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1、Non-Mendelian Inheritance According to Mendels lawThe Law of Segregation (The First Law)The Law of Independent Assortment (The Second Law) Reciprocal cross dont impact phenotype of offspring Mendelian inheriance Any pattern of inheritance in which traits do not segregate in accordance with Mendels l
2、aws. Epigenetic Inheritance（表观遗传）Extranuclear Inheritance （Mitochondrial inheritance，线粒体遗传）Multifactorial inheritance（多因子遗传）Dynamic mutation（动态突变）InheritancegeneticsEPIGENETICS Epigenetics 1，The mechanism of epigenetic modificationDNA methylationModification in the histone and chromatin remodelingNo
3、n-coding RNA2，Genomic imprinting3，Reprogramming of gene expression4， X chromosome inactivation5，Epigenetics and disease Mitochondrial inheritance1，Characteristics of mitochondrial inheritance2，Common mitochondrial diseases Epigenetic phenomenon change in phenotype that is heritable but does not invo
4、lve DNA mutation.( 2004, 69th Cold Spring Harbor Symposium) Epigenetic phenomenon Identify the compositional difference(组成差异) of two distinct structures between the two phenotypic states. Maintained mechanism（维持机制）Research works of epigeneticsLocation of DNA MethylationMaintenance of DNA Methylation
5、I.DNA MethylationDNMT1Donor SAM Cytosine5-methylcytosine，5-mC DNMT1, DNA methytransferaseSAM,S-adenosylmethionine 5-mc occur nearly exclusively at cytosine residues within the CpG dinucleotide.CpG islands：CpG dinucleotides appear in small clusters.Location of DNA methylation DNRCH3CH3CH3CH3DNMTCH3CH
6、3CH3CH3DNR: DNA replicaseMaintaining Methylated mechanismA,CpG岛没有被甲基化的时候，基因表达。B,甲基化之后，基因不表达。These modifications caused chromatin remodeling(染色质重塑)-chromatin conformation is altered. Euchromatin(常染色质） Heterochromatin（异染色质）Modify in the histonePhosphorylation（磷酸化）Acetylation（乙酰化）Methylation（甲基化）II.Chr
7、omatin RemodelingAcetylation of histone can active gene expressionEffect of histone modification depends on the location.Multiple modification together to modulate the behavior of the nucleosomeII.Chromatin RemodelingIII. Functional non-coding RNA (ncRNA)Untranscribed (25%) Protein-coding mRNA (2%)
8、Non-coding RNA (73%) rRNA tRNA snoRNA miRNA piRNA lncRNA (4-9%) Djebali & Davis (2012) Nature Kapranov P. et al. (2007) Science Long ncRNA, lncRNA (200nt) can regulate entire chromosome activity (e.g. X Chr inactivation ) Short ncRNA can regulate one or more gene expression micro RNA(miRNA)：22nt ssR
9、NA small interfering RNA, siRNA：21dsRNA 表观遗传调控 DNA LncRNA 转录调控 pre-mRNA mRNA 加工调控 转运调控 mRNA 翻译调控 mRNA降解调控 蛋白质 失活mRNA 细胞核 细胞质 lncRNA（Long non-coding RNA) Micro RNA(miRNA) is endogenous 22 nt RNAs, that can regulate expression of protein-coding gene to influence the output. MiRNA participates in biolo
10、gical processes (development, proliferate, differenation , etc) Micro RNADNA methylationHistone modificationChromatin remodelingBiological phenomenaTranscription, replication, recombination, repairDevelopment, reprogramming, aging, tumorigenesiseuchromatinheterochromatinNon-coding RNA GI changes sam
11、e actived potential of two copies of every gene. IV. Genomic Imprinting（GI）Genomic Imprinting(GI,基因组印记) is an epigenetic gene regulatory systermImprinted genes(IG) be asymmetry (不对称地) expressed based on their parental origin.（在父本和母本上不对称）Only a few hundred IG in our genome Affect the growth, developm
12、ent, morphology Features of IGOnce established, it must remain on the same parental chr after fertilization(受精).It must be inherited by the same parental chr following each cell division. It must be erasable(擦除) precedes sex determination.Only occurs during gamete formation在性别决定之前被清除，在性别决定之后，如果是男孩，则
13、带有父本的印记，如果是女孩，则带有母本的印记，在细胞分裂过程当中一直保持下去性别决定之前全部印记清除雌性，把母本的印记重新带上雄性，把父本的印记重新带上1956,Missing segment comes from father严重肌张力减退，喂食困难摄食困难，过度肥胖认知有问题手脚小，杏仁眼，上嘴唇薄，强迫症，异焦虑。PWSThe etiology PWS： Missing segment comes from father (70%) Del(15q11-13)父亲的这一段deletion；母亲的这一段印记，不表达 Maternal uniparental disomy (UPD,单亲源二
14、倍体单亲源二倍体) (25%):母亲单亲二倍体母亲单亲二倍体UPD-Patients who inherit both homologous chromosomes Imprinting defects (5%) Imprinting centers（IC，基因印记中心） represent on the 15q11-13.Deletion of IC or epigenetic mutation. Resulting from the mutation of SNRNP gene 1968,Missing segment comes from mather发育迟缓，智力低下语言能力极差平衡能
15、力差，四肢发抖爱激动，频繁地笑突出上颚，宽嘴ASThe etiology AS：Del(15q11-13) Missing segment comes from mother (70-75%) 父亲的这段发生imprinting印记，母亲的这段deletion AS arise by mutation of UBE3A gene (10%) Faternal uniparental disomy (UPD,单亲源二倍体单亲源二倍体) (3-7%)：父亲单亲二倍体：父亲单亲二倍体 Imprinting defects (2-4%) Imprinting centers（IC，基因印记中心） re
16、present on the 15q11-13.Deletion of IC or epigenetic mutation.单亲源二倍体例如克隆羊多莉 Imprinting defects Imprinting centers（IC，基因印记中心） represent on the 15q11-13.Deletion of IC or epigenetic mutation.AS arise by mutation of UBE3A gene; PWS arise by mutation of SNRNP gene .Beckwith-Wiedemann syndrome(BWS)脐突起巨舌巨
17、婴小头畸形易患病体质脐疝脐疝-巨舌巨舌-巨人症综合征巨人症综合征 The 11p15.5,including 12 cluster-Imprinted genes distributed in two Imprinting centers, is related to BWS.The first IC is 5-IGF2-DMR-H19-3 (IGF2:胰岛素样生长因子2，H19：非编码 RNA)The second IC contains maternally expressed KCNQ1(钾离子通道组分), cyclin-dependent kinase inhibitory (细胞周期
18、素依赖的激酶抑制蛋白CDKN1C) and paternally expressed KCNQ1OT1The etiology BWS：Each cell type in our body has its own epigenetic marker (表观遗传标记表观遗传标记) that is reflected in the phenotype of the cell and organism. However, in normal development, some cells undergo major epigenetic “reprogramming”（重编（重编程）程）. V. R
19、eprogramming of Gene Expression Upon fertilization, many gametic markers are replaced with embryonic markers, known collectively as the epigenome （表观基因组）（表观基因组）.Major reprogramming also occurs in primordial germ cells (PGCs,原始生殖细胞原始生殖细胞) in which parental imprints are erased . Some epigenetic marker
20、s in the nucleus are removed and a different set of markers is reestablished. Epigenomics reprogramming in individual developmentoocytespermEmbryonic IGNon-imprinted genesGametic IG The developmental problems of clones are caused by epigenetic defects Serum alteration of the medium Complete during s
21、horter period Epigenetic modification is sensitive to environmental factorAssisted reproductive technologies can cause imprinting diseases Evidence: AS and BWS casesInt J Epidemiol. 2005 Jun;34(3):696-701. Epub 2004 Nov 23.The Lyon hypothesis(莱昂假说莱昂假说) 1. In the somatic cells of female mammals, only
22、 one X chromosome is transcriptionally active. The second X is heterochromatic and inactive and appears in interphase cells as sex chromatin, the Barr body. 2. Inactivation occurs early in embryonic life. 3. In any one female somatic cell, the inactive X may be either the paternal or the maternal X,
23、 namely the inactivation is randomly.Mary F. Lyon （1961）VI. X Chromosome inactivationChromosome inactivation involves multiple levels of epigenetic modificationThe silencing occurs early in development, X inactivation is Developmentally RegulatedSome genes escape X inactivation. (XY pairing region)X
24、-inactivation center(Xic)-The silencing initiated at the location of Xq13.3 (1Mb region) X Chromosome inactivation失活的X染色体部分基因还是可以打开表达的X inactivation is X inactivation is Developmentally RegulatedDevelopmentally RegulatedThe inactive X is reactivated in the inner cell mass(内细胞团) that give rise to the
25、 embryoReversal of X inactivation also occurs in developing primordial germ cells.XistXist, the first gene identified A non-conding RNA X-inactived(Xi) is packed by Xist RNA and start heterochromatic and inactive X-actived(Xa) retains a low level of Xist RNA at first, later is degraded Onset of sile
26、ncing, binding with the protein on chr to form a stable conformationX-inactivation center(Xic)Xce, Xce, X chr controlling elementChoice of which X chr remain activeTsixTsix Negatively regulates Xist ，The presence of CTCF binding sitesXiteXite, X-inactivation intergenic transcription elementA candida
27、te locus of XceModulation of Tsix expressionX-inactivation center(Xic)蛋白质，可以binding在上面，负向调节XistEnvironment-organism interactiveDNA methylation in toxicologyNutrition supplement during pregnancyPaternal dietetic habit influent childs healthEpimutation Aberrant DNA methylation, hitone modification, ch
28、romatin remoding,Hypomethylation can lead to genomic instabilityHypermethylation of CpG islands can lead to inappropriate gene silencingMethylation of tumor suppressor gene in the tumor1983,neurodevelopmental disorder, XD, affects females after birth(nonviable male hemizygous致死性男性半合子)行动不正常，不协调，癫痫，无意
29、识的搓手，语言能力下降(孤独症和自闭症的表现)MeCP2(methyl CpG-binding protein 2,甲基化CpG结合蛋白2) is pathogenic geneMutants focus on methyl-binding domain(MBD) and transcription repression domain(TRD).Mediate the expression of specific targets in the brainRett syndrome(RTT)Rett syndrome(RTT)X-linked disorder, mental retardati
30、on（智力迟缓）Dynamic mutation(动态突变) of 5 end of Fragile X mental retardation 1(FMR1FMR1) gene at Xq27.3,FMRP regulate translation and transport ; synaptic plasticity MethylationMethylation of the expanded CGG repeat and silencing of FMR1 transcription.Produce shRNAshRNA Fragile X syndrome(OMIM 309550)Fra
31、gile X syndrome(OMIM 309550)Oncogene can be activated by hypomethy- lationDemethylation（去甲基化） early in tumorigenesis Abrrant hypermethylation of normal unmethylated genes,which are key tumor suppressor proteinEPIGENETICS AND CANCEREPIGENETICS AND CANCERLoss of imprinting(LOI) of IG raise cancer risk
32、Therapeutic stratege is reactivating epigenetically silenced cancer genes. Using demethylating agent：inhibitor of DNA cytisine methylation(胞嘧啶甲基化抑制剂)DNA methylation patterns can change with ageHypomethylation resulted in ectopic expression(异位表达) in aging cellsHypermethylation of CpG islands in aging
33、 cellsEPIGENETICS AND AGINGEPIGENETICS AND AGING 表观基因组在发育、生长和衰老过程存在着一个动态变化的过程Epigenetic phenomenonInteractional factors in the epigenetic InheritanceLocation of DNA MethylationFeatures of IGWhen did Genomic Imprinting occur (or erasable)?Pathogeny of PWS/AS （uniparental disomy (UPD)）When did reprogr
34、amming of gene expression happen?Environment has effect on epigenetic modificationsEpigenetics and disease (Rett syndrome; Fragile X)To masterEXTRANUCLEAR INHERITANCE EXTRANUCLEAR INHERITANCE （MITOCHONDRIAL MITOCHONDRIAL INHERITANCEINHERITANCE）1894, mitochondria were discoveredIn the past century, s
35、tructure and function（Oxidation and egergy central） 1963,mitochondrial mtDNA was discoveredIndroductionIndroduction1981,confirmed complete sequence of human mtDNA1987,Lebers Disease with mtDNA mutation was discovered IndroductionIndroduction16569bp,double-stranded circular molecule（H,Lstrand）mtDNA c
36、ontains genes coding 13proteins, 22tRNA,2rRNAMaternal inheritanceCharacteristics of mitochondrial Characteristics of mitochondrial inheritanceinheritanceIIIIIIMaternal inheritanceSemiautonomous(半自主) replication of mtDNAmtDNA is still under the control of nDNAThe mtDNA genetic codes is different from
37、 the universal codestRNA has a high compatibility（兼容性）, 22tRNA recognize 48 codonsCharacteristics of mitochondrial Characteristics of mitochondrial inheritanceinheritanceSegregation of mitochondria and mtDNA is stochastic(随机)Heteroplasmy （异质性） All mitochondrial genome in a single cell or tissue are
38、not identical. Mutant mtDNA and wild-type mtDNA within a single cell and tissue.Bottleneck(瓶颈)-mtDNA molecules is less during development of oocyte, limit transfer of mutant. 105 100Mutations in mt DNA occur more frequently Selection pressure to eliminate harmful mutations of mtDNA Threshold Effect(
39、阈值效应) of mtDNA Threshold Least amount of mutant mtDNA arise dysfunction of specific tissue and organ. The threshold depends on the energy requirements of the cell. 中枢神经-骨骼肌-心脏-胰腺-肾脏-肝脏Gene mutations Missense mutationtRNA gene mutantionDeletion and insertion mutationsReduced copy number of mtDNA mole
40、cules Classification of mtDNA MutationClassification of mtDNA MutationMitochondrial diseases is normal mitochondrial functions are damaged.Mutation of mtDNA or mutation of nDNAMaternal inheritance or Mendelian inherianceClinical manifestations Myopathy(肌肉病), cardiomyopathy(心肌症), dementia(痴呆),explode
41、 myoclonus(肌阵挛), deafness(耳聋), anemia(贫血), diabetes (糖尿病)and cerebrovascular dysfunction(脑血管功能障碍)Common mitochondrial diseasesCommon mitochondrial diseasesmitochondrial myopathy(线粒体肌病)mitochondrial encephalomyopathy(线粒体脑肌病)mitochondrial encephalous（线粒体脑病）Classification of mitochondrial Classificatio
42、n of mitochondrial diseasesdiseasesDiagnosisClinic pathological analysisBiochemical analysisUltrastructural analysisCT or MRI (mitochondrial encephalomyopathy)Mutation analysisCommon mutations1820岁发病，男性较多见多数双侧视力同时急剧减退，无痛性中心视野丧失双侧视神经严重萎缩可伴有神经、心血管、骨骼肌等系统异常Lebers Hereditary Optic NeuropathyLebers Hered
43、itary Optic Neuropathy LeberLeber视神经萎缩视神经萎缩Mutations：mtDNA G11778A、T14484C、 G3460AMutations decreased oxidization ability of NAD. NAD is respiratory chain complex I subunitLebers Hereditary Optic NeuropathyLebers Hereditary Optic NeuropathyHeteroplasmyGenetic Bottleneck in mitochondrial inheritanceC
44、haracteristics of mitochondrial inheritanceClassification of mitochondrial diseasesTo masterTo masterOutline Outline Non-mendelian inheritance Epigenetics The mechanism of epigenetic modificationDNA methylationChromatin remodelingModify in the histoneNon-coding RNAGenomic imprintingReprogramming of gene expression X chromosome inactivationEpigenetics and disease EpimutationCancerAgingMitochondrial inheritanceCharacteristics of mitochondrial inheritanceCommon mitochondrial diseasesThank You Thank You
