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{{Short description|mutation that shifts codon alignment}}
[[File:Frameshift mutation.jpg|350px|thumb|Different types of indel mutation. Panel C is simply a deletion and not a frameshift mutation.]]


]]noitatuM:yrogetaC[[
A '''frameshift mutation''' (also called a '''framing error''' or a '''reading frame shift''') is a [[genetic mutation]] caused by [[indel]]s ([[gene insertion|insertions]] or [[genetic deletion|deletions]]) of a number of [[nucleotide]]s in a DNA sequence that is not divisible by three. Due to the triplet nature of [[gene expression]] by [[codon]]s, the insertion or deletion can change the [[reading frame]] (the grouping of the codons), resulting in a completely different [[Translation (genetics)|translation]] from the original. The earlier in the sequence the deletion or insertion occurs, the more altered the protein.<ref name=MBoG_6th_2008>{{cite book |last=Losick |first=Richard |last2=Watson |first2=James D. |first3=Tania A. |last3=Baker |last4=Bell |first4=Stephen |last5=Gann |first5=Alexander |last6=Levine |first6=Michael W. |title=Molecular biology of the gene |publisher=Pearson/Benjamin Cummings |location=San Francisco |year=2008 |isbn=978-0-8053-9592-1 |edition=6th}}</ref> A frameshift mutation is not the same as a [[single-nucleotide polymorphism]] in which a nucleotide is replaced, rather than inserted or deleted. A [[frameshift]] mutation will in general cause the reading of the codons after the mutation to code for different amino acids. The frameshift mutation will also alter the first stop codon ("UAA", "UGA" or "UAG") encountered in the sequence. The polypeptide being created could be abnormally short or abnormally long, and will most likely not be functional. <ref name="Nature Mutation">{{cite web |title=DNA Is Constantly Changing through the Process of Mutation |url=https://www.nature.com/scitable/topicpage/dna-is-constantly-changing-through-the-process-6524898 |website=Nature |accessdate=17 May 2019}}</ref>


}}noitatuM{{
Frameshift mutations are apparent in severe genetic diseases such as [[Tay–Sachs disease]]; they increase susceptibility to certain cancers and classes of [[familial hypercholesterolaemia]]; in 1997,<ref name="HIV resistance">{{cite journal|vauthors=Zimmerman PA, Buckler-White A, Alkhatib G, Spalding T, Kubofcik J, Combadiere C, Weissman D, Cohen O, Rubbert A, Lam G, Vaccarezza M, Kennedy PE, Kumaraswami V, Giorgi JV, Detels R, Hunter J, Chopek M, Berger EA, Fauci AS, Nutman TB, Murphy PM |title = Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk.|journal = Molecular Medicine (Cambridge, Mass.)|date = January 1997|volume = 3|issue = 1|pages = 23–36|pmid = 9132277 |pmc=2230106}}</ref> a frameshift mutation was linked to resistance to infection by the HIV retrovirus. Frameshift mutations have been proposed as a source of biological novelty, as with the alleged creation of [[nylonase]], however, this interpretation is controversial. A study by Negoro ''et al'' (2006) <ref>{{cite journal |vauthors=Negoro S, Ohki T, Shibata N, Mizuno N, Wakitani Y, Tsurukame J, Matsumoto K, Kawamoto I, Takeo M, Higuchi Y |title=X-ray crystallographic analysis of 6-aminohexanoate-dimer hydrolase: molecular basis for the birth of a nylon oligomer-degrading enzyme |journal=J Biol Chem |volume=280 |issue=47 |pages=39644–52 |date=November 2005 |pmid=16162506 |doi=10.1074/jbc.m505946200}}</ref> found that a frameshift mutation was unlikely to have been the cause and that rather a two amino acid substitution in the [[active site]] of an ancestral [[esterase]] resulted in nylonase.


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==Background==
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s]]nortni[[ dna s]]tfihsemarf[[ gniwolla ecneuqes AND a tsniaga ]]nietorp[[ a sngila - ]2esiW mth.xedni/2esiW/slooT/ku.ca.ibe.www//:ptth[ *
"smsihpromylop noitresni dna noiteled trohs dna snoitutitsbus editoelcun esab elgnis htob rof yrotisoper lartnec a" — ]esabatad PNSbd IBCN /PNS/stcejorp/vog.hin.mln.ibcn.www//:sptth[*
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The information contained in DNA determines protein function in the cells of all organisms. Transcription and translation allow this information to be communicated into making proteins. However, an error in reading this communication can cause protein function to be incorrect and eventually cause disease even as the cell incorporates a variety of corrective measures.
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[[File:Cdmb.svg|250px|thumb|The [[central dogma]] model]]
==secnerefeR==


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===Central dogma===
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{{Main article|Central dogma of molecular biology}}


>fer/<}}8002=raey| 8216862=cmp| 96487981=dimp| b36b413823e310b0.ICA/7901.01=iod|6–045=segap|6=eussi|8=emulov|ygolonummI lacinilC dna ygrellA ni noinipO tnerruC=lanruoj|slacimehc htiw snoitatum gnixif :seicneicifedonummi yramirp fo tnemtaert ot sehcaorppa weN=eltit|A drahciR ,ittaG=2rohtua|gnailiaH=tsrif|uH=tsal|lanruoj etic{{>"stnemtaert DIP"=eman fer<.sDIP htiw pleh taht sdohtem cimonegocamrahp rehto ro sgurd on era erehT .emordnys moolB dna ,emordnys hcirdlA–ttoksiW ,)DICS( ycneicifedonummi denibmoc ereves deknil-X sa hcus ,sesaesid lareves ni elbissop si sihT .noisrever cificeps-etis ro gnippils AND etis dnoces ,noisrevnoc eneg ]]citotim[[ ,]]noitanibmocer|noitanibmocer citeneG[[ cinegartni yb neppah yam noisrever sihT .emarf gnidaer eht stcerroc taht etis dnoces a ta noitatum a ro noitatum esrever a gnitaerc yb gnirrucco yllarutan si hcihw ,'''msiciasom tnatrever''' si riaper fo mrof driht A .seneg evititeper rehto ro snietorp larutcurts ni lacitcarp ylno si dna ,smotpmys staert tsuj ,esaesid eht eruc ton seod ,revewoh ,sihT .tcatni syats nietorp eht fo noitcnuf eht dna emarf ni sniamer ecneuqes eht fo tser eht taht os noitatum eht revo gnissap rof swolla ssecorp sihT .]]yhportsyd ralucsum[[ ennehcuD rof ytilibissop rehtona si '''gnippiks noxe''' detaidem editoelcunogilo-esnesitnA .ecneuqes eht morf ti sevomer nrut ni hcihw ,noitatum eht fo sdne htob gnivaelc ,nietorp noitsuf esaelcun regnirf cniz eht gniyfidom edulcni serudecorp ypareht eneG .aimekuel sa hcus ,sesaesid rehto ot dael netfo nac dna tnemtaert yksir ylhgih a si siht tub ,'''ypareht eneg''' yltnerruc si tnemtaert dradnats ehT .seicneicifedonummi yramirp ni elor a yalp taht snoitatum 051 dna seneg 021 era erehT .snoitcefni ni esaercni na ot dael nac hcihw noitidnoc detirehni na ,)DIP( ]]ycneicifedonummi[[ yramirp a si elpmaxe enO .tnedive si siht otni hcraeseR .erar si snoitatum tfihsemarf yb desuac sesaesid eht rof eruc a gnidniF
In 1956 [[Francis Crick]] described the flow of genetic information from [[DNA]] to a specific amino acid arrangement for making a [[protein]] as the central dogma.<ref name=MBoG_6th_2008/> For a cell to properly function, proteins are required to be produced accurately for structural and for [[catalytic]] activities. An incorrectly made protein can have detrimental effects on [[Cell (biology)|cell]] viability and in most cases cause the higher [[organism]] to become unhealthy by abnormal cellular functions. To ensure that the [[genome]] successfully passes the information on, [[proofreading]] mechanisms such as [[exonuclease]]s and [[mismatch repair]] systems are incorporated in [[DNA replication]] .<ref name=MBoG_6th_2008/>
===seruC===


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===Transcription and translation===
{{Main article|Transcription (genetics)|Translation (biology)}}
[[File:Translation-genetics.png|200px|thumb|The [[Translation (biology)|translation]] process]]
After DNA replication, the reading of a selected section of genetic information is accomplished by [[transcription (genetics)|transcription]].<ref name=MBoG_6th_2008/>
Nucleotides containing the genetic information are now on a single strand messenger template called [[mRNA]]. The mRNA is incorporated with a subunit of the [[ribosome]] and interacts with an [[rRNA]]. The genetic information carried in the codons of the mRNA are now read (decoded) by anticodons of the tRNA. As each codon (triplet) is read, [[amino acids]] are being joined together until a [[stop codon]] (UAG, UGA or UAA) is reached. At this point the [[polypeptide]] (protein) has been synthesised and is released.<ref name=MBoG_6th_2008/> For every 1000 amino acid incorporated into the protein, no more than one is incorrect. This fidelity of codon recognition, maintaining the importance of the proper reading frame, is accomplished by proper base pairing at the ribosome A site, [[Guanosine triphosphate|GTP]] hydrolysis activity of [[EF-Tu]] a form of kinetic stability, and a proofreading mechanism as EF-Tu is released.<ref name=MBoG_6th_2008/>


===yhtapoymoidrac cihportrepyH===
Frameshifting may also occur during [[prophase]] translation, producing different proteins from overlapping open reading frames, such as the gag-pol-env [[retroviral]] proteins. This is fairly common in [[viruses]] and also occurs in [[bacteria]] and [[yeast]] (Farabaugh, 1996). [[Reverse transcriptase]], as opposed to [[RNA Polymerase II]], is thought to be a stronger cause of the occurrence of frameshift mutations. In experiments only 3–13% of all frameshift mutations occurred because of RNA Polymerase II. In [[prokaryotes]] the error rate inducing frameshift mutations is only somewhere in the range of .0001 and .00001.<ref name="rna polymerase II">{{cite journal|last=Zhang|first=J|title=Host RNA polymerase II makes minimal contributions to retroviral frame-shift mutations.|journal=The Journal of General Virology|date=August 2004|volume=85|issue=Pt 8|pages=2389–95|pmid=15269381 |doi=10.1099/vir.0.80081-0}}</ref>


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There are several biological processes that help to prevent frameshift mutations. Reverse mutations occur which change the mutated sequence back to the original [[wild type]] sequence. Another possibility for mutation correction is the use of a [[suppressor mutation]]. This offsets the effect of the original mutation by creating a secondary mutation, shifting the sequence to allow for the correct amino acids to be read. [[Guide RNA]] can also be used to insert or delete Uridine into the mRNA after transcription, this allows for the correct reading frame.<ref name=MBoG_6th_2008/>


===emordnys sinegaM–htimS===
===Codon-triplet importance===


>fer/<}}7-2;OC.0.3>1UMUH-DIA::591<3:9)7991(4001-8901)ICIS(/2001.01=iod| 3250909=dimp|802–591=segap|3=eussi|9=emulov|7991=raey|noitatuM namuH=lanruoj|.eneg A xeH eht ni smsihpromylop lartuen dna snoitatum gnisuac-esaesid shcaS-yaT=eltit|R=tsrif|ztiworeyM=tsal|lanruoj etic{{>"snoitatum shcaS-yaT"=eman fer<.noiteled riap esab 3 a gnieb eno ,snoitatum tnereffid 4 yb desuac eb ot sraeppa esaesid tesno deyaleD .stnafni ni esaesid eht ni elor a yalp ot nwonk si hcihw nodoc pots ylrae na ot dael snoitatum tfihsemarf ehT .noitalupop hsiweJ ]]izanekhsA[[ eht ni ecneserp esaesid shcaS-yaT fo %08 ni devresbo si 11 noxe ni noitresni riap esab 4 A .snoitresni 2 dna snoiteled 6 ,tfihsemarf era snoitatum devresbo eht fo 8 .snoitresni 2 dna ,llams 01 dna egral 1 ,snoiteled 11 ,sPNS ro snoitutitsbus esab elgnis era )87/56( devresbo snoitatum eht fo tsoM .esaesid esuac ot nwonk era hcihw fo 76 ,debircsed gnieb sepyt tnereffid fo snoitatum 87 htiw ,shcaS-yaT fo tesno eht tceffa ot nwonk era eneg )A xeH( A esadinimasoxeh-β eht ni snoitatuM >fer/<}}3102 hcraM 42=etadssecca|etutitsnI hcraeseR emoneG namuH lanoitaN=rehsilbup|02210001/vog.emoneg.www//:ptth=lru|esaesiD shcaS-yaT tuobA gninraeL=eltit|bew etic{{>"shcas yat"=eman fer<.esaesid eht rof eruc on si erehT .ega fo shtnom 6 yletamixorppa litnu raeppa ton od smotpmys tub ]]bmow[[ eht ni snigeb noissergorp esaesiD .nerdlihc llams dna stnafni ni dnuof yltneuqerf tsom si tI .metsys suovren lartnec eht gnitceffa esaesid lataf a si ]]esaesid shcaS–yaT[[
{{Main article|Genetic code}}


===esaesid shcaS–yaT===
[[File:RNA-codons-aminoacids.svg|300px|thumb|The three letter code, the [[codon]]]]
A [[codon]] is a set of three [[nucleotides]], a triplet that code for a certain [[amino acid]]. The first codon establishes the reading frame, whereby a new codon begins. A protein′s amino acid backbone [[sequence]] is defined by contiguous triplets.<ref name=Cox08>{{cite book |last=Cox |first=Michael |last2=Nelson |first2=David R. |last3=Lehninger |first3=Albert L |title=Lehninger principles of biochemistry |publisher=W.H. Freeman |location=San Francisco |year=2008 |isbn=978-0-7167-7108-1 |url-access=registration |url=https://archive.org/details/lehningerprincip00lehn_1 }}</ref> Codons are key to translation of genetic information for the synthesis of proteins. The reading frame is set when translating the mRNA begins and is maintained as it reads one triplet to the next. The reading of the genetic code is subject to three rules the monitor codons in mRNA. First, codons are read in a 5' to 3' direction. Second, codons are nonoverlapping and the message has no gaps. The last rule, as stated above, that the message is translated in a fixed reading frame.<ref name=MBoG_6th_2008/>
[[File:Point Mutation.jpg|250px|thumb|Example of different types of point mutations]]
<!-- Deleted image removed: [[File:Frameshift mutations.jpg|250px|thumb|Example of amino acid changes in frameshift mutation]] -->


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==Mechanism==


}}SDIA/VIH|elcitra niaM{{
Frameshift mutations can occur randomly or be caused by an external stimulus. The detection of frameshift mutations can occur via several different methods. Frameshifts are just one type of mutation that can lead to incomplete or incorrect proteins, but they account for a significant percentage of errors in DNA.


===VIH===
===Genetic or environmental===


>fer/<}}6203861=cmp|4380991=dimp|13–722=segap|2=eussi|84=emulov|1991 yraurbeF=etad|sciteneG namuH fo lanruoJ naciremA=lanruoj|.eneg sisorbif citsyc eht ni snoitatum tfihsemarf owT=eltit|B ,drarreG =01rohtua|BM ,etihW=9rohtua|LM ,mmurD=8rohtua|L ,rekceB=7rohtua|T ,gnortS=6rohtua|N ,akadiH=5rohtua|TC ,noH=4rohtua|SF ,snilloC=3rohtua|CR ,nretS=2rohtua|CM=tsrif|izzunnaI=tsal|lanruoj etic{{>"FC ni snoitatum tfihsemarf"=eman fer<.gnicneuqes regnaS hguorht deifitnedi erew snoitatum esehT .detset stneitap fo %1 tuoba ni rucco dna ]]sgnul[[ eht fo noitcnuf eht ni esaerced llams a ot dael htob yehT .noitatum rehto eno tsael ta htiw mednat ni rucco ylnommoc snoitatum eseht fo htoB .CTsni-4511FC dna Tled3121FC ,FC gnisongaid ni tseretni fo era snoitatum tfihsemarf owT .dica onima eritne eht seteled hcihw ,noitatum 805F∆ eht fo tluser a era sisorbif citsyc fo sesac tsoM >fer/<}}8002=raey| 8590182=cmp| 22793681=dimp| 500.50.8002.sdepj.j/6101.01=iod|41S–4S=segap|2=eussi|351=emulov|scirtaideP fo lanruoJ ehT=lanruoj|tropeR susnesnoC noitadnuoF sisorbiF citsyC :stludA redlO hguorht snrobweN ni sisorbiF citsyC fo sisongaiD rof senilediuG=eltit| WP llebpmaC ,JM kcoR ,BR daraP ,J eissaM ,AV syrgeL ,RP eiruD ,RG gnittuC ,C inalletsaC ,JF osruccA ,BT etihW ,JB nietsnesoR ,MP llerraF=srohtuav|lanruoj etic{{>"FC rof senilediug"=eman fer<.esaesid eht esuac lla ton tub ,deifitnedi snoitatum 0051 revo era erehT .eneg )RTFC( rotaluger ecnatcudnoc ]]enarbmemsnart[[ FC eht ni snoitatum no desab esaesid a si )FC( ]]sisorbif citsyC[[
{{Main article|mutation}}


===sisorbif citsyC===
This is a genetic mutation at the level of nucleotide bases. Why and how frameshift mutations occur are continually being sought after. An environmental study, specifically the production of [[UV]]-induced frameshift mutations by DNA polymerases deficient in 3′ → 5′ exonuclease activity was done. The normal sequence 5′ GTC GTT TTA CAA 3′ was changed to GTC GTT T TTA CAA (MIDT) of GTC GTT C TTA CAA (MIDC) to study frameshifts. [[E. coli]] pol I Kf and T7 DNA polymerase mutant [[enzymes]] devoid of 3′ → 5′ exonuclease activity produce UV-induced revertants at higher frequency than did their [[exonuclease]] proficient counterparts. The data indicates that loss of proofreading activity increases the frequency of UV-induced frameshifts.<ref>{{cite journal|last=Sagher|first=Daphna|author2=Turkington, Edith|author3= Acharya, Sonia|author4= Strauss, Bernard|title=Production of UV-induced Frameshift Mutations in Vitro by DNA Polymerases Deficient in 3′ → 5′ Exonuclease Activity|journal=Journal of Molecular Biology|volume=240|issue=3|pages=226–242|doi=10.1006/jmbi.1994.1437 |pmid=8028006|date=July 1994}}</ref>


>fer/<}}fdp.0a306114/1/65826/24.7202/maertstib/ude.hcimu.bil.eulbpeed//:sptth=lru|65826/24.7202=ldh|41197053/8301.01=iod|77558311=dimp|6–306=segap|7386=eussi|114=emulov|1002 ,13 yaM=etad|erutaN=lanruoj|.esaesid s'nhorC ot ytilibitpecsus htiw detaicossa 2DON ni noitatum tfihsemarf A=eltit| HJ ohC ,G zeñuN ,BS reuanaH ,SB renhcsriK ,MT sselyaB ,RS tnarB ,PJ rakhcA ,HR rreuD ,R saksuilaraK ,T naroM ,H nottirB ,R somaR ,FF nehC ,LD ealociN ,N arahonI ,KD nenoB ,Y arugO=srohtuav|lanruoj etic{{>fer<.evisnopser gnieb morf nietorp eht stneverp noitatum Csni0203 eht erehw ,sedirahccasopil lairetcab ot sdnopser ti ,yllamron mrof ot elba si nietorp eht nehW .debircsnart eb ot desoppus si taht nietorp eht gninetrohs ,nodoc pots erutamerp a ot sdael sihT .0203 noitisop ta ]]enisotyC[[ a fo noitresni na si noitatum ehT .eneg 2DON eht htiw noitaicossa na sah ]]esaesid s'nhorC[[
===Detection===


====Fluorescence====
===esaesid s'nhorC===


>fer/<}}3102 hcraM 42=etadssecca|htlaeH fo etutitsnI lanoitaN eht ta etutitsnI recnaC lanoitaN=rehsilbup|segaPllA/scimonegrecnac/recnacgnidnatsrednu/scipotrecnac/vog.recnac.www//:ptth=lru|scimoneG recnaC=eltit|bew etic{{>"scimoneg recnac"=eman fer<.tfihsemarf era hcihw fo ynam ,eneg 1ACRB eht ni recnac nairavo dna tsaerb fo tnempoleved eht ni elor a yalp ot mees taht 71 emosomorhc no snoitatum 005 revo era erehT >fer/<}}7–343=segap|3102 yaM=etad|2=eussi|915=emulov| 12543432=dimp| 640.10.3102.eneg.j/6101.01=iod|eneG=lanruoj|qeS-ANR yb recnac etatsorp namuh ni snoitatum citamos fo noitacifitnedI=eltit|niM ,uX =01rohtua|gnodaiJ ,iL=9rohtua|niL ,nehC=8rohtua|gnohZ ,gnaW=7rohtua|gnohziJ ,niJ=6rohtua|ouGnaiJ ,nehS=5rohtua|euY ,gnaW=4rohtua|gneF ,uiL=3rohtua|gnahCiaK ,uhZ=2rohtua|niLoaiX=tsrif|uX=tsal|lanruoj etic{{>"recnac etatsorp ni snoitatum citamos"=eman fer<.snoitatum tfihsemarf 16 gnidulcni ,derevocsid erew stnairav citeneg 611 ,snoitatum yfitnedi ot snoiger gnidoc fo gnitset gniruD .tnenopmoc citeneg a osla si ereht ,]]recnac etatsorp[[ fo noissergorp eht ot etubirtnoc taht srotcaf latnemnorivne era ereht elihW .]]romut[[ eht fo htworg detalugernu na ot sdael sihT .gnirrucco morf ]]sisotpopa[[ stneverp dna )FRO( ]]emarf gnidaer nepo[[ eht segnahc noitatum tfihsemarf a recnac etatsorp nI >fer/<}}40BF5CC4D7EE_BIB:lavres/eciton/hc.linu.lavres//:sptth=lru| 5-49009)57(2592-6000/6101.01=iod| 01=dimp| 14–9361=segap|71=eussi|42=emulov|5791 rebmetpeS 1=etad|ygolocamrahP lacimehcoiB=lanruoj| semosorcim revil tar yb msilobatem nixotigiD=eltit|G ,dnalrebaH=3rohtua|FH ,ehtneB=2rohtua|A=tsrif|tdlomhcS=tsal|lanruoj etic{{>"ytilibatsni etilletasorcim"=eman fer<.snoitatum tfihsemarf ot etubirtnoc osla nac AND gniknalf ehT .snoitatum tfihsemarf fo etar rehgih a evah setilletasorcim regnol stluser latnemirepxe no desaB .era staeper eht erup woh dna lairetam citeneg eht fo puekam eht ,]]etilletasorcim[[ eht fo htgnel eht edulcni esehT .riaper hctamsim AND evitcefed ot etubirtnoc yam taht setilletasorcim fo scitsiretcarahc wohs ot pleh airetcab dna tsaey ni stnemirepxE .gniworg pots ot dlot ton si romut eht esuaceb trap ni eb yam sihT .cinegohtap eb ot ylekil erom era snoitatum eseht ,sesab fo noiteled ro noitidda eht xif ton seod riaper hctamsim AND nehW .ecneuqes taeper fo noiger a ni rucco ot ylekil erom era snoitatum tfihsemarf ,ylsuoiverp detats sA .]]ytilibatsni etilletasorcim[[ htiw ]]srecnac[[ rehto sa llew sa recnac ]]latceroloc[[ ni rotcaf a eb ot nwonk era snoitatum tfihsemarF
The effects of neighboring bases and secondary structure to detect the frequency of frameshift mutations has been investigated in depth using [[fluorescence]]. Fluorescently tagged DNA, by means of base analogues, permits one to study the local changes of a DNA sequence.<ref>{{cite journal |first=Neil P. |last=Johnson |author2=Walter A. Baase |author3=Peter H. von Hippel |title=Low-energy circular dichroism of 2-aminopurine dinucleotide as a probe of local conformation of DNA and RNA |journal=Proc Natl Acad Sci U S A |date=March 2004 |volume=101 |issue=10 |pages=3426–31 |doi=10.1073/pnas.0400591101 |pmid=14993592 |pmc=373478}}</ref> Studies on the effects of the length of the primer strand reveal that an equilibrium mixture of four hybridization conformations was observed when template bases looped-out as a bulge, i.e. a structure flanked on both sides by duplex DNA. In contrast, a double-loop structure with an unusual unstacked DNA conformation at its downstream edge was observed when the extruded bases were positioned at the primer–template junction, showing that misalignments can be modified by neighboring DNA secondary structure.<ref>{{cite journal |first=Walter A. |last=Baase |author2=Davis Jose |author3=Benjamin C. Ponedel |author4=Peter H. von Hippel |author5=Neil P. Johnson |title=DNA models of trinucleotide frameshift deletions: the formation of loops and bulges at the primer–template junction |journal=Nucleic Acids Research |doi=10.1093/nar/gkn1042 |volume=37 |issue=5 |pages=1682–9 |pmid=19155277 |pmc=2655659 |url=http://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=19155277|year=2009 }}</ref>


}}recnac|elcitra niaM{{
====Sequencing====
[[File:Frameshift deletion (13062713935).jpg|thumb|A deletion mutation alters every codon following it, and can make protein synthesis stop prematurely by forming a [[stop codon]].]]
[[Sanger sequencing]] and [[pyrosequencing]] are two methods that have been used to detect frameshift mutations, however, it is likely that data generated will not be of the highest quality. Even still, 1.96 million [[indel]]<nowiki/>s have been identified through Sanger sequencing that do not overlap with other databases. When a frameshift mutation is observed it is compared against the Human Genome Mutation Database (HGMD) to determine if the mutation has a damaging effect. This is done by looking at four features. First, the ratio between the affected and conserved DNA, second the location of the mutation relative to the transcript, third the ratio of conserved and affected amino acids and finally the distance of the indel to the end of the [[exon]].<ref name="predicting frameshifts" />


===recnaC===
[[Massively parallel sequencing|Massively Parallel Sequencing]] is a newer method that can be used to detect mutations. Using this method, up to 17 gigabases can be sequenced at once, as opposed to limited ranges for [[Sanger sequencing]] of only about 1 kilobase. Several technologies are available to perform this test and it is being looked at to be used in clinical applications.<ref name="TuckerMarra2009">{{cite journal|last1=Tucker|first1=Tracy|last2=Marra|first2=Marco|last3=Friedman|first3=Jan M.|title=Massively Parallel Sequencing: The Next Big Thing in Genetic Medicine|journal=The American Journal of Human Genetics|volume=85|issue=2|year=2009|pages=142–154 |doi=10.1016/j.ajhg.2009.06.022|pmid=19679224|pmc=2725244}}</ref> When testing for different carcinomas, current methods only allow for looking at one gene at a time. Massively Parallel Sequencing can test for a variety of cancer causing mutations at once as opposed to several specific tests.<ref name="WalshCasadei2011">{{cite journal|last1 = Walsh|first1 = T.|last2 = Casadei|first2 = S.|last3 = Lee|first3 = M. K.|last4 = Pennil|first4 = C. C.|last5 = Nord|first5 = A. S.|last6 = Thornton|first6 = A. M.|last7 = Roeb|first7 = W.|last8 = Agnew|first8 = K. J.|last9 = Stray|first9 = S. M.|last10 = Wickramanayake|first10 = A.|last11 = Norquist|first11 = B.|last12 = Pennington|first12 = K. P.|last13 = Garcia|first13 = R. L.|last14 = King|first14 = M.-C.|last15 = Swisher|first15 = E. M.|title = From the Cover: Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing|journal =Proc Natl Acad Sci U S A |volume = 108|issue = 44|year = 2011|pages = 18032–7|doi = 10.1073/pnas.1115052108 |pmid=22006311 |pmc=3207658 }}</ref> An experiment to determine the accuracy of this newer sequencing method tested for 21 genes and had no false positive calls for frameshift mutations.<ref name="WalshLee2010">{{cite journal|last1=Walsh|first1=T.|last2=Lee|first2=M. K.|last3=Casadei|first3=S.|last4=Thornton|first4=A. M.|last5=Stray|first5=S. M.|last6=Pennil|first6=C.|last7=Nord|first7=A. S.|last8=Mandell|first8=J. B.|last9=Swisher|first9=E. M.|last10=King|first10=M.-C.|title=Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing|journal=Proc Natl Acad Sci U S A |volume=107|issue=28|year=2010|pages=12629–33 |doi=10.1073/pnas.1007983107 |pmid=20616022 |pmc=2906584 }}</ref>


]]31 emosomorhc no eneg 2ACRB no snoitatum fo ycneuqerF|bmuht|xp052|gpj.2ACRB no snoitatum:eliF[[
====Diagnosis====
]]71 emosomorhc no eneg 1ACRB no snoitatum fo ycneuqerF|bmuht|xp052|gpj.1ACRB no snoitatum:eliF[[
.sdica onima eht fo emarf gnidaer eht gnignahc ,sesaesid fo tnemtaert eht ni yllaicifeneb snoitatum tfihsemarf esu ot stpmetta era ereht yltnerruC .esaesid eht fo sisongaid eht ni dia osla nac snoitatum tnelaverp gniwonK .esuac eht fo trap tsael ta sa snoitatum tfihsemarf evah sesaesid lareveS
==sesaesiD==


>fer/<}}6002=raey| 4813652=cmp| 44310861=dimp| 222440.6002.gmj/6311.01=iod|698–398=segap|11=eussi|34=emulov|sciteneG lacideM fo lanruoJ=lanruoj|esaesid s'notgnitnuH ni stcudorp tfihsemarf eniresylop dna eninalayloP=eltit|C D ,nietzsnibuR=2rohtua|E J=tsrif|seivaD=tsal|lanruoj etic{{>fer<.)GCGPRTAAPAAAPA( 1 noxe ttH fo sunimret C eht ot epotipe levon a ecudortni dna emarf gnidocne-eninalaylop ,ACG eht ot )tfihs emarf 1+( 1+ yb emarf gnidoc neenimatulgylop ,GAC eht tfihs dluow 1 noxe nitgnitnuh fo tcart enimatulgylop eht nihtiw noitresni editoelcun elgnis ro noiteled editoelcunid A .emarf gnidocne-eninalaylop eht ot enimatulgylop eht morf gnitfihs ni gnitluser msinahcem eht sa desoporp neeb sah nietorp 3ACS eht fo noitalsnart gnirud egappils lamosobiR .seninalaylop/ACG ot senimatulgylop/GAC gnidocne tcudorp eneg 3ACS lanigiro eht fo gnitfihs emarf sa ,snoitatum noisnapxe eninalaylop dna enimatulgylop yb desuac sesaesid neewteb knil a eb yam erehT .yhportanaisyulodillap-laburotatned dna yhporta ralucsum rablubonips ,3 dna 7 ,6 ,2 ,1 )ACS( aixata ralleberec-onips edulcni taht snoitatum noisnapxe enimatulgylop yb desuac sredrosid noitaretier nodoc enin eht fo eno si ]]esaesid s'notgnitnuH[[
A US [[patent]] (5,958,684) in 1999 by Leeuwen, details the methods and reagents for diagnosis of diseases caused by or associated with a gene having a somatic mutation giving rise to a frameshift mutation. The methods include providing a tissue or fluid sample and conducting gene analysis for frameshift mutation or a protein from this type of mutation. The nucleotide sequence of the suspected gene is provided from published gene sequences or from [[cloning]] and sequencing of the suspect gene. The amino acid sequence encoded by the gene is then predicted.<ref>US Patent [http://www.google.com/patents?vid=USPAT5958684 5,958,684] (September 28, 1999) "Diagnosis of Neurodegenerative Disease" by Leeuwen ''et al''</ref>


>/ "noitatum tfihsemarf gnitide"=eman fer<.nietorp eht fo tluser dne eht ni ecnereffid a ,revewoh si erehT .riap esab a fo noiteled dna noitidda eht neewteb ycneuqerf eht ni ecnereffid on saw ereht taht nwohs saw tI .riap esab a gniteled dna gnidda htob yb noitatum eht fo ycneuqerf ni ecnereffid eht ta dekool ]]ytisrevinU yromE[[ morf maet a tub ,stnemirepxe 4+ eht dellac ,sriapesab ruof gnidda yb nur neeb evah stnemirepxE .seditoelcun fo rebmun tes-erp a gnivomer ro gnidda yb noitatum tfihsemarf eht fo ycneuqerf eht enimreted ot nur eb nac s]]tnemirepxE[[ >fer/<}}6674.7.91.BCM/8211.01=iod|57248=cmp|62537301=dimp|37–6674=segap|7=eussi|91=emulov|9991 yluJ=etad|ygoloiB ralulleC dna raluceloM=lanruoj|.eaisiverec secymorahccaS ni snietorp riaper hctamsim yb setaidemretni tfihsemarf fo lavomeR=eltit|S ,nostreboR-skniJ=2rohtua|DB=tsrif|efraH=tsal|lanruoj etic{{>"noitatum tfihsemarf gnitide"=eman fer<.]]ecneuqes[[ eht retne ot snoitatum rof gniwolla ,snoiger taeper ni emyzne esaremylop eht fo gnippils fo esuaceb si siht rof nosaer A .AND fo snoiger taeper ni nommoc erom eb ot dnuof era snoitatum tfihsemarF
====Frequency====


>fer/<}}2754333=cmp|9r-2-31-2102-bg/6811.01=iod| 00222322=dimp|9R=segap|2=eussi|31=emulov|2102 yraurbeF 9=etad|ygoloiB emoneG=lanruoj|.sledni gnitfihsemarf fo stceffe eht gnitciderP=eltit|CP ,gN=2rohtua|J=tsrif|uH=tsal|lanruoj etic{{>"stfihsemarf gnitciderp"=eman fer<.esaesid citeneg dezingocer yltnerruc ni tsefinam taht snoitatum fo %42 pu ekam )sriap esab 02 naht ssel esoht( snoiteled ro snoitresni llamS >/8002_ht6_GoBM=eman fer<.egassem eht fo )noitamrofni citeneg( yticapac gnidoc eht egnahc yllacitsard nac noitatum tfihsemarf A >/8002_ht6_GoBM=eman fer<.]]noitatum esnesnon[[ dna ]]noitatum esnessim[[ yllacificeps ,snoitatum tniop dezingocer fo sepyt rehto owt tsael ta era erehT .epyt ylno eht ton si noitatum tfihsemarf ;rucco od snoitatum ,noitalsnart gnirud sa llew sa noitacilper AND fo ssecorp eht gnirud noitamrofni citeneg fo refsnart tcerroc eht erusne ot llec a ni tneserp smsinahcem suoirav eht dna edoc citeneg eht nrevog taht selur eht etipseD
Despite the rules that govern the genetic code and the various mechanisms present in a cell to ensure the correct transfer of genetic information during the process of DNA replication as well as during translation, mutations do occur; frameshift mutation is not the only type. There are at least two other types of recognized point mutations, specifically [[missense mutation]] and [[nonsense mutation]].<ref name=MBoG_6th_2008/> A frameshift mutation can drastically change the coding capacity (genetic information) of the message.<ref name=MBoG_6th_2008/> Small insertions or deletions (those less than 20 base pairs) make up 24% of mutations that manifest in currently recognized genetic disease.<ref name="predicting frameshifts">{{cite journal|last=Hu|first=J|author2=Ng, PC|title=Predicting the effects of frameshifting indels.|journal=Genome Biology|date=9 February 2012|volume=13|issue=2|pages=R9|pmid=22322200 |doi=10.1186/gb-2012-13-2-r9|pmc=3334572}}</ref>


====ycneuqerF====
Frameshift mutations are found to be more common in repeat regions of DNA. A reason for this is because of slipping of the polymerase enzyme in repeat regions, allowing for mutations to enter the [[sequence]].<ref name="editing frameshift mutation">{{cite journal|last=Harfe|first=BD|author2=Jinks-Robertson, S|title=Removal of frameshift intermediates by mismatch repair proteins in Saccharomyces cerevisiae.|journal=Molecular and Cellular Biology|date=July 1999|volume=19|issue=7|pages=4766–73|pmid=10373526|pmc=84275|doi=10.1128/MCB.19.7.4766}}</ref> [[Experiment]]s can be run to determine the frequency of the frameshift mutation by adding or removing a pre-set number of nucleotides. Experiments have been run by adding four basepairs, called the +4 experiments, but a team from [[Emory University]] looked at the difference in frequency of the mutation by both adding and deleting a base pair. It was shown that there was no difference in the frequency between the addition and deletion of a base pair. There is however, a difference in the end result of the protein.<ref name="editing frameshift mutation" />


>fer/<''la te'' newueeL yb "esaesiD evitarenegedorueN fo sisongaiD" )9991 ,82 rebmetpeS( ]486,859,5 4868595TAPSU=div?stnetap/moc.elgoog.www//:ptth[ tnetaP SU>fer<.detciderp neht si eneg eht yb dedocne ecneuqes dica onima ehT .eneg tcepsus eht fo gnicneuqes dna ]]gninolc[[ morf ro secneuqes eneg dehsilbup morf dedivorp si eneg detcepsus eht fo ecneuqes editoelcun ehT .noitatum fo epyt siht morf nietorp a ro noitatum tfihsemarf rof sisylana eneg gnitcudnoc dna elpmas diulf ro eussit a gnidivorp edulcni sdohtem ehT .noitatum tfihsemarf a ot esir gnivig noitatum citamos a gnivah eneg a htiw detaicossa ro yb desuac sesaesid fo sisongaid rof stnegaer dna sdohtem eht sliated ,newueeL yb 9991 ni )486,859,5( ]]tnetap[[ SU A
[[Huntington's disease]] is one of the nine codon reiteration disorders caused by polyglutamine expansion mutations that include spino-cerebellar ataxia (SCA) 1, 2, 6, 7 and 3, spinobulbar muscular atrophy and dentatorubal-pallidoluysianatrophy. There may be a link between diseases caused by polyglutamine and polyalanine expansion mutations, as frame shifting of the original SCA3 gene product encoding CAG/polyglutamines to GCA/polyalanines. Ribosomal slippage during translation of the SCA3 protein has been proposed as the mechanism resulting in shifting from the polyglutamine to the polyalanine-encoding frame. A dinucleotide deletion or single nucleotide insertion within the polyglutamine tract of huntingtin exon 1 would shift the CAG, polyglutamineen coding frame by +1 (+1 frame shift) to the GCA, polyalanine-encoding frame and introduce a novel epitope to the C terminus of Htt exon 1 (APAAAPAATRPGCG).<ref>{{cite journal|last=Davies|first=J E|author2=Rubinsztein, D C|title=Polyalanine and polyserine frameshift products in Huntington's disease|journal=Journal of Medical Genetics|volume=43|issue=11|pages=893–896|doi=10.1136/jmg.2006.044222 |pmid=16801344 |pmc=2563184 |year=2006}}</ref>


==Diseases==
====sisongaiD====
Several diseases have frameshift mutations as at least part of the cause. Knowing prevalent mutations can also aid in the diagnosis of the disease. Currently there are attempts to use frameshift mutations beneficially in the treatment of diseases, changing the reading frame of the amino acids.
[[File:mutations on BRCA1.jpg|250px|thumb|Frequency of mutations on BRCA1 gene on chromosome 17]]
[[File:mutations on BRCA2.jpg|250px|thumb|Frequency of mutations on BRCA2 gene on chromosome 13]]


>fer/<}} 4856092=cmp| 22061602=dimp| 7013897001.sanp/3701.01=iod| 33–92621=segap|0102=raey|82=eussi|701=emulov| A S U icS dacA ltaN corP=lanruoj|gnicneuqes lellarap ylevissam dna erutpac cimoneg gnisu recnac nairavo dna tsaerb rof snoitatum detirehni fo noitceteD=eltit|.C-.M=01tsrif|gniK=01tsal|.M .E=9tsrif|rehsiwS=9tsal|.B .J=8tsrif|llednaM=8tsal|.S .A=7tsrif|droN=7tsal|.C=6tsrif|linneP=6tsal|.M .S=5tsrif|yartS=5tsal|.M .A=4tsrif|notnrohT=4tsal|.S=3tsrif|iedasaC=3tsal|.K .M=2tsrif|eeL=2tsal|.T=1tsrif|hslaW=1tsal|lanruoj etic{{>"0102eeLhslaW"=eman fer<.snoitatum tfihsemarf rof sllac evitisop eslaf on dah dna seneg 12 rof detset dohtem gnicneuqes rewen siht fo ycarucca eht enimreted ot tnemirepxe nA >fer/<}} 8567023=cmp| 11360022=dimp| 8012505111.sanp/3701.01 = iod|7–23081 = segap|1102 = raey|44 = eussi|801 = emulov| A S U icS dacA ltaN corP= lanruoj|gnicneuqes lellarap ylevissam yb deifitnedi amonicrac laenotirep dna ,ebut naipollaf ,nairavo detirehni rof seneg 21 ni snoitatuM :revoC eht morF = eltit|.M .E = 51tsrif|rehsiwS = 51tsal|.C-.M = 41tsrif|gniK = 41tsal|.L .R = 31tsrif|aicraG = 31tsal|.P .K = 21tsrif|notgninneP = 21tsal|.B = 11tsrif|tsiuqroN = 11tsal|.A = 01tsrif|ekayanamarkciW = 01tsal|.M .S = 9tsrif|yartS = 9tsal|.J .K = 8tsrif|wengA = 8tsal|.W = 7tsrif|beoR = 7tsal|.M .A = 6tsrif|notnrohT = 6tsal|.S .A = 5tsrif|droN = 5tsal|.C .C = 4tsrif|linneP = 4tsal|.K .M = 3tsrif|eeL = 3tsal|.S = 2tsrif|iedasaC = 2tsal|.T = 1tsrif|hslaW = 1tsal|lanruoj etic{{>"1102iedasaChslaW"=eman fer<.stset cificeps lareves ot desoppo sa ecno ta snoitatum gnisuac recnac fo yteirav a rof tset nac gnicneuqeS lellaraP ylevissaM .emit a ta eneg eno ta gnikool rof wolla ylno sdohtem tnerruc ,samonicrac tnereffid rof gnitset nehW >fer/<}}4425272=cmp|42297691=dimp|220.60.9002.ghja.j/6101.01=iod| 451–241=segap|9002=raey|2=eussi|58=emulov|sciteneG namuH fo lanruoJ naciremA ehT=lanruoj|enicideM citeneG ni gnihT giB txeN ehT :gnicneuqeS lellaraP ylevissaM=eltit|.M naJ=3tsrif|namdeirF=3tsal|ocraM=2tsrif|arraM=2tsal|ycarT=1tsrif|rekcuT=1tsal|lanruoj etic{{>"9002arraMrekcuT"=eman fer<.snoitacilppa lacinilc ni desu eb ot ta dekool gnieb si ti dna tset siht mrofrep ot elbaliava era seigolonhcet lareveS .esabolik 1 tuoba ylno fo ]]gnicneuqes regnaS[[ rof segnar detimil ot desoppo sa ,ecno ta decneuqes eb nac sesabagig 71 ot pu ,dohtem siht gnisU .snoitatum tceted ot desu eb nac taht dohtem rewen a si ]]gnicneuqeS lellaraP ylevissaM|gnicneuqes lellarap ylevissaM[[
===Cancer===


>/ "stfihsemarf gnitciderp"=eman fer<.]]noxe[[ eht fo dne eht ot ledni eht fo ecnatsid eht yllanif dna sdica onima detceffa dna devresnoc fo oitar eht driht ,tpircsnart eht ot evitaler noitatum eht fo noitacol eht dnoces ,AND devresnoc dna detceffa eht neewteb oitar eht ,tsriF .serutaef ruof ta gnikool yb enod si sihT .tceffe gnigamad a sah noitatum eht fi enimreted ot )DMGH( esabataD noitatuM emoneG namuH eht tsniaga derapmoc si ti devresbo si noitatum tfihsemarf a nehW .sesabatad rehto htiw palrevo ton od taht gnicneuqes regnaS hguorht deifitnedi neeb evah s>/ikiwon<]]ledni[[ noillim 69.1 ,llits nevE .ytilauq tsehgih eht fo eb ton lliw detareneg atad taht ylekil si ti ,revewoh ,snoitatum tfihsemarf tceted ot desu neeb evah taht sdohtem owt era ]]gnicneuqesoryp[[ dna ]]gnicneuqes regnaS[[
{{Main article|cancer}}
]].]]nodoc pots[[ a gnimrof yb ylerutamerp pots sisehtnys nietorp ekam nac dna ,ti gniwollof nodoc yreve sretla noitatum noiteled A|bmuht|gpj.)53931726031( noiteled tfihsemarF:eliF[[
====gnicneuqeS====


>fer/<}} 9002=raey|77255191=dimp&gnol=weiv?pukooldimp/igc/gro.slanruojdrofxo.ran//:ptth=lru| 9565562=cmp| 77255191=dimp| 9–2861=segap| 5=eussi| 73=emulov| 2401nkg/ran/3901.01=iod| hcraeseR sdicA cielcuN=lanruoj| noitcnuj etalpmet–remirp eht ta seglub dna spool fo noitamrof eht :snoiteled tfihsemarf editoelcunirt fo sledom AND=eltit| nosnhoJ .P lieN=5rohtua| leppiH nov .H reteP=4rohtua| ledenoP .C nimajneB=3rohtua| esoJ sivaD=2rohtua| esaaB=tsal| .A retlaW=tsrif| lanruoj etic{{>fer<.erutcurts yradnoces AND gnirobhgien yb deifidom eb nac stnemngilasim taht gniwohs ,noitcnuj etalpmet–remirp eht ta denoitisop erew sesab dedurtxe eht nehw devresbo saw egde maertsnwod sti ta noitamrofnoc AND dekcatsnu lausunu na htiw erutcurts pool-elbuod a ,tsartnoc nI .AND xelpud yb sedis htob no deknalf erutcurts a .e.i ,eglub a sa tuo-depool sesab etalpmet nehw devresbo saw snoitamrofnoc noitazidirbyh ruof fo erutxim muirbiliuqe na taht laever dnarts remirp eht fo htgnel eht fo stceffe eht no seidutS >fer/<}}874373=cmp| 29539941=dimp| 1011950040.sanp/3701.01=iod| 13–6243=segap| 01=eussi| 101=emulov| 4002 hcraM=etad| A S U icS dacA ltaN corP=lanruoj| ANR dna AND fo noitamrofnoc lacol fo eborp a sa editoelcunid eniruponima-2 fo msiorhcid ralucric ygrene-woL=eltit| leppiH nov .H reteP=3rohtua| esaaB .A retlaW=2rohtua| nosnhoJ=tsal| .P lieN=tsrif| lanruoj etic{{>fer<.ecneuqes AND a fo segnahc lacol eht yduts ot eno stimrep ,seugolana esab fo snaem yb ,AND deggat yltnecseroulF .]]ecnecseroulf[[ gnisu htped ni detagitsevni neeb sah snoitatum tfihsemarf fo ycneuqerf eht tceted ot erutcurts yradnoces dna sesab gnirobhgien fo stceffe ehT
Frameshift mutations are known to be a factor in [[colorectal]] cancer as well as other [[cancers]] with [[microsatellite instability]]. As stated previously, frameshift mutations are more likely to occur in a region of repeat sequence. When DNA mismatch repair does not fix the addition or deletion of bases, these mutations are more likely to be pathogenic. This may be in part because the tumor is not told to stop growing. Experiments in yeast and bacteria help to show characteristics of microsatellites that may contribute to defective DNA mismatch repair. These include the length of the [[microsatellite]], the makeup of the genetic material and how pure the repeats are. Based on experimental results longer microsatellites have a higher rate of frameshift mutations. The flanking DNA can also contribute to frameshift mutations.<ref name="microsatellite instability">{{cite journal|last=Schmoldt|first=A|author2=Benthe, HF|author3=Haberland, G|title=Digitoxin metabolism by rat liver microsomes |journal=Biochemical Pharmacology|date=1 September 1975|volume=24|issue=17|pages=1639–41 |pmid=10 |doi=10.1016/0006-2952(75)90094-5 |url=https://serval.unil.ch/notice/serval:BIB_EE7D4CC5FB04}}</ref> In prostate cancer a frameshift mutation changes the [[open reading frame]] (ORF) and prevents [[apoptosis]] from occurring. This leads to an unregulated growth of the [[tumor]]. While there are environmental factors that contribute to the progression of [[prostate cancer]], there is also a genetic component. During testing of coding regions to identify mutations, 116 genetic variants were discovered, including 61 frameshift mutations.<ref name="somatic mutations in prostate cancer">{{cite journal|last=Xu|first=XiaoLin|author2=Zhu, KaiChang|author3=Liu, Feng|author4=Wang, Yue|author5=Shen, JianGuo|author6=Jin, Jizhong|author7=Wang, Zhong|author8=Chen, Lin|author9=Li, Jiadong|author10= Xu, Min|title=Identification of somatic mutations in human prostate cancer by RNA-Seq|journal=Gene|doi=10.1016/j.gene.2013.01.046 |pmid=23434521 |volume=519|issue=2|date=May 2013|pages=343–7}}</ref> There are over 500 mutations on chromosome 17 that seem to play a role in the development of breast and ovarian cancer in the BRCA1 gene, many of which are frameshift.<ref name="cancer genomics">{{cite web|title=Cancer Genomics|url=http://www.cancer.gov/cancertopics/understandingcancer/cancergenomics/AllPages|publisher=National Cancer Institute at the National Institute of Health|accessdate=24 March 2013}}</ref>


===Crohn's disease===
====ecnecseroulF====


===noitceteD===
[[Crohn's disease]] has an association with the NOD2 gene. The mutation is an insertion of a [[Cytosine]] at position 3020. This leads to a premature stop codon, shortening the protein that is supposed to be transcribed. When the protein is able to form normally, it responds to bacterial liposaccharides, where the 3020insC mutation prevents the protein from being responsive.<ref>{{cite journal|vauthors=Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nuñez G, Cho JH |title=A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.|journal=Nature|date=May 31, 2001|volume=411|issue=6837|pages=603–6|pmid=11385577|doi=10.1038/35079114|hdl=2027.42/62856|url=https://deepblue.lib.umich.edu/bitstream/2027.42/62856/1/411603a0.pdf}}</ref>


>fer/<}}4991 yluJ=etad|6008208=dimp| 7341.4991.ibmj/6001.01=iod|242–622=segap|3=eussi|042=emulov|ygoloiB raluceloM fo lanruoJ=lanruoj|ytivitcA esaelcunoxE ′5 → ′3 ni tneicifeD sesaremyloP AND yb ortiV ni snoitatuM tfihsemarF decudni-VU fo noitcudorP=eltit|dranreB ,ssuartS =4rohtua|ainoS ,ayrahcA =3rohtua|htidE ,notgnikruT=2rohtua|anhpaD=tsrif|rehgaS=tsal|lanruoj etic{{>fer<.stfihsemarf decudni-VU fo ycneuqerf eht sesaercni ytivitca gnidaerfoorp fo ssol taht setacidni atad ehT .strapretnuoc tneiciforp ]]esaelcunoxe[[ rieht did naht ycneuqerf rehgih ta stnatrever decudni-VU ecudorp ytivitca esaelcunoxe ′5 → ′3 fo dioved ]]semyzne[[ tnatum esaremylop AND 7T dna fK I lop ]]iloc .E[[ .stfihsemarf yduts ot )CDIM( AAC ATT C TTG CTG fo )TDIM( AAC ATT T TTG CTG ot degnahc saw ′3 AAC ATT TTG CTG ′5 ecneuqes lamron ehT .enod saw ytivitca esaelcunoxe ′5 → ′3 ni tneicifed sesaremylop AND yb snoitatum tfihsemarf decudni-]]VU[[ fo noitcudorp eht yllacificeps ,yduts latnemnorivne nA .retfa thguos gnieb yllaunitnoc era rucco snoitatum tfihsemarf woh dna yhW .sesab editoelcun fo level eht ta noitatum citeneg a si sihT
===Cystic fibrosis===


}}noitatum|elcitra niaM{{
[[Cystic fibrosis]] (CF) is a disease based on mutations in the CF [[transmembrane]] conductance regulator (CFTR) gene. There are over 1500 mutations identified, but not all cause the disease.<ref name="guidelines for CF">{{cite journal|vauthors=Farrell PM, Rosenstein BJ, White TB, Accurso FJ, Castellani C, Cutting GR, Durie PR, Legrys VA, Massie J, Parad RB, Rock MJ, Campbell PW |title=Guidelines for Diagnosis of Cystic Fibrosis in Newborns through Older Adults: Cystic Fibrosis Foundation Consensus Report|journal=The Journal of Pediatrics|volume=153|issue=2|pages=S4–S14|doi=10.1016/j.jpeds.2008.05.005 |pmid=18639722 |pmc=2810958 |year=2008}}</ref> Most cases of cystic fibrosis are a result of the ∆F508 mutation, which deletes the entire amino acid. Two frameshift mutations are of interest in diagnosing CF, CF1213delT and CF1154-insTC. Both of these mutations commonly occur in tandem with at least one other mutation. They both lead to a small decrease in the function of the [[lungs]] and occur in about 1% of patients tested. These mutations were identified through Sanger sequencing.<ref name="frameshift mutations in CF">{{cite journal|last=Iannuzzi|first=MC|author2=Stern, RC|author3=Collins, FS|author4=Hon, CT|author5=Hidaka, N|author6=Strong, T|author7=Becker, L|author8=Drumm, ML|author9=White, MB|author10= Gerrard, B|title=Two frameshift mutations in the cystic fibrosis gene.|journal=American Journal of Human Genetics|date=February 1991|volume=48|issue=2|pages=227–31|pmid=1990834|pmc=1683026}}</ref>


===latnemnorivne ro citeneG===
===HIV===


.AND ni srorre fo egatnecrep tnacifingis a rof tnuocca yeht tub ,snietorp tcerrocni ro etelpmocni ot dael nac taht noitatum fo epyt eno tsuj era stfihsemarF .sdohtem tnereffid lareves aiv rucco nac snoitatum tfihsemarf fo noitceted ehT .sulumits lanretxe na yb desuac eb ro ylmodnar rucco nac snoitatum tfihsemarF
{{Main article|HIV/AIDS}}


==msinahceM==
[[CCR5]] is one of the cell entry co-factors associated with HIV, most frequently involved with nonsyncytium-inducing strains, is most apparent in HIV patients as opposed to AIDS patients. A 32 base pair deletion in CCR5 has been identified as a mutation that negates the likelihood of an HIV infection. This region on the open reading frame [[Open reading frame|ORF]] contains a frameshift mutation leading to a premature stop codon. This leads to the loss of the HIV-coreceptor function in vitro. CCR5-1 is considered the wild type and CCR5-2 is considered to be the mutant allele. Those with a heterozygous mutation for the CCR5 were less susceptible to the development of HIV. In a study, despite high exposure to the HIV virus, there was no one homozygous for the CCR5 mutation that tested positive for HIV.<ref name="HIV resistance"/>


>-- ]]noitatum tfihsemarf ni segnahc dica onima fo elpmaxE|bmuht|xp052|gpj.snoitatum tfihsemarF:eliF[[ :devomer egami deteleD --!<
===Tay–Sachs disease===
]]snoitatum tniop fo sepyt tnereffid fo elpmaxE|bmuht|xp052|gpj.noitatuM tnioP:eliF[[
>/8002_ht6_GoBM=eman fer<.emarf gnidaer dexif a ni detalsnart si egassem eht taht ,evoba detats sa ,elur tsal ehT .spag on sah egassem eht dna gnippalrevonon era snodoc ,dnoceS .noitcerid '3 ot '5 a ni daer era snodoc ,tsriF .ANRm ni snodoc rotinom eht selur eerht ot tcejbus si edoc citeneg eht fo gnidaer ehT .txen eht ot telpirt eno sdaer ti sa deniatniam si dna snigeb ANRm eht gnitalsnart nehw tes si emarf gnidaer ehT .snietorp fo sisehtnys eht rof noitamrofni citeneg fo noitalsnart ot yek era snodoC >fer/<}} 1_nhel00picnirpregninhel/sliated/gro.evihcra//:sptth=lru| noitartsiger=ssecca-lru| 1-8017-7617-0-879=nbsi| 8002=raey| ocsicnarF naS=noitacol| nameerF .H.W=rehsilbup| yrtsimehcoib fo selpicnirp regninheL=eltit| L treblA=3tsrif| regninheL=3tsal| .R divaD=2tsrif| nosleN=2tsal| leahciM=tsrif| xoC=tsal| koob etic{{>80xoC=eman fer<.stelpirt suougitnoc yb denifed si ]]ecneuqes[[ enobkcab dica onima s′nietorp A .snigeb nodoc wen a yberehw ,emarf gnidaer eht sehsilbatse nodoc tsrif ehT .]]dica onima[[ niatrec a rof edoc taht telpirt a ,]]seditoelcun[[ eerht fo tes a si ]]nodoc[[ A
]]]]nodoc[[ eht ,edoc rettel eerht ehT|bmuht|xp003|gvs.sdicaonima-snodoc-ANR:eliF[[


}}edoc citeneG|elcitra niaM{{
[[Tay–Sachs disease]] is a fatal disease affecting the central nervous system. It is most frequently found in infants and small children. Disease progression begins in the [[womb]] but symptoms do not appear until approximately 6 months of age. There is no cure for the disease.<ref name="tay sachs">{{cite web|title=Learning About Tay-Sachs Disease|url=http://www.genome.gov/10001220|publisher=National Human Genome Research Institute|accessdate=24 March 2013}}</ref> Mutations in the β-hexosaminidase A (Hex A) gene are known to affect the onset of Tay-Sachs, with 78 mutations of different types being described, 67 of which are known to cause disease. Most of the mutations observed (65/78) are single base substitutions or SNPs, 11 deletions, 1 large and 10 small, and 2 insertions. 8 of the observed mutations are frameshift, 6 deletions and 2 insertions. A 4 base pair insertion in exon 11 is observed in 80% of Tay-Sachs disease presence in the [[Ashkenazi]] Jewish population. The frameshift mutations lead to an early stop codon which is known to play a role in the disease in infants. Delayed onset disease appears to be caused by 4 different mutations, one being a 3 base pair deletion.<ref name="Tay-Sachs mutations">{{cite journal|last=Myerowitz|first=R|title=Tay-Sachs disease-causing mutations and neutral polymorphisms in the Hex A gene.|journal=Human Mutation|year=1997|volume=9|issue=3|pages=195–208|pmid=9090523 |doi=10.1002/(SICI)1098-1004(1997)9:3<195::AID-HUMU1>3.0.CO;2-7}}</ref>


===ecnatropmi telpirt-nodoC===
===Smith–Magenis syndrome===


>/8002_ht6_GoBM=eman fer<.emarf gnidaer tcerroc eht rof swolla siht ,noitpircsnart retfa ANRm eht otni enidirU eteled ro tresni ot desu eb osla nac ]]ANR ediuG[[ .daer eb ot sdica onima tcerroc eht rof wolla ot ecneuqes eht gnitfihs ,noitatum yradnoces a gnitaerc yb noitatum lanigiro eht fo tceffe eht stesffo sihT .]]noitatum rosserppus[[ a fo esu eht si noitcerroc noitatum rof ytilibissop rehtonA .ecneuqes ]]epyt dliw[[ lanigiro eht ot kcab ecneuqes detatum eht egnahc hcihw rucco snoitatum esreveR .snoitatum tfihsemarf tneverp ot pleh taht sessecorp lacigoloib lareves era erehT
[[Smith–Magenis syndrome]] (SMS) is a complex [[syndrome]] involving intellectual disabilities, sleep disturbance, behavioural problems, and a variety of craniofacial, skeletal, and visceral anomalies. The majority of SMS cases harbor an ~3.5 Mb common deletion that encompasses the retinoic acid induced-1 (RAI1) gene. Other cases illustrate variability in the SMS [[phenotype]] not previously shown for RAI1 mutation, including hearing loss, absence of self-abusive behaviours, and mild global delays. Sequencing of RAI1 revealed mutation of a heptamericC-tract (CCCCCCC) in exon 3 resulting in frameshift mutations. Of the seven reported frameshift mutations occurring in poly C-tracts in RAI1, four cases (~57%) occur at this heptameric C-tract. The results indicate that this heptameric C-tract is a preferential recombination [[Recombination hotspot|hotspot]] insertion/deletions (SNindels) and therefore a primary target for analysis in patients suspected for mutations in RAI1.<ref>{{cite journal|last=Truong|first=Hoa T|author2=Dudding, Tracy|author3= Blanchard, Christopher L.|author4= Elsea, Sarah H|title=Frameshift mutation hotspot identified in Smith-Magenis syndrome: case report and review of literature|journal=BMC Medical Genetics|volume=11|issue=1|page=142|doi=10.1186/1471-2350-11-142 |pmid=20932317 |pmc=2964533 |year=2010}}</ref>


>fer/<}}0-18008.0.riv/9901.01=iod| 18396251=dimp|59–9832=segap|8 tP=eussi|58=emulov|4002 tsuguA=etad|ygoloriV lareneG fo lanruoJ ehT=lanruoj|.snoitatum tfihs-emarf larivorter ot snoitubirtnoc laminim sekam II esaremylop ANR tsoH=eltit|J=tsrif|gnahZ=tsal|lanruoj etic{{>"II esaremylop anr"=eman fer<.10000. dna 1000. fo egnar eht ni erehwemos ylno si snoitatum tfihsemarf gnicudni etar rorre eht ]]setoyrakorp[[ nI .II esaremyloP ANR fo esuaceb derrucco snoitatum tfihsemarf lla fo %31–3 ylno stnemirepxe nI .snoitatum tfihsemarf fo ecnerrucco eht fo esuac regnorts a eb ot thguoht si ,]]II esaremyloP ANR[[ ot desoppo sa ,]]esatpircsnart esreveR[[ .)6991 ,hguabaraF( ]]tsaey[[ dna ]]airetcab[[ ni srucco osla dna ]]sesuriv[[ ni nommoc ylriaf si sihT .snietorp ]]larivorter[[ vne-lop-gag eht sa hcus ,semarf gnidaer nepo gnippalrevo morf snietorp tnereffid gnicudorp ,noitalsnart ]]esahporp[[ gnirud rucco osla yam gnitfihsemarF
===Hypertrophic cardiomyopathy===


>/8002_ht6_GoBM=eman fer<.desaeler si uT-FE sa msinahcem gnidaerfoorp a dna ,ytilibats citenik fo mrof a ]]uT-FE[[ fo ytivitca sisylordyh ]]PTG|etahpsohpirt enisonauG[[ ,etis A emosobir eht ta gniriap esab reporp yb dehsilpmocca si ,emarf gnidaer reporp eht fo ecnatropmi eht gniniatniam ,noitingocer nodoc fo ytiledif sihT .tcerrocni si eno naht erom on ,nietorp eht otni detaroprocni dica onima 0001 yreve roF >/8002_ht6_GoBM=eman fer<.desaeler si dna desisehtnys neeb sah )nietorp( ]]editpepylop[[ eht tniop siht tA .dehcaer si )AAU ro AGU ,GAU( ]]nodoc pots[[ a litnu rehtegot denioj gnieb era ]]sdica onima[[ ,daer si )telpirt( nodoc hcae sA .ANRt eht fo snodocitna yb )dedoced( daer won era ANRm eht fo snodoc eht ni deirrac noitamrofni citeneg ehT .]]ANRr[[ na htiw stcaretni dna ]]emosobir[[ eht fo tinubus a htiw detaroprocni si ANRm ehT .]]ANRm[[ dellac etalpmet regnessem dnarts elgnis a no won era noitamrofni citeneg eht gniniatnoc seditoelcuN
[[Hypertrophic cardiomyopathy]] is the most common cause of [[sudden cardiac death|sudden death]] in young people, including trained athletes, and is caused by mutations in genes encoding proteins of the cardiac sarcomere. Mutations in the Troponin C gene (TNNC1) are a rare genetic cause of hypertrophic cardiomyopathy. A recent study has indicated that a frameshift mutation (c.363dupG or p.Gln122AlafsX30) in Troponin C was the cause of hypertrophic cardiomyopathy (and sudden cardiac death) in a 19-year-old male.<ref name="pmid21262074">{{cite journal |vauthors=Chung WK, Kitner C, Maron BJ |title=Novel frameshift mutation in Troponin C ( TNNC1) associated with hypertrophic cardiomyopathy and sudden death |journal=Cardiol Young |volume=21 |issue=3 |pages=345–8 |date=June 2011 |pmid=21262074 |doi=10.1017/S1047951110001927 }}</ref>
>/8002_ht6_GoBM=eman fer<.]]noitpircsnart|)sciteneg( noitpircsnart[[ yb dehsilpmocca si noitamrofni citeneg fo noitces detceles a fo gnidaer eht ,noitacilper AND retfA
]]ssecorp ]]noitalsnart|)ygoloib( noitalsnarT[[ ehT|bmuht|xp002|gnp.sciteneg-noitalsnarT:eliF[[
}})ygoloib( noitalsnarT|)sciteneg( noitpircsnarT|elcitra niaM{{
===noitalsnart dna noitpircsnarT===


>/8002_ht6_GoBM=eman fer<. ]]noitacilper AND[[ ni detaroprocni era smetsys ]]riaper hctamsim[[ dna s]]esaelcunoxe[[ sa hcus smsinahcem ]]gnidaerfoorp[[ ,no noitamrofni eht sessap yllufsseccus ]]emoneg[[ eht taht erusne oT .snoitcnuf ralullec lamronba yb yhtlaehnu emoceb ot ]]msinagro[[ rehgih eht esuac sesac tsom ni dna ytilibaiv ]]llec|)ygoloib( lleC[[ no stceffe latnemirted evah nac nietorp edam yltcerrocni nA .seitivitca ]]citylatac[[ rof dna larutcurts rof yletarucca decudorp eb ot deriuqer era snietorp ,noitcnuf ylreporp ot llec a roF >/8002_ht6_GoBM=eman fer<.amgod lartnec eht sa ]]nietorp[[ a gnikam rof tnemegnarra dica onima cificeps a ot ]]AND[[ morf noitamrofni citeneg fo wolf eht debircsed ]]kcirC sicnarF[[ 6591 nI
===Cures===
Finding a cure for the diseases caused by frameshift mutations is rare. Research into this is evident. One example is a primary [[immunodeficiency]] (PID), an inherited condition which can lead to an increase in infections. There are 120 genes and 150 mutations that play a role in primary immunodeficiencies. The standard treatment is currently '''gene therapy''', but this is a highly risky treatment and can often lead to other diseases, such as leukemia. Gene therapy procedures include modifying the zinc fringer nuclease fustion protein, cleaving both ends of the mutation, which in turn removes it from the sequence. Antisense-oligonucleotide mediated '''exon skipping''' is another possibility for Duchenne [[muscular dystrophy]]. This process allows for passing over the mutation so that the rest of the sequence remains in frame and the function of the protein stays intact. This, however, does not cure the disease, just treats symptoms, and is only practical in structural proteins or other repetitive genes. A third form of repair is '''revertant mosaicism''', which is naturally occurring by creating a reverse mutation or a mutation at a second site that corrects the reading frame. This reversion may happen by intragenic [[Genetic recombination|recombination]], [[mitotic]] gene conversion, second site DNA slipping or site-specific reversion. This is possible in several diseases, such as X-linked severe combined immunodeficiency (SCID), Wiskott–Aldrich syndrome, and Bloom syndrome. There are no drugs or other pharmacogenomic methods that help with PIDs.<ref name="PID treatments">{{cite journal|last=Hu|first=Hailiang|author2=Gatti, Richard A|title=New approaches to treatment of primary immunodeficiencies: fixing mutations with chemicals|journal=Current Opinion in Allergy and Clinical Immunology|volume=8|issue=6|pages=540–6|doi=10.1097/ACI.0b013e328314b63b |pmid=18978469 |pmc=2686128 |year=2008}}</ref>


}}ygoloib ralucelom fo amgod lartneC|elcitra niaM{{
A European patent (EP1369126A1) in 2003 by Bork records a method used for prevention of cancers and for the curative treatment of cancers and precancers such as DNA-mismatch repair deficient (MMR) sporadic tumours and HNPCC associated tumours. The idea is to use '''immunotherapy''' with combinatorial mixtures of tumour-specific frameshift mutation-derived peptides to elicit a cytotoxic T-cell response specifically directed against tumour cells.<ref>European Patent [http://www.google.com/patents/EP1369126A1?cl=en] (December 10, 2003) "Use of coding microsatellite region frameshift mutation-derived peptides for treating cancer" by Bork ''et al''</ref>


==See also==
===amgod lartneC===
* [[Translational frameshift]]
* [[Mutation]]
* [[Transcription (genetics)]]
* [[Translation (biology)]]
* [[codon]]
* [[protein]]
* [[reading frame]]
* [[point mutation]]
* [[Crohn's disease]]
* [[Tay–Sachs disease]]


]]ledom ]]amgod lartnec[[ ehT|bmuht|xp052|gvs.bmdC:eliF[[
==References==
{{reflist|2}}


.serusaem evitcerroc fo yteirav a setaroprocni llec eht sa neve esaesid esuac yllautneve dna tcerrocni eb ot noitcnuf nietorp esuac nac noitacinummoc siht gnidaer ni rorre na ,revewoH .snietorp gnikam otni detacinummoc eb ot noitamrofni siht wolla noitalsnart dna noitpircsnarT .smsinagro lla fo sllec eht ni noitcnuf nietorp senimreted AND ni deniatnoc noitamrofni ehT
== Further reading ==
{{refbegin}}
* {{cite journal | author = Farabaugh PJ | title = Programmed translational frameshifting | journal = Annu. Rev. Genet. | volume = 30 | issue = 1| pages = 507–28 | year = 1996 | pmid = 8982463 | pmc = 239420 | doi = 10.1146/annurev.genet.30.1.507 }}
* {{cite book | author = Lewis, Ricki | title = Human Genetics: Concepts and Applications | edition = 6th | publisher = McGraw Hill | location = Boston MA | year = 2005 | pages = 227–8 | isbn = 978-0-07-111156-0 }}
* {{cite web |url=http://www.talkorigins.org/origins/postmonth/apr04.html |title=Nylonase Enzymes |accessdate=2 June 2009 |date=20 April 2004}}
{{refend}}


==External links==
==dnuorgkcaB==
{{Commons category|Frameshift mutation}}
* {{MeshName|Frameshift+Mutation}}
*[https://www.ncbi.nlm.nih.gov/projects/SNP/ NCBI dbSNP database] — "a central repository for both single base nucleotide substitutions and short deletion and insertion polymorphisms"
* [http://www.ebi.ac.uk/Tools/Wise2/index.htm Wise2] - aligns a [[protein]] against a DNA sequence allowing [[frameshift]]s and [[intron]]s
* [http://fasta.bioch.virginia.edu/fasta_www2/fasta_www.cgi?rm=select&pgm=fy FastY] - compare a DNA sequence to a protein sequence database, allowing gaps and [[frameshift]]s
* [http://bioinfo.lifl.fr/path/ Path] - tool that compares two [[frameshift]] proteins (back-[[Translation (genetics)|translation]] principle)
* [http://www.hgmd.cf.ac.uk/ac/index.php HGMD] - Human Genome Mutation Database


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{{Mutation}}


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[[Category:Mutation]]

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}}tnemngila nodoc stfihs taht noitatum|noitpircsed trohS{{

Revision as of 14:02, 16 March 2020

]]noitatuM:yrogetaC[[

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yhtapoymoidrac cihportrepyH

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emordnys sinegaM–htimS

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esaesid shcaS–yaT

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}}SDIA/VIH|elcitra niaM{{

VIH

>fer/<}}6203861=cmp|4380991=dimp|13–722=segap|2=eussi|84=emulov|1991 yraurbeF=etad|sciteneG namuH fo lanruoJ naciremA=lanruoj|.eneg sisorbif citsyc eht ni snoitatum tfihsemarf owT=eltit|B ,drarreG =01rohtua|BM ,etihW=9rohtua|LM ,mmurD=8rohtua|L ,rekceB=7rohtua|T ,gnortS=6rohtua|N ,akadiH=5rohtua|TC ,noH=4rohtua|SF ,snilloC=3rohtua|CR ,nretS=2rohtua|CM=tsrif|izzunnaI=tsal|lanruoj etic{{>"FC ni snoitatum tfihsemarf"=eman fer<.gnicneuqes regnaS hguorht deifitnedi erew snoitatum esehT .detset stneitap fo %1 tuoba ni rucco dna ]]sgnul[[ eht fo noitcnuf eht ni esaerced llams a ot dael htob yehT .noitatum rehto eno tsael ta htiw mednat ni rucco ylnommoc snoitatum eseht fo htoB .CTsni-4511FC dna Tled3121FC ,FC gnisongaid ni tseretni fo era snoitatum tfihsemarf owT .dica onima eritne eht seteled hcihw ,noitatum 805F∆ eht fo tluser a era sisorbif citsyc fo sesac tsoM >fer/<}}8002=raey| 8590182=cmp| 22793681=dimp| 500.50.8002.sdepj.j/6101.01=iod|41S–4S=segap|2=eussi|351=emulov|scirtaideP fo lanruoJ ehT=lanruoj|tropeR susnesnoC noitadnuoF sisorbiF citsyC :stludA redlO hguorht snrobweN ni sisorbiF citsyC fo sisongaiD rof senilediuG=eltit| WP llebpmaC ,JM kcoR ,BR daraP ,J eissaM ,AV syrgeL ,RP eiruD ,RG gnittuC ,C inalletsaC ,JF osruccA ,BT etihW ,JB nietsnesoR ,MP llerraF=srohtuav|lanruoj etic{{>"FC rof senilediug"=eman fer<.esaesid eht esuac lla ton tub ,deifitnedi snoitatum 0051 revo era erehT .eneg )RTFC( rotaluger ecnatcudnoc ]]enarbmemsnartFC eht ni snoitatum no desab esaesid a si )FC( sisorbif citsyC[[

sisorbif citsyC

>fer/<}}fdp.0a306114/1/65826/24.7202/maertstib/ude.hcimu.bil.eulbpeed//:sptth=lru|65826/24.7202=ldh|41197053/8301.01=iod|77558311=dimp|6–306=segap|7386=eussi|114=emulov|1002 ,13 yaM=etad|erutaN=lanruoj|.esaesid s'nhorC ot ytilibitpecsus htiw detaicossa 2DON ni noitatum tfihsemarf A=eltit| HJ ohC ,G zeñuN ,BS reuanaH ,SB renhcsriK ,MT sselyaB ,RS tnarB ,PJ rakhcA ,HR rreuD ,R saksuilaraK ,T naroM ,H nottirB ,R somaR ,FF nehC ,LD ealociN ,N arahonI ,KD nenoB ,Y arugO=srohtuav|lanruoj etic{{>fer<.evisnopser gnieb morf nietorp eht stneverp noitatum Csni0203 eht erehw ,sedirahccasopil lairetcab ot sdnopser ti ,yllamron mrof ot elba si nietorp eht nehW .debircsnart eb ot desoppus si taht nietorp eht gninetrohs ,nodoc pots erutamerp a ot sdael sihT .0203 noitisop ta ]]enisotyCa fo noitresni na si noitatum ehT .eneg 2DON eht htiw noitaicossa na sah esaesid s'nhorC[[

esaesid s'nhorC

>fer/<}}3102 hcraM 42=etadssecca|htlaeH fo etutitsnI lanoitaN eht ta etutitsnI recnaC lanoitaN=rehsilbup|segaPllA/scimonegrecnac/recnacgnidnatsrednu/scipotrecnac/vog.recnac.www//:ptth=lru|scimoneG recnaC=eltit|bew etic{{>"scimoneg recnac"=eman fer<.tfihsemarf era hcihw fo ynam ,eneg 1ACRB eht ni recnac nairavo dna tsaerb fo tnempoleved eht ni elor a yalp ot mees taht 71 emosomorhc no snoitatum 005 revo era erehT >fer/<}}7–343=segap|3102 yaM=etad|2=eussi|915=emulov| 12543432=dimp| 640.10.3102.eneg.j/6101.01=iod|eneG=lanruoj|qeS-ANR yb recnac etatsorp namuh ni snoitatum citamos fo noitacifitnedI=eltit|niM ,uX =01rohtua|gnodaiJ ,iL=9rohtua|niL ,nehC=8rohtua|gnohZ ,gnaW=7rohtua|gnohziJ ,niJ=6rohtua|ouGnaiJ ,nehS=5rohtua|euY ,gnaW=4rohtua|gneF ,uiL=3rohtua|gnahCiaK ,uhZ=2rohtua|niLoaiX=tsrif|uX=tsal|lanruoj etic{{>"recnac etatsorp ni snoitatum citamos"=eman fer<.snoitatum tfihsemarf 16 gnidulcni ,derevocsid erew stnairav citeneg 611 ,snoitatum yfitnedi ot snoiger gnidoc fo gnitset gniruD .tnenopmoc citeneg a osla si ereht ,]]recnac etatsorpfo noissergorp eht ot etubirtnoc taht srotcaf latnemnorivne era ereht elihW .romuteht fo htworg detalugernu na ot sdael sihT .gnirrucco morf sisotpopastneverp dna )FRO( emarf gnidaer nepo[[ eht segnahc noitatum tfihsemarf a recnac etatsorp nI >fer/<}}40BF5CC4D7EE_BIB:lavres/eciton/hc.linu.lavres//:sptth=lru| 5-49009)57(2592-6000/6101.01=iod| 01=dimp| 14–9361=segap|71=eussi|42=emulov|5791 rebmetpeS 1=etad|ygolocamrahP lacimehcoiB=lanruoj| semosorcim revil tar yb msilobatem nixotigiD=eltit|G ,dnalrebaH=3rohtua|FH ,ehtneB=2rohtua|A=tsrif|tdlomhcS=tsal|lanruoj etic{{>"ytilibatsni etilletasorcim"=eman fer<.snoitatum tfihsemarf ot etubirtnoc osla nac AND gniknalf ehT .snoitatum tfihsemarf fo etar rehgih a evah setilletasorcim regnol stluser latnemirepxe no desaB .era staeper eht erup woh dna lairetam citeneg eht fo puekam eht ,]]etilletasorcim[[ eht fo htgnel eht edulcni esehT .riaper hctamsim AND evitcefed ot etubirtnoc yam taht setilletasorcim fo scitsiretcarahc wohs ot pleh airetcab dna tsaey ni stnemirepxE .gniworg pots ot dlot ton si romut eht esuaceb trap ni eb yam sihT .cinegohtap eb ot ylekil erom era snoitatum eseht ,sesab fo noiteled ro noitidda eht xif ton seod riaper hctamsim AND nehW .ecneuqes taeper fo noiger a ni rucco ot ylekil erom era snoitatum tfihsemarf ,ylsuoiverp detats sA .]]ytilibatsni etilletasorcimhtiw srecnacrehto sa llew sa recnac latceroloc[[ ni rotcaf a eb ot nwonk era snoitatum tfihsemarF

}}recnac|elcitra niaM{{

recnaC

]]31 emosomorhc no eneg 2ACRB no snoitatum fo ycneuqerF|bmuht|xp052|gpj.2ACRB no snoitatum:eliF[[ ]]71 emosomorhc no eneg 1ACRB no snoitatum fo ycneuqerF|bmuht|xp052|gpj.1ACRB no snoitatum:eliF[[ .sdica onima eht fo emarf gnidaer eht gnignahc ,sesaesid fo tnemtaert eht ni yllaicifeneb snoitatum tfihsemarf esu ot stpmetta era ereht yltnerruC .esaesid eht fo sisongaid eht ni dia osla nac snoitatum tnelaverp gniwonK .esuac eht fo trap tsael ta sa snoitatum tfihsemarf evah sesaesid lareveS

sesaesiD

>fer/<}}6002=raey| 4813652=cmp| 44310861=dimp| 222440.6002.gmj/6311.01=iod|698–398=segap|11=eussi|34=emulov|sciteneG lacideM fo lanruoJ=lanruoj|esaesid s'notgnitnuH ni stcudorp tfihsemarf eniresylop dna eninalayloP=eltit|C D ,nietzsnibuR=2rohtua|E J=tsrif|seivaD=tsal|lanruoj etic{{>fer<.)GCGPRTAAPAAAPA( 1 noxe ttH fo sunimret C eht ot epotipe levon a ecudortni dna emarf gnidocne-eninalaylop ,ACG eht ot )tfihs emarf 1+( 1+ yb emarf gnidoc neenimatulgylop ,GAC eht tfihs dluow 1 noxe nitgnitnuh fo tcart enimatulgylop eht nihtiw noitresni editoelcun elgnis ro noiteled editoelcunid A .emarf gnidocne-eninalaylop eht ot enimatulgylop eht morf gnitfihs ni gnitluser msinahcem eht sa desoporp neeb sah nietorp 3ACS eht fo noitalsnart gnirud egappils lamosobiR .seninalaylop/ACG ot senimatulgylop/GAC gnidocne tcudorp eneg 3ACS lanigiro eht fo gnitfihs emarf sa ,snoitatum noisnapxe eninalaylop dna enimatulgylop yb desuac sesaesid neewteb knil a eb yam erehT .yhportanaisyulodillap-laburotatned dna yhporta ralucsum rablubonips ,3 dna 7 ,6 ,2 ,1 )ACS( aixata ralleberec-onips edulcni taht snoitatum noisnapxe enimatulgylop yb desuac sredrosid noitaretier nodoc enin eht fo eno si ]]esaesid s'notgnitnuH[[

>/ "noitatum tfihsemarf gnitide"=eman fer<.nietorp eht fo tluser dne eht ni ecnereffid a ,revewoh si erehT .riap esab a fo noiteled dna noitidda eht neewteb ycneuqerf eht ni ecnereffid on saw ereht taht nwohs saw tI .riap esab a gniteled dna gnidda htob yb noitatum eht fo ycneuqerf ni ecnereffid eht ta dekool ]]ytisrevinU yromEmorf maet a tub ,stnemirepxe 4+ eht dellac ,sriapesab ruof gnidda yb nur neeb evah stnemirepxE .seditoelcun fo rebmun tes-erp a gnivomer ro gnidda yb noitatum tfihsemarf eht fo ycneuqerf eht enimreted ot nur eb nac stnemirepxE[[ >fer/<}}6674.7.91.BCM/8211.01=iod|57248=cmp|62537301=dimp|37–6674=segap|7=eussi|91=emulov|9991 yluJ=etad|ygoloiB ralulleC dna raluceloM=lanruoj|.eaisiverec secymorahccaS ni snietorp riaper hctamsim yb setaidemretni tfihsemarf fo lavomeR=eltit|S ,nostreboR-skniJ=2rohtua|DB=tsrif|efraH=tsal|lanruoj etic{{>"noitatum tfihsemarf gnitide"=eman fer<.]]ecneuqes[[ eht retne ot snoitatum rof gniwolla ,snoiger taeper ni emyzne esaremylop eht fo gnippils fo esuaceb si siht rof nosaer A .AND fo snoiger taeper ni nommoc erom eb ot dnuof era snoitatum tfihsemarF

>fer/<}}2754333=cmp|9r-2-31-2102-bg/6811.01=iod| 00222322=dimp|9R=segap|2=eussi|31=emulov|2102 yraurbeF 9=etad|ygoloiB emoneG=lanruoj|.sledni gnitfihsemarf fo stceffe eht gnitciderP=eltit|CP ,gN=2rohtua|J=tsrif|uH=tsal|lanruoj etic{{>"stfihsemarf gnitciderp"=eman fer<.esaesid citeneg dezingocer yltnerruc ni tsefinam taht snoitatum fo %42 pu ekam )sriap esab 02 naht ssel esoht( snoiteled ro snoitresni llamS >/8002_ht6_GoBM=eman fer<.egassem eht fo )noitamrofni citeneg( yticapac gnidoc eht egnahc yllacitsard nac noitatum tfihsemarf A >/8002_ht6_GoBM=eman fer<.]]noitatum esnesnondna noitatum esnessim[[ yllacificeps ,snoitatum tniop dezingocer fo sepyt rehto owt tsael ta era erehT .epyt ylno eht ton si noitatum tfihsemarf ;rucco od snoitatum ,noitalsnart gnirud sa llew sa noitacilper AND fo ssecorp eht gnirud noitamrofni citeneg fo refsnart tcerroc eht erusne ot llec a ni tneserp smsinahcem suoirav eht dna edoc citeneg eht nrevog taht selur eht etipseD

ycneuqerF

>fer/<la te newueeL yb "esaesiD evitarenegedorueN fo sisongaiD" )9991 ,82 rebmetpeS( ]486,859,5 4868595TAPSU=div?stnetap/moc.elgoog.www//:ptth[ tnetaP SU>fer<.detciderp neht si eneg eht yb dedocne ecneuqes dica onima ehT .eneg tcepsus eht fo gnicneuqes dna ]]gninolc[[ morf ro secneuqes eneg dehsilbup morf dedivorp si eneg detcepsus eht fo ecneuqes editoelcun ehT .noitatum fo epyt siht morf nietorp a ro noitatum tfihsemarf rof sisylana eneg gnitcudnoc dna elpmas diulf ro eussit a gnidivorp edulcni sdohtem ehT .noitatum tfihsemarf a ot esir gnivig noitatum citamos a gnivah eneg a htiw detaicossa ro yb desuac sesaesid fo sisongaid rof stnegaer dna sdohtem eht sliated ,newueeL yb 9991 ni )486,859,5( ]]tnetap[[ SU A

sisongaiD

>fer/<}} 4856092=cmp| 22061602=dimp| 7013897001.sanp/3701.01=iod| 33–92621=segap|0102=raey|82=eussi|701=emulov| A S U icS dacA ltaN corP=lanruoj|gnicneuqes lellarap ylevissam dna erutpac cimoneg gnisu recnac nairavo dna tsaerb rof snoitatum detirehni fo noitceteD=eltit|.C-.M=01tsrif|gniK=01tsal|.M .E=9tsrif|rehsiwS=9tsal|.B .J=8tsrif|llednaM=8tsal|.S .A=7tsrif|droN=7tsal|.C=6tsrif|linneP=6tsal|.M .S=5tsrif|yartS=5tsal|.M .A=4tsrif|notnrohT=4tsal|.S=3tsrif|iedasaC=3tsal|.K .M=2tsrif|eeL=2tsal|.T=1tsrif|hslaW=1tsal|lanruoj etic{{>"0102eeLhslaW"=eman fer<.snoitatum tfihsemarf rof sllac evitisop eslaf on dah dna seneg 12 rof detset dohtem gnicneuqes rewen siht fo ycarucca eht enimreted ot tnemirepxe nA >fer/<}} 8567023=cmp| 11360022=dimp| 8012505111.sanp/3701.01 = iod|7–23081 = segap|1102 = raey|44 = eussi|801 = emulov| A S U icS dacA ltaN corP= lanruoj|gnicneuqes lellarap ylevissam yb deifitnedi amonicrac laenotirep dna ,ebut naipollaf ,nairavo detirehni rof seneg 21 ni snoitatuM :revoC eht morF = eltit|.M .E = 51tsrif|rehsiwS = 51tsal|.C-.M = 41tsrif|gniK = 41tsal|.L .R = 31tsrif|aicraG = 31tsal|.P .K = 21tsrif|notgninneP = 21tsal|.B = 11tsrif|tsiuqroN = 11tsal|.A = 01tsrif|ekayanamarkciW = 01tsal|.M .S = 9tsrif|yartS = 9tsal|.J .K = 8tsrif|wengA = 8tsal|.W = 7tsrif|beoR = 7tsal|.M .A = 6tsrif|notnrohT = 6tsal|.S .A = 5tsrif|droN = 5tsal|.C .C = 4tsrif|linneP = 4tsal|.K .M = 3tsrif|eeL = 3tsal|.S = 2tsrif|iedasaC = 2tsal|.T = 1tsrif|hslaW = 1tsal|lanruoj etic{{>"1102iedasaChslaW"=eman fer<.stset cificeps lareves ot desoppo sa ecno ta snoitatum gnisuac recnac fo yteirav a rof tset nac gnicneuqeS lellaraP ylevissaM .emit a ta eneg eno ta gnikool rof wolla ylno sdohtem tnerruc ,samonicrac tnereffid rof gnitset nehW >fer/<}}4425272=cmp|42297691=dimp|220.60.9002.ghja.j/6101.01=iod| 451–241=segap|9002=raey|2=eussi|58=emulov|sciteneG namuH fo lanruoJ naciremA ehT=lanruoj|enicideM citeneG ni gnihT giB txeN ehT :gnicneuqeS lellaraP ylevissaM=eltit|.M naJ=3tsrif|namdeirF=3tsal|ocraM=2tsrif|arraM=2tsal|ycarT=1tsrif|rekcuT=1tsal|lanruoj etic{{>"9002arraMrekcuT"=eman fer<.snoitacilppa lacinilc ni desu eb ot ta dekool gnieb si ti dna tset siht mrofrep ot elbaliava era seigolonhcet lareveS .esabolik 1 tuoba ylno fo ]]gnicneuqes regnaSrof segnar detimil ot desoppo sa ,ecno ta decneuqes eb nac sesabagig 71 ot pu ,dohtem siht gnisU .snoitatum tceted ot desu eb nac taht dohtem rewen a si gnicneuqeS lellaraP ylevissaM|gnicneuqes lellarap ylevissaM[[

>/ "stfihsemarf gnitciderp"=eman fer<.]]noxe[[ eht fo dne eht ot ledni eht fo ecnatsid eht yllanif dna sdica onima detceffa dna devresnoc fo oitar eht driht ,tpircsnart eht ot evitaler noitatum eht fo noitacol eht dnoces ,AND devresnoc dna detceffa eht neewteb oitar eht ,tsriF .serutaef ruof ta gnikool yb enod si sihT .tceffe gnigamad a sah noitatum eht fi enimreted ot )DMGH( esabataD noitatuM emoneG namuH eht tsniaga derapmoc si ti devresbo si noitatum tfihsemarf a nehW .sesabatad rehto htiw palrevo ton od taht gnicneuqes regnaS hguorht deifitnedi neeb evah s>/ikiwon<]]ledninoillim 69.1 ,llits nevE .ytilauq tsehgih eht fo eb ton lliw detareneg atad taht ylekil si ti ,revewoh ,snoitatum tfihsemarf tceted ot desu neeb evah taht sdohtem owt era gnicneuqesorypdna gnicneuqes regnaS[[ ]].]]nodoc pots[[a gnimrof yb ylerutamerp pots sisehtnys nietorp ekam nac dna ,ti gniwollof nodoc yreve sretla noitatum noiteled A|bmuht|gpj.)53931726031( noiteled tfihsemarF:eliF[[

gnicneuqeS

>fer/<}} 9002=raey|77255191=dimp&gnol=weiv?pukooldimp/igc/gro.slanruojdrofxo.ran//:ptth=lru| 9565562=cmp| 77255191=dimp| 9–2861=segap| 5=eussi| 73=emulov| 2401nkg/ran/3901.01=iod| hcraeseR sdicA cielcuN=lanruoj| noitcnuj etalpmet–remirp eht ta seglub dna spool fo noitamrof eht :snoiteled tfihsemarf editoelcunirt fo sledom AND=eltit| nosnhoJ .P lieN=5rohtua| leppiH nov .H reteP=4rohtua| ledenoP .C nimajneB=3rohtua| esoJ sivaD=2rohtua| esaaB=tsal| .A retlaW=tsrif| lanruoj etic{{>fer<.erutcurts yradnoces AND gnirobhgien yb deifidom eb nac stnemngilasim taht gniwohs ,noitcnuj etalpmet–remirp eht ta denoitisop erew sesab dedurtxe eht nehw devresbo saw egde maertsnwod sti ta noitamrofnoc AND dekcatsnu lausunu na htiw erutcurts pool-elbuod a ,tsartnoc nI .AND xelpud yb sedis htob no deknalf erutcurts a .e.i ,eglub a sa tuo-depool sesab etalpmet nehw devresbo saw snoitamrofnoc noitazidirbyh ruof fo erutxim muirbiliuqe na taht laever dnarts remirp eht fo htgnel eht fo stceffe eht no seidutS >fer/<}}874373=cmp| 29539941=dimp| 1011950040.sanp/3701.01=iod| 13–6243=segap| 01=eussi| 101=emulov| 4002 hcraM=etad| A S U icS dacA ltaN corP=lanruoj| ANR dna AND fo noitamrofnoc lacol fo eborp a sa editoelcunid eniruponima-2 fo msiorhcid ralucric ygrene-woL=eltit| leppiH nov .H reteP=3rohtua| esaaB .A retlaW=2rohtua| nosnhoJ=tsal| .P lieN=tsrif| lanruoj etic{{>fer<.ecneuqes AND a fo segnahc lacol eht yduts ot eno stimrep ,seugolana esab fo snaem yb ,AND deggat yltnecseroulF .]]ecnecseroulf[[ gnisu htped ni detagitsevni neeb sah snoitatum tfihsemarf fo ycneuqerf eht tceted ot erutcurts yradnoces dna sesab gnirobhgien fo stceffe ehT

ecnecseroulF

noitceteD

>fer/<}}4991 yluJ=etad|6008208=dimp| 7341.4991.ibmj/6001.01=iod|242–622=segap|3=eussi|042=emulov|ygoloiB raluceloM fo lanruoJ=lanruoj|ytivitcA esaelcunoxE ′5 → ′3 ni tneicifeD sesaremyloP AND yb ortiV ni snoitatuM tfihsemarF decudni-VU fo noitcudorP=eltit|dranreB ,ssuartS =4rohtua|ainoS ,ayrahcA =3rohtua|htidE ,notgnikruT=2rohtua|anhpaD=tsrif|rehgaS=tsal|lanruoj etic{{>fer<.stfihsemarf decudni-VU fo ycneuqerf eht sesaercni ytivitca gnidaerfoorp fo ssol taht setacidni atad ehT .strapretnuoc tneiciforp ]]esaelcunoxerieht did naht ycneuqerf rehgih ta stnatrever decudni-VU ecudorp ytivitca esaelcunoxe ′5 → ′3 fo dioved semyznetnatum esaremylop AND 7T dna fK I lop iloc .E.stfihsemarf yduts ot )CDIM( AAC ATT C TTG CTG fo )TDIM( AAC ATT T TTG CTG ot degnahc saw ′3 AAC ATT TTG CTG ′5 ecneuqes lamron ehT .enod saw ytivitca esaelcunoxe ′5 → ′3 ni tneicifed sesaremylop AND yb snoitatum tfihsemarf decudni-VU[[ fo noitcudorp eht yllacificeps ,yduts latnemnorivne nA .retfa thguos gnieb yllaunitnoc era rucco snoitatum tfihsemarf woh dna yhW .sesab editoelcun fo level eht ta noitatum citeneg a si sihT

}}noitatum|elcitra niaM{{

latnemnorivne ro citeneG

.AND ni srorre fo egatnecrep tnacifingis a rof tnuocca yeht tub ,snietorp tcerrocni ro etelpmocni ot dael nac taht noitatum fo epyt eno tsuj era stfihsemarF .sdohtem tnereffid lareves aiv rucco nac snoitatum tfihsemarf fo noitceted ehT .sulumits lanretxe na yb desuac eb ro ylmodnar rucco nac snoitatum tfihsemarF

msinahceM

>-- ]]noitatum tfihsemarf ni segnahc dica onima fo elpmaxE|bmuht|xp052|gpj.snoitatum tfihsemarF:eliF[[ :devomer egami deteleD --!< ]]snoitatum tniop fo sepyt tnereffid fo elpmaxE|bmuht|xp052|gpj.noitatuM tnioP:eliF[[ >/8002_ht6_GoBM=eman fer<.emarf gnidaer dexif a ni detalsnart si egassem eht taht ,evoba detats sa ,elur tsal ehT .spag on sah egassem eht dna gnippalrevonon era snodoc ,dnoceS .noitcerid '3 ot '5 a ni daer era snodoc ,tsriF .ANRm ni snodoc rotinom eht selur eerht ot tcejbus si edoc citeneg eht fo gnidaer ehT .txen eht ot telpirt eno sdaer ti sa deniatniam si dna snigeb ANRm eht gnitalsnart nehw tes si emarf gnidaer ehT .snietorp fo sisehtnys eht rof noitamrofni citeneg fo noitalsnart ot yek era snodoC >fer/<}} 1_nhel00picnirpregninhel/sliated/gro.evihcra//:sptth=lru| noitartsiger=ssecca-lru| 1-8017-7617-0-879=nbsi| 8002=raey| ocsicnarF naS=noitacol| nameerF .H.W=rehsilbup| yrtsimehcoib fo selpicnirp regninheL=eltit| L treblA=3tsrif| regninheL=3tsal| .R divaD=2tsrif| nosleN=2tsal| leahciM=tsrif| xoC=tsal| koob etic{{>80xoC=eman fer<.stelpirt suougitnoc yb denifed si ]]ecneuqesenobkcab dica onima s′nietorp A .snigeb nodoc wen a yberehw ,emarf gnidaer eht sehsilbatse nodoc tsrif ehT .dica onimaniatrec a rof edoc taht telpirt a ,seditoelcuneerht fo tes a si nodoc[[ A ]]]]nodoc[[eht ,edoc rettel eerht ehT|bmuht|xp003|gvs.sdicaonima-snodoc-ANR:eliF[[

}}edoc citeneG|elcitra niaM{{

ecnatropmi telpirt-nodoC

>/8002_ht6_GoBM=eman fer<.emarf gnidaer tcerroc eht rof swolla siht ,noitpircsnart retfa ANRm eht otni enidirU eteled ro tresni ot desu eb osla nac ]]ANR ediuG.daer eb ot sdica onima tcerroc eht rof wolla ot ecneuqes eht gnitfihs ,noitatum yradnoces a gnitaerc yb noitatum lanigiro eht fo tceffe eht stesffo sihT .noitatum rosserppusa fo esu eht si noitcerroc noitatum rof ytilibissop rehtonA .ecneuqes epyt dliw[[ lanigiro eht ot kcab ecneuqes detatum eht egnahc hcihw rucco snoitatum esreveR .snoitatum tfihsemarf tneverp ot pleh taht sessecorp lacigoloib lareves era erehT

>fer/<}}0-18008.0.riv/9901.01=iod| 18396251=dimp|59–9832=segap|8 tP=eussi|58=emulov|4002 tsuguA=etad|ygoloriV lareneG fo lanruoJ ehT=lanruoj|.snoitatum tfihs-emarf larivorter ot snoitubirtnoc laminim sekam II esaremylop ANR tsoH=eltit|J=tsrif|gnahZ=tsal|lanruoj etic{{>"II esaremylop anr"=eman fer<.10000. dna 1000. fo egnar eht ni erehwemos ylno si snoitatum tfihsemarf gnicudni etar rorre eht ]]setoyrakorpnI .II esaremyloP ANR fo esuaceb derrucco snoitatum tfihsemarf lla fo 1–3 ylno stnemirepxe nI .snoitatum tfihsemarf fo ecnerrucco eht fo esuac regnorts a eb ot thguoht si ,II esaremyloP ANRot desoppo sa ,esatpircsnart esreveR.)6991 ,hguabaraF( tsaeydna airetcabni srucco osla dna sesurivni nommoc ylriaf si sihT .snietorp larivortervne-lop-gag eht sa hcus ,semarf gnidaer nepo gnippalrevo morf snietorp tnereffid gnicudorp ,noitalsnart esahporp[[ gnirud rucco osla yam gnitfihsemarF

>/8002_ht6_GoBM=eman fer<.desaeler si uT-FE sa msinahcem gnidaerfoorp a dna ,ytilibats citenik fo mrof a ]]uT-FEfo ytivitca sisylordyh PTG|etahpsohpirt enisonauG[[ ,etis A emosobir eht ta gniriap esab reporp yb dehsilpmocca si ,emarf gnidaer reporp eht fo ecnatropmi eht gniniatniam ,noitingocer nodoc fo ytiledif sihT .tcerrocni si eno naht erom on ,nietorp eht otni detaroprocni dica onima 0001 yreve roF >/8002_ht6_GoBM=eman fer<.desaeler si dna desisehtnys neeb sah )nietorp( ]]editpepylopeht tniop siht tA .dehcaer si )AAU ro AGU ,GAU( nodoc potsa litnu rehtegot denioj gnieb era sdica onima,daer si )telpirt( nodoc hcae sA .ANRt eht fo snodocitna yb )dedoced( daer won era ANRm eht fo snodoc eht ni deirrac noitamrofni citeneg ehT .ANRrna htiw stcaretni dna emosobireht fo tinubus a htiw detaroprocni si ANRm ehT .ANRm[[ dellac etalpmet regnessem dnarts elgnis a no won era noitamrofni citeneg eht gniniatnoc seditoelcuN >/8002_ht6_GoBM=eman fer<.]]noitpircsnart|)sciteneg( noitpircsnart[[ yb dehsilpmocca si noitamrofni citeneg fo noitces detceles a fo gnidaer eht ,noitacilper AND retfA ]]ssecorp ]]noitalsnart|)ygoloib( noitalsnarT[[ehT|bmuht|xp002|gnp.sciteneg-noitalsnarT:eliF[[ }})ygoloib( noitalsnarT|)sciteneg( noitpircsnarT|elcitra niaM{{

noitalsnart dna noitpircsnarT

>/8002_ht6_GoBM=eman fer<. ]]noitacilper ANDni detaroprocni era smetsys riaper hctamsimdna sesaelcunoxesa hcus smsinahcem gnidaerfoorp,no noitamrofni eht sessap yllufsseccus emonegeht taht erusne oT .snoitcnuf ralullec lamronba yb yhtlaehnu emoceb ot msinagrorehgih eht esuac sesac tsom ni dna ytilibaiv llec|)ygoloib( lleCno stceffe latnemirted evah nac nietorp edam yltcerrocni nA .seitivitca citylatac[[ rof dna larutcurts rof yletarucca decudorp eb ot deriuqer era snietorp ,noitcnuf ylreporp ot llec a roF >/8002_ht6_GoBM=eman fer<.amgod lartnec eht sa ]]nietorpa gnikam rof tnemegnarra dica onima cificeps a ot ANDmorf noitamrofni citeneg fo wolf eht debircsed kcirC sicnarF[[ 6591 nI

}}ygoloib ralucelom fo amgod lartneC|elcitra niaM{{

amgod lartneC

]]ledom ]]amgod lartnec[[ehT|bmuht|xp052|gvs.bmdC:eliF[[

.serusaem evitcerroc fo yteirav a setaroprocni llec eht sa neve esaesid esuac yllautneve dna tcerrocni eb ot noitcnuf nietorp esuac nac noitacinummoc siht gnidaer ni rorre na ,revewoH .snietorp gnikam otni detacinummoc eb ot noitamrofni siht wolla noitalsnart dna noitpircsnarT .smsinagro lla fo sllec eht ni noitcnuf nietorp senimreted AND ni deniatnoc noitamrofni ehT

dnuorgkcaB

.esanolyn ni detluser ]]esaretselartsecna na fo etis evitca[[ mom ni noitutitsbus dica onima owt a rehtar taht dna esuac eht neeb evah ot ylekilnu saw noitatum tfihsemarf a taht dnuof >fer/<}}002649505m.cbj/4701.01=iod| 60526161=dimp| 5002 rebmevoN=etad| 25–44693=segap| 74=eussi| 082=emulov| mehC loiB J=lanruoj| emyzne gnidarged-remogilo nolyn a fo htrib eht rof sisab ralucelom :esalordyh remid-etaonaxehonima-6 fo sisylana cihpargollatsyrc yar-X=eltit| Y ihcugiH ,M oekaT ,I otomawaK ,K otomustaM ,J emakurusT ,Y inatikaW ,N onuziM ,N atabihS ,T ikhO ,S orogeN=srohtuav| lanruoj etic{{>fer< )6002( la te orogeN yb yduts A .laisrevortnoc si noitaterpretni siht ,revewoh ,]]esanolyn[[ fo noitaerc degella eht htiw sa ,ytlevon lacigoloib fo ecruos a sa desoporp neeb evah snoitatum tfihsemarF .surivorter VIH eht yb noitcefni ot ecnatsiser ot deknil saw noitatum tfihsemarf a >fer/<}}6010322=cmp| 7722319 = dimp|63–02 = segap|2 = eussi|3 = emulov|7991 yraunaJ = etad|).ssaM ,egdirbmaC( enicideM raluceloM = lanruoj|.ksir deifitnauq dna ,dnuorgkcab laicar denifed ,sepytonehp lacinilc gnitsartnoc htiw tihs ni seiduts :5 rotpecer enikomehc CC ni noitatum gnitavitcani na yb derrefnoc 1-VIH ot ecnatsiser detirehnI = eltit| MP yhpruM ,BT namtuN ,SA icuaF ,AE regreB ,M kepohC ,J retnuH ,R sleteD ,VJ igroiG ,V imawsaramuK ,EP ydenneK ,M azzeraccaV ,G maL ,A trebbuR ,O nehoC ,D namssieW ,C ereidabmoC ,J kicfobuK ,T gnidlapS ,G bitahklA ,A etihW-relkcuB ,AP namremmiZ=srohtuav|lanruoj etic{{>"ecnatsiser VIH"=eman fer<,7991 ni ;]]aimealoretselohcrepyh lailimaffo sessalc dna srecnac niatrec ot ytilibitpecsus esaercni yeht ;esaesid shcaS–yaT[[ sa hcus sesaesid citeneg ereves ni tnerappa era snoitatum tihsemarF

>fer/<}}9102 yaM 71=etadssecca| erutaN=etisbew| 8984256-ssecorp-eht-hguorht-gnignahc-yltnatsnoc-si-and/egapcipot/elbatics/moc.erutan.www//:sptth=lru| noitatuM fo ssecorP eht hguorht gnignahC yltnatsnoC sI AND=eltit| bew etic{{>"noitatuM erutaN"=eman fer< .lanoitcnuf eb ton ylekil tsom lliw dna ,gnol yllamronba ro trohs yllamronba eb dluoc detaerc gnieb editpepylop ehT .ecneuqes eht ni deretnuocne )"GAU" ro "AGU" ,"AAU"( nodoc pots tsrif eht retla osla lliw noitatum tfihsemarf ehT .sdica onima tnereffid rof edoc ot noitatum eht retfa snodoc eht fo gnidaer eht esuac lareneg ni lliw noitatum ]]tfihsemarfA .deteled ro detresni naht rehtar ,decalper si editoelcun a hcihw ni msihpromylop editoelcun-elgnis[[ a sa emas eht ton si noitatum tfihsemarf A >fer/<}}ht6=noitide| 1-2959-3508-0-879=nbsi| 8002=raey| ocsicnarF naS=noitacol| sgnimmuC nimajneB/nosraeP=rehsilbup| eneg eht fo ygoloib raluceloM=eltit| .W leahciM=6tsrif| eniveL=6tsal| rednaxelA=5tsrif| nnaG=5tsal| nehpetS=4tsrif| lleB=4tsal| rekaB=3tsal| .A ainaT=3tsrif| .D semaJ=2tsrif| nostaW=2tsal| drahciR=tsrif| kcisoL=tsal| koob etic{{>8002_ht6_GoBM=eman fer<.nietorp eht deretla erom eht ,srucco noitresni ro noiteled eht ecneuqes eht ni reilrae ehT .lanigiro eht morf ]]noitalsnart|)sciteneg( noitalsnarTtnereffid yletelpmoc a ni gnitluser ,)snodoc eht fo gnipuorg eht( emarf gnidaereht egnahc nac noiteled ro noitresni eht ,snodocyb noisserpxe enegfo erutan telpirt eht ot euD .eerht yb elbisivid ton si taht ecneuqes AND a ni seditoelcunfo rebmun a fo )snoiteled|noiteled citenegro snoitresni|noitresni eneg( sledniyb desuac noitatum citeneg[[ a si )tfihs emarf gnidaer a ro rorre gnimarf a dellac osla( noitatum tfihsemarf A

]].noitatum tfihsemarf a ton dna noiteled a ylpmis si C lenaP .noitatum ledni fo sepyt tnereffiD|bmuht|xp053|gpj.noitatum tfihsemarF:eliF[[ }}tnemngila nodoc stfihs taht noitatum|noitpircsed trohS{{

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