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1、General organization of the human genome20 000OrganizationofthehumangenomeGenomestructureNuclearvs.mitochondrialgenomesGenefamiliesTransposableelementsOtherrepeatedsequencesOrganizationofthehumangenomeNucleargenome3000Mb23(XX)or24(XY)linearchromosomes20-23,000genes1gene/40kbIntrons3%codingRepetitive
2、DNAsequences(45%)RecombinationMendelianinheritance(X+auto,paternalY)OrganizationofthehumangenomeContrastinggenedensitiesSomeregionsofthegenomearegene-richandothersaregene-poorHLAhighdensityDystrophinlowdensityHistone gene distributionGene Structure and Expression2.2 Gene and genomeHuman Gene Intron
3、Structure15 nt7 nt6 ntGene Sizes Vary a LotOrganization of the human genomeGenefamiliesThoughttobegeneratedbygeneduplicationFunctionallysimilargenesareoccasionallyclustered,butusuallydispersedthroughoutthegenomeOrganization of the human genomeGenesvaryinsizeandexoncontentAgeneralinverserelationship.
4、09_07.jpgExon content vs. length09_07_2.jpg09_07_3.jpgOrganization of the human genomeGeneswithingenesIntron26oftheNF1genecontainsthreeinternalgenes.Organization of the human genomeGenefamilies:1.definedbyextensiveDNAsimilarityAlphaandBetaglobingenes2.definedbylargehighlyconserveddomains3.definedbyc
5、onservedaminoacidmotifsDEADboxWDrepeatsOrganization of the human genomeSuperfamiliesCommonstructuralfeaturesIgsuperfamilyCellsurfacereceptorsOrganization of the human genomeHLAheavychaingenecluster:anexampleGenefragmentsPseudogenesTruncatedgenesOrganization of the human genomeProcessedpseudogenesOri
6、ginatebyreversetranscriptionofaprocessedtranscriptTPRTOrganization of the human genomeMitochondrialgenome:OriginEndosymbiontHypothesisAncientarchaealcellengulfedaproteobacteriumandeventuallycametorelyonthesymbiontforsurvival.Evidence1.Circulargenome2.AutonomousribosomesOrganization of the human geno
7、meMitochondrialgenomeSmall(16.5kb)circularDNA1gene/0.45kbVeryfewrepeatsNointrons93%codingHeavyandLightstrandsOrganization of the human genomeMitochondrialgenesrRNA,tRNAandproteinencodinggenes(37)28encodedbytheheavystrand24RNAproductsand(23s,16s,tRNAs)13proteincodinggenesOrganization of the human gen
8、omeMitochondrialgenesrRNA,tRNAandproteinencodinggenes(37)28encodedbytheheavystrand24RNAproductsand(23s,16s,tRNAs)13proteincodinggenesGenesaretranscribedastwotranscriptionunitsandcleavedafterwardsGenesmayoverlapOrganization of the human genomeLimitedautonomyofmtgenomesmtencodednuclearNADHdehydrog7sub
9、units41subunitsSuccinateCoQred0subunits4subunitsCytochromeb-c1comp1subunit10subunitsCytochromeCoxidase3subunits10subunitsATPsynthasecomplex2subunits14subunitstRNAcomponents22tRNAsnonerRNAcomponents2componentsnoneRibosomalproteinsnone80OthermtproteinsnonemtDNApol,RNApoletc.Organization of the human g
10、enomeSpecialFeaturesMitochondrialgeneticcode(reducedselection)Twoextrastopcodons:AGAandAGGUGA=tryptophan,AUA=Methionine/startNorecombinationMaternalinheritanceOrganization of the human genomeMitochondrialgenomereplicationOHOriginofheavystrandreplicationOLOriginoflightstrandreplicationD-loop2.7 Polym
11、orphismMultiplefunctionalallelesatafrequencyof1%inapopulationApopulationmayhaveextensivepolymorphismatthelevelofgenotypeItmayofferadiagnosticprocedurefordetectingthediseaseItmayleadtoisolationofthegeneRestriction Fragment Length Polymorphism (RFLP)-+Short Tandem Repeat Polymorphism (STRP)/microsatel
12、lite markerApolymorphiclocusconsistingofavariablenumberoftandemlyrepeatedbinucleotide,trinucleotide,ortetranucleotideunitssuchas(TG)n,(CAA)n,or(GATA)nSingle Nucleotide Polymorphism (SNP) ApolymorphisminDNAsequenceconsistingofvariationinasinglebase.Single Nucleotide Variation (SNV) AvariationinDNAseq
13、uenceconsistingofasinglebase.DNA Mutation Mutations change the sequence of DNA:Spontaneous and induced;Germ-line and somatic;Large scale and small scalePoint mutations (nucleotide substitutions), deletions, insertions. DNA Mutation(1) Nucleotide Substitutions (Point Mutations)Missense mutations(amin
14、oacidsubstitutions)Nonsense mutations(prematurestopcodons)RNA processing mutations(destroyconsensussplicesites,capsites,andpolyadenylationsitesorcreatecrypticsites)Splice-site mutationsleadingtoIndel,frameshiftmutationsandprematurestopcodons.Regulatory mutationsaffectingtranscriptionfactorbinding,tr
15、anscriptionalcontrol,orotheraspectsofgeneexpression.6Silencemutations(nucleiotidechanged,butnotaminoacid）(2)Deletions and Insertions (Indel)Additionordeletionofasmallnumberofbases:Largerscalegenedeletions,duplications,andinversions,translocation,fusions:Expansionoftrinucleotiderepeatsequences:dynami
16、c mutationATGStopWhere can a mutation locate?Important to understand each type of mutations!- check the textbookGene Structure, Expression and Mutations2.2 Gene and genomeRegulatory mutationsMissenseNonsenseIndelFrameshift Trinucleotide repeat Expansionmutations-AAAAA“CAP”-Splice-sitemutationPoint m
17、utation HbS-CCT GTG GAG-Pro Val Glu-HbA-CCT GAG GAG-Pro Glu Glu-Sickle cellSickle cellanemiaanemiaSplicing MutationGene FusionMechanism of Large Scale IndelMore to Learn about Human Genome“acompletehumanpan-genomewouldcontain1940Mbofnovelsequencenotpresentintheextantreferencegenome.”28, 5763 (2010)A
18、PersonalGenome=Referencegenome+Readalignment+SNP/indelcalls?+Segmentalinsertions/deletions/inversions/Complexrearrangements+Individual-specificsequencesPersonalgenomeispersonalized.After all, you need a De Novo assembled genome for every individual!Pilotprojecthaveidentified15MSNPsincluding8.5Mnovel
19、SNPs(left)MostnovelSNPsarepopulationspecific(right)Nature. 464, 59-65(2010).Our “other” Genome: MetagenomicsMetagenomicsResearchthe study of metagenomes, genetic material recovereddirectly from environmental samples. The broad fieldmay also be referred to as environmental genomics,ecogenomics or com
20、munity genomics. Traditionalmicrobiology and microbial genome sequencing relyuponcultivatedclonalcultures.Thisrelativelynewfieldofgeneticresearchenablesstudiesoforganismsthatarenoteasilyculturedinalaboratoryaswellasstudiesoforganismsintheirnaturalenvironment.Journal of Microbiological Methods. 79, 2
21、66-271(2009).Nature. 464, 59-65(2010).Andrologia. 40, 6671(2008).PLoS ONE. 4, e4219(2009).Genome Research. 18, 10431050(2008).Metagenomics analysis of human disease10 X human cells, 100 X human genes!Microbial community composition at different body locations in a healthy humanGut microbial dysbiosi
22、s associated with diseaseAssembly and stability of the gut microbiota, and Assembly and stability of the gut microbiota, and environmental factors affecting the gut microbiome during environmental factors affecting the gut microbiome during lifelifeHost genetic variants, their effects on the composi
23、tion of the gut microbiota, and the corresponding host disease stateInternational Human Genome Project (1990-2003)Genome: Blueprint of LifeParticipantcountries:USA,UK,GE,FR,JP,CNHuman Genome ProjectHuman genetic maps:Geneticmapsarebasedonrecombinationfrequenciesbetweenmarkers.Centimorgan:Thedistance
24、onaDNAmoleculewhichhave1%recombinantfrequency.1cM=1000kb.Physical Mapping:ThephysicalmapsdependontheirphysicaldistanceapartonaDNAmolecule.Forexample:RestrictionEndonucleasephysicalmap.DNAsequenceitselfisthefinestphysicalmap.markers RFLP markers:Thefirsthumangeneticmarkermap.Microsatellite markers:Hi
25、ghresolutionhumangeneticmarkermap.SNP:AnewgenerationofhumangeneticmarkermapSTS:sequence-taggedsite.AshortDNAsequence,readilylocatedandamplifiedbyPCR,thatuniquelyidentifiesaphysicalgenomiclocation.Expressed sequence tags (ESTs)areSTSsobtainedfromcDNAs.CenterforGenomics,CASGIwasestablishedinAug,1998Bi
26、oinformatics Center, CAS / Huada Genome Center was established in Sept, 1999寸草成簇根始深，寒冬未过便知春。寸草成簇根始深，寒冬未过便知春。五骏齐趋何须顾，此行万里追鹏鲲。五骏齐趋何须顾，此行万里追鹏鲲。立立石石銘銘蒼天在上磐石作證此時此地一群普普通通的炎黃子孫用他們的淚汗心血和青春為他們古老的民族爭得了一個險些失去的歷史機遇歲月無情他們和他們的支持者都將隨時光而逝去此心昭昭他們的執著奉獻和自信必將作為人類基因圖的一小部分留駐歷史杨焕明一九九九年九月九日九时九分华大成立Important points of HVP30
27、00mb,20,000-25,000genesPhysicalmappingSTS/ESTGeneticmappingCentigorgan:1cM=1000kbMappingmarker:RFLPMicrosatelliteSNPHGP to HapMap to HVP10%? %1%BIO-BANK AND GENETIC DATABASE OF MAJOR DISEASES IN CHINAMing Qi, PhD, FACMG, Dip ABMGCenter for Genetic & Genomic MedicineJames Watson Institute of Genomic
28、Sciences& Medical School of Zhejiang UniversityUniversity of Rochester Medical CenterMcGill University, CanadaFeb 10, 2010Initiation of HVP (China Consortium)Genetic & Genomic Medicine Analytic Platform: ZJU CGGMDatabase & Bioinformatic Platform: Nat CompSci Ctr at ZJU Chinese Student Volunteer Club
29、, internet-teleconferenceHVP LOVD-CHINAUnderstandingthe Structure ofGenomesUnderstandingthe Biology ofGenomesUnderstandingthe Biology ofDiseaseAdvancingthe Science ofMedicineImproving theEffectivenessof Healthcare1990-2003Human Genome Project2004-2010Genomic Accomplishments Across DomainsCourtesyCou
30、rtesyCourtesy from from from Eric Green, Director, NHGRIEric Green, Director, NHGRIEric Green, Director, NHGRIDr. Jim Watson s,Dr. Jim Watson s,Genome Sequenced for 2 Million Genome Sequenced for 2 Million DollarsDollarsannounced on 5/30/2007announced on 5/30/2007Cardiovascular genesTumer suppressor
31、 genesCapability genesAntitoxin genesAlzheimer disease geneco-discoverers of the co-discoverers of the structure of DNAstructure of DNADr. Venters Genome- Mapping own DNA changes scientists lifeMapping own DNA changes scientists life4.1millionDNAvariants,3,213,401SNPs22%eventsCNV,involved74%basesHis
32、fathersfatalheartattack:threegeneslinkedtoincreasedheartattackriskagenelinkedtoAlzheimersdisease(nofamilyhistory!)Now,hetakesstatins,ordrugsthatlowerthecholesterolintheblood,becauseoftheirprovenbeneficialhearteffectsandpossiblememoryprotection.1.5 The Ethical, Legal and Social Implications (ELSI) Ex
33、amined questions of genetic privacy, genetic discrimination and genetic determinism. What should people know before having a genetic test? Who will have access to the information the test generates? How will that information be used? Who owns the genetic information stored in each individuals DNA? W
34、hat is genetic discrimination? 1.5 The Ethical, Legal and Social Implications (ELSI) InformedconsentEstablishandfollowtheinternationalregulationsandguidelinesClinical Practice of Medical Genetics in in North AmericaNorth AmericaPerforming Structure of Medical GeneticsAccreditationPolicy,guidelinesandregulationsrecommendationNational/internationalcollaborationsPracticingGraduateandpostgraduatetrainingContinuemedicaleducationInformationexchangeFundraising
