医学遗传学教学课件：Non-Mendelian Inheritance

1、Non-Mendelian Inheritance,Outline,Familiar type of non-mendelian inheriance Epigenetics The mechanism of epigenetic modification DNA methylation Chromatin remodeling Modify in the histone Non-coding RNA,Genomic imprinting Reprogramming of gene expression X chromosome inactivation Epigenetics and dis

2、ease Epimutation Cancer Aging Mitochondrial inheritance Characteristics of mitochondrial inheritance Common mitochondrial diseases,To according with Mendels law Law of Segregation (The First Law) Law of Independent Assortment (The Second Law) Reciprocal cross dont impact phenotype of offspring,Show

3、a 3:1 ratio in the F2,The phenotypes of two independent traits show a 9:3:3:1 ratio in the F2 generation,Any pattern of inheritance in which traits do not segregate in accordance with Mendels laws. Epigenetic Inheritance（表观遗传） Extranuclear Inheritance （Mitochondrial inheritance，线粒体遗传） Multifactorial

4、 inheritance（多因子遗传） Dynamic mutation（动态突变,Any pattern of inheritance in which traits do not segregate in accordance with Mendels laws. 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,Inheritance,genetics,

5、EPIGENETICS,1941-1951,“Position effect variegation” (PEV,位置效应花斑) 1956, Controlling element could suppress expression of gene 1961, One X chr is heterochromatic and inactive,Epigenetic phenomenon,Epigenetic phenomenon change in phenotype that is heritable but does not involve DNA mutation.( 2004, 69t

6、h 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 epigenetics,Location of DNA Methylation Maintenance of DNA Methylation,DNA Methylation,5-mc occur

7、 nearly exclusively at cytosine residues within the CpG dinucleotide. CpG islands：CpG dinucleotides appear in small clusters,Location of DNA methylation,DNR,DNMT,DNR: DNA replicase,Maintaining Methylated mechanism,These modifications caused chromatin remodeling(染色质重塑)-chromatin conformation is alter

8、ed. Euchromatin(常染色质） Heterochromatin（异染色质） Modify in the histone Phosphorylation（磷酸化） Acetylation（乙酰化） Methylation（甲基化,Chromatin Remodeling,Acetylation of histone can active gene expression Effect of histone modification depends on the location. Multiple modification together to modulate the behavi

9、or of the nucleosome,Chromatin Remodeling,Long ncRNA,lncRNA (200nt)can regulate entire chromosome activity (e.g. X Chromosome inactivation ) Short ncRNA can regulate one or more gene expression micro RNA(miRNA)：22nt ssRNA small interfering RNA, siRNA：21dsRNA,Functional non-coding RNA(ncRNA,Micro RNA

10、(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 RNA,DNA methylation,Histone modification,Chromatin remodeling,Biological phenomena Transcript

11、ion, replication, recombination, repair Development, reprogramming, aging, tumorigenesis,euchromatin,heterochromatin,Non-coding RNA,Gene active,Gene silencing,GI changes same actived potential of two copies of every gene,Genomic Imprinting（GI,Genomic Imprinting(GI,基因组印记) is an epigenetic gene regula

12、tory systerm Imprinted genes(IG) be asymmetry (不对称地) expressed based on their parental origin. Only a few hundred IG in our genome Only occurs during gamete formation,Features of IG Once established, it must remain on the same parental chr after fertilization(受精). It must be inherited by the same pa

13、rental chr following each cell division. It must be erasable(擦除) precedes sex determination. Function of IG Affect the growth, development, morphology,Prader-Willi/Angelman (PWS/AS,Del(15q11-13,Missing segment comes from father, that result in PWS or maternal uniparental disomy(UPD,单亲源二倍体). UPD-Pati

14、ents who inherit both homologous chromosomes Missing segment comes from mather, that result in AS or faternal UPD,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,PWS,1968,Missing segment comes from mather,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,AS,Imprin

15、ting 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 巨婴 偏身肥大 易患病体质,脐疝-巨舌-巨人症综合征,The 11p15,included 12 cluster-Imprinted genes, distri

16、buted in two Imprinting centers, relatived to the BWS. Fist IC is 5-IGF2-DMR-H19-3 (IGF2:胰岛素样生长因子2，H19：非编码 RNA) Sencond 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 KCNQ1OT1,Insulator(绝缘子) is defined as an element

17、 that blocks enhancer and promoter interactions when placed between them. CTCF is involved in insulator activity,DMR: differentially methylated region,增强子/染色体屏障调控模式,The 11p15,included 12 cluster-Imprinted genes, distributed in two Imprinting centers, relatived to the BWS. Fist IC is 5-IGF2-DMR-H19-3

18、 (IGF2:胰岛素样生长因子2，H19：非编码 RNA) Sencond 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 KCNQ1OT1,Paternal duplications encompassing IGF2 Paternal UPD for 11p15.5 Loss of function mutations in the maternal allele of CDK

19、N1C Thanslocations on the maternal chr disrupting KCNQ1 which affect imprinting of IGF2 but curiously not ICR2 Most commonly, loss of imprinting for ICR2/KCNQ1OT1 which again alters imprinting of IGF2 这表明父本表达的等位基因对胚胎的生长有促进作用，而母本表达的等位基因对胚胎的发育起到限制作用,Tissue- and cell- specific gene express model are es

20、tablished and maintained ,it is required own epigenetic marker. Major reprogramming only occurs in primordial germ cells(PGCs,原生殖细胞) and in the early embryo Many gametic markers are replaced with embryonic markers after fertilization,Reprogramming of Gene Expression,Epigenomics reprogramming in indi

21、vidual development,oocyte,sperm,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 factor,Assisted reproductive technologies can cause imprinting diseases Evidence:

22、AS and BWS cases,Int J Epidemiol. 2005 Jun;34(3):696-701. Epub 2004 Nov 23.,The Lyon hypothesis(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 appears in interphase cells as sex chromatin, the Barr b

23、ody. 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,X Chromosome inactivation,Chromosome inactivation involves multiple levels of epigenetic modific

24、ation The silencing occurs early in development, approximately 7 to 10 days after fertilization X inactivation is Developmentally Regulated Some genes escape X inactivation. (XY pairing region) X-inactivation center(Xic)-The silencing initiated at the location of Xq13.3 (1Mb region,X Chromosome inac

25、tivation,X inactivation is Developmentally Regulated,The inactive X is reactivated in the inner cell mass(内细胞团) that give rise to the embryo Reversal of X inactivation also occurs in developing primordial germ cells,Xist, the first gene identified A non-conding RNA X-inactived(Xi) is packed by Xist

26、RNA and 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 conformation,X-inactivation center(Xic,Xce, X chr controlling element Choice of which X chr remain active Tsix Neg

27、atively regulates Xist ， The presence of CTCF binding sites Xite, X-inactivation intergenic transcription element A candidate locus of Xce Modulation of Tsix expression,X-inactivation center(Xic,Environment-organism interactive DNA methylation in toxicology Nutrition supplement during pregnancy Pate

28、rnal dietetic habit influent childs health,Epimutation Aberrant DNA methylation, hitone modification, chromatin remoding, Hypomethylation can lead to genomic instability Hypermethylation of CpG islands can lead to inappropriate gene silencing Methylation of tumor suppressor gene in the tumor,1983,ne

29、urodevelopmental 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 gene Mutants focus on methyl-binding domain(MBD) and transcription repression domain(TRD). Mediate the ex

30、pression of specific targets in the brain,Rett syndrome(RTT,X-linked disorder, mental retardation（智力迟缓） Dynamic mutation(动态突变) 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 repeat and sil

31、encing of FMR1 transcription. Produce shRNA,Fragile X syndrome(OMIM 309550,X-linked disease, MR and genital abnormalities ATRX encodes an ATP-dependent chromatin-remodeling protein Location of ATRX: pericentromeric heterochromatin ATRX associate with heterochromatin protein 1 and Histone-lysine N-me

32、thyltransferase EZH2 ,EZH2 Patients have DNA methylation defects(hyper-,hypo,Alpha-thalassemia/mental-retardation syndrome,X-linked (ATRX,OMIM301040,Immunodeficiency,centromeric instability and facial anomalies(免疫缺陷、着丝粒区域不稳定以及面部异常综合症) Mutation of DNA甲基转移酶基因DNMT3B Hypomethylation and decondensation o

33、f pericentromeric heterochromatin（satellite2 and 3） on chr1 and 16(着丝粒周边异染色质的低甲基化和去凝缩化) Other genes involved in immune function are not hypomethylated,ICF syndrome,Oncogene can be activated by hypomethy-lated Demethylation（去甲基化） early in tumorigenesis Abrrant hypermethylation of normal unmethylated

34、genes,which are key tumor suppressor protein,EPIGENETICS AND CANCER,Loss of imprinting(LOI) of IG raise cancer risk 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

35、 with age Hypomethylation resulted in ectopic expression(异位表达) in aging cells Hypermethylation of CpG islands in aging cells,EPIGENETICS 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 Methylation Interactional factors in the epigenetic Inheritan

36、ce Features of IG Pathogeny of PWS/AS First IC in 11p15 relatived to the BWS When did Genomic Imprinting occur(or erasable)? When did reprogramming of gene expression happen,To master,Environment has effect on epigenetic modifications Epigenetics and disease (Rett syndrome; Fragile X; ATRX; ICF synd

37、rome,To master,Extranuclear Inheritance （Mitochondrial inheritance,1894, mitochondria were discovered In the past century, structure and function（Oxidation and egergy central） 1963,mitochondrial mtDNA was discovered,Indroduction,1981,confimed complete sequence of human mtDNA 1987,Lebers Disease with

38、 mtDNA mutation was discovered,Indroduction,16569bp,double-stranded circular molecule（H,Lstrand） mtDNA contains genes coding 13proteins, 22tRNA,2rRNA,Maternal inheritance Semiautonomous(半自主) replication of mtDNA mtDNA is still under the control of nDNA The mtDNA genetic codes is different from the u

39、niversal codes tRNA has a high compatibility（兼容性）, 22tRNA recognize 48 codons,Characteristics of mitochondrial inheritance,Maternal inheritance,Characteristics of mitochondrial inheritance,I,II,III,Maternal inheritance Semiautonomous(半自主) replication of mtDNA mtDNA is still under the control of nDNA

40、 The mtDNA genetic codes is different from the universal codes tRNA has a high compatibility（兼容性）, 22tRNA recognize 48 codons,Characteristics of mitochondrial inheritance,Segregation of mitochondria and mtDNA is stochastic(随机) Heterogeneity (异质性) of mtDNA: All mitochondrisl genome in a single cell o

41、r tissue not are identical. Bottleneck(瓶颈)-mtDNA molecules is less during development of oocyte, limit transfer of mutant. 105 100 Mutations in mt DNA occur more frequently Selection pressure to eliminate harmful mutations of mtDNA,Threshold Effect(阈值效应) of mtDNA Homoplasmy（同质性） All mitochondrisl genome in a single cell or tissue are identical Heteroplasmy （异质性）mutant mtDNA and wild-type mtDNA within a single cell and tissue. Threshold Least amount of mutant mtDNA arise dysfunct