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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（表观遗传） Extranuclear Inheritance (Mitochondrial inheritance,线粒体粒体遗传) Multifactorial inheritance（多因子（多因子遗传） Dynamic mutation（动态突突变）Non-Mendelian Inheritance Any pattern of inheritance in which traits do not segregate in accordance with Mendels laws. Epigenetic Inheritance（
3、表（表观遗传） Extranuclear Inheritance (Mitochondrial inheritance,线粒体粒体遗传) Multifactorial inheritance（多因子（多因子遗传） Dynamic mutation（动态突突变）Non-Mendelian Inheritance Epigenetics 1，The mechanism of epigenetic modificationDNA methylationModification in the histone and chromatin remodelingNon-coding RNA2，Genomic
4、 imprinting3，Reprogramming of gene expression4， X chromosome inactivation5，Epigenetics and disease Mitochondrial inheritance1，Characteristics of mitochondrial inheritance2，Common mitochondrial diseasesInheritanceGeneticsEPIGENETICS Epigenetic phenomenon change in phenotype that is heritable but does
5、 not involve 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 epigenetics1，The mechanism of epigenetic modification Loc
6、ation of DNA Methylation Maintenance of DNA MethylationI.DNA MethylationDNMT1Donor SAM Cytosine 胞嘧啶胞嘧啶5-methylcytosine，5-mC 5-甲基胞嘧啶甲基胞嘧啶 DNMT1, DNA methytransferase （DNA甲基转移酶）SAM,S-adenosylmethionine （S-腺苷甲硫氨酸）Location of DNA methylation5-mC occur nearly exclusively at cytosine residues within the C
7、pG dinucleotide（ CpG二核苷酸）.CpG islands：CpG dinucleotides appear in small clusters.Location of DNA methylation DNRCH3CH3CH3CH3DNMTCH3CH3CH3CH3DNR: DNA replicase（复制酶）Maintenance of DNA MethylationModifications in the histone Phosphorylation（磷酸化） Acetylation（乙酰化） Methylation（甲基化）Such modifications inclu
8、ding histone methylation, phosphorylation and acetylation caused chromatin remodeling(染色染色质重塑重塑)-chromatin conformation is altered. II.Modification in the histone and chromatin remodeling Acetylation of histone can active gene expression Effect of histone modification depends on the location Multipl
9、e modification together to modulate the behavior of the nucleosomeII.Modification in the histone and chromatin remodelingIII. Functional non-coding RNA (ncRNA)Untranscribed (25%) Protein-coding mRNA (2%) Non-coding RNA (73%) rRNA tRNA snoRNA miRNA piRNA lncRNA (4-9%) Djebali & Davis (2012) Nature Ka
10、pranov 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 ssRNA 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
11、 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 biological processes (development, proliferate, differenation , etc) Micro RNAProduction mechanism o
12、f microRNAs:Function mechanism of microRNAs:DNA methylationHistone modificationChromatin remodelingBiological phenomenaTranscription, replication, recombination, repairDevelopment, reprogramming, aging, tumorigenesiseuchromatinheterochromatinNon-coding RNA2，Genomic Imprinting（GI）Genomic Imprinting (
13、GI,基因基因组印印记) is an epigenetic gene regulatory systermImprinted genes(IG) be asymmetry (不不对称地称地) expressed based on their parental origin.Only a few hundred IG in our genome Affect the growth, development, morphology Genomic Imprinting（GI）Features of IG Once established, it must remain on the same pa
14、rental chr after fertilization (受精受精). It must be inherited by the same parental chr following each cell division. It must be erasable (擦除擦除) precedes sex determination. Only occurs during gamete formation Genomic Imprinting（GI） Prader-Willi (PWS)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。The et
15、iology PWS： Missing segment comes from father (70%) Del(15q11-13) Maternal uniparental disomy (UPD,单亲源二倍体单亲源二倍体) (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 mutat
16、ion. Resulting from the mutation of SNRNP gene 考 试 通 知 4月月4号的实验课因清明节放假调至号的实验课因清明节放假调至3月月28号下午上，涉及到的班级口腔号下午上，涉及到的班级口腔15-1，2及及 口腔技术班口腔技术班时间考场考生备注考试时间考试时间4月月14日日(周五周五)18：00-20：005教留临床14-6、7、8、9 (47人)医实15 (45人)留口腔14-1（7人）答疑时间:4月12日(周三)上午10:00-12:004月13日（周四）上午9:00-10:00地点:解剖楼234逸夫楼402口腔15-2(28人)医英14(41人)
17、逸夫楼414口腔15-1(33人)医检15（31人）逸夫楼502逸夫楼514预防15-1(41人)口技15-1 （11人）预防15-2(42人)发育迟缓，智力低下语言能力极差平衡能力差，四肢发抖爱激动，频繁地笑突出上颚，宽嘴Angelman syndrome (AS) The etiology AS：Del(15q11-13) Missing segment comes from mother (70-75%) 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
18、%)：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） represent on the 15q11-13.Deletion of IC or epigenetic mutation.Beckwith-Wiedemann syndrome(BWS)脐突起巨舌巨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
19、 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 (细胞周期素依赖的激酶抑制蛋白CDKN1C) and paternally expressed KCNQ1OT1The etiology BWS： Major reprogramming only occurs in primordial germ cel
20、ls (PGCs,原始生殖原始生殖细胞胞) and in the early embryo. Tissue- and cell- specific gene express models are established and maintained , it is required own epigenetic marker. Many gametic markers are replaced with embryonic markers after fertilization.3，Reprogramming of Gene ExpressionEpigenomics reprogrammin
21、g in individual developmentoocytespermEmbryonic IGNon-imprinted genesGametic IG The developmental problems of clones are caused by epigenetic defects Serum alteration of the medium Complete during shorter period Epigenetic modification is sensitive to environmental factorAssisted reproductive techno
22、logies 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 one X chromosome is transcriptionally active. The second X is heterochromatic and inactive and appear
23、s 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, namely the inactivation is randomly.Mary F. Lyon （1961）4，X Chromosome inactivationChromosome inactiva
24、tion involves multiple levels of epigenetic modificationThe silencing occurs early in development, X inactivation is Developmentally RegulatedSome genes escape X inactivation. (XY pairing region)X-inactivation center(Xic)-The silencing initiated at the location of Xq13.3 (1Mb region) X Chromosome in
25、activationX inactivation is Developmentally RegulatedThe inactive X is reactivated and give rise to the embryoReversal of X inactivation also occurs in developing primordial germ cells. Xist, the first gene identified Encodes a large non-conding RNA （17kb） X-inactived (Xi) is coated by Xist RNA and
26、start heterochromatic and inactive X-actived (Xa) retains a low level of Xist RNA at first, later is degraded Onset of silencing, binding with the protein on chr to form a stable conformationX-inactivation center(Xic) Xce, X chr controlling elementChoice of which X chr remain active Tsix Negatively
27、regulates Xist ，The presence of CTCF binding sites Xite, X-inactivation intergenic transcription elementA candidate locus of XceModulation of Tsix expressionX-inactivation center(Xic)Environment-organism interactiveDNA methylation in toxicologyNutrition supplement during pregnancyPaternal dietetic h
28、abit influent childs health Aberrant DNA methylation, hitone modification, chromatin remoding Hypomethylation (低甲基化低甲基化) can lead to genomic instability Hypermethylation (超甲基化超甲基化) of CpG islands can lead to inappropriate gene silencing Methylation of tumor suppressor gene in the tumorEpimutation (表
29、表观突突变)1983,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).Me
30、diate the expression of specific targets in the brainRett syndrome (RTT)X-linked disorder, mental retardation（智力（智力迟缓）Dynamic mutation(动态突突变) of 5 end of Fragile X mental retardation 1(FMR1) gene at Xq27.3,FMRP regulate translation and transport ; synaptic plasticity Methylation of the expanded CGG
31、repeat and silencing of FMR1 transcription.Fragile X syndrome (OMIM 309550) Oncogene can be activated by hypomethy- lated Demethylation（去甲基化）（去甲基化） early in tumorigenesis Abrrant hypermethylation of normal unmethylated genes that are key tumor suppressor proteinsEPIGENETICS AND CANCERLoss of imprint
32、ing (LOI) of IG raise cancer riskTherapeutic stratege is reactivating epigenetically silenced cancer genes. Using demethylating agent：inhibitor of DNA cytisine methylation(胞胞嘧啶甲基化抑制甲基化抑制剂) DNA methylation patterns can change with age Hypomethylation resulted in ectopic expression(异位表达异位表达) in aging
33、cells Hypermethylation of CpG islands in aging cellsEPIGENETICS 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 phenomenon; uniparental disomy(UPD)Location of DNA MethylationInteractional factors in the epigenetic InheritanceFeatures of IGPathogeny of PWS/ASWhen did Genomic Imprinting occur (or era
34、sable)? When did reprogramming of gene expression happen?Environment has effect on epigenetic modificationsEpigenetics and disease (Rett syndrome; Fragile X)To masterEXTRANUCLEAR INHERITANCE （MITOCHONDRIAL INHERITANCE） 1894, mitochondria were discovered In the past century, structure and function（Ox
35、idation and energy central） 1963,mitochondrial DNA（mtDNA）was discoveredIndroduction1981, the complete sequence of human mtDNA was confirmed 1987,Lebers Disease with mtDNA mutation was discovered 16569bp,double-stranded circular molecule（H and L strand）mtDNA contains 37 genes coding 13proteins, 22tRN
36、A,2rRNAIndroductionMaternal inheritanceSemiautonomous(半自主半自主) replication of mtDNA mtDNA is still under the control of nDNAThe mtDNA genetic codes is different from the universal codes tRNA has a high compatibility（兼容性）（兼容性）, 22tRNA recognize 48 codonsCharacteristics of mitochondrial inheritanceMate
37、rnal inheritanceIIIIIICharacteristics of mitochondrial inheritanceCharacteristics of mitochondrial inheritanceMaternal inheritanceSemiautonomous(半自主半自主) replication of mtDNA mtDNA is still under the control of nDNAThe mtDNA genetic codes is different from the universal codes tRNA has a high compatib
38、ility（兼容性）（兼容性）, 22tRNA recognize 48 codonsSegregation of mitochondria and mtDNA is stochastic (随机的随机的)l Heteroplasmy （异（异质性）性） All mitochondrial genomes in a single cell or tissue are not identical. Mutant mtDNAs and wild-type mtDNAs are in a single cell or tissue.lGenetic bottleneck effect (遗传瓶瓶颈效
39、效应)-mtDNA molecules become less during the development of the oocyte, limit transfer of mutant. 105 100Mutations in mt DNA occur more frequently l Selection pressure can eliminate the harmful mutations of mtDNA Threshold Effect (阈值效应阈值效应) of mtDNA Threshold Least amount of mutant mtDNA that can caus
40、e the 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 mutation（错义突突变） t/rRNA gene mutantion Deletion and insertion mutations Reduced copy number of mtDNA molecules Classification of mtDNA MutationMit
41、ochondrial diseases is normal mitochondrial functions are damaged.Mutation of mtDNA or mutation of nDNAMaternal inheritance or Mendelian inherianceClinical manifestations Myopathy(肌肉病肌肉病), cardiomyopathy(心肌症心肌症), dementia(痴呆痴呆),explode myoclonus(肌肌阵挛), deafness(耳耳聋), anemia(贫血血), diabetes (糖尿病糖尿病)an
42、d cerebrovascular dysfunction(脑血管功血管功能障碍能障碍)Common mitochondrial diseasesmitochondrial myopathy(线粒体肌病粒体肌病)mitochondrial encephalomyopathy(线粒体粒体脑肌病肌病)mitochondrial encephalous（线粒体粒体脑病病）Classification of mitochondrial diseasesClinic pathological analysisBiochemical analysisUltrastructural analysisCT o
43、r MRI (mitochondrial encephalomyopathy)Mutation analysisCommon mutationsDiagnosis1820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 Neuropathy Leber视神神经萎萎缩Mutations：mtDNA G11778A、T14484C、 G3460AMutations decreased oxidization ability of NAD. NAD is respiratory chai
44、n complex I subunitLebers Hereditary Optic NeuropathyHeteroplasmyGenetic Bottleneck in mitochondrial inheritanceCharacteristics of mitochondrial inheritanceClassification of mitochondrial diseasesTo masterKey PointsNon-mendelian inheriance Epigenetics The mechanism of epigenetic modificationDNA meth
45、ylationModification in the histone and Chromatin remodelingNon-coding RNAGenomic imprintingReprogramming of gene expression X chromosome inactivationEpigenetics and disease EpimutationCancerAgingMitochondrial inheritanceCharacteristics of mitochondrial inheritanceCommon mitochondrial diseasesThank You
