Genetic basis and analysis of quantitative traits

Mapping quantitative trait loci (QTL) – genetic architecture

Fine-mapping and cloning – molecular basis

1. What is the genetic architecture and molecular basis of phenotypic variation in natural populations?

2. Why is there phenotypic variation in natural populations?

Phenotype (P) = Genotype (G) + Environment (E)

Phenotypic variation – mutation & selection

Correlate genotype with phenotype

1. Linkage mapping -QTL mapping-family data

2. Linkage disequilibrium-association study-population data

Mapping quantitative trait loci

A/aVar(E) = 1

A = 0; a = 10Var(G) = 25

A = 0; a = 0.1Var(G) = 0.1

A = 0; a = 1Var(G) = 1.0

QTL mapping

QTL mapping

i=abgiei

LOD=log10L a , b , 2/L A ,0, B1

2

For single markers: LOD scores are confounded with the effect size

Interval mapping: Lander and Botstein 1989

Tight linkage or large effect Weak linkage or small effect

La ,b , 2=∏

i[Gi0Li0Gi 1 Li 1]

LOD Thresholds for Significance

Sample size for interval mapping

Molecular basis of quantitative traits

QTL mapping

AssociationFine-mapping

Quantitative complementationReciprocal hemizygosity

Model organism resources

Fine-mapping

Fine-mapping

Quantitative complementation(addition or subtraction)

*

*

Addition (plasmid, transposon) Subtraction (deficiency, mutation)

*

( )( )

( )

( )

Quantitative complementation(deficiency mapping)

Deficiency mapping

Deficiency mapping

Reciprocal hemizygosity

Bristle Number in Fruit flies: A model for quantitative traits

ST = sternopleural bristlesSC = scutellar bristlesAB = abdominal bristles

(apparent) Stabilizing selection on bristle number

Quantitative traits response to selection

Selection on bristle number

Linkage versus linkage disequilibrium

In a single generation (meiosis-family):Probability of no recombination = (1-θ)n

In two generations:Probability of no recombination = (1-θ)2n

In t generations:Probability of no recombination = (1-θ)nt

B1/B

2

A1/A

2

Haplotype Frequency A1B1 x11

A1B2 x12

A2B1 x21

A2B2 x22

Allele Frequency A1 p1 = x11 + x12

A2 p2 = x21 + x22

B1 q1 = x11 + x21

B2 q2 = x12 + x22

Linkage Disequilibrium

D = x11 - p1 q1

correlation coefficient r = D

p1 p2q1q2B

1/B

2

A1/A

2

Decay of linkage disequilibrium

Linkage versus association

Genetic variance (population) is a function of allele frequency

Linkage disequilibrium

Lai et al (1994)

Molecular Quantitative Genetics: Sporulation in Yeast

Molecular Quantitative Genetics: Sporulation in Yeast

Deutschbauer and Davis (2005)RME1 – 1bp insertion in a mononucleotide repeat, noncodingTAO3 – missenseMKT1 – missense92% of variation explained

Reciprocal Hemizygosity TestsAllele-Replacements

Quantitative Trait Nucleotide Frequencies

Genetic Interactions AmongQuantitative Trait Nucleotides

Molecular Quantitative Genetics: Sporulation in Yeast

Deutschbauer and Davis (2005)RME1 – 1bp insertion in a repeat, noncodingTAO3 – missenseMKT1 – missense92% of variation explained

Ben-Ari et al (2006)RAS2 – 1bp insertion in repeat, noncodingPMS1SWS2FKH260 kb region on Chr14

Gerke et al (2009)RME1 – 1bp insertion in a repeat, noncodingIME1 – missense and noncodingRSF1 – missense80-90% variation explained

RME1 – Regulator of meiosis, TF represses IME1.

IME1 – Inducer of meiosis, TF.

RSF1 – Respiration factor, mediates transition to respiratory growth.

TAO3 – Transcriptional activator, involved in polarized morphogenesis.

MKT1 – Maintenance of K2 killer toxin.

RAS2 – GTP binding protein that regulates nitrogen starvation response, sporulation, filamentous growth.

PMS1 – ATP binding protein required for mismatch repair.

SWS2 – mitochondrial ribosomal protein of the small subunit.

FKH2 – Forkhead TF, regulates G2/M phase genes, silencing and transcriptional elongation.

Linkage versus association

Method Frequency Effect size

Linkage rare large

Association common small