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Lecture 24: Genetic Bases of Quantitative Traits
November 26, 2012
Last Time
Recombination and LD
Drift and LD
Mutation and LD
Selection and LD
Hitchhiking and selective sweeps
Some factors that affect LD
Factor Effect
Recombination rate Higher recombination lowers LD
Genetic Drift Increases LD
Inbreeding Increases LD
Mutation rate High mutation rate decreases overall LD,
Epistasis Increases LD
Selection Locally increased LD
Why Do African Populations have Lower LD than Caucasian and Asian Populations?
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 50,000 100,000 150,000Distance (bp)
Mea
n |D
'|
CaucasianAfrican-AmericanAsianYoruban
Figure from K. Ritland
LD Provides evidence of recent selection
Voight et al. 2006 Plos Biology 4: 446-458
Regions under recent selection experience selective sweep, show high LD locally
Patterns of LD in human genome provide signature of selection:
ratio of LD decay of ancestral versus derived alleles (iHS)
Signatures of selection across the entire genome!
Today
Quantitative traits
Linking phenotype to genotype
QTL analysis Association Genetics
Quantitative trait
16 64 76 88 28 40 52 Height
Mendelian trait Individual
10 9 8 7 6 5 4 3 2 1
12 11 22 22 11 22 12 11 22 12 Genotype =
Allele A1
Allele A2
Courtesy of Glenn Howe
Quantitative traits are polygenic
Blakeslee 1914
50 55 60 65 70 75 80 850
1
2
3
4
5
6
7x 10
4
As the number of loci controlling a trait
increases, the distribution of trait
values in a population becomes bell-shaped
Hartl and Clark 2007
3 loci, 2 additive alleles
Uppercase alleles contribute 1 unit to phenotype (e.g., shade of color)
Hartl, D. 1987. A primer of Population Genetics.
Expected Number of Genotypes Determined by combining expected numbers by locus. Assuming equal allele frequencies and random mating:
=⎟⎠
⎞⎜⎝
⎛ ++⎟⎠
⎞⎜⎝
⎛ ++ bbBbBBaaAaAA41
21
41
41
21
41
aabbaaBbaaBBAabbAaBb
AaBBAAbbAABbAABB
161
81
161
81
41
81
161
81
161
++++
++++
Number of genotypic classes (G) for n biallelic loci:
What will determine phenotypic ratios?
nG 3=
Environmental Effects on Quantitative traits
2 loci, 2 alleles affecting pigment
Phenotypic classes broaden due to environmental variation
Mean = 67 ± 2.7 in.
Mean = 70 ± 3 in.
Blakeslee 1914
Strausbaugh 1996
Schilling et al. 2002. Amer. Stat. 56: 223-229
Influence of Environment on Human Height
By Country Height vs GDP (1925-1949)
Baten 2006
By Gross Domestic Product
Environment
+
Phenotype
=
Genotype
The phenotype is the outward manifestation of the genotype
σ2P σ2
E σ2G
Courtesy of Glenn Howe
Types of genetic variance (σ2G)
Additive (σ2A): effects of individual alleles
Dominance (σ2D): effects of allele
interactions within locus
Interaction (σ2I): effects of interactions
among loci (epistasis)
σ2G = σ2
A + σ2D + σ2
I
Non-additive
Main cause for resemblance between relatives
Heritability Phenotype vs Genotype
Var(phenotype) = Var(genotype) + Var(environment)
Heritability: Var(genotype) / Var(phenotype)
Two types of heritability
Broad-Sense Heritability includes all genetic effects: dominance, epistasis, and additivity
− For example, the degree to which clones or monozygotic twins have the same phenotype
Narrow-Sense Heritability includes only additive effects
− For example, degree to which offspring resemble their parents
Heritability (continued) Characteristic of a trait measured in a particular population
in a particular environment
Best estimated in experiments (controlled environments)
Estimated from resemblance between relatives
The higher the heritability, the better the prediction of genotype from phenotype (and vice versa)
h² = 0.1 h² = 0.5 h² = 0.9
http://psych.colorado.edu/~carey/hgss/hgssapplets/heritability/heritability1/heritability1.html
P P P
G G G
Narrow-Sense Heritability of some Common Traits
Har
tl a
nd C
lark
200
7
Nar
row
-Sen
se H
erita
bilit
y
Traits related to fitness tend to have low heritability
Why might that be?
Humans
Effect of Genetic Variation on Heritability
Traits near fixation have low variation
Low heritability due to small numerator?
H 2 =!G2
! P2
Identifying Genes Underlying Quantitative Traits Many individual loci are responsible for
quantitative traits, even those with high heritability
Identification of these loci is a major goal of breeding programs
Allows mechanistic understanding of adaptive variation
Methods usually rely on correlations between molecular marker polymorphisms and phenotypes
Quantitative Trait Locus Mapping
HEIG
HT
GENOTYPE BB Bb bb
♦ ♦
♦ ♦ ♦
♦ ♦ ♦
♦
modified from D. Neale
a b c
A B C
ABC
Parent 1 Parent 2
X a b c
F1 F1
X A B C
a b c
A B C
a b c
ABc
a B c
a B c
A b c
A B c
a B c
A b c
A b c
a b c
A b c
A B C
A B c
A b c
a B c
a B c
A b c
a B c
a B c
B b
Bb BB BB BB bb bb BB Bb Bb
Quantitative Trait Locus Analysis
Step 1: Make a controlled cross to create a large family (or a collection of families)
Parents should differ for phenotypes of interest Segregation of trait in the progeny
Step 2: Create a genetic map
Large number of markers phenotyped for all progeny
Step 3: Measure phenotypes
Need phenotypes with high heritability
Step 1: Construct Pedigree Cross two individuals with
contrasting characteristics
Create population with segregating traits
Ideally: inbred parents crossed to produce F1s, which are intercrossed to produce F2s
Recombinant Inbred Lines created by repeated intercrossing
Allows precise phenotyping, isolation of allelic effects
Grisel 2000 Alchohol Research & Health 24:169
Step 2: Construct Genetic Map Number of recombinations
between markers is a function of map distance
Gives overview of structure of entire genome
Anonymous markers are cheap and efficient: AFLP
Codominant markers much more informative: SSR, SNP
Genotyping by Sequencing gives best of both worlds: cheap, abundant, codominant markers!
Step 3: Determine Phenotypes of Offspring
Phenotype must be segregating in pedigree
Must differentiate genotype and environment effects
How? Works best with phenotypes
with high heritability
0.1
0.5
0.9
Step 4: Detect Associations between Markers and Phenotypes Single-marker associations are
simplest
Simple ANOVA, correcting for multiple comparisons
Log likelihood ratio: LOD (Log10 of odds)
If QTL is between two markers, situation more complex
Recombination between QTL and markers (genotype doesn't predict phenotype)
'Ghost' QTL due to adjacent QTL
Use interval mapping or composite interval mapping
Simultaneously consider pairs of loci across the genome
LOD = log10Pr(Data |QTL)Pr(Data | noQTL)
Step 5: Identify underlying molecular mechanisms
QTG: Quantitative Trait Gene
QTN: Quantitative Trait Nucleotide
chromosome
Genetic Marker
Adapted from Richard Mott, Wellcome Trust Center for Human Genetics
QTL
QTL Limitations
Huge regions of genome underly QTL, usually hundreds of genes
How to distinguish among candidates?
Biased toward detection of large-effect loci
Need very large pedigrees to do this properly
Limited genetic base: QTL may only apply to the two individuals in the cross!
Genotype x Environment interactions rampant: some QTL only appear in certain environments
QTL Vary by Year, Site, and Population Loblolly pine QTL measured in different years at same site, in
different sites, and with a different genetic background Stippled: not repeated across years
wood-specific gravity
% latewood
Brown et al
Environmental Variation in Maize QTL
Different components of Maize grain yield measured in 7 field experiments in Mexico and Zimbabwe under well-watered (ww) and water-stressed (ws) conditions Shading is proportional to degree of overlap in QTL
among
Poor correspondence between environments and conditions for major QTL controlling yield traits same family
Messmer et al. 2009, Theoret and Appl Genet. 119: 913-930