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Biometrical Genetics

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Genetic principles for linkage and association analyses. Manuel Ferreira & Pak Sham ... If a locus regulates a trait, Trait Variance and Covariance between individuals ... – PowerPoint PPT presentation

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Title: Biometrical Genetics


1
Genetic principles for linkage and association
analyses
Manuel Ferreira Pak Sham
Boulder, 2009
2
Gene mapping
LOCALIZE and then IDENTIFY a locus that regulates
a trait
Association analysis
Linkage analysis
3
Linkage
If a locus regulates a trait, Trait Variance and
Covariance between individuals will be influenced
by this locus.
Association
If a locus regulates a trait, Trait Mean in the
population will also be influenced by this locus.
4
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
  • Mean
  • Variance
  • 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.
5
Outline
1. Genetic concepts
2. Very basic statistical concepts
3. Biometrical model
4. Introduction to linkage analysis
6
1. Genetic concepts
7
A. DNA level
DNA structure, organization
recombination
G
G
G
G
G
G
B. Population level
G
G
G
Allele and genotype frequencies
G
G
G
G
G
G
G
G
G
G
G
C. Transmission level
G
G
Mendelian segregation
Genetic relatedness
G
G
D. Phenotype level
Biometrical model
P
P
Additive and dominance components
8
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
9
DNA polymorphisms
Microsatellites gt100,000 Many alleles, eg. (CA)n
repeats, very informative
SNPs 14,708,752 (build 129, 03 Mar 09) Most
with 2 alleles (up to 4), not very informative
A
Copy Number Variants gt5,000 Many alleles, just
recently automated
B
10
DNA organization
22 1
2 (22 1)
2 (22 1)
2 (22 1)
?
?
?
A -
A -
A -
?
B -
?
?
?
?
Mitosis
B -
B -
chr1
A -
A -
A -
A -
- A
- A
?
?
?
B -
B -
B -
B -
- B
- B
A -
- A
- A
B -
- B
chr1
- B
G1 phase
S phase
M phase
Haploid gametes
Diploid zygote 1 cell
Diploid zygote gt1 cell
11
DNA recombination
22 1
22 1
A -
NR
(?)
B -
A -
- A
chr1
2 (22 1)
2 (22 1)
B -
- B
?
- A
Meiosis
R
chr1
(?)
(?)
?
?
- B
A -
A -
- A
- A
chr1
B -
B -
- B
- B
A -
R
chr1
chr1
chr1
chr1
(?)
A -
- A
B -
chr1
Diploid gamete precursor cell
B -
- B
- A
chr1
NR
- B
Haploid gamete precursors
chr1
Hap. gametes
12
DNA recombination between linked loci
22 1
A -
NR
B -
(?)
A -
- A
B -
- B
2 (22 1)
?
- A
Meiosis
NR
- B
(?)
(?)
?
?
A -
A -
- A
- A
B -
B -
- B
- B
A -
NR
B -
(?)
A -
- A
B -
- B
Diploid gamete precursor
- A
- B
NR
Haploid gamete precursors
Hap. gametes
13
B. Population level
1. Allele frequencies
A single locus, with two alleles - Biallelic
- Single nucleotide polymorphism, SNP
A
a
a
a
a
A
a
a
A
A
A
a
A
a
Alleles A and a - Frequency of A is p -
Frequency of a is q 1 p
A
A
A
A
A
a
A
a
A
A
A
a
a
A genotype is the combination of the two alleles

A
a
Aa
14
B. Population level
2. Genotype frequencies (Random mating)
Allele 1
A (p)
a (q)
A (p)
AA (p2)
Aa (pq)
Allele 2
a (q)
aA (qp)
aa (q2)
Hardy-Weinberg Equilibrium frequencies
P (AA) p2
P (Aa) 2pq
p2 2pq q2 1
P (aa) q2
15
C. Transmission level
Mendels law of segregation
Mother (A3A4)
Segregation (Meiosis)
Gametes
A3 (½)
A4 (½)
A1 (½)
A1A3 (¼)
A1A4 (¼)
Father (A1A2)
A2 (½)
A2A4 (¼)
A2A3 (¼)
16
D. Phenotype level
1. Classical Mendelian traits
Dominant trait - AA, Aa 1 - aa 0
Huntingtons disease (CAG)n repeat, huntingtin
gene
Recessive trait - AA 1 - aa, Aa 0
Cystic fibrosis 3 bp deletion exon 10 CFTR gene
17
D. Phenotype level
2. Quantitative traits
e.g. cholesterol levels
18
D. Phenotype level
Aa
P(X)
aa
AA
X
AA
Aa
aa
m
19
D. Phenotype level
Aa
P(X)
Biometric Model
AA
aa
X
AA
Aa
aa
m
d
a
a
Genotypic effect
20
2. Very basic statistical concepts
21
Mean, variance, covariance
1. Mean (X)
22
Mean, variance, covariance
2. Variance (X)
23
Mean, variance, covariance
3. Covariance (X,Y)
24
3. Biometrical model
25
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 Mendels 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
26
Biometrical model for single biallelic QTL
1. Contribution of the QTL to the Mean (X)
e.g. cholesterol levels in the population
aa
Aa
Genotypes
AA
a
d
-a
Effect, x
p2
2pq
q2
Frequencies, f(x)
a(p2) d(2pq) a(q2)
Mean (X)
a(p-q) 2pqd
27
Biometrical model for single biallelic QTL
2. Contribution of the QTL to the Variance (X)
aa
Aa
Genotypes
AA
a
d
-a
Effect, x
p2
2pq
q2
Frequencies, f(x)
(a-m)2p2 (d-m)22pq (-a-m)2q2
Var (X)
VQTL
Heritability of X at this locus VQTL / V Total
28
Biometrical model for single biallelic QTL
(a-m)2p2 (d-m)22pq (-a-m)2q2
Var (X)
2pqa(q-p)d2 (2pqd)2
m a(p-q) 2pqd
VAQTL VDQTL
Additive effects the main effects of individual
alleles
Dominance effects represent the interaction
between alleles
29
Biometrical model for single biallelic QTL
d 0 (no dominance)
d
a
a
a
a
m 0
aa
Aa
AA
Additive model
30
Biometrical model for single biallelic QTL
d gt 0 (dominance)
d
a
a
ad
a-d
m 0
aa
Aa
AA
Dominant model
31
Biometrical model for single biallelic QTL
d lt 0 (dominance)
d
a
a
a-d
ad
m 0
aa
Aa
AA
Recessive model
32
Statistical definition of dominance is scale
dependent
4
4
0.7
0.4
log (x)
aa
Aa
AA
aa
Aa
AA
No departure from additivity
Significant departure from additivity
33
Biometrical model for single biallelic QTL
a
0
Genotypic mean
-a
aa
Aa
AA
aa
Aa
AA
aa
Aa
AA
aa
Aa
AA
Additive
Dominant
Recessive
Var (X) Regression Variance Residual
Variance
Additive Variance Dominance Variance
VAQTL VDQTL
34
Practical
H\manuel\biometric\sgene.exe
35
Practical
Aim
Visualize graphically how allele frequencies,
genetic effects, dominance, etc, influence trait
mean and variance
Ex1
a0, d0, p0.4, Residual Variance 0.04, Scale
2. Vary a from 0 to 1.
Ex2
a1, d0, p0.4, Residual Variance 0.04, Scale
2. Vary d from -1 to 1.
Ex3
a1, d0, p0.4, Residual Variance 0.04, Scale
2. Vary p from 0 to 1.
Look at scatter-plot, histogram and variance
components.
36
Some conclusions
  • Additive genetic variance depends on
  • allele frequency p
  • additive genetic value a
  • as well as
  • dominance deviation d
  • Additive genetic variance typically greater than
    dominance variance

37
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)
38
Biometrical model for single biallelic QTL
3. Contribution of the QTL to the Cov (X,Y)
(a-m)
AA
Aa
aa
(d-m)
(-a-m)
(a-m)
(a-m)2
AA
(d-m)
(a-m)
(d-m)
(d-m)2
Aa
aa
(-a-m)
(-a-m)
(d-m)
(-a-m)
(-a-m)2
(a-m)
39
Biometrical model for single biallelic QTL
3A. Contribution of the QTL to the Cov (X,Y) MZ
twins
(a-m)
AA
Aa
aa
(d-m)
(-a-m)
(a-m)
(a-m)2
p2
AA
(d-m)
(a-m)
(d-m)
(d-m)2
Aa
0
2pq
aa
(-a-m)
(-a-m)
(d-m)
(-a-m)
(-a-m)2
(a-m)
0
0
q2
(a-m)2p2 (d-m)22pq (-a-m)2q2
Cov(X,Y)
VAQTL VDQTL
2pqa(q-p)d2 (2pqd)2
40
Biometrical model for single biallelic QTL
3B. Contribution of the QTL to the Cov (X,Y)
Parent-Offspring
(a-m)
AA
Aa
aa
(d-m)
(-a-m)
(a-m)
(a-m)2
p3
AA
(d-m)
(a-m)
(d-m)
(d-m)2
Aa
p2q
pq
aa
(-a-m)
(-a-m)
(d-m)
(-a-m)
(-a-m)2
(a-m)
0
pq2
q3
41
  • 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(pq)
  • p3

42
Biometrical model for single biallelic QTL
3B. Contribution of the QTL to the Cov (X,Y)
Parent-Offspring
(a-m)
AA
Aa
aa
(d-m)
(-a-m)
(a-m)
(a-m)2
p3
AA
(d-m)
(a-m)
(d-m)
(d-m)2
Aa
p2q
pq
aa
(-a-m)
(-a-m)
(d-m)
(-a-m)
(-a-m)2
(a-m)
0
pq2
q3
(a-m)2p3 (-a-m)2q3
Cov (X,Y)
½VAQTL
pqa(q-p)d2
43
Biometrical model for single biallelic QTL
3C. Contribution of the QTL to the Cov (X,Y)
Unrelated individuals
(a-m)
AA
Aa
aa
(d-m)
(-a-m)
(a-m)
(a-m)2
p4
AA
(d-m)
(a-m)
(d-m)
(d-m)2
Aa
2p3q
4p2q2
aa
(-a-m)
(-a-m)
(d-m)
(-a-m)
(-a-m)2
(a-m)
p2q2
2pq3
q4
(a-m)2p4 (-a-m)2q4
Cov (X,Y)
0
44
Biometrical model for single biallelic QTL
3D. Contribution of the QTL to the Cov (X,Y) DZ
twins and full sibs
¼ genome
¼ genome
¼ genome
¼ genome
identical alleles inherited from parents
0
1 (mother)
1 (father)
2
¼ (2 alleles) ½ (1 allele)
¼ (0 alleles)
MZ twins
Unrelateds
P-O
Cov (X,Y)
¼ Cov(MZ) ½ Cov(P-O) ¼ Cov(Unrel)
¼(VAQTLVDQTL) ½ (½ VAQTL) ¼ (0)
½ VAQTL ¼VDQTL
45
Summary so far
46
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
VAQTL VDQTL
Var (X)
VAQTL VDQTL
Cov (MZ)
On average!
½VAQTL ¼VDQTL
Cov (DZ)
For a given locus, do two sibs have 0, 1 or 2
alleles in common?
0 or 1
0, 1/2 or 1
IBD estimation / Linkage
47
4. Introduction to Linkage analysis
48
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
Can only detect very large effects
identify a QTL that regulates the trait
Association
Population-specific phenomenon Affected
individuals in a population share the same
predisposing DNA segment at a given QTL
Can detect weaker effects
49
Controls
Families
Cases
No Linkage
No Association
Linkage
No Association
Linkage
Association
50
Non-parametric linkage approach
Linkage tests co-segregation between a marker and
a trait
If a trait locus truly regulates the expression
of a phenotype, then two relatives with similar
phenotypes should have inherited from a
common ancestor the same predisposing allele at a
marker near the trait locus, and
vice-versa. Interest correlation between
phenotypic similarity and genetic similarity at a
locus
51
Phenotypic similarity between relatives
Squared trait differences
Squared trait sums
Trait cross-product
Trait variance-covariance matrix
Affection concordance
T2
T1
52
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
M3
M1
M2
M3
Q3
Q1
Q2
Q4
IBD Alleles shared Identical By Descent are
a copy of the same ancestor allele
M1
M2
M3
M3
Q1
Q2
Q3
Q4
IBS
IBD
M1
M3
M1
M3
2
1
Q1
Q3
Q1
Q4
0
0
0
1
1
Inheritance vector (M)
53
Genotypic similarity between relatives -
Number of alleles shared IBD
Proportion of alleles shared IBD -
Inheritance vector (M)
M2
M3
M1
M3
0
0
0
0
1
1
Q2
Q4
Q1
Q3
M1
M3
M1
M3
0.5
0
0
0
1
1
Q1
Q3
Q1
Q4
M1
M1
M3
M3
2
1
0
0
0
0
Q1
Q1
Q3
Q3
54
Genotypic similarity between relatives -
A
B
C
D
22n
55
VAQTL VDQTL
Var (X)
VAQTL VDQTL
Cov (MZ)
½VAQTL ¼VDQTL
Cov (DZ)
On average!
For a given locus
Cov (DZ)
VAQTL VDQTL
Cov (DZ)
VAQTL
56
(No Transcript)
57
Statistics that incorporate both phenotypic and
genotypic similarities to test VQTL
Regression-based methods
Haseman-Elston, MERLIN-regress
-2 VAQTL
(X1-X2)2
Variance components methods
Mx, MERLIN, SOLAR, GENEHUNTER
58
Should we still use linkage analysis?
Given dense SNP data
Rare genetic variant (not covered by the
genotyping platform)
... or allelic heterogeneity (multiple disease
variants in the same gene)
AND strong effect on phenotype...
Linkage analysis can complement association and
provide an additional approach to localise a
disease locus (with no loss).
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