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TheHumanGenomeProject://www.020wj.netIntroduction•Untiltheearly1970’s,DNAwasthemostdifficultcellularmoleculeforbiochemiststoanalyze.•DNAisnowtheeasiestmoleculetoanalyze–wecannowisolateaspecificregionofthegenome,produceavirtuallyunlimitednumberofcopiesofit,anddetermineitsnucleotidesequenceovernight.MolecularBiologyOfTheCell.Albertsetal.491-495Introduction•AttheheightoftheHumanGenomeProject,sequencingfactoriesweregeneratingDNAsequencesatarateof1000nucleotidespersecond24/7.•TechnicalbreakthroughsthatallowedtheHumanGenomeProjecttobecompletedhavehadanenormousimpactonallofbiology…..MolecularBiologyOfTheCell.Albertsetal.491-495HumanGenomeProjectGoals:■identifyalltheapproximate30,000genesinhumanDNA,■determinethesequencesofthe3billionchemicalbasepairsthatmakeuphumanDNA,■storethisinformationindatabases,■improvetoolsfordataanalysis,■transferrelatedtechnologiestotheprivatesector,and■addresstheethical,legal,andsocialissues(ELSI)thatmayarisefromtheproject.Milestones:■1990:ProjectinitiatedasjointeffortofU.S.DepartmentofEnergyandtheNationalInstitutesofHealth■June2000:Completionofaworkingdraftoftheentirehumangenome(covers90%ofthegenometoadepthof3-4xredundantsequence)■February2001:Analysesoftheworkingdraftarepublished■April2003:HGPsequencingiscompletedandProjectisdeclaredfinishedtwoyearsaheadofscheduleU.S.DepartmentofEnergyGenomePrograms,GenomicsandItsImpactonScienceandSociety,2003://www.sanger.ac.uk/HGP/overview.shtmlWhatdoesthedrafthumangenomesequencetellus?BytheNumbers•Thehumangenomecontains3billionchemicalnucleotidebases(A,C,T,andG).•Theaveragegeneconsistsof3000bases,butsizesvarygreatly,withthelargestknownhumangenebeingdystrophinat2.4millionbases.•Thetotalnumberofgenesisestimatedataround30,000--muchlowerthanpreviousestimatesof80,000to140,000.•Almostall(99.9%)nucleotidebasesareexactlythesameinallpeople.•Thefunctionsareunknownforover50%ofdiscoveredgenes.U.S.DepartmentofEnergyGenomePrograms,GenomicsandItsImpactonScienceandSociety,2003?HowIt'sArranged•Thehumangenome'sgene-denseurbancentersarepredominantlycomposedoftheDNAbuildingblocksGandC.•Incontrast,thegene-poordesertsarerichintheDNAbuildingblocksAandT.GC-andAT-richregionsusuallycanbeseenthroughamicroscopeaslightanddarkbandsonchromosomes.•Genesappeartobeconcentratedinrandomareasalongthegenome,withvastexpansesofnoncodingDNAbetween.•Stretchesofupto30,000CandGbasesrepeatingoverandoveroftenoccuradjacenttogene-richareas,formingabarrierbetweenthegenesandthejunkDNA.TheseCpGislandsarebelievedtohelpregulategeneactivity.•Chromosome1hasthemostgenes(2968),andtheYchromosomehasthefewest(231).U.S.DepartmentofEnergyGenomePrograms,GenomicsandItsImpactonScienceandSociety,2003?TheWheatfromtheChaff•Lessthan2%ofthegenomecodesforproteins.•Repeatedsequencesthatdonotcodeforproteins(junkDNA)makeupatleast50%ofthehumangenome.•Repetitivesequencesarethoughttohavenodirectfunctions,buttheyshedlightonchromosomestructureanddynamics.Overtime,theserepeatsreshapethegenomebyrearrangingit,creatingentirelynewgenes,andmodifyingandreshufflingexistinggenes.•Thehumangenomehasamuchgreaterportion(50%)ofrepeatsequencesthanthemustardweed(11%),theworm(7%),andthefly(3%).U.S.DepartmentofEnergyGenomePrograms,GenomicsandItsImpactonScienceandSociety,2003?HowtheHumanCompareswithOtherOrganisms•Unlikethehuman'sseeminglyrandomdistributionofgene-richareas,manyotherorganisms'genomesaremoreuniform,withgenesevenlyspacedthroughout.•HumanshaveonaveragethreetimesasmanykindsofproteinsastheflyorwormbecauseofmRNAtranscriptalternativesplicingandchemicalmodificationstotheproteins.Thisprocesscanyielddifferentproteinproductsfromthesamegene.•Humanssharemostofthesameproteinfamilieswithworms,flies,andplants;butthenumberofgenefamilymembershasexpandedinhumans,especiallyinproteinsinvolvedindevelopmentandimmunity.•AlthoughhumansappeartohavestoppedaccumulatingrepeatedDNAover50millionyearsago,thereseemstobenosuchdeclineinrodents.Thismayaccountforsomeofthefundamentaldifferencesbetweenhominidsandrodents,althoughgeneestimatesaresimilarinthesespecies.Scientistshaveproposedmanytheoriestoexplainevolutionarycontrastsbetweenhumansandotherorganisms,includingthoseoflifespan,littersizes,inbreeding,andgeneticdrift.U.S.DepartmentofEnergyGenomePrograms,GenomicsandItsImpactonScienceandSociety,2003?VariationsandMutations•Scientistshaveidentifiedabout3millionlocationswheresingle-baseDNAdifferences(SNPs)occurinhumans.Thisinformationpromisestorevolutionizetheprocessesoffindingchromosomallocationsfordisease-associatedsequencesandtracinghumanhistory.•Theratioofgermline(spermoreggcell)mutationsis2:1inmalesvsfemales.Researcherspointtoseveralreasonsforthehighermutationrateinthemalegermline,includingthegreaternumberofcelldivi