Genetic dissection of region around the Sa gene on rat chromosome 1 - Evidence for multiple loci affecting blood pressure

A region with a major effect on blood pressure (BP) is located on rat chrom osome 1 in the vicinity of the Sa gene, a candidate gene for BP regulation. Previously, we observed a single linkage peak for BP in this region in sec ond filial generation rats derived from a cross of the spontaneously hypert ensive rat (SHR) with the Wistar-Kyoto rat (WKY), and we have reported the isolation of the region containing the BP effect in reciprocal congenic str ains (WKY.SHR-Sa) and (SHR.WKY-Sa) derived from these animals. Here, we rep ort the further genetic dissection of this region. Two congenic substrains each were derived from WKY.SHR-Sa (WISA1 and WISA2) and SHR.WKY-Sa (SISA1 a nd SISA2) by backcrossing to WKY and SHR, respectively. Although there was some overlap of the introgressed regions retained in the various substrains , the segments in WISA1 and SISA1 did not overlap. Furthermore, although th e Sa allele in WISA1, WISA2, and SISA2 remained donor in origin, recombinat ion in SISA1 reverted it back to the recipient (SHR) allele. Surprisingly, all 4 substrains demonstrated a highly significant BP difference compared w ith that of their respective parental strain, which was of a magnitude simi lar to those seen in the original congenic strains. The findings strongly i ndicate that there are at least 2 quantitative trait loci (QTLs) affecting BP in this region of rat chromosome 1. Furthermore, the BP effect seen in S ISA1 indicates that at least a proportion of the BP effect of this region o f rat chromosome 1 cannot be due to the Sa gene. SISA1 contains an introgre ssed segment of <3 cM, and this will facilitate the physical mapping of the BP QTL(s) located within it and the identification of the susceptibility-c onferring genes. Our observations serve to illustrate the complexity of QTL dissection and the care needed to interpret findings from congenic studies .