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Director: Robert Hitzemann
Co-Directors: John Belknap, Kari Buck, Tamara Phillips

This component implements a high throughput strategy for the detection of quantitative trait genes (QTGs) associated with ethanol preference. The preference phenotype under investigation is identical to that used in component 5 and used during past years of PARC funding.

The proposed research strategy integrates several different experimental approaches; these include multiple cross mapping, fine mapping in heterogenous stock animals, the integration of QTL analysis and functional genomics, the use of short term selective breeding to confirm QTLs and follow gene segregation and QTL confirmation in BAC transgenic mice.

The component has five specific aims:

1. To fine map in heterogeneous stock (HS) animals (to a resolution of 1 cM or less) known QTLs for ethanol preference (two-bottle choice).
2. To determine which genes within the QTL interval (aim 1) show the genotype x phenotype appropriate expression pattern.
3. To integrate short-term selective breeding (STSB) in HS animals and gene expression analysis.
4. To determine which genes within the QTL interval are cis-regulated.
5. To use all available strategies to provide additional proof of QTL -> QTG (see Belknap et al. 2001).

We first suggested an integrated analysis strategy in Belknap et al. (2001) and Phillips et al. (2001). This strategy was developed as part of the PARC effort to move past QTL detection to the detection of QTGs. The strategy emphasized the importance of new advances in gene expression analysis, the completion of sequencing multiple mouse genomes and the ability to integrate these data through bioinformatics.

The initial "proof of principle" for the integrated strategy is found in Hitzemann et al. (2003, 2004). This component interacts strongly with research components 5 and 6, both of which also focus on the detection of QTGs. However, there will also be substantial interaction with Component 8 as the STSB lines (Aim 3) will be tested for impulsivity. This Component also makes substantial use of Components 2-4 for the proposed studies.

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by Mark Rutledge-Gorman
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