醫(yī)學(xué)遺傳學(xué)教學(xué)課件：Chapter 3 Human Genomics II

HumanGenomicsII1HumanGenomicshaschangedmedicine:(1)Biochips2Stamp-sizedOnespotperDNAfragmentThousandsofspots/chipSamplesmaybefromdifferenttissuesofpatientsandhealthypeople,orvirus,pathogens,andsoonDNA-basedbiochipsTwotypes:Detectionofmutationsinspecificgenesasdiagnostic"markers"oftheonsetofaparticulardiseaseBasis:SNPsDetectionofthedifferencesingeneexpressionlevelsbetweenpatientsandthehealthyBasis:mRNAlevel3SNP-basedExamplesAffymetrixGeneChipbaseonthemutation(SNPs):p53GeneChipHIVGeneChipP450GeneChipBreastcancergene,BRCA1Bacterialpathogens4Expression-basedexamplesAsadiagnostictoolFordrugdesignUniquetargetsthatarepresentonlyindiseasedcells.Forexample,duringtheprocessofcancertransformationoncogenesandproto-oncogenesareactivated,whichneveroccursinhealthycells.5Biochipcanallowrapidscreeningofanytypeofcancerinprinciple,justlookandseewhatSNPispresentinthecancerpatient.Example:Intwoformsofleukemiaeachgenechangesfromnormal,butimportantly,thechangesweredifferentineachcase.EachhadtheirowncharacteristicSNP.6Biochipexampletoscreenforcancer7Disease

possibleSNPsGWAS:Genome-wideassociationstudytocompileadatabaseofthousandsofSNPs8FactsandApplicationApproximately95%ofthehumangenomecomprisesnon-codingDNAMorethan85%ofSNPsidentifiedtobeassociatedwithdiseaseingenome-widestudies(GWAS)occurwithinnon-codingregionsThus,examiningtheroleoftheseregionsofthegenomewillbeimportantforunderstandingandpotentiallytreatingdiseaseApplication:screentheassociatedgenes9Gotodoctor:“Firstcheckmygenome,doctor”10DebateaboutGWASAgood-natureddebateaboutwhetherGWASwilleventuallyhelpunravelthegeneticbasisofhumanhypertensionentertainedmanyattherecentAmerican

Society

of

Hypertension

2010

Scientific

Meeting.Arguingthatsuchstudieshave"costmillionsofdollars"butfailedtoliveuptoexpectationsinthefieldofhypertension,Dr

Theodore

W

Kurtz(UniversityofCalifornia,SanFrancisco)saidthatitwastimetoputastoptofurtherGWAS:"Theyhavetaughtuslittleaboutthegenetics,pathophysiology,ortreatmentofhypertension.Dr

Anna

Dominiczak(UniversityofGlasgow,Scotland),takingtheopposingposition,saidthatalthoughitistruethatGWAShavesofaryieldedonlyafewgeneticvariants,whichexplainaverysmallproportionofthetotalvariationinbloodpressure,"thebestisyettocome."11Biochipraisecriticalissueofpersonalprivacy12SCARINGyou,yourhealth,yourbehavior,yourfuturepotentialPhilosophy:ManyscientistsandphysiciansthinkthatmanymedicalbenefitscouldflowfromknowingthelocationandsequencesofallthegenesSuchknowledgewouldfacilitatelocatinggenesthatareassociatedwithdiseasesordiseasesusceptibilityHumanGenomicshaschangedmedicine:(2)Genetherapy13Whatis“GeneTherapy”?Tointroduceanormalgene,viageneticallyengineeredcell,intoindividualswhodonotpossessafunctionalcopyofthisgene,fortherapeuticpurposes.14GeneTherapyforSCIDSGenetherapyhasbeensuccessfullyusedtotreatseverecombinedimmunedeficiencysyndrome(SCIDS)FataldiseaseinwhichachildisbornwithoutafunctionalimmunesystemUnabletofightinfectionsThesechildrendiefromtheslightinfectionunlesstheyarelivedintotalisolation:Boy/girlinabubbletreatmentEnzymethatcontrolSCIDS:Adenosinedeaminase(ADA)Itsgeneislocatedonchromosome2015SCIDDeficiencyofADAwillcauseSCID,whilegenetherapycantransfergeneforADAintoimmunecellsofpatients,inwhichthereisdysfunctionofbothBandTlymphocyteswithimpairedcellularimmunityanddecreasedproductionofimmunoglobulins.16Adeno-associatedvirus(AVV)AVVCloning17AssemblyAVVparticleTreatment1819202122(3)--Newdrugs23242526272829DesignthedrugsBeyondtheHumanGenomeTheDNAsequencetellsonlyasmallfractionofthestoryaboutwhataspecificcellisdoingWithalltheDNAthatcodesforahumaninhand,researchersbeginamorechallengingtask:Proteomics3031GeneproteinDisease2-Dgel323334353637BeyondtheHGP:What’sNext?HapMapSystemsBiologyExploringMicrobialGenomesforEnergyandtheEnvironmentChartgeneticvariation

withinthehumangenome38BeyondtheHGP...

What’snext?-cont’NextprojectforDOE:GTL(GenomestoLife)BuildsondataandresourcesfromtheHumanGenomeProject,theMicrobialGenomeProgram,andsystemsbiologyGoalistoaccelerateunderstandingofdynamiclivingsystemsforenergyandenvironmentalapplications.Specificusesinenergyproduction