We have identified four major genes (quantitative trait loci or QTLs) that determine loss of righting reflex (LORR) induced by ethanol. Taken together, these genes (Lore-1, -2, -4, -5) explain more than 50% of the difference in ethanol-induced LORR between the ILS and ISS selected, inbred lines of mice. Each QTL is defined as a portion of a mouse chromosome. We have completed the process of isolating each QTL on the alternate genetic background i.e., each ILS QTL has been placed on an otherwise ISS background and vice versa. In a parallel breeding project, we have progressively narrowed the region of the chromosome in which the QTL is located. In this renewal, we propose to continue this fine-scale mapping so as to achieve a sufficiently small region to allow for gene identification. Simultaneously, we will use gene sequence data available for both mice and humans to identify candidate genes in our QTL regions and test the hypotheses that these candidates differ between ILS and ISS and actually map to the refined Lore interval. Candidate genes meeting these expectations will be assayed for differential expression between ILS and ISS using microarrays carrying complementary sequence. Differential expression will be confirmed using quantitative PCR and/or in situ hybridization methods. Confirmed genes will be mapped again, to the further reduced QTL region.
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