High-throughput sequence identification of gene coding variants within alcohol-related QTLs

Low initial response to alcohol has been shown to be among the best predict ors of development of alcoholism. A similar phenotypic measure, difference in initial sensitivity to ethanol, has been used for the genetic selection of two mouse strains, the Inbred Long-Sleep (ILS) and Inbred Short-Sleep (I SS) mice, and for the subsequent identification of four quantitative trait loci (QTLs) for alcohol sensitivity. We now report the application of high throughput comparative gene sequencing in the search for genes underlying t hese four QTLs. To carry out this search, over 1.7 million bases of compara tive DNA sequence were generated from 68 candidate genes within the QTL int ervals, corresponding to a survey of over 36,000 amino acids. Eight central nervous system genes, located within these QTLs, were identified that cont ain a total of 36 changes in protein coding sequence. Some of these coding variants are likely to contribute to the phenotypic variation between ILS/I SS animals, including sensitivity to alcohol, providing specific new geneti c targets potentially important to the neuronal actions of alcohol.