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From QTL to QTG: Are we getting closer? Sagiv Shifman and Ariel Darvasi. The Hebrew University of Jerusalem. Presentation Outline. Overview of fine QTL mapping strategies Inbred strain sequence/haplotype information for fine QTL mapping

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From qtl to qtg are we getting closer sagiv shifman and ariel darvasi l.jpg

From QTL to QTG: Are we getting closer?Sagiv Shifman and Ariel Darvasi

The Hebrew University of Jerusalem


Presentation outline l.jpg
Presentation Outline

  • Overview of fine QTL mapping strategies

  • Inbred strain sequence/haplotype information for fine QTL mapping

  • Yin-Yang crosses: A framework for applying inbred strain sequence/haplotype information to fine map QTLs

  • Simulation analysis using Celera’s sequence information of 4 inbred strains (C57, A/J, DBA, 129)


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The Difficulties

  • Genetics

    • Genotype/phenotype correlation

    • Recombination

  • Functional

    • The “end-game” (knockout, transgenic, mutation analysis, RNAi, etc.)


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Fine Mapping Strategies

Genomewide-based strategies:

  • Large scale BC, F2, half sibs, etc.

  • Advanced Intercross Lines (AIL)

  • The heterogeneous stock (HS)

    Locus-based strategies:

  • Selective phenotyping

  • Recombinant progeny testing

  • Interval specific congenic strains (ISCS)

  • Recombinant inbred segregation test (RIST)



Slide6 l.jpg

Ft

F1

F2

F3

P

Advanced intercross lines (AIL)

Semi-random intercrossing

CI = CIF2 / (t/2)


Slide7 l.jpg

AIL - experimental results

HDL – QTL

Wang et al. 2003


The heterogeneous stock hs l.jpg
The heterogeneous stock (HS)

Eight-way cross of:

C57BL/6, BALB/C, RIII, AKR, DBA/2, I, A/J C3H

Established 30 years ago (~60 generations)

by

McClearn et al.


Hs experimental results l.jpg
HS - Experimental results

Open field activity

Talbot et al. 1999

0 0.2 0.4 0.6 0.8 1.0 1.2 1.4

cM


Locus based strategies selective phenotyping sph l.jpg
Locus-based strategies:Selective phenotyping (SPh)

  • Theoretical basis: Only recombinants increase mapping accuracy for a detected QTL.

  • Procedure: Only individuals recombinant at a QTL-containing interval are subsequently phenotyped.


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SPh - Experimental results

Lesions density

Paigen et al.

BC

SPh-BC


Recombinant progeny testing l.jpg

QTL

Recombinant progeny testing

Males, recombinant at an interval of interest, are progeny

tested to check which QTL allele was retained.


Interval specific congenic strains iscs l.jpg

QTL

Interval specific congenic strains (ISCS)

ISCS are produced by a series of backcrosses and intercrosses


Recombinant inbred segregation test rist l.jpg
Recombinant inbred segregation test (RIST)

P1

RI P2

QTL

x

x

F1,1

F1,2

F2,1

F2,2


Rist experimental results l.jpg
RIST - Experimental results

D2MIT64

Obesity QTL

B. Taylor

A. Darvasi

D2MIT200

C57L

AKXL-16

AKR

F21

F22

P=0.02

P=0.41


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In silico mapping of complex disease-related traits in mice

Grupe et al. 2001

Comment:

Chesler et al. 2001

Darvasi 2001


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Genome-wide single-nucleotide polymorphism analysis defines haplotype patterns in mouse

Wiltshire et al. 2003

Unexpected complexity in the haplotypes of commonly used inbred strains of laboratory mice

Yalcin et al. 2004

Multiple Cross and Inbred Strain Haplotype Mapping of Complex-Trait Candidate Genes

Park et al. 2003


Yin yang crosses a framework for multiple cross inbred strain haplotype mapping l.jpg
Yin-Yang Crosses : A framework for Multiple Cross Inbred Strain Haplotype Mapping

QTL detection with two inbred lines (P1 and P2)

Estimating QTL map location

Sequence based fine mapping

Selecting an optimal new inbred strain (Pi)

Yin-Yang crosses


Qtl mapped in a axb cross l.jpg
QTL mapped in a AxB cross Strain Haplotype Mapping

A

B


Sequence haplotype information l.jpg
Sequence/Haplotype Information Strain Haplotype Mapping

A

B


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Yin-Yang Crosses Strain Haplotype Mapping

A

C

B


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Simulation Analysis Strain Haplotype Mapping

  • Initial cross between A/JxC57

  • 22,814 SNPs, each at its turn, simulated as the QTN

  • The strain closest to being half similar to A/J and half to C57 was selected first for Yin-Yang crosses (DBA or 129)

  • The forth strain was subsequently introduced

  • At each stage the number of the remaining SNPs that can be the QTN, and the size of the QTL containing interval were estimated


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2 strains Strain Haplotype Mapping

3 strains

4 strains

Mapping Resolution: Chromosome 16


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Low resolution region Strain Haplotype Mapping

High resolution region


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Mean Reduction in Interval Length Strain Haplotype Mapping


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Distribution of Mapping Resolution with 4 Inbred Strains Strain Haplotype Mapping

Proportion

Interval length


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Conclusions Strain Haplotype Mapping

  • Using inbred strain sequence/haplotype information combined with multiple crosses (Yin-Yang crosses) can efficiently aid QTL fine mapping

  • With 4 strains most regions exhibit modest mapping resolution.

  • The significant haplotype variation observed in 4 strains may suggest that with a large number of strains in hand significant resolution can be achieved.

  • With sequence information in hand, resolution maps and algorithms can be established to guide the researchers to the optimal strain selection strategy and provide the resolution expected for their region of interest.

  • A large number of sequenced strains will allow the actual selection of a very small number of strains for additional crosses.


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So, Do We Need the 1K RI Set? Strain Haplotype Mapping

YES

Until we have the 1K RI set any QTL mapping strategy is like riding a bike: it’s fun and we can get very far –

Once we get something with an engine though, we will feel the difference!

… we are still missing an engine for the “end-game” – Genetics is not everything