医学遗传学人类基因

医学遗传学人类基因第1页，课件共49页，创作于2023年2月

Genesareentitiesthatparentspasstooffspringduringreproduction.第2页，课件共49页，创作于2023年2月

Theseentitiesencodeinformationessentialfortheconstructionandregulationofproteins(suchasenzymes)andothermoleculesthatdeterminethegrowthandfunctioningoftheorganism.

第3页，课件共49页，创作于2023年2月1.GeneChemistryComposedasa"doublehelix"-twolinkedchemicalstrands.

第4页，课件共49页，创作于2023年2月Linkedtogetherbybasepairsthatcanassumeoneoffourvariantforms:

thymine(T)

guanine(G)

adenine(A)

cytosine(C)

第5页，课件共49页，创作于2023年2月JamesWatsonandFrancisCrickdisplaytheirnewlydiscoveredmodelofDNA,themolecularbasisofgenetics.

第6页，课件共49页，创作于2023年2月Basesequenceformthe"geneticcode"thatinitiatesthetwomajorfunctionsofgenes:proteinsysthesisandreplication.第7页，课件共49页，创作于2023年2月第8页，课件共49页，创作于2023年2月2.GeneStructureRichardJ.RobertsandPhillipA.Sharp(1993NobelPrizewinner)madetheiramazingdiscoveryoftheexistenceofsplitgenesintheadenovirus,whentheyexaminedahybridizednucleicacidmoleculemadebetweenaadenoviralmRNAanditstemplateDNAintheelectronmicroscope.第9页，课件共49页，创作于2023年2月TheyobservedthatthemRNAwasmuchshorterinlengthandthuswasnotencodedasanequalcolinear

segmentoftheDNAmolecule.Instead,largeloopsofunhybridizedDNA(A,BandCinfigure)wereseen.TheirinterpretationwasthatthematuremessengerRNAwasderivedfromfourdiscountinuoussegmentsontheviralDNA.第10页，课件共49页，创作于2023年2月ThesegmentsretainedinthemRNAtheycalledexons

andtheinterveningsequences(A,BandC),whichareexcisedduringmRNAprocessingandmaturation,arecalledintrons.第11页，课件共49页，创作于2023年2月第12页，课件共49页，创作于2023年2月第13页，课件共49页，创作于2023年2月第14页，课件共49页，创作于2023年2月第15页，课件共49页，创作于2023年2月GT-AG

rule

Thepredominanceofthis'GT-AG'rulesupportsthehypothesisthatspliceosomalintronsaresplicedinyeasts,asinmosteukaryotes,byaconservedmechanism.

第16页，课件共49页，创作于2023年2月第17页，课件共49页，创作于2023年2月2.HumanGenomeAgenomeisalltheDNAinanorganism,includingitsgenes.Genescarryinformationformakingalltheproteinsrequiredbyallorganisms.Theseproteinsdetermine,amongotherthings,howtheorganismlooks,howwellitsbodymetabolizesfoodorfightsinfection,andsometimesevenhowitbehaves.第18页，课件共49页，创作于2023年2月第19页，课件共49页，创作于2023年2月SimpleSequenceDNAAlleukaryoteshavemorethanonetypeofsimplesequenceDNA.Therepeatunitlengthisusually5-10bpbutmaybeasshortas2oraslongas200.Theserepeatunitsarearrangedinheadtotailtandemarrayswhichvaryinlength.ThelongesttandemarrayknownsofaristhatofhumanalphoidDNAwhichhasatotalarraylengthofapproximately5millionbasepairsbutcertainsimplesequenceshaveanarraylengthofonlyafewhundredbasepairs.第20页，课件共49页，创作于2023年2月MostsimplesequenceDNAisfoundinheterochromatin-particularlyatthecentromereandattheendsortelomeresofchromosomes-thoughsomesimplesequencesarescatteredatdifferentpositionsondifferentchromosomes.第21页，课件共49页，创作于2023年2月SomesimplesequencefamiliesformthebasisforDNAfingerprinting.Thesefamiliesarecalledminisatellites.Minisatelliteshavearepeatunitlengthof15-100bpandatotalarraylengthof0.5to30kb.TheshortarraylengthisthereasontheyarecalledminisatellitestodistinguishthemfromnormalsatelliteDNAwhichhasarraylengthsintherangeofafewhundredkb.

第22页，课件共49页，创作于2023年2月第23页，课件共49页，创作于2023年2月MicrosatelliteDNAMicrosatelliteDNAdiffersfromminisatelliteDNAinthattherepeatunitsarelessthan5bpinlengthforexample(TG)nor(AAT)n.Thesemicrosatellitesarehighlypolymorphicinthelengthoftheirrepeatarraysandsotheycanalsobeusedinforensicanalysis,aswellastoidentifyrelatedgroupsofindividualswithinpopulations.第24页，课件共49页，创作于2023年2月TheadvantageofmicrosatellitesoverminisatellitesisthatthesizeofeachalleleismuchsmallerandtheyarethereforemoreamenabletoPCRanalysis.TheirsmallsizealsomeansthattheyaremorelikelytoremainintactinhighlydegradedDNAsuchasthatfromforensicsamplesorfromancientDNA-forexamplefromEgyptianmummies.第25页，课件共49页，创作于2023年2月Microsatellitesarealsoinvolvedinanumberofhumangeneticdiseaseswhichhavebeenshowntobeduetovariationsinthenumbersoftrinucleotiderepeats.第26页，课件共49页，创作于2023年2月HumangenomeprojectCollectivename(HumanGenomeInitiative)forseveralprojectsbegunin1986byDOEtocreateanorderedsetofDNAsegmentsfromknownchromosomallocations,developnewcomputationalmethodsforanalyzinggeneticmapandDNAsequencedata,anddevelopnewtechniquesandinstrumentsfordetectingandanalyzingDNA.ThisDOEinitiativeisnowknownastheHumanGenomeProgram.Thejointnationaleffort,ledbyDOEandNIH,isknownastheHumanGenomeProject.第27页，课件共49页，创作于2023年2月Begunformallyin1990,theU.S.HumanGenomeProjectwasa13-yeareffortcoordinatedbytheU.S.DepartmentofEnergyandtheNationalInstitutesofHealth.Theprojectoriginallywasplannedtolast15years,butrapidtechnologicaladvancesacceleratedthecompletiondateto2003.第28页，课件共49页，创作于2023年2月identifyalltheapproximately20,000-25,000genesinhumanDNA,determinethesequencesofthe3billionchemicalbasepairsthatmakeuphumanDNA,storethisinformationindatabases,improvetoolsfordataanalysis,transferrelatedtechnologiestotheprivatesector,andaddresstheethical,legal,andsocialissues(ELSI)thatmayarisefromtheproject.第29页，课件共49页，创作于2023年2月3.DNAreplicationBeforeacellcandivide,itmustduplicateallitsDNA.Ineukaryotes,thisoccursduringSphaseofthecellcycle.第30页，课件共49页，创作于2023年2月TheSteps:1.Aportionofthedoublehelixisunwoundbyahelicase.

2.AmoleculeofaDNApolymerasebindstoonestrandoftheDNAandbeginsmovingalongitinthe3'to5'direction,usingitasatemplateforassemblingaleadingstrandofnucleotidesandreformingadoublehelix.Ineukaryotes,thismoleculeiscalledDNApolymerasedelta(δ).第31页，课件共49页，创作于2023年2月3.BecauseDNAsynthesiscanonlyoccur5'to3',amoleculeofasecondtypeofDNApolymerase(epsilon,ε,ineukaryotes)bindstotheothertemplatestrandasthedoublehelixopens.Thismoleculemustsynthesizediscontinuoussegmentsofpolynucleotides(Okazakifragments).Anotherenzyme,DNAligaseIthenstitchesthesetogetherintothelaggingstrand.第32页，课件共49页，创作于2023年2月第33页，课件共49页，创作于2023年2月Whenthereplicationprocessiscomplete,twoDNAmolecules—identicaltoeachotherandidenticaltotheoriginal—havebeenproduced.Eachstrandoftheoriginalmoleculehasremainedintactasitservedasthetemplateforthesynthesisofacomplementarystrand.Thismodeofreplicationisdescribedassemi-conservative:one-halfofeachnewmoleculeofDNAisold;one-halfnew.第34页，课件共49页，创作于2023年2月第35页，课件共49页，创作于2023年2月4.GeneExpressionThemajorityofgenesareexpressedastheproteinstheyencode.Theprocessoccursintwosteps:Transcription=DNA→RNA

Translation=RNA→proteinTakentogether,theymakeupthe"centraldogma"ofbiology:DNA→RNA→protein.

第36页，课件共49页，创作于2023年2月Hereisanoverview

第37页，课件共49页，创作于2023年2月GeneTranscription:DNA→RNADNAservesasthetemplateforthesynthesisofRNAmuchasitdoesforitsownreplication.第38页，课件共49页，创作于2023年2月Some50differentproteintranscriptionfactorsbindtopromoter

sites,usuallyonthe5′sideofthegenetobetranscribed.Anenzyme,anRNApolymerase,bindstothecomplexoftranscriptionfactors.Workingtogether,theyopentheDNAdoublehelix.TheRNApolymeraseproceedsdownonestrandmovinginthe3′→5′direction.Ineukaryotes,thisrequires—atleastforprotein-encodinggenes—thatthenucleosomesinfrontoftheadvancingRNApolymerase(RNAPII)beremoved.Acomplexofproteinsisresponsibleforthis.ThesamecomplexreplacesthenucleosomesaftertheDNAhasbeentranscribedandRNAPIIhasmovedon.第39页，课件共49页，创作于2023年2月AstheRNApolymerasetravelsalongtheDNAstrand,itassemblesribonucleotidesintoastrandofRNA.EachribonucleotideisinsertedintothegrowingRNAstrandfollowingtherulesofbasepairing.ThusforeachCencounteredontheDNAstrand,aGisinsertedintheRNA;foreachG,aC;andforeachT,anA.However,eachAontheDNAguidestheinsertionofthepyrimidineuracil.ThereisnoTinRNA.SynthesisoftheRNAproceedsinthe5′→3′.Aseachnucleosidetriphosphateisbroughtintoaddtothe3′endofthegrowingstrand,thetwoterminalphosphatesareremoved.Whentranscriptioniscomplete,thetranscriptisreleasedfromthepolymeraseand,shortlythereafter,thepolymeraseisreleasedfromtheDNA.第40页，课件共49页，创作于2023年2月TypesofRNAmRNA.Thiswilllaterbetranslatedintoapolypeptide.rRNA.Thiswillbeusedinthebuildingofribosomes:machineryforsynthesizingproteinsbytranslatingmRNA.tRNA.RNAmoleculesthatcarryaminoacidstothegrowingpolypeptide.snRNA

(smallnuclearRNA).DNAtranscriptionofthegenesformRNA,rRNA,andtRNAproduceslargeprecursormolecules("primarytranscripts")thatmustbeprocessedwithinthenucleustoproducethefunctionalmoleculesforexporttothecytosol.SomeoftheseprocessingstepsaremediatedbysnRNAs.snoRNA(smallnucleolarRNA).TheseRNAswithinthenucleolushaveseveralfunctions(describedbelow).miRNA

(microRNA).Thesearetiny(~22nts)RNAmoleculesthatappeartoregulatetheexpressionofmessengerRNA(mRNA)molecules.[Discussion]XISTRNA.ThisinactivatesoneofthetwoXchromosomesinfemalevertebrates.第41页，课件共49页，创作于2023年2月SmallNuclearRNA(snRNA)ApproximatelyadozendifferentgenesforsnRNAs,eachpresentinmultiplecopies,havebeenidentified.ThesnRNAshavevariousrolesintheprocessingoftheotherclassesofRNA.Forexample,severalsnRNAsarepartofthespliceosomethatparticipatesinconvertingpre-mRNAintomRNAbyexcisingtheintronsandsplicingtheexons.第42页，课件共49页，创作于2023年2月SmallNucleolarRNA(snoRNA)Asthenamesuggests,thesesmall(60–300nts)RNAsarefoundinthenucleoluswheretheyareresponsibleforseveralfunctions:Someparticipateinmakingribosomesbyhelpingt