Download Chapter 6 Polygenic Inheritance

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