The physical and functional mapping of a blood pressure quantitative trait locus on rat chromosome 1
The aim of the studies presented in this thesis was to investigate the blood pressure (BP) quantitative trait locus (QTL) identified on rat chromosome 1 in a cross of the spontaneously hypertensive rat (SHR) and Wistar Kyoto (WKY) rat, and isolated in reciprocal congenic strains derived from the SHR and WKY.;Complementary strategies were employed to define the mechanism of the BP QTL effect, refine its genomic location and identify strong candidate genes located within the relevant chromosomal region. A kidney transplantation experiment demonstrated that the BP effect of the QTL could be physically 'carried' over with the graft, as the normotensive WKY recipients of kidneys from the hypertensive WConSa congenic donors developed significantly higher BP. This result implies that the BP QTL mediates its BP via renal genetic factors. A gene profiling experiment was carried out using a specifically constructed cDNA microarray containing 615 probes from genes and expression sequence tags known to be located within the congenic region. Comparison of expression profiles of SHR, WKY and congenic strain kidneys identified 13 differentially expressed genes which may imply a role for renal sodium transport and fatty acid metabolism pathways in the BP effect of the QTL. An overlapping YAC and BAC contig map of the WConSa BP QTL region was produced, to provide a useful resource for filling in gaps not covered by the Rat Genome Sequence and identifying gene and DNA marker locations. New subcongenic strains derived from the Sisal congenic strain were constructed (Sisa3), using polymorphic markers tested and confirmed as residing within the QTL region. The Sisa3 strains refined the genomic location of the BP QTL from a 3-5cM area to a region half its original size and reduced the number of potential candidate genes to 30.