Selective Breeding&

cDNA Microarrays

Toni Reverter 

Bioinformatics GroupCSIRO Livestock Industries

Queensland Bioscience Precinct306 Carmody Rd., St. Lucia, QLD 4067, Australia

Bribie Island – 26-27 July 2004

Applied quantitative genetics in a genomics world

cDNA “A” Cy5 cDNA “B” Cy3

Tissue Samples

Treat A Treat B

mRNA Extraction & Amplification

Hybridization

Laser 1 Laser 2

Optical Scanner

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Image Capture

Analysis

Bribie Island – 26-27 July 2004

Applied quantitative genetics in a genomics worldSelective Breeding & cDNA Microarray

The Process

Bribie Island – 26-27 July 2004

Determine genes which are differentially expressed (DE).

Connect DE genes to sequence databases to search for common upstream regions.

Overlay DE genes on pathway diagrams.

Relate expression levels to other information on cells, e.g. tumor types.

Identify temporal and spatial trends in gene expression.

Seek roles of genes based on patterns of co-regulation.

…Applications to Selective Breeding Schemes?

The Possibilities

Applied quantitative genetics in a genomics worldSelective Breeding & cDNA Microarray

How to relate them?

Bribie Island – 26-27 July 2004

3 Types of Data

Applied quantitative genetics in a genomics worldSelective Breeding & cDNA Microarray

Phenotype+ Pedigree

Phenotype+ Marker

GeneExpression

Applied quantitative genetics in a genomics worldSelective Breeding & cDNA Microarray

Bribie Island – 26-27 July 2004

Phenotype+ Pedigree

Phenotype+ Marker

GeneExpression

eqZuZXβy 21 Mixed-Inheritance Model

Wang, Fernando & Grossman, 1998Many authors and many speciesNB: Segregation Variance Issues

eqZXβy 2 Genetical Genomics

Jansen and Nap, 2001 (arabidopsis)Brem et al, 2002 (yeast)Schadt et al., 2003 (mice)

eWαXβy Dimension Reduction

XΛKWT

21

ˆˆ

TKΛΛX )Cov(Chiaromonte & Matinelli, 2002(leukemia, humans)

Predict Future Performance

Infinitesimal Model

euZXβy 1

Henderson, 1975

2)Var( uAu eqZXβy 2

ANOVA Model

Many authors and many species

egZXβy 3

ANOVA Model

Cui and Churchill, 2003

Applied quantitative genetics in a genomics worldSelective Breeding & cDNA Microarray

Bribie Island – 26-27 July 2004

Use arrays to identify genes that are DE in relevant tissues of individualssorted by QTL genotype. If those DE genes map the chromosome regionOf interest, they would become very strong candidates for QTL.

Source: Jansen and Nap, 2001

Genetical Genomics

Applied quantitative genetics in a genomics worldSelective Breeding & cDNA Microarray

Bribie Island – 26-27 July 2004

Use arrays to identify genes that are DE in relevant tissues of individualssorted by QTL genotype. If those DE genes map the chromosome regionOf interest, they would become very strong candidates for QTL.

Genetical Genomics

For lots of $, this will find lots of genes affecting a trait of interest.…….……Selective Breeding Needs Additivity:

High EBV Low EBV

GeneStarMarblingGenotype

(N Stars/Alleles)

0

1

2

2

1

0

1

2

3

4

5

6

7 8

Applied quantitative genetics in a genomics worldSelective Breeding & cDNA Microarray

Bribie Island – 26-27 July 2004

Use arrays to identify genes that are DE in relevant tissues of individualssorted by QTL genotype. If those DE genes map the chromosome regionOf interest, they would become very strong candidates for QTL.

Genetical Genomics

…………particularly useful for:

1. Speed up and enhance power to finding New QTL

2. Developing “Diagnostic Kits”

3. Deciphering the genetics of Complex Traits

A trait that is affected by many, ofteninteracting, environmental and geneticfactors such that no factor is completelysufficient nor are all factors necessary.

(Andersson and Georges, 2004)Ability to score individuals rapidly (andcheaply) at a very large number of loci.

Never enough! …not greed but algebra:

pqda

pq

2q 2V

Applied quantitative genetics in a genomics worldSelective Breeding & cDNA Microarray

Where does this leave us (Quantitative Geneticists)?Where does this leave Phenotypes (the need to measure)?

Final Thoughts

Very well, ………I’m afraid

Quantitative Geneticists:

Never enough QTL Association studies Study of variation

When QTL not additive, the individual is needed but not so

with BLUP

Phenotypes:

Mutation is continuously generating new variation

Selective breeding on genotypes reduces effective population size

Integration of the 3 types of data

Bribie Island – 26-27 July 2004

Applied quantitative genetics in a genomics worldSelective Breeding & cDNA Microarray References

Bribie Island – 26-27 July 2004

Jansen, R.C. and J.P. Nap (2001) Genetical genomics: the added value fromsegregation. Trend Genet., 17:388-391.

Schadt, E.E., Monks, S.A., Drake, T.A., et al. (2003) Genetics of gene expressionsurveyed in maize, mouse and man. Nature 422:297-302.

Chiaromonte, F., and Martinelli, J. (2002) Dimension reduction strategies foranalysing global gene expression data with a response. Math. Biosciences, 176:123-144.

Cui, X., and G. A. Churchill. (2003) Statistical tests for differential expression incDNA microarray experiments. Genome Biol., 4:210.

Henderson, C.R. (1975) Best linear unbiased estimation and prediction under aselection model. Biometrics, 31:423.

Wang, T., R.L. Fernando, and M. Grossman (1998) Genetic evaluation by best linearunbiased prediction using marker and trait information in a multibreed population.Genetics, 148:507-515.

Brem, R.B., G. Yvert, R. Clinton, and L. Kruglyak. (2002) Genetic dissection oftranscriptional regulation in budding yeast. Science 296:752-755.

Andersson, L. and Georges (2004) Domestic-animal genomics: deciphering thegenetics of complex traits. Nature Reviews 5:202-212.