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

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0.5

0.6

0.7

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0.9

1

0 50,000 100,000 150,000Distance (bp)

Mea

n |D

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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

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AaBBAAbbAABbAABB

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++++

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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

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  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

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a b c

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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