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Transcript
Chapter 6 Polygenic Inheritance Outline Polygenic inheritance Polygenic disease (multifactorial disease) characteristics recurrence risk Polygenic inheritance refer to the inheritance of quantitative traits which are influenced by multiple genes at different loci, and environment may be involved. Genetic factor Minor gene: a gene that has small observable effects upon the phenotype Major gene: a gene that has large observable effects upon the phenotype Codominance Additive effect Environmental factor Qualitative traits vs. Quantitative traits Qualitative traits (Discontinuous traits) : each trait has two, or a few, very different unambiguous states Quantitative traits (Continuous traits) : each trait has numerous slightly different variants Qualitative traits vs. quantitative traits Discontinuous Trait Continuous Trait Polygenic Inheritance Most traits follow a normal distribution Polygenic Inheritance Several loci are involved in the expression of the trait. There is no dominance or recessive at each of these loci. The loci act in concert in an additive fashion, each adding or detracting a small amount from the phenotype. The environment interacts with the genotype to produce the final phenotype. Polygenic Inheritance Homozygous parental pops. : still show some environmental variation F1 - intermediate :shows some variability (environmental) F2 - much greater variability : mean is intermediate genetic and envir. Polygenic diseases Common malformation or diseases, PF >0.1%; Tend to aggregate in families, but the recurrence risks in families often fall in the range of 1% to10% ; Resulted from an interaction between multiple genes and often multiple environmental factors Polygenic Disorders Adult Onset Diseases Congenital Malformations diabetes mellitus cleft lip / palate epilepsy congenital dislocation of the hip glaucoma congenital heart defects hypertension neural tube defects manic depression pyloric stenosis Schizophrenia Talipes Asthma congenital heart disease spondylitis ankylopoietica Susceptibility: recurrence risk is determined by the genetic basis of a certain polygenic disorder. Liability: recurrence risk is determined by genetic and environmental factors simultaneously. Threshold model is a useful tool for our research on polygenetic disorders. Threshold model Mean of population The threshold model for multifactorial traits. Threshold : the minimal gene number leading to polygenic disorder in a certain environment. Below the threshold the trait is not expressed. Individuals above the threshold have the disease . Normal distribution of liability 16% 2.3% 0.13% 95% of values lie within 2 standard deviations of mean; Threshold model The curve for relatives is shifted to the right compared to the general population the closer the relationship the greater the shift to the right Heritability proportion of the phenotypic variation is due to genes Phenotypic variance Genetic Environmental variance variance VP = VG + VE h2=VG / Vp Heritability Trait H=1 genes only H=0 environment only Clubfoot Height Blood pressure Body mass Fingerprint ridge count Intelligence Total serum cholesterol Heritability 0.8 0.8 0.6 0.5 0.9 0.5-0.8 0.6 Heritability h2=b/r r: coefficient of relationship b= (Xg-Xr)/ag ( population study) or b=p (Xc-Xr)/ac ( case-control study) Coefficient of Relationship (r) the fraction of alleles shared by two individuals A C E A(B) –C(D) : r = 1/2 B D F How about C & D? Coefficient of Relationship (r) B A 1/2 C 1/2 D 1/2 x 1/2 = 1/4 = fraction of alleles C & D share from dad 1/2 C 1/2 D 1/2 x 1/2 = 1/4 = fraction of alleles C & D share from mom 1/4 + 1/4 = 1/2= fraction of alleles C & D share Coefficient of Relationship (r) the fraction of alleles shared by two individuals A C E A(B) –C(D) : r = 1/2 B D F 1/4 + 1/4 = 1/2= fraction of alleles C & D share How about C & F? A 1/2 C B 1/2 1/2 D C 1/2 D 1/2 1/2 F F 1/2 x 1/2 x 1/2 =1/8 = fraction of alleles C & F share from common ancestor (A) 1/2 x 1/2 x 1/2 =1/8 = fraction of alleles C & F share from common ancestor (B) 1/8 + 1/8 = 1/4 = fraction of alleles C & F share Coefficient of Relationship (r) the fraction of alleles shared by two individuals A C E A(B) –C(D) : r = 1/2 B D F C & F : r = 1/4 E&F? A 1/2 C 1/2 E B 1/2 1/2 D C 1/2 F 1/2 x 1/2 x 1/2 x 1/2 = 1/16 = fraction of alleles E & F share from common grandfather 1/2 E 1/2 D 1/2 F 1/2 x 1/2 x 1/2 x 1/2 = 1/16 = fraction of alleles E & F share from common grandmother 1/16 + 1/16 = 1/8 = fraction of alleles E & F share Coefficient of Relationship (r) r=1/2 1st degree (parent, sib, child) r=1/4 2nd degree (uncle, niece, grandchild) r=1/8 3rd degree (first cousin, great-grand) Characteristics of Polygenic diseases 1. 2. 3. 4. 5. The incidence of the condition is greater in relatives of the affected individuals than that in general population, but much less than 25%; The risk is same among the same degree relatives The risk is greatest for the first degree relatives and decreases rapidly in more distant relatives Consanguinity slightly increases the probability of an affected child for a polygenic disorder Different risk in different race. threshold GⅢ Ⅱ Ⅰ liability Estimating Recurrence Risk For single gene diseases, the recurrence risk is easy to calculate. For polygenic diseases, the recurrence risk must be derived empirically (i.e. from observations in large samples). Recurrence risks Empiric risk of cleft palate Relationship Recurrence Risk General population 0.1% First cousin 0.3% Niece or nephew 0.8% Child 3.5% Sibling 4.1% Identical twin 40.0% Recurrence risks 1. If p is the frequency of a polygenic disease in the population, the risk for first degree related individuals is approximately the square root of p, f=√p. (PF= 0.1%-1%; h2= 70-80%) e.g. Cleft palate, PF=0.16%, h2=76% ? ? RR=4% Recurrence risks 2.Increase with the number of affected relatives ? ? Family A RR Family A ? Family C Family B < Family B < Family C Recurrence Risk for Cleft Lip Depends on Family History No. of Parents Affected No. of Siblings Affected 0 0 0.1 1 2 1 2 3 34 3 11 40 8 19 45 Recurrence risks 3.Increase with the severity of the condition In multifactorial traits, the more severely affected the individual, the more genes he/she has to transmit, and the higher the recurrence risk. TWO THRESHOLD DISEASES 4.In many multifactorial diseases the two sexes have different probabilities of being affected. Pyloric stenosis occurs in about 1/200 newborn males but only in about 1/1000 newborn females. This means that there is a double threshold, one for females and one for males, with the female threshold farther from the mean than that for the male. However, since it takes more deleterious genes to create an affected female, she has more genes to pass on to the next generation. Her male offspring are at a relative high risk of being affected when compared to the population risk. Recurrence risks ? Family A ? Family B RR: Family A < Family B Identify the gene of polygenic disorder Pedigree: complex segregation analysis Linkage analysis Case---control affected sib pair analysis SNP association GWAS( Genomic wide association analysis