Characterization of a 793 Kilobase Segment of the Rat Genome in Blood Pressure Regulation
The etiology of essential hypertension (EH) is greatly impacted by individual genetic constitution. This provides the rationale to identify genes that have a role in BP regulation. Human studies are confounded by genetic heterogeneity making it difficult to conclusively identify the underlying genetic causes of EH. Alternatively, by using homozygous inbred rat strains, genetic variability and environmental influences are minimized. The Dahl salt-sensitive (S) and Lewis (LEW) inbred rat strains differ in their susceptibility to hypertension. To identify the genomic region accounting for the contrasting BP phenotype, congenic strains (S.LEW) was generated and tested for BP. S.LEW refers to the incorporation of a segment of the LEW rat genome (normotensive donor strain) into the S rat (hypertensive recipient strain) genetic background. The presence of LEW alleles lowered BP significantly in two S.LEW congenic rat strains compared to the S. These results implicate a locus on rat chromosome 1, spanning 793 kilobases (Kb), in BP regulation. This research has focused on identifying and characterizing the genetic differences between S and LEW within this region. This has been accomplished by 1) Fine resolution substitution mapping: Screening a large F2 population (n=2652) for meiotic recombination, within the 793 Kb interval, resulted in three congenic substrains: S.LEW(D1MCO4X1X3BX1X1), S.LEW(D1MCO4X1X3BX1X2 ) and S.LEW(D1MCO4X1X3BX2X1). BP measurements of these strains are anticipated to provide in vivo evidence for the further localization of crucial BP regulating segments. 2) Characterizing coding sequence variations: Coding sequence analysis of the two predicted genes within the 793 Kb region revealed two naturally occurring amino acid changes in LOC306664 (Adamts16) between S and LEW and 3) Utilizing in silico analysis to detection segments within the 793 Kb region that contain regulatory elements and noncoding conserved sequences which do not encode for protein. The identification of genetic elements controlling BP can open new avenues for the treatment and management of EH.
School:University of Toledo Health Science Campus
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:blood pressure hypertension genetics rat models quantitative traits essential
Date of Publication:01/01/2007