Genome-tagged mice to identify behavior genes

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DESCRIPTION (provided by applicant): Understanding the genetics of behavior remains a difficult problem with important practical implications. To facilitate mapping of behavioral traits, we have employed genome-tagged mice (GTMs). These overlapping sets of "speed" congenic mouse strains span the whole genome and offer the possibilities of superior mapping power and reproducibility. We investigated 4 GTM strains from a set of 60 consisting of ~23 cM DBA/2J genomic intervals introgressed onto a C57BL/6J background. These 4 strains were chosen because the corresponding genomic regions had been identified from complex trait mapping as containing loci for learning and memory. The analysis using the GTMs confirmed the presence of learning and memory loci and fine mapped 1 locus on chromosome 3 to an 8.8 cM region. Loci for behaviors related to sensorimotor gating, anxiety, depression and pain sensitivity were also localized using a battery of tests. In this proposal, we describe 2 specific aims. (1) The first aim is to identify the chromosome 3 learning and memory locus. (i) High resolution F2 mapping will use the relevant GTMs as parental strains. The resulting simplification of genetic background should provide excellent mapping power. (ii) For additional fine mapping of the locus, subcongenic strains will be constructed using marker assisted breeding. (iii) Expression profiling of the hippocampus from selected congenic strains will be employed to facilitate positional cloning of the locus. (iv) Bioinformatics study of the 8.8 cM critical region will help identify candidate alleles. (v) Transgenic studies will confirm the identity of the responsible mutation. (2) The second aim is to analyze the entire set of GTMs using the battery of behavioral tests and localize additional loci of interest genome-wide.