单基因病的遗传方式-医学遗传学课件.ppt

《单基因病的遗传方式-医学遗传学课件.ppt》由会员分享，可在线阅读，更多相关《单基因病的遗传方式-医学遗传学课件.ppt（82页珍藏版）》请在淘文阁 - 分享文档赚钱的网站上搜索。

1、手机：QQ：657896959Chapter 5 Inheritance Patterns of Single-gene Disorders单基因病的遗传方式单基因病的遗传方式Single-gene Disorder(SGD)(Monogenic Disease)单基因病A disorder due to one or a pair of mutant alleles(等位基因）at a single locus.AA(C)Aa(B)aa(A)5.1 Pedigree（系谱）and Proband（先证者）SGD is characterized by the pattern of trans

2、mission in families.Pedigree Analysis most powerful tools in human genetic studyPedigrees（系谱）a graphic representations of a family tree（家系）drawn with use of standard symbols.biological relationship inheritance pattern of genetic trait or diseaseGuide for diagnosis and therapyI 1 2II 1 2 3 4 5 6 7 8

3、9 10 11 12III 1 2 3 4 5 6 7 8 9 10 11 12Pedigree and ClinicDiagnosis and therapy base on Inheritance analysis 1243123451234567846525033962IIIIIIA family with familial hypercholesterolemia(家族性高胆固醇血症家族性高胆固醇血症)先症者:25岁心绞痛30岁心梗33岁冠状动脉搭桥Cell fail to catch LDL from bloodExercise 1:Draw a pedigree 医生通过对患多指症

4、医生通过对患多指症的男子的男子A A的询问，得知其的询问，得知其家族情况：家族情况：A A的祖父多指，的祖父多指，祖母正常；祖母正常；A A的父亲是老的父亲是老大，有大，有2 2个弟弟和个弟弟和2 2个妹妹，个妹妹，其中其中A A父及其父及其1 1个弟弟和个弟弟和1 1个个妹妹多指；妹妹多指；A A有有1 1兄兄1 1妹，妹妹，妹多指。多指。v符号符号v世代数世代数v个体数个体数(年年龄顺序龄顺序)v先证者先证者v(姓名姓名)draw a pedigree 绘制系谱绘制系谱Pedigree of a family with polydactylAI 1 2II 1 2 3 4 5 6III 1

5、 2 3Draw the pedigree?I 1 2II 1 2 3 4III 1 2 3 4 5 6IV 1 2 3CathyDonaldCharles Colin Cindy CarolynDebbieBob BettyBarbaraCalvinThere are five basis patterns of single-gene inheritanceAutosomal dominant（AD，常显）Autosomal recessive（AR，常隐）X-linked dominant（XD，X连显）X-linked recessive（XR，X连隐）Y-linked5.2 Auto

6、somal Dominant Inheritance （常染色体显性遗传，AD）The mutant gene is on an autosome.The mutant gene is dominant.A affected phenotype is expressed in both homozygotes（纯合子）and heterozygotes（杂合子）.Pedigree of a family with brachydactyly,type A1(BDA1，短指症 A1型)Pattern of inheritance:AD complete dominant（完全显性）5.2.2 C

7、haracteristics of Autosomal Dominant Inheritance（1）Male and female are equally likely to transmit the phenotype(表型）to children of either sex.（男女患病机会相等）（2）Phenotypically normal family members do not transmit the phenotype to their children.（父母正常，孩子就正常）5.2.2 Characteristics of Autosomal dominant Inher

8、itance（3）Any child of an affected parent has a genotype of Aa and a 50%risk of inheriting the trait.（病人的每个孩子都有50%的发病风险,其基因型为Aa）AaAaaaaAaaa（4）The phenotype appears in every generation,each affected person has an affected parent.（连续传递,患者双亲之一患病）50%50%5.2.3 Main Types of ADComplete Dominance（完全显性）Incomp

9、lete Dominance（不完全显性）Irregular Dominance（不规则显性）Codominance（共显性）Delayed Dominance（延迟显性）Complete Dominance完全显性Heterozygotes(Aa)and homozygotes(AA)for the mutant allele are both affected equally.Parental mating Aa Aa A a A aOffspring AA Aa Aa aaSame phenotypeBrachydactyly(短指症)achondroplasia（软骨发育不全）Acho

10、ndroplasia is a incompletely dominant skeletal disorder of short-limbed dwarfism and large head.achondroplasiaHomozygous commonly do not survive the immediate postnatal period.(纯合子纯合子AA一般在新生儿期死亡一般在新生儿期死亡)Heterozygotes are patients with achondroplasia.(杂合子杂合子Aa为软骨发育不全患者为软骨发育不全患者)familial hypercholest

11、erolemia (家族性高胆固醇血症）an autosomal dominant disorder leading to premature coronary heart disease(早发冠心病）.Irregular Dominance （不规则显性）（不规则显性）Some disorders are not expressed at all in an individual despite his having the same genotype that causes the disorder in others in his family.（某些个体有致病基因，但不表达。）Some

12、 unaffected parents have affected children in the pedigree.Irregular Dominance123412341234Pedigree of polydactyl（多指症）shows irregular Dominance in I3.Reduced penetrance（外显不全）Reduced penetrance:when the frequency（频率）of expression of a phenotype is less than 100%，the gene is said to show Reduced penetr

13、ance.Risk reducing.习题：P4717、在一个特定人群中，多指症（AD）的 外显率为80%。一个女患者与表型正常的男子结婚，他们的孩子患多指症的风险是：A、25%B、40%C、50%D、75%Codominance（共显性）If both alleles of a pair are expressed in the heterozygous state,the alleles are codominant.Inheritance pattern of the traits determined by them is codominance.Codominance and ABO

14、 blood groupgenotypeBlood typeiiOIAIA 、IAiAIBIB 、IBiBIAIBABlThe alleles IA and IB are codominant.lInheritance pattern of AB blood type is codominance.Delayed Dominance （延迟显性）Genetic disorders can appear at any time in the lifetime of an individul.Delayed Dominance:some genes causing disorders are no

15、t expressed until the age at onset(发病年龄）.Some dominant disorders are late-onset(迟发）.Spinocerebellar ataxia (小脑共济失调）the age at onsetI 1 2 II 1 2 3 4 5 6III 1 2 3 4 5 6 7 8 9 10 11 12 13 14IV 1 2 3 4 5 640352341282421Huntington disease (慢性进行性舞蹈病慢性进行性舞蹈病)IV 1 2I 1 2 III 1 2 3 4 5 6 7 8 9 10 11II 1 2 3

16、4 5 6454144424630205.3 Autosomal Recessive Inheritance (AR)The mutant gene is on an autosome.The mutant gene is recessive.A phenotype is expressed only in homozygotes.5.3.1 Risk in The Offspring Parental Offspring Risk to Offspring matingcarrier by carrierAa Aacarrier by affectedAa aaaffected by aff

17、ectedaa aa AA,Aa aa unaffected affected Aa aa unaffected affected aa All affected AaAaaaaAaaaAaAaAaAaAAAaAaaaaaaaaaaapedigree of a family with albinism(白化病白化病)I 1 2 II 1 2 3 4 5 III 1 2 3 4 5 6 5.3.2 Typical Pedigree Showing Autosomal Recessive InheritanceTypical pedigree showing autosomal recessive

18、 inheritance 1212345612345612Pedigree of a family with inborn deafnesspituitary dwarfism(垂体性株儒垂体性株儒)progressive muscular dystrophy(进行性肌营养不良进行性肌营养不良(肩带型肩带型)Wilson disease肝豆状核变性肝豆状核变性5.3.3 Characteristics of Autosomal recessive InheritanceFor most AR diseases,males and females are equally affected.（男女

19、患病机会相等）Parents of the affected child are asymptomatic（无症状的）carriers of mutant alleles.（患者父母正常，但肯定是携带者）5.3.3 Characteristics of Autosomal dominant InheritanceThe recurrence risk for each sib of an affected person is 1 in 4.（患者同胞的再发风险为1/4）The parents of the affected person may be consanguineous（近亲）in

20、some cases.（在有些案例中，患者的父母是近亲）5.3.4 Consanguineous Marriage and Coefficient of Relationship（近亲婚配和亲缘系数）（近亲婚配和亲缘系数）Consanguinity（近亲,close relative)Consanguinity is defined as a union of individuals related to each other as close as or closer than second cousins（二级表亲）.家系中，四家系中，四代及四代以内有代及四代以内有共同祖先的个体共同祖先的

21、个体都是近亲。都是近亲。first cousinssecond cousinsConsanguineous MarriageThe same mutant genes come from a single common ancestor.The chance that both husband and wife are carriers of a mutant allele at the same locus is increased.The chance that their children are homozygous(affected)is increased.first cousin

22、ssecond cousinsGrade of RelativesCoefficient of RelationshipGrade of RelativesConsanguineous(1/2)1=1/2(1/2)2=1/4(1/2)3=1/81o（一级亲属）（一级亲属）2o（二级亲属）（二级亲属）3o（三级亲属）（三级亲属）parent,child,brother,sisteruncle,aunt,niece,nephew,grandparent,grandchildfirst cousinI 1 2II 1 2 3 4 5 6III 1 2 3 4 5 6IV 1 25.3.5 Risk

23、to the offspring of Consanguineous Marriage1o(1/2)1=1/22o(1/2)2=1/43o(1/2)3=1/8Grade of relativeCoefficient of RelationshipI2-II5II3-III6III3-III2Pay attention to:The grade of relative to the couple.(配偶的亲属级别)The probability that both wife and husband are carriers.(夫妻都是携带者的概率。)Example 1 The frequency

24、 of Tay-sachs(台萨斯）carrier is 1/100 in a population.(1)A couple with normal phenotype is unrelated.What is the risk of Tay-sachs disease for their children?(1)A normal man is married to his first cousin.What is the risk of Tay-sachs disease for their children?Analysis:The probability that anyone,exce

25、pt the members coming from affected families,carries a mutant gene causing Tay-sacha is about 1/100 in this population.The risk to the children of positive carriers（肯定携带者）is 1/4.Analysis and answer(1)The probability that both wife and husband are carriers is 1/100 1/100=1/10000 The risk of their chi

26、ldren is 1/10000 1/4=1/40000Analysis and Answer(2)In consanguineous marriage,the probability that both wife and husband are carriers is increased.It is 1/1001/8=1/800The risk of their children is 1/800 1/4=1/3200example 2A positive carrier of albinism(白化病）marries his first cousin.What is the risk of

27、 their children?answer:The probability that both wife and husband are carriers is 11/8=1/8The risk of their children is 1/41/8=1/32example 3Edward marries Emily,his paternal aunts daughter（姑表妹）.They are both normal.Edison is Edwards brother,who suffer from phenylketonuria（苯丙酮尿症）.(1)Draw the pedigree

28、.(2)What are the genotypes of Edison and his parents.(3)What is the probability that a child of Edward would be phenylketonuric?Analysis and Answers(1)(2)IIIIII122134123aaAaAaEdison Edward Emily?Analysis and Answers(3)What is the probability that Edward is the carrier?-2/3What is the probability tha

29、t Emily is the carrier?-1/4(2with II2)What is the probability that both Edward and Emily are the carriers?-2/31/4(3)-2/31/41/4=1/24IIIIII122134123aaAaAaEdison Edward Emily?5.4 X-linked Dominant(XD)InheritanceThe mutant gene is on X chromosome.The mutant gene is dominant.XAXA XAXa XaXaXAY XaYaffected

30、unaffectedaffectedunaffectedhemizygous 半合子Genotypes:Phenotypes:femalemale5.4.2 Typical Pedigree Showing X-linked Dominant InheritancePedigree of a family with vitamin D resistant rickets（抗维生素D佝偻病）.Also called X-linked hypophosphatemic richets（X-连锁低磷酸盐软骨病）.I 1 2 II 1 2 3 4 5 6III 1 2 3 4 5 6 7 8 9 10

31、 11 12 13 5.4.3 Characteristics of X-linked Dominant InheritanceAffected females are about twice as common as affacted males,but affected females typically have milder(although variable)expression of phenotypes.女患者大约是男患者的两倍，但通常女患者症状较轻（尽管多变）。I 1 2 II 1 2 3 4 5 6III 1 2 3 4 5 6 7 8 9 10 11 12 13 5.4.3

32、 Characteristics of X-linked Dominant InheritanceAffected males with normal mates have no affected sons and no normal daughters.(criss-cross inheritance)男患者与正常女性婚配，儿子都正常，女儿都患病。（交叉遗传）XaXa XAY XaXA Y Xa XAXa Y Daughter:all affectedSon:all unaffected5.4.3 Characteristics of X-linked Dominant Inheritanc

33、eBoth males and females of offspring of heterozygotes（female）have a 50%risk of inheriting the phenotype.This is the same as the autosomal dominant inheritance.女性杂合子的后代，无论男孩或女孩，发病风险均为50%。这与常染色体显性遗传相同。XAXa XaY XA XaXa YXA Xa,Xa Xa,XA Y,Xa YDaughter:1/2 affectedSon:1/2 affected5.5 X-linked Recessive(XR

34、)InheritanceThe mutant gene is on X chromosome.The mutant gene is recessive.XAXA XAXa XaXaXAY XaYgenotypes of femalegenotypes of maleaffectedunaffectedunaffectedaffectedhemizygous（半合子）5.5.2 Typical Pedigree Showing X-linked Recessive InheritanceA pedigree with hemophilia A(血友病A)12213456712345678假肥大型

35、肌营养不良征假肥大型肌营养不良征I 1 2 II 1 2 3 4 5 6 7III 1 2 3 4 5 6 7 8 9 5.5.3 Characteristics of X-linked Recessive Inheritance(1)The incidence of the trait is much higher in males than in females.男性患者远多于女性患者。122134567123456785.5.3 Characteristics of X-linked Recessive Inheritance（2）The mutate gene is transmitt

36、ed from an affected man through all his daughters.Any of his daughters sons has a 50%chance of inheriting it.男性患者将致病基因遗传给所有的女儿，女儿再传给她的儿子的几率是50%。XAXA XaY XAXa Y XA Xa,XA Y XA Y Xa YXA YYXAXAXa5.5.3 Characteristics of X-linked Recessive Inheritance（3）The gene is never transmitted directly from father

37、to son.致病基因不会由患病的父亲传给儿子。XAXA XaY XAXa Y XA Xa XA Y 5.5.3 Characteristics of X-linked Recessive Inheritance（4）The gene may be transmitted through a series of carrier female;if so,the affected males in a kindred are related through females.突变基因可能是通过几代女性携带者遗传的；倘若如此，家系中的男性患者都是由女性遗传的。12213456712345678英国维

38、多利亚女皇血友病英国维多利亚女皇血友病A A系谱系谱5.6 Y-linked inheritanceThe mutant gene is on Y chromosome.The gene is transmitted from father to son.(holandric inheritance 全男性遗传)I 1 2 II 1 2 3 4 5 III 1 2 3 4 5 6 外耳道多毛症外耳道多毛症(External auditory canal hirsutism)5.7 Factors Influencing on Pedigree Analysis5.7.1 Incomplete

39、Dominance (不完全显性遗传不完全显性遗传)5.7.2 Codominance(共显性遗传共显性遗传)5.7.3 Delayed Dominance (延迟显性遗传延迟显性遗传)5.7.4 Irregular Dominance (不规则显性遗传不规则显性遗传)5.7.5 Expressivitythe severity（严重程度）of expression of the phenotype among individuals with the same disease-causing genotype.The individuals with hyperdactylia have v

40、ariable expressivity（表现度变异）.123412341234Neurofibromatosis(神经纤维瘤）(NF1)The individuals with neurofibromatosis have variable expressivity.5.7.6 Pleiotropy 基因的多效性Mutiple phenotypic effects of a single allele or a pair of alleles.Case:Marfan syndromeI 1 2II 1 2 3 4 5 III 1 2 3 4 5 IV 1 2 35.7.7 Genetic H

41、eterogeneity 遗传异质性Genetic Heterogeneitymeans that different mutations can cause an identical or similar phenotype.(不同的突变引起相同的表型）IIIIIIIV12343456789101112131412123456789101112123456 Pedigree of a family with congenital deafness(AR)aaBBAAbbAaBb第第IV代所有个体听力均代所有个体听力均正常，他们可能是两个正常，他们可能是两个基因位点的双杂合子基因位点的双杂合子

42、5.7.9 anticipation（遗传早现）The progressively earlier onset and increased severity of certain disease in successive generations of a family.某种遗传病在家系中发病年龄逐代提早，病情逐代加重的现象。Pedigree a family with spinocerebellar ataxiaI 1 2 II 1 2 3 4 5 6III 1 2 3 4 5 6 7 8 9 10 11 12 13 14IV 1 2 3 4 5 6403523412824215.7.10

43、Genetic Imprinting (遗传印记遗传印记)The phenomenon of different expression of alleles depending on the parent of origin.等位基因因源自父方或母方的不同，其表达的性状有差异。IV 1 2I 1 2 III 1 2 3 4 5 6 7 8 9 10 11II 1 2 3 4 5 645414442463020 父源基因使子代发病年龄提前；母源基因则不改变父源基因使子代发病年龄提前；母源基因则不改变子代发病年龄。子代发病年龄。A pedigree of Huntington disease5.7

44、.11 sex-influenced inheritancesex-influenced inheritance(从性遗传从性遗传)autosomal traits that are influenced by sex.A trait showed will take one recessive allele for male,while will take two recessive for the female.从性遗传是指常染色体上的基因所控制的性状，由于性别差异而从性遗传是指常染色体上的基因所控制的性状，由于性别差异而显示出男女性分布比例或表现程度上的差别。显示出男女性分布比例或表现程

45、度上的差别。例：例：genetic baldness(genetic baldness(早秃早秃)5.7.12 sex-limited inheritance(限性遗传)Expression of a phenotype in only one sex;may be due to either a sex-linked or autosomal gene 限性遗传限性遗传指基因由于性别指基因由于性别的限制，只在一种性别中表达，的限制，只在一种性别中表达，而在另一种性别中完全不表达。而在另一种性别中完全不表达。例如：女性子宫阴道积水例如：女性子宫阴道积水（AD）男性的尿道下裂（男性的尿道下裂（A

46、D）A,Sagittal ultrasound of the pelvis in a neonate with a large pelvic hydrometrocolpos secondary to distal vaginal atresia.“M”delineates the mass(hydrometrocolpos),and“BL”defines the anteriorly displaced and compressed bladder.B,Catheter drainage of released white mucoid drainage,with disappearance of the pelvic mass.