Download Chapter 9 Polygenic Inheritance

Chapter 9
Polygenic Inheritance
U
P l
Polygenic
i inheritance
i h i
U
P l
Polygenic
i disease
di
((multifactorial
ltif t i l disease)
di
)
U Characteristics
U recurrence risk
9.1 Polygenic inheritance
Minor gene
Genetic factor
codominance
Additive effect
Environmental factor
2 P
2.
Polygenic
l
i Inheritance
I h it
™
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
g or detracting
g a small amount from the
adding
phenotype.
™
The environment interacts with the genotype to
produce the final phenotype.
1. Qualitative traits vs. quantitative traits
™
Qualitative traits (Discontinuous traits)
- each trait has two, or a few, very different
unambiguous
bi
states
t t
™
Quantitative traits (Continuous traits)
- each trait has numerous slightly different
variants
Normal
N
m distribution
u
•Symmetric
Symmetric, “bell-shaped”
bell shaped curve
•95% of values lie within 2 standard deviations of
mean
•Many quantitative traits are distributed “normally”
Birth weights of babies born to teenagers in
P tl d Oregon
Portland,
O
in
i 1992.
1992
5000 British women
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Skin pigmentation
P l
Polygenic
ni Inh
Inheritance
it n
Homozygous parental
pops. - still show some
environmental
variation
F1 - intermediate shows some
variability
(environmental)
F2 - much greater
variability - mean is
intermediate
genetic + envir.
Genes and Disease
Environmental
Diseases
Di
Monogenic Diseases
Complex Diseases
z Huntington
Di
Disease
z Alzheimer disease
z Influenza
z Cardiovascular
Disease
z Hepatitis
z Spinocerebellar
Ataxia
z Autism
z Spastic Paraplegia
z Parkinson Disease
z Measles
z Tuberous Sclerosis
- Environment
- Genes
9.2 Polygenic diseases
™
Common malformation or diseases, PF >0.1%
™
Tend to aggregate in families
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
™
Congenital
g
Malformations
\ cleft lip / palate 唇腭裂
\ congenital dislocation of
the hip 先天性髋关节脱位
\ congenital heart defects
先天性心脏缺陷
\ neural tube defects
神经管缺陷
\ pyloric stenosis 幽门狭窄
\ talipes 畸形足
\ congenital megacolon
先天性巨结肠
™
Adult Onset Diseases
\ diabetes mellitus
糖尿病
\ epilepsy 癫痫
\ glaucoma 青光眼
\ hypertension 高血压
\ Schizophrenia
p
精神分裂症
congenital megacolon
Congenital Dislocation of Hip Joint
neural tube defects
cleft lip / palate
1. How to study polygenic disorders?
Liability
y of p
polygenic
yg
disorder is determined by
y
genetic and environmental factors
simultaneously;
y;
Susceptibility is determined by the genetic basis
of a certain polygenic disorder;
Threshold model is a useful tool for our research
on polygenetic disorders
disorders.
2. Threshold model
™
A threshold model has often been proposed as a way
to explain the inheritance patterns of multifactorial
conditions. In this model, there is a continuous
distribution of a genetically determined liability for a
given
i
condition,
diti
but
b t only
l some proportion
ti off
individuals above a certain threshold of genetic
liability
y will develop
p the condition,, especially
p
y if
exposed to environmental factors that can trigger the
development of the trait.
Th
Threshold
h ld model
d l
The threshold model for multifactorial traits.
p
Below the threshold the trait is not expressed.
Individuals above the threshold have the disease.
Th
Threshold
h ld model
d l
™
™
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.
3 Heritability
3.
Phenotypic
variance
Genetic E
Environmental
i
t l
variance
variance
VP = VG + VE
™
Heritability-- Fraction of the phenotypic variance
Heritability
due to genetic effects
h2=VG / Vp
H it bilit
Heritability
™
™
H=1
genes only
H=0
environment
only
Trait
Clubfoot
Height
Heritability
0.8
08
0.8
Blood pressure
B d mass
Body
Verbal aptitude
Math aptitude
Spelling aptitude
Fingerprint ridge count
Intelligence
Total serum cholesterol
0.6
05
0.5
0.7
0.3
0.5
0.9
0.5-0.8
0.6
C ffi i t of
Coefficient
f Relationship
R l ti
hi ((r))
™
the proportion of all genes in two
individuals which are identical by
descent.
descent
A
C
E
A(B) –C(D)
C(D) : r = 1/2
B
D
F
How about C & D?
C ffi i t of
Coefficient
f Relationship
R l ti
hi ((r))
r=1/2
1st degree
(parent sib
(parent,
sib, child)
r=1/4
2nd degree
(uncle, niece, grandchild)
r=1/8
3rd degree
(first cousin, great-grand)
r=1/2
1/2
r=1/4
r=1/8
r=1/4
1/4
4. Characteristics of Polygenic diseases
™
The incidence
Th
i id
of
f th
the condition
diti iis greater
t iin
relatives of the affected individuals than that in
general population,
g
p p
, but much less than 25%.
™
The
h risk
r
is same
am among
am ng the
th same
am degree
gr
relatives.
r at
.
™
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.
5 Estimating Recurrence Risk
5.
™
For single
g gene
g
diseases,, the recurrence
risk is easy to calculate.
™
For polygenic diseases, the recurrence
risk must be derived empirically (i
(i.e.
e from
observations in large samples).
Estimate of Recurrence Risk
¾
Edward formula
Incidence ≈ 0.1%～
0.1%～1%
Heritability
H i bili ≈ 70％～
70％
70
％ 80％
％～80
80％
f = P
In
ncidence of
ffirst deg
gree rellative (%
%)
40
20
10 100
8 90
6
80
4 70
60
2 50
1 40
0.8 30
0.6
20
0.4
10
0.2 0
0.1
0.2
0.4 0.6 0.8 1
2
4
6 8 10
Incidence of population (%)
R
Recurrence
risks
i k
™
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 (PF 0.1%-1%;h2 70-80%)
e.g. Cleft
Cl f palate,
l
PF
PF=0.16%,
0 16% h2=76%
76%
?
?
RR 4%
RR=4%
R
Recurrence
risks
i k
E i i risk
Empiric
i k of
f cleft
l ft palate
l t
Relationship
General population
Recurrence
Risk
0.1%
First cousin
0.3%
Niece or nephew
0.8%
Child
3.5%
Sibling
4.1%
Identical twin
40.0%
threshold
G Ⅲ Ⅱ Ⅰ
liability
R
Recurrence
risks
i k
™
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
p
Depends on Family History
No. of
Parents
Affected
No. of
Siblings
Aff t d
Affected
0
1
2
0
1
2
0.1
3
8
3
11
19
34
40
45
R
Recurrence
risks
i k
™
Increase with the severity of the condition
In multifactorial traits,
traits the more severely
affected the individual, the more genes
he/she has to transmit
transmit, and the higher the
recurrence risk.
TWO THRESHOLD
THRE HOLD DISEASES
DI E E
™
IIn many multifactorial
ltif t i l diseases
di
the
th two
t
sexes have
h
different probabilities of being affected. For
example,
p , pyloric
py
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
threshold,
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.
TWO THRESHOLD
THRE HOLD DISEASES
DI E E
Threshold for males
Threshold for females
liability
R
Recurrence
risks
i k - pyloric
l i stenosis
t
i
?
Family A
?
Family B
RR:
Family A < Family B
Recurrence risks –
congenital dislocation of the hip
Hallmarks for Polygenic Diseases
™
Most affected children have normal parents.
™
Recurrence risk increases with the number of
affected
ff
d children
hild
in
i a family.
f il
Recurrence risk increases with severity of the
defect.
Consanguinity slightly increases the risk for an
affected child.
™
™
™
Risk of affected relatives falls off very quickly with
the degree of relationship.
™
If the two sexes have a different probability of being
affected, the least likely sex, if affected, is the most
likely sex to produce an affected offspring.
offspring