The primary goal of this revised proposal is to identify genes underlying quantitative trait loci (QTLs) related to alcohol action. Considerable progress has been made toward this goal in the first five-year funding period and now important new mouse genomics resources and strategies will be utilized that should significantly accelerate this process even further. The research plan for the coming funding period will be composed of two primary areas of focus: The first (Specific Aims 1-2) will be on four Lore QTLs related to initial sensitivity to ethanol in the ILS and ISS mice. Considerable prior work has been carried out on the Lore2 QTL which will now be added to this proposal. The proposed gene identification efforts will involve the continued characterization and fine mapping of three altered Lore QTL genes we have identified, comparative sequencing of additional, newly identified Lore candidate genes, and identification of regulatory sequence variations within differentially expressed QTL genes. Lore-specific custom gene chips have been created that together with standard mouse chips will allow the expression level of all Lore genes to be compared between ILS and ISS strains. The second (Specific Aims 3-4) will be on application of a novel in silico method we have recently developed for rapidly identifying gene variants in alcohol-related QTLs identified using the C57BL/6J (B6) and DBA/2J (D2) strains. This method represents a powerful new tool that will be used to identify gene variants in two alcohol-related B6xD2 QTLs. These four specific aims have been designed to be comprehensive, and will be used to search for potentially important interstrain changes by surveying both the protein coding and regulatory regions of QTL genes. These analyses will utilize a combination of high throughput comparative DNA sequencing, high density microarray studies and the new in silico methods that take advantage of strain-specific whole genome sequences that have just become available. In response to the last review, Specific Aim 5 has been significantly modified and reduced in scope from the previous proposal.
This aim will now focus on the development of BAC genomic libraries for the ILS and ISS mice, which will set the stage for functional studies using transgenic animals. These experiments represent a logical extension of previous work from this laboratory and provide a comprehensive approach to the identification of QTL genes involved in alcohol action.
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