内容案例遗传-genetics2013.3

1、 Genetics of Disorders with Complex Inheritance Tao Zhang Department of Medical Genetics PKU Qualitative Trait and Quantitative TraitQualitative Trait (质量性状): monogenic trait present or absent discrete distributionQuantitative Trait (数量性状): polygenic trait measurable Normal (Gaussian) distribution Q

2、ualitative Trait120 cm 165 cm aa AA / AaHeight distribution of Pituitary dwarf vs normal populationPituitary dwarf Qualitative Trait05% 4550% 100% aa Aa AA PAH activity of PKU Quantitative Trait (stature) AABBCC X AABBCCAABBCC 0 1 2 3 4 5 6 1 6 15 20 15 6 1 F1F2F2heightlow2015156611 0 1 2 3 4 5 6 Ch

3、aracteristics of Polygenic Inheritance 1. The mean of the F1 is approximately intermediate between the means of the two parent type. 2. The means of the F1 and the F2 generations are similar. 3. The F2 generation is considerably more variable than F1 4. There is an overlap in measurements of the ext

4、reme type in the F2 and in the distributions of values for the two parental type. Complex disorderdiabetes hypertension schizophrenia myocardial infarctioncleft palate neural tube defects obesityMost common diseasesAlzheimer disease cancer Complex Disorder Multifactorial Disorder Polygenic Disorder

5、most of common diseases common congenital malformation Cleft lipCleft palateneural tube defects Characteristics of Complex Disease2022/9/1017multiple genesinteraction of genetic and environmental factors aggregate in families, is not a simple inheritance patternincidence 1/1000, recurrence rate 1%10

6、%EnvironmentComplex diseasesGenes Genetic Analysis of Quantitative TraitsMinor gene (微效基因)Additive effect (加性效应)Susceptibility (易感性)Liability (易患性)Threshold (阈值) Susceptibility Characterize the genetic factors that affect the probability of multifactorial disorder. Liability Be a measure of all of t

7、he factors that affect the probability of multifactorial disorder, both genetic and environmental.2022/9/1020 As the number of loci increases, the Liability distribution looks increasingly like a Normal distribution, also called Gaussian Distribution or the Bell-shaped Curve. Liability distribution

8、Normal distribution Threshold Theory605040302010Low HighLiabilityVariabilityThresholdAffected Heritability (遗传率)Statistical Definition: The proportion of phenotypic variance attributable to additive genetic variance.Common Definition: The extent to which genetic individual differences contribute to

9、individual differences in phenotypic individual differences. Estimates of Heritability of Various DiseasesDisorder Frequency(%) HeritabilitySchizophrenia 1 85Asthma 4 80Cleft lipcleft palate 0.1 76Pyloric stenosis 0.3 75Ankylosing spondylitis 0.2 70Club foot 0.1 68Coronary artery disease 3 65Hyperte

10、nsion (essential) 5 62Peptic ulcer 4 37Congenital heart disease 0.5 35 Estimates of The Recurrence Risk for Polygenetic Diseases? 1. Edward formula： f = p f: The recurrence risk for first degree relatives p: The frequency of disease among general population Frequency= 0.1% 1% Heritability=70%80% Rec

11、urrence Risk Incidence in General population ( )Incidence in First degree relatives of probands ( )HCleft lipP=0.17%H=76%2. The risk increases with the number of affected relatives 3. The risk increases with the severity of the malformation or disease.4. The recurrence risk for relatives will declin

12、e sharply as the degree of relatedness decreases. Recurrence Risk -continued Increased Risk Threshold Among Patient Relatives Recurrence Risk -continued 5. When the sex ratio of affected probands deviates significantly from unity,offspring of affected probands of the less frequently affected sex are at higher relative risk. Recurrence Risk Sex Differences in Liability Threshold Master:Conception: Quantit