Applicability of a "speed" congenic strategy to dissect blood pressure quantitative trait loci on rat chromosome 2.
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 approximately 20 and approximately 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.
Jeffs
B
B
Department of Medicine and Therapeutics, University of Glasgow, Western Infirmary, Glasgow, UK. anna.dominiczak@clinmed.gla.ac.uk
Negrin
C D
CD
Graham
D
D
Clark
J S
JS
Anderson
N H
NH
Gauguier
D
D
Dominiczak
A F
AF
D000818:Animals; D001794:Blood Pressure / Q000235:genetics*; D002874:Chromosome Mapping; D002940:Circadian Rhythm; D004276:DNA, Satellite / Q000032:analysis; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006720:Homozygote; D006973:Hypertension / Q000235:genetics*; D008297:Male; D019655:Quantitative Trait, Heritable; D051381:Rats; D011918:Rats, Inbred SHR / Q000235:genetics*; D011921:Rats, Inbred WKY; D013045:Species Specificity; D020521:Stroke / Q000235:genetics
D004276:DNA, Satellite; D005819:Genetic Markers