成果医学遗传学1,3

1、General organization of the human genome20 000Organization of the human genomeGenome structureNuclear vs. mitochondrial genomesGene familiesTransposable elementsOther repeated sequencesOrganization of the human genomeNuclear genome3000 Mb23 (XX) or 24 (XY) linear chromosomes20-23,000 genes1 gene/40k

2、bIntrons3% codingRepetitive DNA sequences (45%) bination Mendelian inheritance (X + auto, paternal Y)Organization of the human genomeContrasting gene densitiesSome regions of the genome are gene-rich and others are gene-poorHLA high densityDystrophin low densityHistone gene distributionGene Structur

3、e and Expression2.2 Gene and genomeHuman Gene Intron Structure15 nt7 nt6 ntGene Sizes Vary a LotOrganization of the human genomeGene familiesThought to be generated by gene duplicationFunctionally similar genes are occasionally clustered, but usually dispersed throughout the genomeOrganization of th

4、e human genomeGenes vary in size and exon contentA general inverse relationship.09_07.jpgExon content vs. length09_07_2.jpg09_07_3.jpgOrganization of the human genomeGenes within genesIntron 26 of the NF1 gene contains three internal genes.Organization of the human genomeGene families:defined by ext

5、ensive DNA similarityAlpha and Beta globin genesdefined by large highly conserved domainsdefined by conserved amino acid motifsDEAD boxWD repeatsOrganization of the human genomeSuperfamiliesCommon structural featuresIg superfamilyCell surface receptorsOrganization of the human genomeHLA heavy chain

6、gene cluster: an exampleGene fragmentsPseudogenesTruncated genesOrganization of the human genomeProcessed pseudogenesOriginate by reverse transcription of a processed transcriptTPRTOrganization of the human genomeMitochondrial genome: OriginEndosymbiont HypothesisAncient archaeal cell engulfed a pro

7、teobacterium and eventually came to rely on the symbiont for survival.EvidenceCircular genomeAutonomous ribosomesOrganization of the human genomeMitochondrial genomeSmall (16.5 kb) circular DNA1 gene/0.45 kbVery few repeatsNo introns93% codingHeavy and Light strandsOrganization of the human genomeMi

8、tochondrial genesrRNA, tRNA and protein encoding genes (37)28 encoded by the heavy strand24 RNA products and (23s, 16s, tRNAs)13 protein coding genesOrganization of the human genomeMitochondrial genesrRNA, tRNA and protein encoding genes (37)28 encoded by the heavy strand24 RNA products and (23s, 16

9、s, tRNAs)13 protein coding genesGenes are transcribed as two transcription units and cleaved afterwardsGenes may overlapOrganization of the human genomeLimited autonomy of mt genomesmt encodednuclearNADH dehydrog 7 subunits41 subunitsSuccinate CoQ red0 subunits4 subunitsCytochrome b-c1 comp1 subunit

10、10 subunitsCytochrome C oxidase 3 subunits10 subunitsATP synthase complex2 subunits14 subunitstRNA components22 tRNAsnonerRNA components 2 componentsnoneRibosomal proteins none 80 Other mt proteinsnonemtDNA pol, RNA pol etc.Organization of the human genomeSpecial Features Mitochondrial genetic code

11、(reduced selection) Two extra stop codons: AGA and AGGUGA = tryptophan, AUA = Methionine/startNo binationMaternal inheritanceOrganization of the human genomeMitochondrial genome replicationOH Origin of heavy strand replicationOL Origin of light strand replicationD-loop2.7 Polymorphism Multiple funct

12、ional alleles at a frequency of 1% in a populationA population may have extensive polymorphism at the level of genotype It may offer a diagnostic procedure for detecting the disease It may lead to isolation of the gene Restriction Fragment Length Polymorphism (RFLP) -+Short Tandem Repeat Polymorphis

13、m (STRP) / microsatellite marker A polymorphic locus consisting of a variable number of tandemly repeated binucleotide, trinucleotide, or tetranucleotide units such as (TG)n, (CAA)n, or (GATA)n Single Nucleotide Polymorphism (SNP) A polymorphism in DNA sequence consisting of variation in a single ba

14、se.Single Nucleotide Variation (SNV) A variation in DNA sequence consisting of a single base.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) N

15、ucleotide Substitutions (Point Mutations) Missense mutations (amino acid substitutions) Nonsense mutations (premature stop codons) RNA processing mutations (destroy consensus splice sites, cap sites, and polyadenylation sites or create cryptic sites) Splice-site mutations leading to Indel, frameshif

16、t mutations and premature stop codons. Regulatory mutations affecting transcription factor binding, transcriptional control, or other aspects of gene expression.6 Silence mutations (nucleiotide changed, but not amino acid ）(2) Deletions and Insertions (Indel) Addition or deletion of a small number o

17、f bases: Larger scale gene deletions, duplications, and inversions, translocation, fusions : Expansion of trinucleotide repeat sequences: dynamic mutation ATGStopWhere can a mutation locate?Important to understand each type of mutations!- check the textbookGene Structure, Expression and Mutations2.2

18、 Gene and genomeRegulatory mutations MissenseNonsenseIndelFrameshift Trinucleotide repeat Expansionmutations-AAAAA“CAP”-Splice-sitemutationPoint mutation HbS-CCT GTG GAG-Pro Val Glu-HbA-CCT GAG GAG-Pro Glu Glu-Sickle cellanemiaSplicing MutationGene FusionMechanism of Large Scale IndelMore to Learn a

19、bout Human Genome“a complete human pan-genome would contain 1940Mb of novel sequence not present in the extant reference genome.” 28, 5763 (2010)A Personal Genome = Reference genome + Read alignment + SNP/indel calls?+Segmental plex rearrangements+Individual-specific sequencesPersonal genome is pers

20、onalized.After all, you need a De Novo assembled genome for every individual!Pilot project have identified 15M SNPs including 8.5M novel SNPs (left)Most novel SNPs are population specific (right)Nature. 464, 59-65(2010).Our “other” Genome: MetagenomicsMetagenomicsResearch the study of metagenomes, g

21、enetic material recovered directly from environmental samples. The broad field may also be referred to as environmental genomics, ecogenomics or community genomics. Traditional microbiology and microbial genome sequencing rely upon cultivated clonal cultures. This relatively new field of genetic res

22、earch enables studies of organisms that are not easily cultured in a laboratory as well as studies of organisms in their natural environment.Journal of Microbiological Methods. 79, 266-271(2009).Nature. 464, 59-65(2010).Andrologia. 40, 6671(2008).PLoS ONE. 4, e4219(2009).Genome Research. 18, 1043105

23、0(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 dysbiosis associated with diseaseAssembly and stability of the gut microbiota, and environmental factors affecting the gut mic

24、robiome during lifeHost genetic variants, their effects on the composition of the gut microbiota, and the corresponding host disease state International Human Genome Project (1990-2003)Genome: Blueprint of LifeParticipant countries: USA, UK, GE, FR, JP, CNHuman Genome Project Human genetic maps: Gen

25、etic maps are based on bination frequencies between markers. Centimorgan: The distance on a DNA molecule which have 1% binant frequency. 1 cM =1000kb.Physical Mapping: The physical maps depend on their physical distance apart on a DNA molecule. For example: Restriction Endonuclease physical map. DNA

26、 sequence itself is the finest physical map. markers RFLP markers: The first human genetic marker map. Microsatellite markers: High resolution human genetic marker map.SNP: A new generation of human genetic marker map STS: sequence-tagged site. A short DNA sequence, readily located and amplified by

27、PCR, that uniquely identifies a physical genomic location. Expressed sequence tags (ESTs) are STSs obtained from cDNAs. Center for Genomics, CAS GI was established in Aug, 1998Bioinformatics Center, CAS / Huada Genome Center was established in Sept, 1999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。立石銘蒼天在上磐石作證此時此

28、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 HVP3000 mb, 20,000-25,000 genesPhysical mappingSTS / ESTGenetic mappingCentigorgan: 1 cM = 1000kbMapping marker: RFLPMicrosatelliteSNPHGP to HapMap to HVP10%? %1%

29、BIO-BANK AND GENETIC DATABASE OF MAJOR DISEASES IN CHINA Ming Qi, PhD, FACMG, Dip ABMGCenter for Genetic & Genomic MedicineJames Watson Institute of Genomic Sciences& Medical School of Zhejiang UniversityUniversity of Rochester Medical CenterMcGill University, CanadaFeb 10, 2010Initiation of HVP (Ch

30、ina Consortium)Genetic & Genomic Medicine Analytic Platform: ZJU CGGMDatabase & Bioinformatic Platform: Nat CompSci Ctr at ZJU Chinese Student Volunteer Club, internet-teleconferenceHVP LOVD-CHINAUnderstandingthe Structure ofGenomesUnderstandingthe Biology ofGenomesUnderstandingthe Biology ofDisease

31、Advancingthe Science ofMedicineImproving theEffectivenessof Healthcare1990-2003Human Genome Project2004-2010Genomic plishments Across DomainsCourtesy from Eric Green, Director, NHGRIDr. Jim Watson s, Genome Sequenced for 2 Million Dollars announced on 5/30/2007Cardiovascular genesTumer suppressor genesCapability genesAntitoxin genesAlzheimer disease geneco-discoverers of the structure of DNADr. Venters Genome- Mapping own DNA changes scientists life4.1 million DNA variants,3,213,401 SNPs22% events CNV, involved 74% basesHis fathers fatal heart attack: three gen