Download ppt - QIMR Genetic Epidemiology

Genetic Theory
Manuel AR Ferreira
Massachusetts General Hospital
Harvard Medical School
Boston
Boulder, 2007
Outline
1. Aim of this talk
2. Genetic concepts
3. Very basic statistical concepts
4. Biometrical model
5. Introduction to linkage analysis
1. Aim of this talk
Gene mapping
LOCALIZE and then IDENTIFY a locus that regulates a trait
Linkage
analysis
Association
analysis
Linkage:
If a locus regulates a trait, Trait Variance and
Covariance between individuals can be
expressed as a function of this locus.
Association: If a locus regulates a trait, Trait Mean in the
population can be expressed as a function of this
locus.
Revisit common genetic parameters - such as allele frequencies,
genetic effects, dominance, variance components, etc
Use these parameters to construct a biometric genetic model
Model that expresses the:
(1) Mean
(2) Variance
(3) Covariance between individuals
for a quantitative phenotype as a function of the genetic parameters of a
given locus.
See how the biometric model provides a useful framework for
linkage and association methods.
2. Genetic concepts
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A. DNA level
DNA structure, organization
recombination
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B. Population level
Allele and genotype frequencies
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C. Transmission level
Mendelian segregation
Genetic relatedness
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D. Phenotype level
Biometrical model
Additive and dominance components
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A. DNA level
A DNA molecule is a linear backbone
of alternating sugar residues and
phosphate groups
Attached to carbon atom 1’ of each sugar
is a nitrogenous base: A, C, G or T
Two DNA molecules are held together
in anti-parallel fashion by hydrogen
bonds between bases [Watson-Crick
rules] Antiparallel double helix
A gene is a segment of DNA which
is transcribed to give a protein or
RNA product
Only one strand is read during gene
transcription
Nucleotide: 1 phosphate group + 1 sugar + 1 base
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DNA polymorphisms
Microsatellites
>100,000
Many alleles, (CA)n repeats, very
informative, even, easily automated
SNPs
11,961,761 (build 126, 03 Mar ‘07)
Most with 2 alleles (up to 4), not very
informative, even, easily automated
A
Copy Number polymorphisms
~2000-3000 (?)
Many alleles, even, not yet
automated
B
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(CA)n
C -G
G -C
T -G
DNA organization
22 + 1
♂
A-
B-
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2 (22 + 1)
♁
chr1
A-
B-
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B-
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♂
♁
♂
♁
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A
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A
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2 (22 + 1)
♁
♂
A-
A-
2 (22 + 1)
A-
B-
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A-
B-
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♁
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-A A-
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-B B-
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Mitosis
-A
-B
chr1
G1 phase
Haploid
gametes
Diploid zygote
1 cell
S phase
B-
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A-
B-
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♁
♂
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-A
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-A
-B
M phase
Diploid zygote
>1 cell
22 + 1
DNA recombination
22 + 1
A-
(♂)
A-
2 (22 + 1)
2 (22 + 1)
B-
♁
Meiosis
♂
A-
B-
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(♂)
♁
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chr1
-A A-
-B B-
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-A
-B
chr1
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-A
B-
-B
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(♁)
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NR
chr1
chr1
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-A
R
-B
chr1
A-
chr1 chr1
(♁)
A-
Diploid gamete
precursor cell
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-
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A
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-A
-B
chr1
Haploid gamete
precursors
B-
C
A
A
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C
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A
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C
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A
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-
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R
chr1
C
A
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-
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-A
NR
-B
chr1
Hap. gametes
DNA recombination between linked loci
22 + 1
(♂)
AB-
2 (22 + 1)
♁
♂
AB-
C
A
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-
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C
Meiosis
(♂)
♁
-
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-A A-B B-
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-A
-B
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-
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C
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A
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-A
-B
(♁)
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-
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A
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AB-
(♁)
AB-
Diploid gamete
precursor
AB-
C
A
A
T
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C
T
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T
A
A
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C
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A
T
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A
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A
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-A
-B
Haploid gamete
precursors
-
G
T
T
A
C
G
A
A
A
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G
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C
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-
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NR
-A
-B
NR
NR
-A
-B
NR
Hap. gametes
B. Population level
1. Allele frequencies
A
a
A single locus, with two alleles
- Biallelic
- Single nucleotide polymorphism, SNP
Alleles A and a
- Frequency of A is p
- Frequency of a is q = 1 – p
Every individual inherits two alleles
- A genotype is the combination of the two alleles
- e.g. AA, aa (the homozygotes) or Aa (the heterozygote)
A
a
B. Population level
2. Genotype frequencies (Random mating)
Allele 1
Allele 2
A (p)
a (q)
A (p)
AA (p2) Aa (pq)
a (q)
aA (qp)
aa (q2)
Hardy-Weinberg Equilibrium frequencies
P (AA) = p2
P (Aa) = 2pq
P (aa) = q2
p2 + 2pq + q2 = 1
C. Transmission level
Mendel’s law of segregation
Mother (A3A4)
Segregation (Meiosis)
Father
(A1A2)
A3 (½)
A4 (½)
A1 (½)
A1A3 (¼)
A1A4 (¼)
A2 (½)
A2A3 (¼)
A2A4 (¼)
Gametes
G
D. Phenotype level
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G G G
G
1. Classical Mendelian traits
Dominant trait
- AA, Aa
- aa
1
0
Recessive trait
- AA, Aa
- aa
0
1
Codominant trait
- AA
- Aa
- aa
X
Y
Z
G
G
G
G
P
P
D. Phenotype level
2. Quantitative traits
g==-1
g==0
.128205
.072
Fraction
AA
g==-1
.128205
.128205
g==-1
g==0
g==1
g==0
-3.90647
Fraction
.128205
0
Fraction
Fraction
Aa
0
g==1
.128205
0
0
g==1
-3.90647
-3.90647
.128205
-3.90647
2.7156
2.7156
qt
Histograms by g
aa
0
-3.90647
2.7156
qt
e.g. cholesterol levels
0
-3.90647
0
-3.90647
2.7156
qt
Histograms by g
2.7156
qt
Histograms by g
D. Phenotype level
P(X)
Aa
aa
Biometric Model
AA
X
aa Aa AA
m
D. Phenotype level
P(X)
Aa
aa
Biometric Model
AA
X
aa
Aa
AA
m
–a
m–a
d
m+d
+a
Genotypic effect
m+a
Genotypic means
3. Very basic statistical concepts
Mean, variance, covariance
1. Mean (X)
X  
x
i
i
n
  xi f xi 
i
X
x1
x2
x3
x4
…
xn
Mean, variance, covariance
2. Variance (X)
 x   
2
Var ( X ) 
i
i
n 1
   xi    f  xi 
2
i
X
X-μ
(X-μ )2
x1
x1-μ
(x1-μ )2
x2
x2-μ
(x2-μ )
x3
x3-μ
(x3-μ )2
x4
…
xn
x4-μ
…
xn-μ
(x4-μ )2
…
(xn-μ )2
2
Mean, variance, covariance
3. Covariance (X,Y)
Cov( X , Y ) 
 x    y   
i
X
i
Y
i
n 1
  xi   X  yi  Y  f xi , yi 
i
X Y
X-μ X
Y-μ Y
x1 y1
x1-μ X
y1-μ Y
x2 y2
x2-μ X
y2-μ Y
x3 y3
x3-μ X
y3-μ Y
x4 y4
… …
xn yn
x4-μ X
…
xn-μ X
y4-μ Y
…
yn-μ Y
4. Biometrical model
Biometrical model for single biallelic QTL
Biallelic locus
- Genotypes: AA, Aa, aa
- Genotype frequencies: p2, 2pq, q2
Alleles at this locus are transmitted from P-O according to
Mendel’s law of segregation
Genotypes for this locus influence the expression of a
quantitative trait X (i.e. locus is a QTL)
Biometrical genetic model that estimates the contribution of this QTL
towards the (1) Mean, (2) Variance and (3) Covariance between
individuals for this quantitative trait X
Biometrical model for single biallelic QTL
   xi f xi 
1. Contribution of the QTL to the Mean (X)
i
e.g. cholesterol levels in the population
Genotypes
AA
Aa
aa
Effect, x
a
d
-a
Frequencies, f(x)
p2
2pq
q2
Mean (X) = a(p2) + d(2pq) – a(q2) = a(p-q) + 2pqd
Biometrical model for single biallelic QTL
Var   xi    f xi 
2
2. Contribution of the QTL to the Variance (X)
i
Genotypes
AA
Aa
aa
Effect, x
a
d
-a
Frequencies, f(x)
p2
2pq
q2
Var (X) = (a-m)2p2 + (d-m)22pq + (-a-m)2q2
= VQTL
Broad-sense heritability of X at this locus = VQTL / V Total
Biometrical model for single biallelic QTL
Var (X) = (a-m)2p2 + (d-m)22pq + (-a-m)2q2
m = a(p-q) + 2pqd
= 2pq[a+(q-p)d]2 + (2pqd)2
= VAQTL + VDQTL
Demonstration: final 3 slides
Additive effects: the main effects of individual alleles
Dominance effects: represent the interaction between alleles
Biometrical model for single biallelic QTL
d=0
–a
+a
d
+a
+a
m=0
aa
Aa
AA
Additive
Biometrical model for single biallelic QTL
d>0
–a
+a+d
d +a-d +a
m=0
aa
Aa
AA
Dominant
Biometrical model for single biallelic QTL
d<0
–a
d
+a-d
+a+d
+a
m=0
aa Aa
AA
Recessive
Statistical definition of dominance is scale dependent
+4
+4
+0.7
+0.4
log (x)
aa
Aa
AA
No departure from
additivity
aa
Aa AA
Significant departure
from additivity
Genotypic mean
Biometrical model for single biallelic QTL
a
0
-a
aa
Aa
AA
aa
Aa
AA
Additive
aa
Aa
AA
Dominant
aa
Aa
AA
Recessive
Var (X) = Regression Variance + Residual Variance
= Additive Variance + Dominance Variance
= VAQTL + VDQTL
Practical
H:\ferreira\GeneticTheory\sgene.exe
Practical
Aim
Visualize graphically how allele frequencies, genetic
effects, dominance, etc, influence trait mean and variance
Ex1
a=0, d=0, p=0.4, Residual Variance = 0.04, Scale = 2.
Vary a from 0 to 1.
Ex2
a=1, d=0, p=0.4, Residual Variance = 0.04, Scale = 2.
Vary d from -1 to 1.
Ex3
a=1, d=0, p=0.4, Residual Variance = 0.04, Scale = 2.
Vary p from 0 to 1.
Look at scatter-plot, histogram and variance components.
Some conclusions
1. Additive genetic variance depends on
allele frequency
p
& additive genetic value
a
as well as
dominance deviation
d
2. Additive genetic variance typically greater
than dominance variance
Biometrical model for single biallelic QTL
1. Contribution of the QTL to the Mean (X)
2. Contribution of the QTL to the Variance (X)
3. Contribution of the QTL to the Covariance (X,Y)
Biometrical model for single biallelic QTL
3. Contribution of the QTL to the Cov (X,Y)
Cov( X , Y )   xi   X  yi  Y  f xi , yi 
i
AA (a-m)
Aa (d-m)
AA (a-m)
(a-m)2
Aa (d-m)
(a-m) (d-m)
(d-m)2
aa (-a-m)
(a-m) (-a-m)
(d-m)(-a-m)
aa (-a-m)
(-a-m)2
Biometrical model for single biallelic QTL
3A. Contribution of the QTL to the Cov (X,Y) – MZ twins
Cov( X , Y )   xi   X  yi  Y  f xi , yi 
i
AA (a-m)
AA (a-m)
p2(a-m)2
Aa (d-m)
0 (a-m) (d-m)
aa (-a-m)
0 (a-m) (-a-m)
Cov(X,Y)
Aa (d-m)
aa (-a-m)
2pq (d-m)2
0 (d-m)(-a-m)
q2 (-a-m)2
= (a-m)2p2 + (d-m)22pq + (-a-m)2q2
= 2pq[a+(q-p)d]2 + (2pqd)2 = VAQTL + VDQTL
Biometrical model for single biallelic QTL
3B. Contribution of the QTL to the Cov (X,Y) – Parent-Offspring
AA (a-m)
AA (a-m)
Aa (d-m)
aa (-a-m)
p3(a-m)2
Aa (d-m)
p2q (a-m) (d-m)
aa (-a-m)
0 (a-m) (-a-m)
pq (d-m)2
pq2 (d-m)(-a-m)
q3 (-a-m)2
• e.g. given an AA father, an AA offspring can come from either
AA x AA or AA x Aa parental mating types
AA x AA
will occur p2 × p2 = p4
and have AA offspring Prob()=1
AA x Aa
will occur p2 × 2pq = 2p3q
and have AA offspring Prob()=0.5
and have Aa offspring Prob()=0.5
Therefore, P(AA father & AA offspring)
= p4 + p3q
= p3(p+q)
= p3
Biometrical model for single biallelic QTL
3B. Contribution of the QTL to the Cov (X,Y) – Parent-Offspring
AA (a-m)
AA (a-m)
aa (-a-m)
p3(a-m)2
Aa (d-m)
p2q (a-m) (d-m)
aa (-a-m)
0 (a-m) (-a-m)
Cov (X,Y)
Aa (d-m)
pq (d-m)2
pq2 (d-m)(-a-m)
= (a-m)2p3 + … + (-a-m)2q3
= pq[a+(q-p)d]2 = ½VAQTL
q3 (-a-m)2
Biometrical model for single biallelic QTL
3C. Contribution of the QTL to the Cov (X,Y) – Unrelated individuals
AA (a-m)
AA (a-m)
Aa (d-m)
aa (-a-m)
p4(a-m)2
Aa (d-m) 2p3q (a-m) (d-m) 4p2q2 (d-m)2
aa (-a-m) p2q2(a-m) (-a-m) 2pq3 (d-m)(-a-m)
Cov (X,Y)
= (a-m)2p4 + … + (-a-m)2q4
=0
q4 (-a-m)2
Biometrical model for single biallelic QTL
3D. Contribution of the QTL to the Cov (X,Y) – DZ twins and full sibs
¼ genome
# identical alleles
inherited from
parents
¼ genome
2
¼ (2 alleles)
1
1
(father)
(mother)
+
½ (1 allele) +
MZ twins
Cov (X,Y)
¼ genome
P-O
¼ genome
0
¼ (0 alleles)
Unrelateds
= ¼ Cov(MZ) + ½ Cov(P-O) + ¼ Cov(Unrel)
= ¼(VAQTL+VDQTL) + ½ (½ VAQTL) + ¼ (0)
= ½ VAQTL + ¼VDQTL
Summary so far…
Biometrical model predicts contribution of a QTL to the mean,
variance and covariances of a trait
Association
analysis
Mean (X) = a(p-q) + 2pqd
Linkage
analysis
Var (X) = VAQTL + VDQTL
Cov (MZ) = VAQTL + VDQTL
On average!
Cov (DZ) = ½VAQTL + ¼VDQTL
0, 1/2 or 1
0 or 1
For a sib-pair, do the two sibs
have 0, 1 or 2 alleles in common?
IBD estimation / Linkage
5. Introduction to Linkage Analysis
For a heritable trait...
Linkage:
localize region of the genome where a QTL that
regulates the trait is likely to be harboured
Family-specific phenomenon:
Affected individuals in a family share the same
ancestral predisposing DNA segment at a given QTL
Association: identify a QTL that regulates the trait
Population-specific phenomenon:
Affected individuals in a population share the same
ancestral predisposing DNA segment at a given QTL
Linkage Analysis: Parametric vs. Nonparametric
Gene
M
Recombination
Genetic factors
Q
A
Mode of
inheritance
Correlation
Chromosome
Phe
D
Dominant trait
1 - AA, Aa
0 - aa
C
Environmental
factors
E
Adapted from Weiss & Terwilliger 2000
Approach
Parametric: genotypes marker locus & genotypes trait locus
(latter inferred from phenotype according to a specific disease model)
Parameter of interest: θ between marker and trait loci
Nonparametric: genotypes marker locus & phenotype
If a trait locus truly regulates the expression of a phenotype, then two
relatives with similar phenotypes should have similar genotypes at a
marker in the vicinity of the trait locus, and vice-versa.
Interest: correlation between phenotypic similarity and marker genotypic
similarity
No need to specify mode of inheritance, allele frequencies, etc...
Phenotypic similarity between relatives
Squared trait differences
 X 1  X 2 2
Squared trait sums
 X 1  X 2 2
Trait cross-product
Trait variance-covariance matrix
X1    X 2   
 Var X 1  Cov X 1 X 2 






Cov
X
X
Var
X
1 2
2


Affection concordance
T2
T1
Genotypic similarity between relatives
IBS
Alleles shared Identical By State “look the same”, may have the
same DNA sequence but they are not necessarily derived from a
known common ancestor
IBD
M1
Q1
Alleles shared
M2
Q2
M3
Q3
M3
Q4
Identical By Descent
are a copy of the
same
M1 M2
Q1 Q2
M3 M 3
Q 3 Q4
ancestor
allele
M1 M3
Q1 Q 3
Inheritance vector (M)
0
0
M1 M3
Q1 Q4
0
1
IBS
IBD
2
1
1
Genotypic similarity between relatives Inheritance vector
(M)
Number of alleles
shared IBD

Proportion of alleles
shared IBD -

M1 M3
Q1 Q3
M2 M3
Q2 Q4
0
0
1
1
0
0
M1 M3
Q1 Q3
M1 M3
Q1 Q 4
0
0
0
1
1
0.5
M1 M3
Q 1 Q3
M1 M3
Q1 Q 3
0
0
0
0
2
1
ˆ
Genotypic similarity between relatives A
B
A1A2
2
x0/x1
1
x0/x1
22n
A1A2
A1A3
D
C
A1/A3
A3A2
A1/A2
A1/A2
A1/A3
A3/A2
A1/A2
3
4
Inheritance
vector
IBD
Prior
probability
Posterior
probability
Posterior
probability
Posterior
probability
x0/x0
x0/x0
x0/x0
x0/x0
x0/x1
x0/x1
x0/x1
x0/x1
x1/x0
x1/x0
x1/x0
x1/x0
x1/x1
x1/x1
x1/x1
x1/x1
x0/x0
x0/x1
x1/x0
x1/x1
x0/x0
x0/x1
x1/x0
x1/x1
x0/x0
x0/x1
x1/x0
x1/x1
x0/x0
x0/x1
x1/x0
x1/x1
0000
0001
0010
0011
0100
0101
0110
0111
1000
1001
1010
1011
1100
1101
1110
1111
2
1
1
0
1
2
0
1
1
0
2
1
0
1
1
2
1/16
1/16
1/16
1/16
1/16
1/16
1/16
1/16
1/16
1/16
1/16
1/16
1/16
1/16
1/16
1/16
0
1/12
1/12
1/12
1/12
0
1/12
1/12
1/12
1/12
0
1/12
1/12
1/12
1/12
0
0
1/4
0
0
1/4
0
0
0
0
0
0
1/4
0
0
1/4
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
P (IBD=0)
P (IBD=1)
P (IBD=2)
1/4
1/2
1/4
1/3
2/3
0
0
1
0
0
1
0
0
1
2 1
ˆ   0    1    2     2
2
2
2 2
Var (X) = VAQTL + VDQTL
Cov (MZ) = VAQTL + VDQTL
Cov (DZ) = ½VAQTL + ¼VDQTL
Cov (DZ) =
̂  VAQTL +  2  VDQTL
On average!
For a given twin pair
Cov (DZ) =
̂  VA
Cov (DZ) =
VAQTL  ̂
Phenotypic similarity
QTL
Slope ~ VAQTL
0
0.5
1

Genotypic similarity ( ˆ)
Statistics that incorporate both phenotypic and
genotypic similarities to test VQTL
Regression-based methods
Haseman-Elston, MERLIN-regress
Variance components methods
Mx, MERLIN, SOLAR, GENEHUNTER
Biometrical model for single biallelic QTL
1/3
2A. Average allelic effect (α)
The deviation of the allelic mean from the population mean
Mean (X)
Allele a
Population
Allele A
?
a(p-q) + 2pqd
?
a
A
a
AA
Aa
aa
a
d
-a
p
q
p
q
αa
αA
A
Allelic mean
Average allelic effect (α)
ap+dq
dp-aq
q(a+d(q-p))
-p(a+d(q-p))
Biometrical model for single biallelic QTL
Denote the average allelic effects
- αA = q(a+d(q-p))
- αa = -p(a+d(q-p))
If only two alleles exist, we can define the average effect of
allele substitution
- α = αA - αa
- α = (q-(-p))(a+d(q-p)) = (a+d(q-p))
Therefore:
- αA = qα
- αa = -pα
2/3