The Long-Sleep and Short-Sleep lines of mice were selected to be differentially sensitive to the anesthetizing action of alcohol (McClearn and Kakihana, 1981). Using recombinant inbred (RI) strains generated by crosses between the LS and SS lines, DeFries et al. (1989) estimated that seven genes are responsible for this differential alcohol sensitivity. We propose to map these genes genetically (quantitative trait loci or QTLs) using a multi-point mapping strategy, recently outlined by Lander and Botstein (1989) and usefully employed by Paterson et al. (1988, 1990). The genes that specify sensitivity to alcohol will be mapped by establishing linkage between the QTLs specifying sleep time and previously localized restriction fragment length polymorphisms (RFLPs) and sequence- tagged-sites (STSs). The basis of QTL mapping relies on the following truism. If a population of mice is sorted by a genomic site (RFLP or STS) that is linked to such a QTL, the average sleep time of those mice carrying the LS allelic-type of site will differ significantly from the average sleep time of those mice carrying the SS allelic type. Additional localization and the estimation of the contribution of this locus to total sleep time will also be derived. The final stage of the project then entails the isolation of """"""""candidate genes"""""""" and cloning of the genes responsible for differential neurosensitivity to the effects of alcohol. We plan to accomplish this massive project in several well defined stages. A negative result at any stage tentatively rules out the locus assayed by that particular site as being linked to a gene specifying the sleep-time difference. A positive result means that the genetic locus defined by the RFLP or STS may be linked to such a gene and suggests the use of that RFLP or STS in the next stage of analysis.
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