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1、ZhejiangProvincialKeyLabofMedicalGenetics9PopulationGeneticsGeneticsinMedicine医学遗传学医学遗传学李伟李伟4B312ZhejiangProvincialKeyLabofMedicalGeneticsPaternalMaternalAaGenotypeAlleleAA;Aa;aaA;a基因频率基因频率Gene Frequency基因型频率基因型频率Genotype FrequencyZhejiangProvincialKeyLabofMedicalGeneticsAaAA aaAa- - - - - - -123nFr
2、equency(AA)Frequency(Aa)Frequency(aa)ZhejiangProvincialKeyLabofMedicalGeneticsTheHardyWeinbergprinciple(HWP)The HardyWeinberg principle states that both allele andgenotypefrequenciesinapopulationremainconstantthatis,theyareinequilibriumfromgenerationtogenerationunlessspecificdisturbing influences ar
3、e introduced. Those disturbing influencesincludenon-random mating,mutations,selection,limited population size,random genetic driftandgene flow.Wilhelm Weinberg G.H. HardyZhejiangProvincialKeyLabofMedicalGeneticsAaAA aaAa- - - - - - -123nf(A)=pf(a)=qp+q=1ZhejiangProvincialKeyLabofMedicalGeneticsSperm
4、sA(p)A(q)EggsA(p)AAAaa(q)Aaaap2pqpq q2ZhejiangProvincialKeyLabofMedicalGeneticsGenotypefrequenciesinapopulationareinequilibriumfromgenerationtogenerationAA(p2)Aa(2pq)aa(q2)AA(p2)AAAA(p4)AAAa(2p3q)AAaa(p2q2)Aa(2pq)AaAA(2p3q)AaAa(4p2q2)Aaaa(2pq3)aa(q2)aaAA(p2q2)aaAa(2pq3)aaaa(q4)ThesecondgenerationZhe
5、jiangProvincialKeyLabofMedicalGeneticsMatingf offspringsAAAaaaAAAAAAAaAAaaAaAaAaaaaaaap44p3q2p2q24p2q24pq3q4p42p3qp2q22p3q2p2q22p2q22pq3p2q22pq3q4ZhejiangProvincialKeyLabofMedicalGeneticsZhejiangProvincialKeyLabofMedicalGeneticsRandom mating,(随机婚配）随机婚配）No mutations,（没有突变）（没有突变）No selection,（没有选择）（没有
6、选择）Unlimited population size,（无限大群体）（无限大群体）No random genetic driftandgene flow.（无大规模迁移的基因流）（无大规模迁移的基因流）ZhejiangProvincialKeyLabofMedicalGeneticsHowtotesttheHWPTestingdeviationfromtheHWPisgenerallyperformedusingPearsons chi-squared test, using the observed genotypefrequenciesobtainedfromthedataandthe
7、expected genotypefrequenciesobtainedusingtheHWP.ZhejiangProvincialKeyLabofMedicalGenetics基因型个体数TTTttt tt实际观察值(O)预期理论值(E)p2N2pq Nq2NX=(Oi-Ei) /Eip=q=计算计算X值值：推出推出P值值：得出最后结论得出最后结论:ZhejiangProvincialKeyLabofMedicalGeneticsExampleHardyWeinbergprinciplecalculationGenotype(AA)(Aa)(aa)TotalNumber60034060100
8、0GenotypeexpectedobservedAA592.9(p21000)600Aa/aA354.2(2pq1000)340aa52.9(q21000)60ZhejiangProvincialKeyLabofMedicalGeneticsGeneralizationformorethantwoallelesConsideranextraallelefrequency,r.Thetwo-allelecaseisthebinomialexpansionof(p+q)2,andthusthethree-allelecaseisthetrinomialexpansionof(p+q+r)2.Mo
9、regenerally,considertheallelesA1,.Aigivenbytheallelefrequenciesp1topi;givingforallhomozygotes:andforallheterozygotes:ZhejiangProvincialKeyLabofMedicalGeneticsApplication in genetic counselingCystic fibrosis, 1/2000PhenotypeNormalCystic fibrosisGenotypeAAAaaafp22pqq2=1/2000q=0.022，p=1-0.022=0.978;Car
10、riers:2pq=20.9780.022=0.043ZhejiangProvincialKeyLabofMedicalGeneticsForrareAR,q2patients,incidenceF(q)Carriers(2pq)Carrier/patient(2pq/q2)1/10001/321/161000/16=62.51/50001/711/365000/36=1391/100001/1001/5010000/50=2001/500001/2441/11250000/112=4461/1000001/3161/518100000/158=633ZhejiangProvincialKey
11、LabofMedicalGeneticsMaleFemaleGenotypeX1YX2YX1X1X1X2X2X2fpq=1/12p22pqq2q1/12，Sop11/122pq21/1211/1222/144q21/144。15%offemaleswillbecarriers，while0.7%affected.X-linkedRecessiveZhejiangProvincialKeyLabofMedicalGeneticsNon -Random matingMutationsSelectionLimited population sizeRandom genetic driftandgen
12、e flow.ZhejiangProvincialKeyLabofMedicalGeneticsNon -Random mating1.Assortativemating2.ConsanguinousmatingZhejiangProvincialKeyLabofMedicalGenetics亲属级别亲缘系数双亲-子女一级亲属1/2同胞(兄弟姐妹)一级亲属1/2叔(姑、舅、姨)-侄(甥)二级亲属1/4祖-孙二级亲属1/4表/堂兄妹三级亲属1/8Coefficientofkinship(k)Inbreedingcoefficient(F)ZhejiangProvincialKeyLabofMed
13、icalGeneticsl亲缘系数亲缘系数有共同祖先的两个人，在某一基因座上带有相有共同祖先的两个人，在某一基因座上带有相同基因的概率。同基因的概率。l近近亲亲婚婚配配中中的的2人人，他他们们可可能能从从共共同同祖祖先先继继承承到到同同一一基基因因，婚婚后后又又可可能能把把同同一一基基因因传传递递到到他他们们子子女女，这这样样，子子女女的的这这一一对对基基因因就就是是相相同同的的。近近亲亲婚婚配配使使子子女女得得到到这样一对相同基因的概率，称为这样一对相同基因的概率，称为近婚系数近婚系数.ZhejiangProvincialKeyLabofMedicalGeneticsP1、P2为父、母；B1
14、、B2为兄、妹；S为子女同胞兄妹婚配中等位基因的传递图解同胞兄妹婚配中等位基因的传递图解FullsiblingsA1:1/2A1:1/2A1:1/2A1:1/2ZhejiangProvincialKeyLabofMedicalGenetics舅甥女婚配中等位基因的传递图解舅甥女婚配中等位基因的传递图解A1:1/2A1:1/2A1:1/2A1:1/2A1:1/2ZhejiangProvincialKeyLabofMedicalGenetics表兄妹婚配中等位基因的传递图解表兄妹婚配中等位基因的传递图解ZhejiangProvincialKeyLabofMedicalGenetics二级表兄妹婚配
15、中等位基因的传递图解二级表兄妹婚配中等位基因的传递图解ZhejiangProvincialKeyLabofMedicalGenetics如如果果是是X染染色色体体上上的的等等位位基基因因，因因为为女女性性有有两两条条X染染色色体体，所所以以她她可可能能形形成成纯纯合合子子，会会受受到到近近亲亲婚婚配配的的影影响响；男男性性是是半半合合子子，近近亲亲婚婚配配对对他他没没有有影影响响。因因此此，在在计计算算X连连锁锁基基因因的的近近婚婚系系数数时时，只只计计算算女女性性的的F值值。从从传传递递特特点点来来看看，男男性性的的X连连锁锁基基因因一一定定传传给给其其女女儿儿，传传递递概概率率为为1；相相
16、反反，男男性性的的X连连锁基因不可能传给他的儿子，传递概率为锁基因不可能传给他的儿子，传递概率为0。ZhejiangProvincialKeyLabofMedicalGenetics姨表兄妹婚配中，姨表兄妹婚配中，X连锁基因的传递图解连锁基因的传递图解X1: 1X1: 1/2X1: 1/2X1: 1X1: 1/2X1: 1X2:1/2X2:1/2X2: 1X2:1/2X2:1/2X2:1/2ZhejiangProvincialKeyLabofMedicalGenetics舅表兄妹婚配中，舅表兄妹婚配中，X连锁基因的传递图解连锁基因的传递图解X1: 0X2:1/2X2:1/2X2:1/2X2:1
17、X2:1X2:1/2ZhejiangProvincialKeyLabofMedicalGenetics姑表兄妹婚配中，姑表兄妹婚配中，X连锁基因的传递图解连锁基因的传递图解X1:0X2:0ZhejiangProvincialKeyLabofMedicalGenetics堂兄妹婚配中，堂兄妹婚配中，X连锁基因的传递图解连锁基因的传递图解X1:0X2:0ZhejiangProvincialKeyLabofMedicalGeneticsInbreeding may result in a far higher phenotypicexpression of deleterious recessive
18、 genes within apopulationthanwouldnormallybeexpectedZhejiangProvincialKeyLabofMedicalGenetics（1-F）q2=（15/16）q2Fq=（1/16）q（1/16）q+（15/16）q2=q/16（1+15q） =pq/16+q2 ZhejiangProvincialKeyLabofMedicalGeneticsq2pq/16q2+pq/16q2+pq/16:q20.200.100.040.020.010.0010.040.010.00160.00040.00010.0000010.010.0056250.
19、00240.0012250.0006190.00006250.050.0156250.0040.0016250.0007190.00006351.251.562.504.067.1963.5表亲婚配和随机婚配生出隐性纯合子的概率ZhejiangProvincialKeyLabofMedicalGeneticsNon -Random matingMutationsSelectionLimited population sizeRandom genetic driftandgene flow.ZhejiangProvincialKeyLabofMedicalGenetics1.突变（mutatio
20、n)自然突变率:=nx10-6/配子/位点/代ZhejiangProvincialKeyLabofMedicalGenetics2.选择（selection)（1）生殖适合度（f）:为后代提供基因能力的一种量度，以正常的生育力为1作比较。如调查软骨发育不全症患者108人，有孩子27人；患者未受累同胞457人，有孩子582人。如果软骨发育不全症患者生育能力与正常同胞相同，108人中应有多少孩子？582x(108/457)=137.5f=27/137.5=0.1963s=1-fZhejiangProvincialKeyLabofMedicalGenetics常染色体显性疾病:=sp常染色体隐性疾病
21、:=sq2X-连锁隐性疾病:=1/3sqZhejiangProvincialKeyLabofMedicalGenetics（2）杂合子优势(heterozygoteadvantage)在某些隐性遗传病中，在特定的条件下杂合子可能比正常纯合子个体更有利与生存而繁殖后代。ZhejiangProvincialKeyLabofMedicalGeneticsZhejiangProvincialKeyLabofMedicalGenetics3、随机遗传漂变(radomgeneticdrift)小群体或隔离的人群中，基因频率的随机波动称为遗传漂变。例如北美印第安人红细胞血型大部分是O型。ZhejiangProvincialKeyLabofMedicalGenetics4、迁移(migration)不同种族和不同民族的基因频率可有差异。迁移的结果使不同人群通婚，彼此掺入外来基因，导致基因流动，可改变原来群体的基因频率。ZhejiangProvincialKeyLabofMedicalGenetics5、选型婚配(assortativemating)非随机婚配根据肤色/身高/智力状况等因素来择偶正选型婚配负选型婚配
