多基因病的分子遗传学.

PolygenicDisordersPolygenicDisorders:由两对以上等位基因和环境因素共同作用所致的疾病，称为多基因病。PolygenicDisordersarethosewhichresultfromaninteractionbetweenmultiplegenesandmultipleenvironmentalfactors.Section1PolygenicInheritance一、Definition1.Geneticbasis:multiplegenes3.Minorgene，Additiveeffect2.Codominance4.multipleenvironmentalfactors一些遗传性状或遗传病受两对或更多对等位基因控制，每对基因彼此间没有显性与隐性的关系，而是共显性。每对等位基因对表型的效应都很小，但是各对基因的作用有累加效应，此外，这些遗传性状或遗传病也受环境因素的作用，这种遗传方式称为多基因遗传（poly-genicinheritance）。二、CharacteristicsQualitativeTraitandQuantitativeTraitQualitativeTraitMonogenictraitPituitarydwarfismQualitativeTraitMonogenictrait120cm165cmaaAAORAaHeightofpituitarydwarfism&normal0~5%45~50%100%aaAaAAPAHactivityofPKU,carrier&normalQualitativetrait:genetictraitswhicharepresentorabsent.Onehasthetraitornot.单基因遗传的性状在群体中，往往可以分出具有和不具有该性状的2~3个小群体，这一性状的变异在一个群体中的分布是不连续的，称为质量性状。QuantitativeTraitQuantitativetrait:genetictraitswhicharemeasurablecharacteristics.多基因遗传的性状在一个群体中的变异分布是连续的，只有一个峰，称为数量性状。130140150160170180190200Height(cm)8070605040302010VariabilityGaussiandistributionPthetallesttheshortestAABBA’A’B’B’F1themedianAA’BB’F2ABAB’A’BA’B’ABAABBAABB’AA’BBAA’BB’AB’AABB’AAB’B’AA’BB’AA’B’B’A’BAA’BBAA’BB’A’A’BBA’A’BB’A’B’AA’BB’AA’B’B’A’A’BB’A’A’B’B’A’A’B’B’AAB’B’A’A’BBAABBA’A’BB’AABB’AA’B’B’AA’BBAA’BB’14641PAABBCCA’A’B’B’C’C’F1AA’BB’CC’Total01234561615201561F2ABCA’BCAB’CABC’A’B’CAB’C’A’BC’A’B’C’ABCA’BCAB’CABC’A’B’CAB’C’A’BC’A’B’C’AABBCCAA’BBCCAABB’CCAABBCC’AA’BB’CCAABB’CC’AA’BBCC’AA’BB’CC’AA’BBCCA’A’BBCCAA’BB’CCAA’BBCC’A’A’BB’CCAA’BB’CC’A’A’BBCC’A’A’BB’CC’AABB’CCAA’BB’CCAAB’B’CCAABB’CC’AA’B’B’CCAAB’B’CC’AA’BB’CC’AA’B’B’CC’AA’BB’CCAA’BBCC’AABB’CC’AABBC’C’AA’BB’CC’AABB’C’C’AA’BBC’C’AA’BB’C’C’AA’BB’CCA’A’BB’CCAA’B’B’CCAA’BB’CC’A’A’B’B’CCAA’B’B’CC’A’A’BB’CC’A’A’B’B’CC’AABB’CC’AA’BB’CC’AAB’B’CC’AABB’C’C’AA’B’B’CC’AAB’B’C’C’AA’BB’C’C’AA’B’B’C’C’AA’BBCC’A’A’BBCC’AA’BB’CC’AA’BBC’C’A’A’BB’CC’AA’BB’C’C’A’A’BBC’C’A’A’BB’C’C’AA’BB’CC’A’A’BB’CC’AA’B’B’CC’AA’BB’C’C’A’A’B’B’CC’AA’B’B’C’C’A’A’BB’C’C’A’A’B’B’C’C’201515661101234562.HybridizationofF1ofintermediatetype3.Randomhybridization1.Hybridizationoftwoextremevariant(Homozygote)CharacteristicsofPolygenicInheritanceSection2PolygenicDisorders一、LiabilityandThresholdTheorySusceptibility:characterizethegeneticfactorsthataffecttheprobabilityofmultifactorialdisorder.在多基因遗传病中，由遗传基础决定一个个体患病的风险称为易感性。Liability:beameasureofallofthefactorsthataffecttheprobabilityofmultifactorialdisorder,bothgenetic(innate)andenvironmental.在多基因遗传病中，由遗传因素和环境因素共同作用并决定一个个体是否易患某种遗传病的可能性则称为易患性。605040302010LowHighLiabilityVariabilityThresholdAffected由易患性决定的多基因病的发病限度称为阈值。二、HeritabilityHeritability(H,h2)Measure(%)oftheproportionofthetotalphenotypicvariancethatisduetothegeneticbasis.在多基因遗传病中，易患性的高低受遗传因素和环境因素的双重影响。其中遗传因素在决定该疾病中所起的作用的大小，称之为遗传率。IfHishigh——phenotypicvariationislargelygeneticIfHislow——phenotypicvariationislargelyenvironmental常见多基因遗传病和先天性畸形的患病率和遗传率疾病与畸形群体患病率（%）患者一级亲属患病率遗传率哮喘4.02080精神分裂症1.01080原发性高血压4~820~3062消化性溃疡4.0837强直性脊椎炎0.2男性先证者770女性先证者2早发性糖尿病0.22~575迟发性糖尿病2~335冠状动脉硬化性心脏病2.5735先天性幽门狭窄0.3男性先证者275女性先证者10常见多基因遗传病和先天性畸形的患病率和遗传率疾病与畸形群体患病率（%）患者一级亲属患病率遗传率先天性髋关节脱位0.07470先天性畸形足0.1368先天性巨结肠0.02男性先证者280女性先证者8无脑畸形0.2260脊柱裂0.3460唇裂+腭裂0.17476腭裂0.04276三、CharacteristicsofPolygenicDisorders1.Mostofcommondiseasesandcommoncongenitalmalformation,incidence＞1/1000.2.Tendtoaggregateinfamilies.Recurrencerate≈1%～10%3.Ethnicdifference病名发病率日本美国脊柱裂0.0030.002无脑儿0.0060.005唇裂±腭裂0.00170.001先天性畸形足0.0140.055先天性髋关节脱位0.010.0071.Mostofcommondiseasesandcommoncongenitalmalformation,incidence＞1/1000.2.Tendtoaggregateinfamilies.Recurrencerate≈1%～10%3.Ethnicdifference4.Consanguinityalsoincreasestheprobabilityofanaffectedchildforamultifactorialtrait.1.Mostofcommondiseasesandcommoncongenitalmalformation,incidence＞1/1000.2.Tendtoaggregateinfamilies.Recurrencerate≈1%～10%3.Ethnicdifference4.Consanguinityalsoincreasestheprobabilityofanaffectedchildforamultifactorialtrait.5.Firstdegreerelativeshavethesameriskofaffected.1.Mostofcommondiseasesandcommoncongenitalmalformation,incidence＞1/1000.2.Tendtoaggregateinfamilies.Recurrencerate≈1%～10%3.Ethnicdifference4.Consanguinityalsoincreasestheprobabilityofanaffectedchildforamultifactorialtrait.5.Firstdegreerelativeshavethesameriskofaffected.6.Riskofaffectedrelativesfallsoffveryquicklywiththedegreeofrelationship.亲属级别发病风险唇裂先天性髋关节脱位先天性幽门狭窄一般群体0.0010.0020.005一卵双生0.400.400.15一级亲属0.040.050.05二级亲属0.0070.0060.025四、EstimateofRecurrenceRiskEdwardformulaIncidence≈0.1%~1%Heritability≈70%~80%fP1.IncidenceandHeritability如：CleftLip0.17%76%RR=√0.17%=4.1%Anencephalyandcleftspine0.38％60％4％2.TendtoaggregateinfamiliesRiskofaffectedrelativesfallsoffveryquicklywiththedegreeofrelationship.3.Recurrenceriskincreaseswiththenumberofaffectedinafamily.Chilopalatognathus0.17％00.17％14％210％4.Recurrenceriskincreaseswithseverityofthedefect.单侧唇裂2.46％单侧唇裂+腭裂4.0％双侧唇裂+腭裂5.6％5.Ifthetwosexeshaveadifferentprobabilityofbeingaffected,thresholdsoftwosexesaredifferent.群体患病率较低即阈值较高的那种性别罹患，则患者亲属的发病风险较高。这种情况又称为卡特效应（Carter＇seffect)。CongenitalStenosisofPylorusThreshold♀♂0.5％0.1％CongenitalStenosisofPylorusCongenitalStenosi