Genetic factors can contribute to the development of alcoholism, a complex human disorder. The long-term goal of this proposal is to identify human genes that predispose to alcohol abuse. Identification of the genetic risk factors offers the potential for prevention and treatment of alcohol abuse. However, identification of human quantitative trait loci (QTLs) for alcoholism has been difficult. The purpose of this work is to continue our studies using animal models of alcoholism, and to focus on the identification and fine mapping of QTLs that affect alcohol preference. For the genetic analysis of complex traits quasi-congenic Recombinant QTL Introgression (RQI) mouse strains were developed in our laboratory. We recently mapped provisional QTLs for ethanol preference to small segments of chromosomes 1, 2, and 15, in a series of RQI strains. Location of these QTLs will be verified and we will search for additional QTLs in a larger series of RQI strains.
The specific aims of the present proposal are: (1) to investigate gender differences in preference for 12% (v/v) ethyl alcohol solution by carrying out standard two-bottle-choice experiments with male and female RQI mice, (2) to decrease the current average distance between genetic markers in the quasi-congenic RQI strains by characterizing the strains for 610 microsatellite markers, and to map additional alcohol preference QTLs at 2.5 cM marker spacing in a set of >100 RQI strains, (3) to confirm or reject provisional QTLs in segregating generations, and (4) to reduce the length of chromosome segments that harbor confirmed QTLs to less than 1 cM intervals by utilizing individuals that carry recombinant chromosome segments in segregating populations. Identification of a <1 cM region will allow the identification of candidate genes and ESTs. We will map each identified and confirmed QTL.
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