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Mamm Genome 2001 Aug;12(8):657-63

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

Ehringer MA, Thompson J, Conroy O, Xu Y, Yang F, Canniff J, Beeson M, Gordon L, Bennett B, Johnson TE, Sikela JM.

Department of Pharmacology, University of Colorado Health Sciences Center, 4200 East Ninth Ave., Denver, Colorado 80262, USA; Human Medical Genetics Program, University of Colorado Health Sciences Center, 4200 East Ninth Ave, Denver, Colorado 80262, USA.

Low initial response to alcohol has been shown to be among the best predictors 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 (ISS) 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 these four QTLs. To carry out this search, over 1.7 million bases of comparative DNA sequence were generated from 68 candidate genes within the QTL intervals, corresponding to a survey of over 36,000 amino acids. Eight central nervous system genes, located within these QTLs, were identified that contain a total of 36 changes in protein coding sequence. Some of these coding variants are likely to contribute to the phenotypic variation between ILS/ISS animals, including sensitivity to alcohol, providing specific new genetic targets potentially important to the neuronal actions of alcohol.