人类基因组中的保守非编码元件

HEREDITAS(Beijing)200911,31(11):1067―1076ISSN0253-9772综述收稿日期:2009−02−24;修回日期:2009−04−05作者简介:(1982−),,,E-mail:[e-mail]通讯作者:(1969−),,,,,Tel:[phone];E-mail:[e-mail]:10.3724/SP.J.1005.2009.01067人类基因组中的保守非编码元件田靖,赵志虎,陈惠鹏,100071比较基因组学的研究发现:人类基因组中约5%的序列受到选择压力的限制,但编码序列只占其中很小一部分,约3.5%是保守、非编码序列。这些保守非编码元件具有重要功能。可能在染色质构型(高级结构)、DNA转录和RNA加工等不同水平参与了基因的表达调控,与哺乳动物的形态发生和人类疾病相关。文章简要综述了保守非编码元件的识别、功能及验证、起源演化以及与人类疾病的关系。保守非编码元件;比较基因组学;基因调节Conservednon-codingelementsinhumangenomeTIANJing,ZHAOZhi-Hu,CHENHui-PengInstituteofBiotechnology,AcademyofMilitaryMedicalScience,Beijing100071,ChinaAbstract:Studyofcomparativegenomicshasrevealedthatabout5%ofthehumangenomeareunderpurifyingselection,3.5%ofwhichareconservednon-codingelements(CNEs).Whilethecodingregionscompriseofonlyasmallpart.Inhu-man,theCNEsarefunctionallyimportant,whichmaybeassociatedwiththeprocessoftheestablishmentandmaintainofchromatinarchitecture,transcriptionregulation,andpre-mRNAprocessing.Theyarealsorelatedtoontogenyofmammalsandhumandiseases.Thisreviewoutlinedtheidentification,functionalsignificance,evolutionaryorigin,andeffectsonhumangeneticdefectsoftheCNEs.Keywords:conservednon-codingelement;comparativegenomics;generegulation,2006518116,30,;RNADNA,,:5%,,,1.5%,2%,3%~3.5%()RNARNAMARs(Matrixattachmentsites,)[1],1068HEREDITAS(Beijing)200931:(Purifyingselection)(Negativeselection),,,,,[2~6],,,RNA,1,,;,,,,1.12002,,,40%[7],5%,1.5%,2/3RNA,[8~10]100bp70%,327000,65%,35%,,(),-,,,,;,-40%,5%,,,,,481200bp100%(Ultra-conservedelements,UCEs),,[11]1.2(Fugurubripes,pufferfish)45,,,(Generepertoire),,1373CNE(Conservednon-codingelement)[6],CNE273kb,21Y,93~740bp,74%~98%CNE,165,93%(154/165)CNE500kb(trans-dev),11,5,1,1AUTS2,41.3,,Bejerano[12]4,5()411:106927HCE(Highlyconservedelement),,,HCE,0.14%,80%UCE,,Margulies[5]117q311.8Mb,RNA,,1.4,():,,;,,phylogeneticshadowing[13](),,(-),,,,,,,2(trans-dev),HoxPax6Pax9Sox9Otx2Sox2ShhDlxDach[14~22];-(Uitra-conservedregion,UCR)[8],50UCR412,,HoxDNkx6.1Nkx2.2Pbx3,CNE[23],CNE156,40CNECNE,,,CNE2.1,[24][25]“”(“Stabledeserts”)“”(“Variabledeserts”)12%,,53%(HCE)Dach1Otx2Sox2,;Irx[26]CNE[19,26,27]Woofle[6],1400,4(Sox21Pax6Hlxb9Shh)25UCE,23Pennacchio[28]-1070HEREDITAS(Beijing)200931CNE-UCE167,45%11.5d2.2,RNAmRNA,RNA5(5-UTR)RNADNA,3-UTRDNARNA(NOVA1ELAVL4ZFHX1BBCL11ASYNCRIP)3UTR,3UTR,mRNAmRNAmRNAmRNA[29]miRNA,3-UTRmRNA,miRNA3-UTR,miR-196HOXB83UTR1135bpCNE,Hoxb8,mRNAmiRNA3-UTRHCE,EIF4ECpGMeCPDNAMYCMYCNNBPHOXUBE3AHCEmiRNA,miRNA3-UTRCNERNA,RNA,,“”“”“”,RNAGRIA3(),UCE600bp13,13,2.3DNA[30],CNE10%CNEMARs,Loop,,,,trans-dev,trans-devCNECNE(),CNE,()CNEDNA,[31]GCCNE,CNE[32],CNE,CNEA+T,A+T(motif),,CNEA+T,CNEA+TDNACNEDNA,CNE[33],,DNA,AA/TTDNA,CNEDNA,DNACNE311:1071,DNaseI(TFBS);,,,,[34][35]PCRβ-EGFP,GFP,,GFP,CNE,[36],,,,,,;,CNE,,(ncRNA)[33],()[35],,ENCODE4CNECNE,CNE[27]2300-CNE,124dCNE(DuplicatedCNE,CNE),5dCNE,dCNE,dCNE,,CNECNE,CNE,CNECNE,CNE,“”,,“DNA”DoolittleSapienza[37],,,,exaptationSINE(Shortinterspersedelements,),SINE,Bejerano[38]HCNESINE;CNE[39]AmmSINEI[40],AmmSINE(AmnlotaSINEs),(),310Mya1072HEREDITAS(Beijing)2009311000AmmSINEI(),105AmnSINE1AmmSINEI,,,,,CNE,,,,(Mutationcoldspots)[41],[42],,,UCE,[43]100%UCE[44],[45]UCEUCE,,,,UCE5(Autism)[46]Rett[47],HCNE,HCNEmiRNA,“”,“”(“Bystander”gene)[48],HCNE,(Synteny),HCNE“”(Genomicregulatoryblocks,GRB),GRBGRB,,GRBGRB,,HCNE,GRB6,,,,“”,,,,[49],DNA,,,ENCODE[50],55%,,11:1073,Fisher[51],RET,(Cis-regulatorymodule,CRM)[52],,RET,,(10/13)GFP,RET,RET,RET,,,,CNESun[53]CNE,,CNE,HCNEFrazer[10],2CNE,CNE;CNEHCNE,CNE,HCNE(HCNEar-rays)TFR(Transposonfreeregion)[54],TFR,,,,,,,,,参考文献(References):[1]GlazkoGV,KooninEV,RogozinIB,ShabalinaSA.Asig-nificantfractionofconservednoncodingDNAinhumanandmouseconsistsofpredictedmatrixattachmentregions.TrendsGenet,2003,19(3):119–124.[2]LootsGG,LocksleyRM,BlankespoorCM,WangZE,MillerW,RubinEM,FrazerKA.Identificationofacoor-dinateregulatorofinterleukins4,13,and5bycross-spe-ciessequencecomparisons.Science,2000,288(5463):136–140.[3]BoffelliD,McAuliffeJ,OvcharenkoD,LewisKD,OvcharenkoI,PachterL,RubinEM.Phylogeneticshadow-ingofprimatesequencestofindfunctionalregionsofthehumangenome.Science,2003,299(5611):1391–1394.[4]KellisM,PattersonN,EndrizziM,BirrenB,LanderES.Sequencingandcomparisonofyeastspeciestoidentifygenesandregulatoryelements.Nature,2003,423(6937):241–254.[5]MarguliesEH,BlanchetteM;NISCComparativeSe-quencingProgram,HausslerD,GreenED.Identificationandcharacterizationofmulti-speciesconservedsequences.GenomeRes,2003,13(12):2507–2518.[6]WoolfeA,GoodsonM,GoodeDK,SnellP,McEwenGK,VavouriT,SmithSF,NorthP,CallawayH,KellyK,Wal-terK,AbnizovaI,GilksW,EdwardsYJ,CookeJE,ElgarG.Highlyconservednon-codingsequencesareassociatedwithvertebratedevelopment.PLoSBiol,2005,3(1):e7.[7]DermitzakisET,ReymondA,AntonarakisSE.Conservednon-genicsequences-anunexpectedfeatureofmammaliangenomes.NatRevGenet,2005,6(2):151–157.[8]SandelinA,BaileyP,BruceS,EngströmPG,KlosJM,WassermanWW,EricsonJ,LenhardB.Arraysofultra-conservednon-codingregionsspanthelociofkeydevel-opmentalgenesinvertebrategenomes.BMCGenomics,2004,5(1):