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Course Outline
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Introduction: QTL and heritability
Quantitative Mutagenesis
QTL Mapping
QTN Mapping
Microarrays and Genomics
Evolutionary genetics
Introduction
• Genetic analysis of common human diseases, animal and plant
breeding, and evolutionary biology all require the tools of
quantitative genetics.
• Quantitative genetics is the study of the variation in continuous
traits.
• Small effects of many individual genes add together and interact
with the environment, to produce natural variation
• Modern molecular quantitative genetics is focused on identifying
the underlying genes and describing how variation at the DNA
level translates into phenotypic variation
Oligogenic effects
1 Locus
Frequency
Frequency
2 Loci
1
2
-
+
-
1
+
+
1
4
- - -
+ - -
Frequency
3 Loci
1
- - - - -
6
15 20 15
+
+ - - - - - +
+
+ - - +
- - +
- - +
-
+
+ - +
- - +
+ + +
- -
6
1
+ + +
+ +
- - + + + + + +
+ - + + + -
6
+
+
+
+
-
4
+ +
+ -
1
+ +
+ +
Heritability
• Heritability is the proportion of phenotypic
variation in a population that is due to genotypic
variation
• Heritability describes the relative contributions of
genotype and environment to phenotypic variation
• Heritability is a measure of a population, not an
individual, and does not say anything about the
genetic difference between populations.
• There are three common approaches to measuring
heritability.
Parent-Offspring Regression
Offspring Phenotype
6
5
4
3
2
1
1
2
3
4
Parental Phenotype
5
6
Variance among Lines
High heritability
6
6
5
5
4
4
Phenotype
Phenotype
Low heritability
3
3
2
2
1
1
1
2
3
Line Number
4
1
2
3
Line Number
4
Realized heritability
Frequency
Initial
population
Selected
sample
O
R
S
R
Progeny of
selected
sample
Phenotype
S
Polygenes
• The number of genes that affect a trait can be
estimated from the variance segregating in an F2
generation
• There is a wide range in the number of genes that
affect traits
• As the number of genes influencing a trait
increases, the relative number of individuals with
extreme phenotypes decreases.
• Transgressive segregation occurs when
grandchildren have more extreme phenotypes than
either grandparent.
Simple additive model
¼
AA (0)
½
Aa (1)
¼
aa (2)
¼ BB (0)
1/16 (0)
1/8 (1)
1/16 (2)
½ Bb (1)
1/8 (1)
1/4 (2)
1/8 (3)
¼ Bb (2)
1/16 (2)
1/8 (3)
1/16 (4)
Polygenic effects
Frequency
Parental samples
Frequency
F2 samples
Frequency
F1 sample
Phenotype
Transgressive segregation
Parental samples
Frequency
A.
-
;
+
+
; -- ;
-
+
+
;
-
; ++ ;
+
+
B.
F2
F1
F2 samples
Frequency
P2
Frequency
P1
25 35 45 55 65 75 85 95 105 115
Plant height (cm)
-
;
-
; -- ;
-
+
+
Phenotype
;
+
+
; ++ ;
+
+
VP = VA + VD + VI + VGxE + VE
• Loci are said to have Additive effects if the
contributions of each individual allele can simply
be added algebraically to arrive at a prediction of a
phenotype given a genotype.
• Dominance refers to the observation that
heterozygotes resemble one class of homozygotes
more than the other.
• Epistasis refers to a locus-by-locus Interaction,
such as when alleles at two loci antagonize or
synergize with one another.
• VE is the environmental variance
Mean phenotype
Dominance ratio
20
18
16
14
12
10
8
6
4
2
0
bb
Bb
a
d
d = 16-10
= 6
a = 18-10
= 8
0
Expected mid-value
= (18+2)/2 = 10
BB
-a
0
1
Number of “b” alleles
2
Epistasis
OBSERVED
38
37
36
35
34
33
32
31
EXPECTED
38
37
36
35
34
33
32
31
BB
Bb
bb
AA
Aa
BB
Bb
bb
aa
AA
EPISTATIC DEVIATIONS
1.00
0.75
0.50
0.25
0.00
- 0.25
- 0.50
- 0.75
- 1.00
Bb
bb
BB
AA
Aa
aa
Aa
aa
Quantitative Mutagenesis
• Quantitative genetic variation is constantly
produced by mutation accumulation
• Quantitative measurement of P-elements
can uncover novel genes regulating
complex traits
• Deficiency complementation mapping is a
way to infer that segregating variation
affects a trait
Mutation accumulation
H1
H2
H3
Number of Bristles
20
15
10
5
0
20
L1
L2
L3
40
60
80
Generation
100
120
P screen for bristle number
Df Complementation
Df
wt
X
Vs
wt
wt
Bal
wt
140.00
120.00
Survival Time
Df
Bal
Females
100.00
80.00
60.00
40.00
20.00
0.00
Mutant
Wildtype
Introgression
X
X
X
X
omb
bs/DSRF
Gap1
sbb
ptc
ed
egfr
star
osa
drk
Argos
spi
dad
mam
Mad
ksr
pnt
tkv
Trl
rho- 2
dpp
ast
src42A
sd
mam
cbl
tkv
cos
mad
psq
cv-2
dpp
babo
drk
brinker
sax
tsh
sax
PKA-C-3
RAS85D
CG3957
rho1 kinsahn
se
rho- AP
PKA
p38b
rho- 6
cs
RAS-GAw
P
rho- 6
-LOG(P)
P’s affect wing shape
50
45
40
GENOTYPE
GENOTYPE*BACKGROUND
35
30
25
20
15
10
5
0
LINE
QTL Mapping
• A QTL is a locus that has a quantitative effect
on a trait
• QTL mapping is similar to linkage mapping for
Mendelian traits, except that genotypes are
only correlated with phenotypes
• In the laboratory, F2, Backcross and RIL
designs are commonly employed to map QTL
• Molecular markers include RFLPs,
Microsatellites, and SNPs
Principle of QTL mapping
+ +
+ +
- +
-
- -
-
+ +
X
-
+
-
112 cm
- +
- -
+ +
-
- -
+ +
+ +
-
94 cm
-
88 cm
-
+ +
-
+ -
- -
100 cm
- +
+ -
+
-
93 cm
-
101 cm
A QTL Profile
QTL Mapping Designs
A. F2 design
X
X
B. BC design
X
C. RIL design
X
X
Types of Molecular Marker
A. Single nucleotide polymorphism
ACCGTTCAGCAGATCAG
TGGCAAGTCGTCTAGTC
ACCGTTCAACAGATCAG
TGGCAAGTTGTCTAGTC
B. Indel Polymorphism
ACCGTTCAGCAGATCAG
TGGCAAGTCGTCTAGTC
ACCGTTCA---GATCAG
TGGCAAGT---CTAGTC
C. Microsatellite polymorphism
ACCGTGTGTGTGTTCAG
TGGCACACACACAAGTC
ACCGTGTGTGTGTGTTCAG
TGGCACACACACACAAGTC
Likelihood Ratio
Likelihood Ratio
Interval Mapping
0
20
40
60
80
Position (cM)
100
0
20
40
60
80
Position (cM)
100
QTN Mapping
• Linkage disequilibrium (LD) mapping uses all of
the recombinational history in a population to
increase the resolution of QTL mapping
• Modern human quantitative genetics utilizes the
HapMap project for Association Mapping
• Different organisms have different LD structure,
so the power of QTL mapping is somewhat
species-specific
• In flies, there is so little LD that genome scans are
precluded; however, resolution may be to the QTN
(Quanitative Trait Nucleotide) level
Principle of LD Mapping
1,000 generations
Genotypes and Haplotypes
Random Polymorphisms
Haplotype Blocks
1
2
A G C A T A T C A G C C
A C A G C A C C A A C T
1
2
A C C G T T C G A G C T
A C C G C A T C A G C T
3
4
T C A G C A C G A G C T
A C C A C T T G T G A T
3
4
T G A A C A T C A G C T
A C C G C A T C T A A C
5
6
A G A G T A T C A G C T
A G C A C A T C A A C C
2
4
A C C G C A T C A G C T
A C C G C A T C T A A C
7
8
A C C G C A T C A G A T
T G C G T T T C A G C T
2
5
A C C G C A T C A G C T
T G A A T T C G A G C T
9
3
T C C A C T T C T G C T
T C A G C A C G A G C T
3
5
T G A A C A T C A G C T
T G A A T T C G A G C T
LD in EGFR
A QTN Profile
5
C1
4.5
30200
4
Significance
5
3.5
3.5
3
2.5
2.5
2
2
1.5
1.5
1
1
0.5
0.5
0
0
W1
5
4.5
Significance
39389
4
3
5
D1
4.5
40110
6065
W9
4.5
4
4
3.5
3.5
3
3
2.5
2.5
2
2
1.5
1.5
1
1
0.5
0.5
0
0
Location of SNP
Location of SNP
Quantitative Genomics
• A collaborative cross has been proposed for
fine-structure mapping of a wide range of
traits in D. melanogaster and D. simulans
• Microarrays have many applications from
modeling the evolution of transcription to
identifying candidate genes for quantitative
traits
• The future lies in network analysis
Gene Expression Among Lines
Adaptation
• The relative roles of genetic drift, selection, mutation,
migration and other evolutionary processes in
biological evolution continue to be debated
• Adaptive walks occur by the successive fixation of
alleles, at least one of which is expected to have a
major effect on the trait
• Soft selection refers to adaptation that starts with
hidden genetic variation whose effect on fitness
appears when the environment changes, whereas hard
selection starts from newly arising mutations
Wright’s Shifting Balance
Phase 1
Phase 2
Phase 3
An Adaptive Walk
A.
B.
C.
Canalization
• Canalization is the evolution of buffering of
physiological or developmental systems.
• Homeostasis is buffering due to the
structure of genetic networks, and/or the
function of biochemical mechanisms
• Canalization allows the build up of cryptic
genetic variation that is available to modify
phenotypes upon genetic or environmental
perturbation
Canalization


Perturbed
population

Phenotype
Frequency
Canalized
population
Fundamental Questions
• What maintains genetic variation in natural
populations?
• Is most quantitative genetic variation due to
common alleles of small effect, or rare
alleles of large effect?
• What is the origin of dominance?
• How pervasive is epistasis, and does it
contribute meaningfully to evolution?