Download Polygenic Disorders

Polygenic and Multifactorial
Disorders
4. Polygenic and Multifactorial Disorders
1
Single gene trait
Environment
GENE
PHENOTYPE
Other Genes
4. Polygenic and Multifactorial Disorders
2
Contribution of Genes or
Environment
• Genes rarely act completely alone
• Environmental factors and other genes may
modify expression
• Traits can be described as
– Mendelian or primarily due
to a single gene
– Polygenic or primarily due to multiple genes
– Multifactorial or complex due to an interaction
between genes and the environment
4. Polygenic and Multifactorial Disorders
3
Polygenic trait
Environment
Gene1
PHENOTYPE
Gene 2
Gene 3
Gene 4
4. Polygenic and Multifactorial Disorders
4
Single gene diseases
versus
polygenic diseases
Whereas the mutations causing single gene
diseases have a major impact on the function of
the gene product, and are therefore rare,
those causing polygenic disease have a more
moderate effect, and are therefore
relatively common
4. Polygenic and Multifactorial Disorders
5
Polygenic trait characteristics
• Common
– Unlike single gene traits
• Multi-gene involvement
– Each gene has varying effects on
trait occurrence and development
• Often have major non-genetic influences
– i.e. environmental factors
• Unclear transmittance patterns
4. Polygenic and Multifactorial Disorders
6
Polygenic Traits
• Variation is continuous, not discrete
• Individual genes follow Mendel’s laws
• Effect of genes is additive or synergistic
• Also called quantitative trait loci (QTL)
• Genes can have major or minor impacts
Examples:
– Height
– Hair color
– Body weight
– Cholesterol levels
4. Polygenic and Multifactorial Disorders
7
Inheritance of Height (1920s)
4. Polygenic and Multifactorial Disorders
8
Inheritance of Height (1997)
4. Polygenic and Multifactorial Disorders
9
An Example of
Variations in Eye Color
• The number of human eye color genes is unknown
• Analysis will probably reveal many genes
• Mice have more than 60 eye color genes
4. Polygenic and Multifactorial Disorders
10
Multifactorial Traits
• Are influenced by interaction of genes
and by the environment
• Examples:
– Fingerprint, many genes and prenatal
contact
– Height, many genes and nutrition
– Skin color, many genes and UV
exposure
4. Polygenic and Multifactorial Disorders
11
Model for Variation in Skin Color
4. Polygenic and Multifactorial Disorders
12
Skin Color
• Melanin production - skin pigmentation and
protects skin from UV radiation
• Skin color is a phenotype  interaction
between
pigment genes + environment
• In a genetic sense, race based on skin color
has little meaning
• Medical treatment differences/difficulties
4. Polygenic and Multifactorial Disorders
Analyzing Multifactorial Traits
• Difficult, requires multiple techniques
• Use human genome sequences,
population,
and
family studies
• The frequency in a specific population =
Empiric risk
• The amount of inheritance due to genes =
Heritability
4. Polygenic and Multifactorial Disorders
14
Empiric Risk of Cleft Palate
The chance that a disease will occur in a family based upon
experience (past history, medical records, etc.) rather than theory.
4. Polygenic and Multifactorial Disorders
Heritability (H)
Estimates the proportion of the phenotypic variation
in a population due to genetic differences
Heritability asks how
much genetics are
playing a role in
differences in height
between people.
This is not the same as
asking how much
genetics usually cause
height in any one
person.
4. Polygenic and Multifactorial Disorders
16
4. Polygenic and Multifactorial Disorders
Heritability:
The proportion of
total phenotypic
variation in a
population that is
due to genetic
variation,
mathematically this
is expressed as
H2=Vg/Vp.
the effects of one
gene are modified
by one or several
other genes
17
Heritability Values
• Heritability is estimated from
the proportion of people
sharing a trait compared to
the proportion predicted to
share the trait
• May vary between
populations and time period
4. Polygenic and Multifactorial Disorders
18
How does one initially assess whether
such a disease has a genetic component?
• Twin pair studies
• Relative risk studies
4. Polygenic and Multifactorial Disorders
19
Analyzing Multifactorial Traits
• Comparisons between and within families
– Twins dizygotic and monozygotic
– Twins raised apart
– Adopted children
4. Polygenic and Multifactorial Disorders
20
Twin-pair studies
1 in 89 deliveries
1/3 Monozygotic
2/3 Dizygotic
4. Polygenic and Multifactorial Disorders
21
Separating Genes and
Environment
• Dizygotic twins:
• Monozygotic twins:
• Twins raised apart:
• Adopted individuals:
Shared environment
and 50% of genes
Identical genotype, and
shared environment
Shared genotype but
not environment
Shared environment
but not genes
4. Polygenic and Multifactorial Disorders
22
Figure 7.7
Studies of twins reared apart suggest that
they are remarkably similar
4. Polygenic and Multifactorial Disorders
23
Concordance
• Concordance - the percentage of pairs in
which both twins express the trait
• Used to determine heritability
4. Polygenic and Multifactorial Disorders
24
% Concordance rates
The presence of the same trait in both members of a pair of twins
MZ
DZ
Cystic Fibrosis 100
25
Die on a Tuesday
14
14
Hypertension
30
10
Rheumatoid
30
Arthritis
Type I diabetes (IDDM) 36
4. Polygenic and Multifactorial Disorders
5
5
25
Potential pitfalls (drawback) of twin pair studies
• MZ twins are the same sex whereas 50% DZ twins aren’t
– Remedy - use same-sex DZ twins
• MZ twins often treated differently than DZ twins, which
could influence behavioral traits
– Remedy - study twins separated at birth (if enough!)
• Intrauterine differences
– MZ twins share more intrauterine tissues than DZ twins during gestation,
making it difficult to distinguish intrauterine environmental causes from
genetic causes
• Bias of ascertainment
– People often focus on twins who have strikingly similar behavioral traits but
overlook those who don’t
4. Polygenic and Multifactorial Disorders
26
Coefficients of Relatedness
for Pairs of Relatives
Table 7.4
Figure 7.6
4. Polygenic and Multifactorial Disorders
27
Allele sharing in relatives
Degree of
relationship
2nd
Percent
shared genes
2nd
25%
25
2nd
25
0
1st
50
1st
50
1st
3rd
50
12.5
proband
4. Polygenic and Multifactorial Disorders
28
Allele sharing in sibs
What is the frequency of disease in the siblings of affected
individuals compared to the population frequency?
Sibling recurrence risk ratio - s
s =
Risk to a sib
Population prevalence
4. Polygenic and Multifactorial Disorders
29
Overall,
twin pair and relative risk studies enable
one to assess whether a common disease
has a genetic component
4. Polygenic and Multifactorial Disorders
30
4. Polygenic and Multifactorial Disorders
Two types of polygenic traits
• Continuous
– Also termed quantitative
• Discontinuous
– Also termed dichotomous or qualitative
31
4. Polygenic and Multifactorial Disorders
32
Continuous trait
F
R
E
Q
U
E
N
C
Y
Phenotype parameter
i.e. Height , Blood pressure
4. Polygenic and Multifactorial Disorders
33
How do genes generate such a normal
distribution?
4. Polygenic and Multifactorial Disorders
34
One locus with two alleles of
equal frequency
A - big effect
a - small effect
genotype frequency
1
Aa
70
80
0
2
aa
AA
90 100 110
Trait measure
Number of copies of
a “big effect” allele
120
4. Polygenic and Multifactorial Disorders
130
35
genotype frequency
Two loci with two alleles each
1
Aabb
aaBb
2
AAbb
AaBb
aaBB
0
aabb
70
80
Number of copies of
a “big effect” allele
3
AABb
AaBB
4
AABB
90 100 110
Trait measure
120
4. Polygenic and Multifactorial Disorders
130
36
Three loci with two alleles each
genotype frequency
3
2
1
0
AAbbcc
AaBbcc
AabbCc
aaBbCc
aabbCC
aaBBcc
AABbcc
AAbbCc
AaBbCc
AabbCC
4
AaBBcc
aaBBCc AABBcc
aaBbCC AABbCc
AAbbCC
AaBbCC
AaBBCc
aaBBCC
Aabbcc
aaBbcc
aabbCc
Number of copies of
a “big effect” allele
5
AABBCc
AABbCC
AaBBCC
aabbcc
70
6
AABBCC
80
90 100 110
Trait measure
120
4. Polygenic and Multifactorial Disorders
130
37
genotype frequency
Three loci with two alleles each
70
80
90 100 110
Trait measure
120
4. Polygenic and Multifactorial Disorders
130
38
Conclusion:
genes can generate a continuous trait
when they act together
4. Polygenic and Multifactorial Disorders
39
Discontinuous Traits
• Yes/No characteristic
• For example: colour mutations, birth defects,
and common behavioral disorders.
• The disease manifests once a certain threshold
of susceptibility has been surpassed (exceeded)
Threshold Model of Susceptibility
4. Polygenic and Multifactorial Disorders
40
Distribution of liability (responsibility)
The threshold model is used to explain
discontinuous traits.
It simply states that the
underlying variable has
a continuous distribution
(as shown by the graph),
but the disorder does
not appear until
a certain threshold
is reached
(the dotted line).
low
liability
Threshold
unaffected
average
liability
4. Polygenic and Multifactorial Disorders
affected
high
liability
41
Crossing the threshold
 A combination
of the genes one has
inherited and the exposure one has had to
environmental risk factors
4. Polygenic and Multifactorial Disorders
42
Recurrence risk
• Risk that a disease will occur elsewhere in a
pedigree, given that at least one member of
the pedigree exhibits the disease
• RR increases as the number of affected family
members increase
4. Polygenic and Multifactorial Disorders
43
Type II diabetes
• Hyperglycaemia, developing in the adult
– Pancreas produces insulin but cells are resistant
• Polygenic disease with major environmental risk
factors
– High calorie intake and low exercise
– Up to 10 times more prevalent in the obese
• Prevalence is increasing as populations become
“westernized”
4. Polygenic and Multifactorial Disorders
44
Type II diabetes and the thrifty
gene hypothesis
4. Polygenic and Multifactorial Disorders
45
Type II diabetes and the thrifty
gene hypothesis
• Metabolically thrifty genes
– Permit efficient food utilization, fat deposition and weight
gain at occasional times of food abundance
– Make the bearer able to survive periods of famine
• Examples of thrifty genes include those resulting in
high levels of insulin and leptin
– Insulin - mediates the uptake of glucose by cells
– Leptin - hormone released by fat cells that regulates
appetite
4. Polygenic and Multifactorial Disorders
46
Pre-modern times
Feast
Famine
Feast
Survive
Genes persist as they offer a survival advantage
Modern times
Feast
Feast
Premature death
Genes lost? Frequency of disease will peak and then reduce?
4. Polygenic and Multifactorial Disorders
47