International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

E13 Characterisation of a Rat Chromosome 7 Blood Pressure/Cardiac Mass Quantitative Trait Locus using Congenic Substrains

George T. Cicila, Michael R. Garrett, Oksana Dukhanina, Howard Dene, Jun Liu, Soon Jin Lee, and John P. Rapp. Department of Physiology and Molecular Medicine, Medical College of Ohio, Toledo, OH, USA

Blood pressure is a quantitative trait that shows continuous variation, from low to high values in the individuals that comprise outbred populations of humans or animals. As with most quantitative traits, differences in blood pressure result from the contributions of many genes (i.e., is a polygenic trait) interacting with each other and the environment. The inbred Dahl salt-sensitive (S) rat is the most widely-studied genetic model of salt-sensitive hypertension. In this strain supplemental dietary NaCl increases blood pressure whereas in the Dahl salt-resistant (R) strain, supplemental dietary NaCl has little or no effect. Dahl S rats are also genetically-hypertensive, developing high blood pressures over time, even when maintained on low or normal levels of dietary NaCl. Segregating populations and congenic strains derived from these inbred strains can be used to screen for (and confirm) genes leading to heritable differences in blood pressure as well as genes underlying the gene x environment (dietary NaCl intake) interactions responsible for blood pressure salt-sensitivity and salt-resistance.

11ß-hydroxylase (Cyp11b1), located on rat chromosome 7, was the first gene where coding sequence mutations were linked to 1) blood pressure and 2) an altered protein activity that could logically affect blood pressure in an animal model of genetic hypertension. Additional blood pressure QTL in the inbred Dahl S rat model were identified using both candidate gene and genome scanning approaches on 12 rat chromosomes. This putative rat chromosome 7 QTL was confirmed by introgressing the low blood pressure QTL allele from the normotensive strain into the S strain, creating a congenic strain, S.R-Cyp11b, with lower blood pressure and cardiac mass compared to the S strain.

Congenic substrains were developed so that strains could be identified that carried low blood pressure QTL alleles in progressively smaller introgressed chromosomal segments. Male rats from each congenic substrain (n =20) and an equal number of male S rats were studied simultaneously. 37-day old rats were maintained on a 2% NaCl diet for 24 days at which time systolic blood pressure, heart weight, and body weight were determined. These congenic substrains for S.R-Cyp11b localized the rat chromosome 7 blood pressure/cardiac QTL to a 0.7 cM region. This chromosomal region harboring the blood pressure/cardiac mass QTL is defined by the overlap between the introgressed regions of R-rat derived chromosome carried by the Cyp11bx4 and Cyp11bx5 congenic substrains. These substrains, which contain a <0.7 cM region of introgressed R-rat derived chromosome in common, both had significantly lower blood pressure and cardiac mass compared to the parental S strain. The simplest interpretation of this data is that the gene(s) responsible for the chromosome 7 blood pressure/cardiac mass QTL lie in the region of R-derived chromosome 7 common to these two substrains.

11ß-hydroxylase remains a candidate gene for the blood pressure/cardiac mass QTL because all congenic strains having significantly lower blood pressure and cardiac mass, also have the significantly decreased adrenal capacity to synthesize the mineralocorticoid 18-hydroxy-deoxycorticosterone associated with the R-rat 11ß-hydroxylase allele, compared to the S-rat allele. Furthermore, results with the Cyp11bx4 congenic substrain suggest that the tightly-linked and homologous gene, aldosterone synthase, is not a candidate. This is because while the Cyp11bx4 strain has significantly lower blood pressure and heart weight compared to the parental S strain and carries the R-rat allele for 11ß-hydroxylase, it also carries the S-rat allele for aldosterone synthase.

 


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