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203.343 Advanced Genetics
and Genomics
Lecture 5
July 27th 2015
Olin Silander
Mary-Claire King and BRCA1
Listen: http://themoth.org/posts/storytellers/mary-claire-king
Gene Linkage and Linkage Disequilibrium
Why do different loci have the same demographic histories?
Tishkoff et al. (2007)
LCTlactase-phlorizin
hydrolase
Gene Linkage and Linkage Disequilibrium
selection increases LD
selection decreases local nucleotide diversity
selection increases the frequency of rare alleles relative to what you would expect
Gene Linkage and Linkage Disequilibrium
Tajima’s D: quantifies the expected rarity of alleles
TK Oleksyk et al. (2009) Phil Tr RSB
Negative Tajima’s D implies excess rare alleles and selection
Gene Linkage and Linkage Disequilibrium
TK Oleksyk et al. (2009) Phil Tr RSB
Negative Tajima’s D implies excess rare alleles and selection
Tajima’s D: quantifies the expected rarity of alleles
Gene Linkage and Linkage Disequilibrium
Why do different loci have the same demographic histories?
H Alhaddad, R Khan et al. (2013) PLOS One
?
? ?
Birman♀♂ pair
after WWII
Burmesesingle ♀in 1930
Manxbred since
1800
Gene Linkage and Linkage Disequilibrium
Why do different loci have the same demographic histories?
Burmese
BirmanManx
population bottleneck (drift)
Birman♀♂ pair
after WWII
Burmesesingle ♀in 1930
Manxbred since
1800
H Alhaddad, R Khan et al. (2013) PLOS One
Linkage Disequilibrium - Data
Paigen and Petkov (2010) Nat. Rev. Gen.
recombination rate varies by >10-fold
SNP diversity and effective population size
SNP diversity and effective population size
SNP diversity
HapMap III
Linkage analysis
Parametric Linkage Analysis
Used for single gene disorders (typically) to define (parametrise) genetic and phenotypic similarity
Linkage analysis
Parametric Linkage Analysis
Used for single gene disorders (typically) to define (parametrise) genetic and phenotypic similarity
Requires: (1) Pedigree (2) Phenotypes (3) Marker genotypes
Linkage analysis
Parametric Linkage Analysis
Used for single gene disorders (typically) to define (parametrise) genetic and phenotypic similarity
Requires: (1) Pedigree (2) Phenotypes (3) Marker genotypes
Linkage map
linkage group
Linkage analysis
Parametric Linkage Analysis
Used for single gene disorders (typically) to define (parametrise) genetic and phenotypic similarity
Estimates the recombination fraction between a disease locus and a genetic marker
Parametric Linkage Analysis
Marker locus with two Alleles, A1 and A2
Hypothesis: disease mutation is dominant
Hypothesis: disease locus is linked to marker locus
A2/A2 A1/A1
A1/A1A1/A2
A1/A2A1/A2A1/A2A1/A1A1/A1A1/A2A1/A2
Parametric Linkage Analysis
Disease originally associated with marker allele A2
A2/A2 A1/A1
A1/A1A1/A2
A1/A2A1/A2A1/A2A1/A1A1/A1A1/A2A1/A2
Parametric Linkage Analysis
Disease originally associated with marker allele A2
Segregates with marker allele A2 in 6 meioses (disease allele is dominant)
A2/A2 A1/A1
A1/A1A1/A2
A1/A2A1/A2A1/A2A1/A1A1/A1A1/A2A1/A2
Parametric Linkage Analysis
Disease originally associated with marker allele A2
Segregates with marker allele A2 in 6 meioses (disease allele is dominant)
Separates from marker allele A2 in one instance
disease allele no longer with marker allele A2 → recombination
event must have occurred
Parametric Linkage Analysis
Need to compare two Likelihoods to understand whether the A locus is linked to the disease
Need to compare two Likelihoods to understand whether the A locus is linked to the disease
Parametric Linkage Analysis
likelihood of the data if locus A and disease locus (D) are linked
Need to compare two Likelihoods to understand whether the A locus is linked to the disease
Parametric Linkage Analysis
likelihood of the data if locus A and disease locus (D) are linked
likelihood of the data if locus A and the disease locus are not linked
A D
A
D
Parametric Linkage Analysis
Summarised as the ratio of the likelihoods
L( recomb.)
L( recomb = 1/2 )LOD = log10 [ ]
^
best estimate
A2/A2 A1/A1
A1/A1A1/A2
A1/A2A1/A2A1/A2A1/A1A1/A1A1/A2A1/A2
Parametric Linkage Analysis
Disease originally associated with marker allele A2
Segregates with marker allele A2 in 6 meioses (disease allele is dominant)
Separates from marker allele A2 in one instance
calculating likelihoods
Parametric Linkage Analysis
A2/A2 A1/A1
A1/A1A1/A2
A1/A2A1/A2A1/A2A1/A1A1/A1A1/A2A1/A2
Parametric Linkage Analysis
maximum likelihood recombination rate between locus A and D = 0.14 likelihood = 0.057
if recomb. rate between locus A and D = 0.5 likelihood = 0.0078
Parametric Linkage Analysis
maximum likelihood recombination rate between locus A and D = 0.14 likelihood = 0.057
if recomb. rate between locus A and D = 0.5 likelihood = 0.0078
L( recomb.)
L( recomb = 1/2 )LOD = log10 [ ]
^
best estimate (maximum likelihood estimate)
Parametric Linkage Analysis
maximum likelihood recombination rate between locus A and D = 0.14 likelihood = 0.057
if recomb. rate between locus A and D = 0.5 likelihood = 0.0078
L( recomb.)
L( recomb = 1/2 )LOD = log10 [ ]
^
best estimate (maximum likelihood estimate)
LOD = 0.86
Need LOD > 2 to have some confidence that marker and disease locus are linked.
LOD > 3 strong evidence of linkage
A2/A2 A1/A1
A1/A1A1/A2
A1/A2A1/A2A1/A2A1/A1A1/A1A1/A2A1/A2
Parametric Linkage Analysis
maximum likelihood recombination rate between
locus A and D = 0.08 likelihood = 0.032
if recomb. rate between locus A and D = 0.5 likelihood = 0.00024
A2/A2 A1/A1
A1/A1A1/A2
A1/A2A1/A2A1/A2A1/A1A1/A1A1/A2A1/A2
Two families Disease allele segregates with A2 in 11 instances
Disease allele separates from A2 in 1 instance
LOD = 2.12 → some confidence that locus A and the disease locus are linked
Parametric Linkage Analysis
E DCBA F G HDisease locus
Marker loci0
12
34
Marker (arranged in chromosomal order)
LOD
sco
re
A B C E F D H
Parametric Linkage Analysis
Parametric Linkage Analysis
Parametric Linkage Analysis
Parametric Linkage Analysis
Association Studies
Linkage Studies (pedigrees)
Association Studies (populations)
Association Studies
June 2006
June 2007
June 2009
June 2011
June 2013
Association Studies
A/A A/C C/C230
review!
260 23
Association Studies
A/A A/C C/C230
review!
260 23
minor allele?
Association Studies
A/A A/C C/C230
review!
260 23
A - 750 (0.73) C - 276 (0.27)
Association Studies
A/A A/C C/C230
review!
260 23
A - 750 (0.73) C - 276 (0.27)
HWE?
Association Studies
A/A A/C C/C230
review!
260 23274 202
A - 750 (0.73) C - 276 (0.27)
37
Association Studies
A/A A/C C/C230
review!
260 23274 202 37
0.72 3.88 5.29
HWE?UNLIKELY
Association Studies
Association Studies
casecasecasecasecasecase
controlcontrolcontrolcontrolcontrolcontrol
0 1 2 1 0 2 1 0 20 1 2 1 0 2 1 1 12 1 2 1 0 2 0 0 20 2 2 2 1 1 2 0 01 2 2 1 1 2 1 2 20 1 2 0 0 1 0 2 2
1 0 0 0 1 0 2 1 22 1 0 1 0 2 1 0 00 1 0 1 0 2 2 1 21 0 0 2 0 2 1 0 20 1 0 1 0 2 1 0 10 2 0 1 2 1 0 2 2
Association Studies
casecasecasecasecasecase
controlcontrolcontrolcontrolcontrolcontrol
0 1 2 1 0 2 1 0 20 1 2 1 0 2 1 1 12 1 2 1 0 2 0 0 20 2 2 2 1 1 2 0 01 2 2 1 1 2 1 2 20 1 2 0 0 1 0 2 2
1 0 0 0 1 0 2 1 22 1 0 1 0 2 1 0 00 1 0 1 0 2 2 1 21 0 0 2 0 2 1 0 20 1 0 1 0 2 1 0 10 2 0 1 2 1 0 2 2
Parametric Linkage Analysis
