案例成果遗传-zy2013single gene2013.3

1、Patterns of Single-GeneinheritanceTao Zhang Department of Medical Genetics PKUSingle-gene traits（单基因性状）Major gene (主基因) Single-gene disorders（单基因病）Mendelian inheritance (孟德尔遗传) Single-gene disorderOMIM Statistics for February 7, 2012 Autosomal 19775X-linked 1170Y-linked 59Mitochondrial 6521069 Conce

2、ptiongene locus(基因座)allele(等位基因) genotype(基因型, AA, Aa, aa)phenotype(表型)homozygote(纯合子,AA,aa) & heterozygote(杂合子Aa)dominant(显性, A ) & recessive(隐性, a ) Pedigree (系谱) A graphical representation of a familytree, using standard symbols for documenting biological relationships in families and the presenc

3、e of traits or diseases. proband(先证者)or index case(索引病例) The member through whom a family with a genetic disorder is first brought to attention pedigree analysis(系谱分析)Determining the mode of inheritance of genetic diseases.Identify a virulence gene running through a familyDetermining who in the fami

4、ly is at risk of being affectedPedigree symbols Autosomal dominance inheritance (AD)Gene : A, aGenotype : AA, Aa, aaAutosomal dominance inheritance(AD)A aa aP1 : 1F1GA aA aA aa aa aa aa aA a 1 : 1 : 1 : 1 Autosomal dominant inheritance (AD) Characteristics of Autosomal Dominant inheritance 1. The ph

5、enotype usually appears in every generation, each affected person having an affected parent Exceptions : (1)fresh mutation (2)the disorder is not expressed or is expressed only subtly in a person who has inherited the responsible gene. 2. Any child of an affected parent has a 50 percent risk of inhe

6、riting the trait 3. both males and females are affected in a 1 : 1 ratio AD typesComplete dominance(完全显性遗传)Complete dominancePhenotype Aa AA 1 2 1 2 3 4 1Syndactyly type 并指型 (MIM 185900 )AD types plete dominance(不完全显性遗传)Complete dominance(完全显性遗传) plete dominanceSemidominance (半显性) Phenotype AA Aa aa

7、 1 2 1 2 3 1Achondroplasia软骨发育不全(MIM 100800) expressivity(表现度)AD typesIrregular dominance(不规则显性遗传)Complete dominance(完全显性遗传) plete dominance(不完全显性遗传) Irregular dominance Aa ? Skipped generation (隔代)Polydactyly postaxial 多指轴后型 (MIM 174200) 1 2 3 1 2 3 1 2 31 2 Penetrance(外显率)Complete penetrance (完全外显

8、,100) plete penetrance (不完全外显,？)Irregular dominancePolydactyly postaxial 多指轴后型 (MIM 174200) 1 2 3 1 2 3 1 2 31 2 modifier gene(修饰基因)AD typesCodominance(共显性遗传)Irregular dominance(不规则显性遗传)Complete dominance (完全显性遗传) plete dominance(不完全显性遗传)CodominanceABO blood group system (MIM 110300)MN blood group s

9、ystem (MIM 111300)blood typered cell antigens antibodygenotypeAAIAIA, IAiBBIBIB, IBiABABIAIBO, iiABO blood typeDelayed dominance(延迟显性遗传)Codominance(共显性遗传)Irregular dominance (不规则显性遗传)Complete dominance(完全显性遗传) plete dominance(不完全显性遗传)AD typesDelayed dominance AaHuntington,s chorea Huntington舞蹈病 (MIM

10、 143100) 1 2 3 4 5 1 2 1 2 34042452132Age of onset (years) () PenetranceGene( IT15 )：4p16.3Dynamic mutation (动态突变)Exon: (CAG)n N 40Genetic Imprinting (遗传印记）Delayed dominanceHuntington,s chorea Huntington舞蹈病 (MIM 143100) 1 2 3 4 5 1 2 1 2 34042452132 AaAutosomal RecessiveInheritance(AR)Gene : A , a G

11、enotype: AA, Aa, aaCarrier(携带者) : AaCharacteristics of Autosomal Recessive InheritanceP1 : 1 : 1 : 1F1GA aA aA aA aA Aa aAutosomal Recessive Inheritance (AR) Autosomal Recessive Inheritance (AR) Characteristics of Autosomal Recessive Inheritance 1. An autosomal Recessive phenotype,typically is seen

12、only in the sibship of the proband, not in parents, offspring, or other relatives. 2. both sexes are affected with equal frequency at a ratio of 1:1 3. Parents of an affected child are asymptomatic carriers of mutant alleles. heterazygous parents have a risk of 25% of affected offspring 4. The paren

13、ts of the affected person may in some cases be consanguineous. This is especially likely if the mutant gene is rare in the population. Albinism（白化病） (MIM 203100) characterized by absence of tyrosinase with complete absence of melanin in the eyes, skin and hair.X-linked Dominant Inheritance(XD) Male

14、XAY , XaY Hemizygote(半合子)Gene: XA , XaGenotype : Female XAXA, XAXa, XaXa Criss-cross inheritance (交叉遗传) Male(XY) Male(XY) Female(XX) Son (XY) Daught(XX)Characteristics of X-linked Dominant Inheritance1:1P1:1:1:1F1GXA XaXa Y XA XaXa Y Xa XaXAYXa XaXAYXA XaXa Y X-linked Dominant Inheritance (XD) Chara

15、cteristics of X-linked Dominant Inheritance 1. The incidence of the trait is much higher in females than in males (about twice) ,but affected females typically have milder (variable) expression of the phenotype. 2. Affected males with normal mates have normal sons and Affected daughters. 3. Both mal

16、e and female offspring of Affected female have a 50 percent risk of inheriting the phenotype. 4.The pedigree pattern is the same as autosomal dominant inheritance. Vitamin D resistant rickets抗维生素D佝偻病(MIM 307800)Characteristics of X-linked Dominant InheritanceCharacteristics of X-linked Recessive Inh

17、eritance Gene : XA , Xa Female XA XA , XA Xa , Xa Xa Male XAY , XaYGenotype:Characteristics of X-linked Recessive Inheritance1:1P1:1:1:1F1G1:1:1:1 XA Xa XA Xa XA Xa XAXa XA Xa XA XA XA XA XAYXAYXAYXAYXa YXa YXa YXa YXa Xa X-linked Recessive Inheritance (XR) Characteristics of X-Linked Recessive Inhe

18、ritance 1. The incidence of the trait is much higher in males than in females. 2. The gene is ordinarily never transmitted directly from father to son(male-to-male), but it is transmitted by an affected male to all his daughters . 3. A carrier Femal for an X-chromosomal mutation has a risk of 50% Fo

19、r an affected son. 4. The gene may be transmitted through a series of carrier females; affected males inherit the mutant allele from the mother only Muscular dystrophy,MD(肌营养不良) Gower signe Gower征Becker (BMD) MIM 300376Duchenne (DMD) MIM 31020042DMD(XR) 假肥大型肌营养不良Xp21.2-p21.3,75 exon, 2300kb (MIM 306

20、700)XR ( Xq28 )blood coagulation factor VIII凝血因子VIIIHemophilia A甲型血友病King George Prince Albert Queen Victoria Elizabeth 2423332722Hemophilia A(MIM 306700)Y-linked inheritance Gene : YA YaGenotype : XYA XYaholandric inheritance(全男性遗传)male-to-male Y-linked inheritance hairy ears 多毛耳(MIM 425500)Y-linke

21、d inheritance Influence Factors in Single-gene disordersexpressivity(表现度)Penetrance(外显率,)Aa ?Expressivity blue sclera 蓝色巩膜 multiple fracture 多发性骨折transmission hearing loss传导性耳聋 Dysosteogenesis type 成骨发育不全 型(MIM 166200)Expressivityblue scleramultiple fracturetransmission hearing lossDysosteogenesis t

22、ype (MIM 166200) 1 2 3 1 2 3 1 2 3 1 2pleiotropy(多效性)Influence Factors in Single-gene disordersExpressivity and Penetrancepleiotropy (多效性)First effect(初始效应)Secondary effect(次级效应)pleiotropyGalactosemia (MIM 230400)pleiotropyInfluence Factors in Single-gene disorders expressivity and Penetrance geneti

23、c heterogeneity(遗传异质性)Genetic heterogeneityallelic heterogeneity(等位基因异质性) -thalassemia , gene mutation 100locus heterogeneity(基因座异质性) Congenital deafness ( AR) , 35 gene locusA similar phenotype being caused by different hereditary basis.pleiotropyInfluence Factors in Single-gene disorders Expressiv

24、ity and Penetrance genetic heterogeneity sex-conditioned inheritance(从性遗传) sex-limited inheritance(限性遗传 )sex-conditioned inheritance sex-limited inheritancesex-conditioned inheritance: baldness (秃顶) (MIM 109200) male Aa sex-limited inheritance: male-limited Precocious puberty(性早熟) male-limited Precocious pubertysex-limited inheritancepleiotropyInfluence Factors in Single-gene disordersexpressivity and Penetrance genetic heterogeneity genetic Imprinting (遗传印记） anticipation(早现) sex-conditioned inheritan