Applicability of a “Speed” Congenic Strategy to Dissect Blood Pressure Quantitative Trait Loci on Rat Chromosome 2

Abstract

Abstract —The identification of any quantitative trait locus (QTL) via a genome scan is only the first step toward the ultimate goal of gene identification. The next step is the production of congenic strains by which the existence of a QTL may be verified and the implicated chromosomal region be reduced to a size applicable to positional cloning of the causal gene. We used a speed congenic breeding protocol previously verified in mice for 2 blood pressure QTLs on rat chromosome 2. Four congenic strains were produced through introgression of various segments of chromosome 2 from Wistar-Kyoto rats from Glasgow colonies [WKY (Gla) rats] into the recipient stroke-prone spontaneously hypertensive rats from Glasgow colonies [SHRSP (Gla) ], and vice versa. The number of backcross generations required for each strain to achieve complete homozygosity at 83 background genetic markers in a “best” male varied between 3 and 4. Transfer of the region of rat chromosome 2 containing both QTLs from WKY (Gla) into an SHRSP (Gla) genetic background lowered both baseline and salt-loaded systolic blood pressure by ≈20 and ≈40 mm Hg in male congenic rats compared with the SHRSP parental strain ( F =53.4, P <0.005; F =28.0, P < 0.0005, respectively). In contrast, control animals for stowaway heterozygosity presented no deviation from the blood pressure values recorded for the SHRSP (Gla) , indicating that if such heterozygosity exists, its effect on blood pressure is negligible. A reciprocal strategy in which 1 or both QTLs on rat chromosome 2 were transferred from SHRSP (Gla) into a WKY (Gla) genetic background resulted in statistically significant but smaller blood pressure increases for 1 of these QTLs. These results confirm the existence of blood pressure QTLs on rat chromosome 2 and demonstrate the applicability of a speed congenic strategy in the rat and emphasize the important role of the genetic background.