1

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

2

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

4

QTL mapping

�i=a�bgi�ei

LOD=log10�L� �a , �b , ��2�/L� ��A ,0, ��B1

2 ��

5

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

L�a ,b ,� 2�=�i

[Gi�0�Li�0��Gi �1� Li �1�]

6

LOD Thresholds for Significance

7

Sample size for interval mapping

8

Molecular basis of quantitative traits

QTL mapping

AssociationFine-mapping

Quantitative complementationReciprocal hemizygosity

9

Model organism resources

10

Fine-mapping

11

Fine-mapping

12

Quantitative complementation(addition or subtraction)

*

*

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

*

( )

( )

( )

( )

13

Quantitative complementation(deficiency mapping)

15

Deficiency mapping

18

(apparent) Stabilizing selection on bristle number

22

Linkage versus linkage disequilibrium

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

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

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

B1/B

2

A1/A

2

23

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 p2q1q2�B

1/B

2

A1/A

2

25

Linkage versus association

29

Molecular Quantitative Genetics: Sporulation in Yeast

31

Reciprocal Hemizygosity TestsAllele-Replacements

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Quantitative Trait Nucleotide Frequencies

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Genetic Interactions AmongQuantitative Trait Nucleotides

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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.

35

Linkage versus association

Method Frequency Effect size

Linkage rare large

Association common small