Almost all ethanol abuse-related traits show multilocus (polygenic) inheritance as well as multiple environmental influences; thus, they are quantitative traits. The chromosome sites containing genes (alleles) that influence a quantitative trait are known as quantitative trait loci, or QTLs. Recently developed molecular and statistical methods utilizing PCR- based marker loci now make it possible to detect and genetically map several QTLs influencing virtually any ethanol-related trait in the mouse. This project proposes to use presently existing selectively-bred lines for ethanol sensitivity because the alleles (genes) predisposing toward very high and very low ethanol sensitivity have essentially been isolated in these bidirectionally selected lines, making them and their crosses a valuable resource for gene mapping studies. These include the WSP (Withdrawal Seizure Prone) and WSR (Resistant) lines bred for high and low ethanol withdrawal intensity, respectively; the FAST and SLOW lines bred for increased and reduced sensitivity to ethanol-induced locomotor activation, respectively; and the HOT and COLD lines bred for minimal or severe ethanol-induced hypothermia (body temperature loss). All three were developed by Dr. John Crabbe in Portland. We propose to identify relevant QTLs underlying withdrawal intensity, locomotor activation and hypothermia by carrying out either limited or full genome searches, as necessary, to reliably detect all QTLs accounting for 25% or more of the genetic variance in all three ethanol-related traits. The QTL data can be interfaced with the wealth of behavioral, neurochemical and pharmacological data collected on these lines over the past decade to gain insight into QTL identity and function. Given the large number of previously mapped genes in the mouse of obvious neurochemical import, it is likely that our QTL amp sites will immediately suggest plausible candidate genes for further study using functional and higher resolution mapping studies. Given the extensive homology (linkage conservation) between mouse and portions of the human genome, it is highly likely that the mouse QTL sites will immediately suggest homologous regions in the human genome for further study in human populations. The Component will be active in all years of requested Center support.
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