FINE GENETIC MAPPING OF BLOOD PRESSURE QTL

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The overall objective of my work is to identify the quantitative trait loci (QTL) controlling blood pressure in the rat. A paradigm for doing this has the following components: (a) identify genetic markers that cosegregate with blood pressure in the rat; (b) develop linkage maps at a resolution of 5-10 centiMorgans (cM) for the rat chromosomal regions involved in order to obtain a crude localization of the blood pressure QTL by interval mapping; (c) produce congenic strains for each low-blood- pressure QTL allele on the genetic background of the inbred Dahl salt- hypertension sensitive (S) rat; d) develop rat linkage maps at a resolution of 1-2 cM for QTL-containing chromosomal regions; e) refine the genetic mapping of blood pressure QTL by substituting progressively smaller and smaller regions of chromosome containing the low-blood- pressure QTL allele on the S genetic background; f) and ultimately prepare physical maps for at least one such QTL region and attempt positional cloning. The present proposal concentrates on the production of dense genetic maps and the production of congenic strains for blood pressure QTL on rat chromosomes 1, 2 and 10, and the production of congenic substrains for fine genetic mapping of the blood pressure QTL on these chromosomes. Preparation of first order maps and localization of the blood pressure QTL on chromosomes 9 and 13 are also proposed. A full genome scan of an population derived from S and Lewis rats will be performed to complete the description of this particularly informative cross which has so far yielded four blood pressure QTL accounting for 105 mmHg. The proposed studies are important because they will: (a) provide genetic markers that can be used to study genetic (essential) hypertension in humans; (b) provide congenic strains in which the effects of one blood pressure QTL are isolated from all other blood pressure QTL in order that such strains can be used to define the physiological function of the QTL;(c) provide the basis for positional cloning and identification of blood pressure QTL, thus adding substantially to the fundamental understanding of the mechanisms of genetic hypertension.