may occur within acodon in a manner that does not alter the final aminoacid sequence. The phrase silent mutation is oftenused interchangeably with the phrase synonymousmutation; however, synonymous mutations are asubcategory of the former, occurring only withinexons (and necessarily exactly preserving the amino

acid sequence of the protein). Synonymous mutationsoccur due to the degeneratenature of the geneticcode. (See Genetic code.)

By inheritance[edit]

A mutation has caused this garden moss rosetoproduce flowers of different colors. This is a somaticmutation that may also be passed on in the germ line.
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Inmulticellular organismswith dedicated reproductivecells, mutations can be subdivided into germ linemutations, which can be passed on to descendants

through their reproductive cells, and somaticmutations(also called acquired mutations),[64]

which involve cellsoutside the dedicated reproductive group and which arenot usually transmitted to descendants.

A germline mutation gives rise to a constitutionalmutation in the offspring, that is, a mutation that ispresent in every cell. A constitutional mutation can alsooccur very soon afterfertilisation, or continue from aprevious constitutional mutation in a parent.[65]

The distinction between germline and somatic mutationsis important in animals that have a dedicated germ lineto produce reproductive cells. However, it is of littlevalue in understanding the effects of mutations inplants, which lack dedicated germ line. The distinction isalso blurred in those animals thatreproduce asexuallythrough mechanisms suchasbudding, because the cells that give rise to thedaughter organisms also give rise to that organismsgerm line. A new mutation that was not inherited fromeither parent is called a de novomutation.

Diploid organisms (e.g. humans) contain two copies ofeach gene a paternal and a maternal allele. Based onthe occurrence of mutation on each chromosome, wemay classify mutations into three types.

A heterozygous mutation is a mutation of only oneallele.
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A homozygous mutation is an identical mutation ofboth the paternal and maternal alleles.

Compound heterozygousmutations or a genetic

compound comprises two different mutations in thepaternal and maternal alleles.[66]

A wildtype orhomozygous non-mutated organism isone in which neither allele is mutated.

Special classes[edit]

Conditional mutation is a mutation that has wild-type (or less severe) phenotype under certain"permissive" environmental conditions and a mutantphenotype under certain "restrictive" conditions. Forexample, a temperature-sensitive mutation can causecell death at high temperature (restrictive condition),but might have no deleterious consequences at alower temperature (permissive condition).

Nomenclature[edit]

A committee of the Human Genome Variation Society(HGVS) has developed the standard human sequencevariant nomenclature,

[67]which should be used by

researchers and DNA diagnosticcenters to generateunambiguous mutation descriptions. In principle, thisnomenclature can also be used to describe mutations inother organisms. The nomenclature specifies the type of

mutation and base or amino acid changes.

Nucleotide substitution (e.g. 76A>T) The number isthe position of the nucleotide from the 5' end, the firstletter represents the wild type nucleotide, and thesecond letter represents the nucleotide which
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replaced the wild type. In the given example, theadenine at the 76th position was replaced by athymine.

If it becomes necessary to differentiate betweenmutations in genomic DNA, mitochondrial DNA,and RNA, a simple convention is used. Forexample, if the 100th base of a nucleotidesequence mutated from G to C, then it would bewritten as g.100G>C if the mutation occurred ingenomic DNA, m.100G>C if the mutation occurredin 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 letteris the one letter code of the wild type amino acid, thenumber is the position of the amino acid from theN-terminus, and the second letter is the one letter codeof the amino acid present in the mutation. Nonsense

mutations are represented with an X for the secondamino acid (e.g. D111X).

Amino acid deletion (e.g. F508) The Greek letter (delta) indicates a deletion. The letter refers to theamino acid present in the wild type and the number isthe position from the N terminus of the amino acidwere it to be present as in the wild type.

Mutation rates[edit]Further information: Mutation rate

Mutation ratesvary across species. Evolutionarybiologists[citation needed] have theorized that higher mutationrates are beneficial in some situations, because they
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allow organisms to evolve and therefore adapt morequickly to their environments. For example, repeatedexposure of bacteria to antibiotics, and selection of

resistant mutants, can result in the selection of bacteriathat have a much higher mutation rate than the originalpopulation (mutator strains).

According to one study, two children of different parentshad 35 and 49 new mutations. Of them, in one case92% were from the paternal germline, in another case,64% were from the maternal germline.

[68]

Harmful mutations[edit]Changes in DNA caused by mutation can cause errorsinproteinsequence, creating partially or completelynon-functional proteins. Each cell, in order to functioncorrectly, depends on thousands of proteins to functionin the right places at the right times. When a mutationalters a protein that plays a critical role in the body, a

medical condition can result. A condition caused bymutations in one or more genes is called a geneticdisorder. Some mutations alter a gene's DNA basesequence but do not change the function of the proteinmade by the gene. One study on the comparison ofgenes between different species ofDrosophila suggeststhat if a mutation does change a protein, this will

probably be harmful, with an estimated 70 percent ofamino acid polymorphisms having damaging effects,and the remainder being either neutral or weaklybeneficial.

[4]Studies have shown that only 7% of point

mutations in non-coding DNA ofyeastare deleterious
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and 12% in coding DNA are deleterious. The rest of themutations are either neutral or slightly beneficial.

[69]

If a mutation is present in a germ cell, it can give rise to

offspring that carries the mutation in all of its cells. Thisis the case in hereditary diseases. In particular, if thereis a mutation in a DNA repair gene within a germ cell,humans carrying such germ-line mutations may have anincreased risk of cancer. A list of 34 such germ-linemutations is given in the article DNA repair-deficiencydisorder. On the other hand, a mutation may occur inasomatic cellof an organism. Such mutations will bepresent in all descendants of this cell within the sameorganism, and certain mutations can cause the cell tobecome malignant, and thus cause cancer.

[70]

A DNA damage can cause an error when the DNA isreplicated, and this error of replication can cause a genemutation that, in turn, could cause a genetic disorder.DNA damages are repaired by the DNA repairsystemof the cell. Each cell has a number of pathways throughwhich enzymes recognize and repair damages in DNA.Because DNA can be damaged in many ways, theprocess of DNA repair is an important way in which thebody protects itself from disease. Once a DNA damagehas given rise to a mutation, the mutation cannot berepaired. DNA repair pathways can only recognize and

act on "abnormal" structures in the DNA. Once amutation occurs in a gene sequence it then has normalDNA structure and cannot be repaired.

Beneficial mutations[edit]
http://en.wikipedia.org/wiki/Mutation#cite_note-69http://en.wikipedia.org/wiki/Mutation#cite_note-69http://en.wikipedia.org/wiki/Germ_cellhttp://en.wikipedia.org/wiki/Germ_cellhttp://en.wikipedia.org/wiki/Hereditary_diseasehttp://en.wikipedia.org/wiki/Hereditary_diseasehttp://en.wikipedia.org/wiki/DNA_repair-deficiency_disorderhttp://en.wikipedia.org/wiki/DNA_repair-deficiency_disorderhttp://en.wikipedia.org/wiki/DNA_repair-deficiency_disorderhttp://en.wikipedia.org/wiki/Somatic_cellhttp://en.wikipedia.org/wiki/Somatic_cellhttp://en.wikipedia.org/wiki/Somatic_cellhttp://en.wikipedia.org/wiki/Cancerhttp://en.wikipedia.org/wiki/Cancerhttp://en.wikipedia.org/wiki/Mutation#cite_note-70http://en.wikipedia.org/wiki/DNA_repairhttp://en.wikipedia.org/w/index.php?title=Mutation&action=edit&section=18http://en.wikipedia.org/w/index.php?title=Mutation&action=edit&section=18http://en.wikipedia.org/w/index.php?title=Mutation&action=edit&section=18http://en.wikipedia.org/wiki/DNA_repairhttp://en.wikipedia.org/wiki/Mutation#cite_note-70http://en.wikipedia.org/wiki/Cancerhttp://en.wikipedia.org/wiki/Somatic_cellhttp://en.wikipedia.org/wiki/DNA_repair-deficiency_disorderhttp://en.wikipedia.org/wiki/DNA_repair-deficiency_disorderhttp://en.wikipedia.org/wiki/Hereditary_diseasehttp://en.wikipedia.org/wiki/Germ_cellhttp://en.wikipedia.org/wiki/Mutation#cite_note-69


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Although mutations that change in protein sequencescan be harmful to an organism; on occasions, the effectmay be positive in a given environment. In this case, the

mutation may enable the mutant organism to withstandparticular environmental stresses better than wild-typeorganisms, or reproduce more quickly. In these cases amutation will tend to become more common in apopulation through natural selection.

For example, a specific 32 base pairdeletion inhumanCCR5(CCR5-32) confers HIVresistancetohomozygotesand delaysAIDSonsetinheterozygotes.[71]The CCR5 mutation is morecommon in those of European descent. One possibleexplanation of the etiologyof the relatively highfrequency of CCR5-32 in the European population isthat it conferred resistance to thebubonic plaguein mid-14th century Europe. People with this mutation weremore likely to survive infection; thus its frequency in the

population increased.[72] This theory could explain whythis mutation is not found in southern Africa, whichremained untouched by bubonic plague. A newer theorysuggests that the selective pressureon the CCR5 Delta32 mutation was caused bysmallpoxinstead of thebubonic plague.

[73]

Another example is Sickle cell disease, a blood disorder

in which the body produces an abnormal type of theoxygen-carrying substance hemoglobinin the red bloodcells. One-third of allindigenousinhabitants ofSub-Saharan Africacarry the gene,

[74]because in areas

where malaria is common, there is a survival valuein
http://en.wikipedia.org/wiki/Natural_selectionhttp://en.wikipedia.org/wiki/Natural_selectionhttp://en.wikipedia.org/wiki/Base_pairhttp://en.wikipedia.org/wiki/Base_pairhttp://en.wikipedia.org/wiki/CCR5http://en.wikipedia.org/wiki/CCR5http://en.wikipedia.org/wiki/CCR5http://en.wikipedia.org/wiki/CCR5#CCR5-.CE.9432http://en.wikipedia.org/wiki/CCR5#CCR5-.CE.9432http://en.wikipedia.org/wiki/CCR5#CCR5-.CE.9432http://en.wikipedia.org/wiki/HIVhttp://en.wikipedia.org/wiki/HIVhttp://en.wikipedia.org/wiki/Zygosityhttp://en.wikipedia.org/wiki/Zygosityhttp://en.wikipedia.org/wiki/Zygosityhttp://en.wikipedia.org/wiki/AIDShttp://en.wikipedia.org/wiki/AIDShttp://en.wikipedia.org/wiki/Zygosityhttp://en.wikipedia.org/wiki/Zygosityhttp://en.wikipedia.org/wiki/Zygosityhttp://en.wikipedia.org/wiki/Mutation#cite_note-71http://en.wikipedia.org/wiki/Mutation#cite_note-71http://en.wikipedia.org/wiki/Etiologyhttp://en.wikipedia.org/wiki/Etiologyhttp://en.wikipedia.org/wiki/Bubonic_plaguehttp://en.wikipedia.org/wiki/Bubonic_plaguehttp://en.wikipedia.org/wiki/Mutation#cite_note-72http://en.wikipedia.org/wiki/Selective_pressurehttp://en.wikipedia.org/wiki/Selective_pressurehttp://en.wikipedia.org/wiki/Smallpoxhttp://en.wikipedia.org/wiki/Smallpoxhttp://en.wikipedia.org/wiki/Mutation#cite_note-73http://en.wikipedia.org/wiki/Sickle_cell_diseasehttp://en.wikipedia.org/wiki/Sickle_cell_diseasehttp://en.wikipedia.org/wiki/Hemoglobinhttp://en.wikipedia.org/wiki/Hemoglobinhttp://en.wikipedia.org/wiki/Red_blood_cellshttp://en.wikipedia.org/wiki/Red_blood_cellshttp://en.wikipedia.org/wiki/Red_blood_cellshttp://en.wikipedia.org/wiki/Indigenous_peopleshttp://en.wikipedia.org/wiki/Indigenous_peopleshttp://en.wikipedia.org/wiki/Indigenous_peopleshttp://en.wikipedia.org/wiki/Sub-Saharan_Africahttp://en.wikipedia.org/wiki/Sub-Saharan_Africahttp://en.wikipedia.org/wiki/Sub-Saharan_Africahttp://en.wikipedia.org/wiki/Sub-Saharan_Africahttp://en.wikipedia.org/wiki/Mutation#cite_note-74http://en.wikipedia.org/wiki/Evolutionhttp://en.wikipedia.org/wiki/Evolutionhttp://en.wikipedia.org/wiki/Evolutionhttp://en.wikipedia.org/wiki/Mutation#cite_note-74http://en.wikipedia.org/wiki/Sub-Saharan_Africahttp://en.wikipedia.org/wiki/Sub-Saharan_Africahttp://en.wikipedia.org/wiki/Indigenous_peopleshttp://en.wikipedia.org/wiki/Red_blood_cellshttp://en.wikipedia.org/wiki/Red_blood_cellshttp://en.wikipedia.org/wiki/Hemoglobinhttp://en.wikipedia.org/wiki/Sickle_cell_diseasehttp://en.wikipedia.org/wiki/Mutation#cite_note-73http://en.wikipedia.org/wiki/Smallpoxhttp://en.wikipedia.org/wiki/Selective_pressurehttp://en.wikipedia.org/wiki/Mutation#cite_note-72http://en.wikipedia.org/wiki/Bubonic_plaguehttp://en.wikipedia.org/wiki/Etiologyhttp://en.wikipedia.org/wiki/Mutation#cite_note-71http://en.wikipedia.org/wiki/Zygosityhttp://en.wikipedia.org/wiki/AIDShttp://en.wikipedia.org/wiki/Zygosityhttp://en.wikipedia.org/wiki/HIVhttp://en.wikipedia.org/wiki/CCR5#CCR5-.CE.9432http://en.wikipedia.org/wiki/CCR5http://en.wikipedia.org/wiki/Base_pairhttp://en.wikipedia.org/wiki/Natural_selection


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carrying only a single sickle-cell gene (sickle celltrait).

[75]Those with only one of the twoalleles of the

sickle-cell disease are more resistant to malaria, since

the infestation of the malaria plasmodium is halted bythe sickling of the cells which it infests.

Prion mutations[edit]

Prionsare proteins and do not contain genetic material.However, prion replication has been shown to besubject to mutation and natural selectionjust like otherforms of replication.

[76]

Somatic mutations[edit]

Main article:Loss of heterozygosity

See also: Carcinogenesis

A change in the genetic structure that is not inheritedfrom a parent, and also not passed to offspring, is calleda somatic cell genetic mutation oracquired mutation.

[77]

Cells with heterozygous mutations (one good copy ofgene and one mutated copy) may function normally withthe unmutated copy until the good copy has beenspontaneously somatically mutated. This kind ofmutation happens all the time in living organisms, but itis difficult to measure the rate. Measuring this rate isimportant in predicting the rate at which people may

develop cancer.[78]

Point mutationsmay arise from spontaneous mutationsthat occur during DNA replication. The rate of mutationmay be increased by mutagens. Mutagens can bephysical, such as radiation fromUV rays,X-raysor
http://en.wikipedia.org/wiki/Sickle_cell_traithttp://en.wikipedia.org/wiki/Sickle_cell_traithttp://en.wikipedia.org/wiki/Mutation#cite_note-75http://en.wikipedia.org/wiki/Mutation#cite_note-75http://en.wikipedia.org/wiki/Alleleshttp://en.wikipedia.org/wiki/Alleleshttp://en.wikipedia.org/w/index.php?title=Mutation&action=edit

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