Identifying candidate genes for blood pressure quantitative trait loci using differential gene expression and a panel of congenic strains

The most difficult step in dissecting the molecular basis of a quantitative trait is proceeding from chromosomal locations associated with this trait (i.e., quantitative trait locus, QTL) to determining what gene(s) in the QT L region is causative. Using standard positional cloning methodology to ide ntify candidate genes for a particular QTL has three drawbacks: 1) it is la bor intensive; 2) defining variants in genes causing quantitative variation from sequence information alone is difficult or impossible; and 3) many (o r most) genes in a particular chromosomal interval will not be relevant for a specific disease/trait because they are not expressed in critical candid ate organs. Instead of positional cloning, we propose using a panel of cong enic strains, where each carries an allele for a different QTL on a similar genetic background, in conjunction with identification of differentially-e xpressed genes in target organs of inbred strains of contrasting phenotype. This will identify genes having altered expression in organs critical to r egulating blood pressure and the development of hypertension. Radiation hyb rid mapping of such genes will result in a transcription map of differentia lly expressed genes in a target organ of a rat model of genetic hypertensio n. This approach could rapidly identify genes mapping to genomic regions ne ar QTL, which will be strong candidates to explain, in part, the observed s train differences in blood pressure. This novel approach, which uses a pane l of congenic strains to facilitate the mapping and subsequent identificati on of differentially-expressed and QTL-associated genes, should be applicab le to any genetic model for identifying candidate genes located near QTL, g iven the availability of a panel of congenic strains.