epistasis / multi-locus modelling shaun purcell, pak sham sgdp, iop, london, uk
TRANSCRIPT
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Epistasis / Multi-locus Modelling
Shaun Purcell, Pak Sham
SGDP, IoP, London, UK
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T T T
I
M MM
QTL
Multiplex (larger families)
I
T
M
QTL
T
I
M
QTL
T T T T
Multivariate (more traits)
M M M M
Multipoint (more markers)
Multilocus (modelling more QTLs)
QTL QTLQTL QTLQTL QTL
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Single locus model
TQTL1
QTL3
QTL4
QTL2
QTL5
E3
E4
E2
E1
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Multilocus model
TQTL1
QTL2
QTL4
QTL3
QTL5
E3
E4
E2
E1
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GENE x GENE Interaction
GENE x GENE INTERACTION : Epistasis
Additive genetic effects :
alleles at a locus and across loci independently sum to
result in a net phenotypic effect
Nonadditive genetic effects :
effects of an allele modified by the presence of other
alleles (either at the same locus or at different loci)
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Nonadditive genetic effects
Dominance
an allele allele interaction occurring within one locus
Epistasis
an interaction occurring between the alleles at two (or
more) different loci
Additionally, nonadditivity may arise if the effect of an allele
is modified by the presence of certain environments
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Separate analysis
locus A shows an association with the trait
locus B appears unrelated
AA Aa aa BB Bb bb
Locus A Locus B
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Joint analysis
locus B modifies the effects of locus A
BB Bb bb
AA
Aa
aa
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Genotypic Means
Locus A
Locus B AA Aa aa
BB AABB AaBB aaBB BB
Bb AABb AaBb aaBb Bb
bb Aabb Aabb aabb bb
AA Aa aa
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Partitioning of effects
Locus A
Locus B
M P
M P
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4 main effects
M
P
M
P
Additiveeffects
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6 twoway interactions
M P
M P
Dominance
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6 twoway interactions
M
PM
P
Additive-additive epistasis
M
PP
M
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4 threeway interactions
M P M
P
M
P
M P
M P
M P
Additive-dominance epistasis
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1 fourway interaction
M M P Dominance-dominance epistasis
P
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One locus
Genotypic
means
AA m + a
Aa m + d
aa m - a
0
d +a-a
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Two loci
AA Aa aa
BB
Bb
bb
m
m
m
m
m
m
m
m
m
+ aA
+ aA
+ aA
– aA
– aA
– aA
+ dA
+ dA
+ dA
+ aB + aB+ aB
– aB – aB – aB
+ dB + dB + dB
– aa
– aa
+ aa
+ aa
+ dd+ ad
– da
+ da
– ad
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Research questions
How can epistasis be modelled under a variance
components framework?
How powerful is QTL linkage to detect epistasis?
How does the presence of epistasis impact QTL
detection when epistasis is not modelled?
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Variance components
QTL linkage : single locus model
P = A + D + S + N
Var (P) = 2A + 2
D + 2S + 2
N
Under H1 :
Cov(P1,P2) = 2A + z2
D + 2S
where = proportion of alleles shared identical-by-descent (ibd) between siblings at that locus
z = probability of complete allele sharing ibdbetween siblings at that locus
Under H0 :
Cov(P1,P2) = ½2A + ¼2
D + 2S
where ½ = proportion of alleles shared identical-by- descent (ibd) between siblings
¼ = prior probability of complete allele sharing ibd between siblings
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Covariance matrix
Sib 1 Sib 2
Sib 1 2A + 2
D + 2S + 2
N 2A + z2
D + 2S
Sib 2 2A + z2
D + 2S 2
A + 2D + 2
S + 2N
Sib 1 Sib 2
Sib 1 2A + 2
D + 2S + 2
N ½2A + ¼2
D + 2S
Sib 2 ½2A + ¼2
D + 2S 2
A + 2D + 2
S + 2N
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QTL linkage : two locus model
P = A1 + D1 + A2 + D2
+ A1A1 + A1D2 + D1A2 + D1D2
+ S + N
Var (P) = 2A + 2
D + 2A + 2
D
+ 2AA + 2
AD + 2DA + 2
DD
+ 2S + 2
N
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Under linkage :
Cov(P1,P2) = 2A + z2
D + 2A + z2
D
+ 2A + z2
AD + z2DA + zz2
DD
+ 2S
Under null :
Cov(P1,P2) = ½2A + ¼2
D + ½2A + ¼2
D
+ E()2A+E(z)2
AD +E(z)2DA+ E(zz)2
DD
+ 2S
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IBD locus1 2 Expected Sib Correlation
0 1 2A/2 + 2
S
0 2 2A + 2
D + 2S
1 0 2A/2 + 2
S
1 1 2A/2 + 2
A/2 + 2AA/4 + 2
S
1 2 2A/2 + 2
A + 2D + 2
AA/2 + 2AD/2 + 2
S
2 0 2A + 2
D + 2S
2 1 2A + 2
D + 2A/2 + 2
AA/2 + 2DA/2 + 2
S
2 2 2A + 2
D + 2A + 2
D+ 2AA + 2
AD + 2DA + 2
DD + 2S
0 0 2S
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Joint IBD sharing for two loci
For unlinked loci,
Locus A
0 1 2
Locus B 0 1/16 1/8 1/16 1/4
1 1/8 1/4 1/8 1/2
2 1/16 1/8 1/16 1/4
1/4 1/2 1/4
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22 )1(
4/2 2/)1( 4/)1( 2
4/22/)1( 4/)1( 2
2/)1( 2/)1( 2/))1(21(
0
1/2
1
0 1/2 1
at QTL 1 at QTL 2
Joint IBD sharing for two linked loci
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Potential importance of epistasis
“… a gene’s effect might only be detected within a
framework that accommodates epistasis…”
Locus A
A1A1 A1A2 A2A2 Marginal
Freq. 0.25 0.50 0.25
B1B1 0.25 0 0 1 0.25
Locus B B1B2 0.50 0 0.5 0 0.25
B2B2 0.25 1 0 0 0.25
Marginal 0.25 0.25 0.25
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Power calculations for epistasis
Specify
genotypic means,
allele frequencies
residual variance
Calculate
under full model and submodels
variance components
expected non-centrality parameter
(NCP)
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Submodels
Apparent variance components
- biased estimate of variance component
- i.e. if we assumed a certain model (i.e. no
epistasis) which, in reality, is different from the
true model (i.e. epistasis)
Enables us to explore the effect of misspecifying
the model
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Detecting epistasis
The test for epistasis is based on the difference in
fit between
- a model with single locus effects and epistatic effects
and
- a model with only single locus effects,
Enables us to investigate the power of the variance
components method to detect epistasis
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A B
Y
a b
True Model
A
Y
a*
Assumed Model
a* is the apparent co-efficienta* will deviate from a to the extent that A and B are correlated
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- DD V*A1 V*D1 V*A2 V*D2 V*AA V*AD V*DA -
- AD V*A1 V*D1 V*A2 V*D2 V*AA - - -
- AA V*A1 V*D1 V*A2 V*D2 - - - -
- D V*A1 - V*A2 - - - - -
- A V*A1 - - - - - - -
H0 - - - - - - - -
Full VA1 VD1 VA2 VD2 VAA VAD VDA VDD
VS and VN estimated in all models
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Example 1 : epi1.mx
Genotypic Means B1B1 B1B2 B2B2
A1A1 0 0 1
A1A2 0 0.5 0
A2A2 1 0 0
Allele frequencies A1 = 50% ; B1 = 50%
QTL variance 20%
Shared residual variance40%
Nonshared residual variance 40%
Sample N 10, 000 unselected pairs
Recombination fraction Unlinked (0.5)
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Example 2 : epi2.mx
Genotypic Means B1B1 B1B2 B2B2
A1A1 0 1 2
A1A2 0 1 2
A2A2 2 1 0
Allele frequencies A1 = 90% ; B1 = 50%
QTL variance 10%
Shared residual variance20%
Nonshared residual variance 70%
Sample N 2, 000 unselected pairs
Recombination fraction 0.1
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Exercise
Using the module, are there any configurations of
means, allele frequencies and recombination
fraction that result in only epistatic components of
variance?
How does linkage between two epistatically
interacting loci impact on multilocus analysis?
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Poor power to detect epistasis
Detection = reduction in model fit when a term is
dropped
Apparent variance components “soak up” variance
attributable to the dropped term
artificially reduces the size of the reduction
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Epistasis as main effect
Epistatic effects detected as additive effects
“Main effect” versus “interaction effect” blurred
for linkage, main effects and interaction effects are
partially confounded
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Probability Function Calculator
http://statgen.iop.kcl.ac.uk/bgim/
Genetic Power Calculator
http://statgen.iop.kcl.ac.uk/gpc/