Expression profiling identifies novel candidate genes for ethanol sensitivity QTLs

Abstract

The Inbred Long Sleep (ILS) and Inbred Short Sleep (ISS) mouse strains have a 16-fold difference in duration of loss of the righting response (LORR) following administration of a sedative dose of ethanol. Four quantitative trait loci (QTLs) have been mapped in these strains for this trait. Underlying each of these QTLs must be one or more genetic differences (polymorphisms in either gene coding or regulatory regions) influencing ethanol sensitivity. Because prior studies have tended to focus on differences in coding regions, genomewide expression profiling in cerebellum was used here to identify candidate genes for regulatory region differences in these two strains. Fifteen differentially expressed genes were found that map to the QTL regions and polymorphisms were identified in the promoter regions of four of these genes by direct sequencing of ILS and ISS genomic DNA. Polymorphisms in the promoters of three of these genes, Slc22a4, Rassf2, and Tax1bp3, disrupt putative transcription factor binding sites. Slc22a4 and another candidate, Xrcc5, have human orthologs that map to genomic regions associated with human ethanol sensitivity in genetic linkage studies. These genes represent novel candidates for the LORR phenotype and provide new targets for future studies into the neuronal processes underlying ethanol sensitivity.

Role of Endocannabinoids in Alcohol Consumption and Intoxication: Studies of Mice Lacking Fatty Acid Amide Hydrolase

“…Because ethanol LORR is mediated by multiple molecular mechanisms, it is likely that distinct molecular mechanisms are responsible for hypnotic effect of different doses of ethanol. For example, at least four quantitative trait loci on different mouse chromosomes and 23 candidate genes have been identified, which are largely responsible for the heritable component of hypnotic sensitivity to ethanol in selected ILS and ISS strains of mice (Markel et al, 1997;Bennett and Johnson, 1998;Ehringer et al, 2001;MacLaren et al, 2006). Furthermore, genotypic differences in duration of ethanol-induced LORR can reflect differences in sensitivity, acute tolerance or ethanol clearance (Radcliffe et al, 2005).…”

Confirmation and Fine Mapping of Ethanol Sensitivity Quantitative Trait Loci, and Candidate Gene Testing in the LXS Recombinant Inbred Mice

“…In both cohorts analyzed separately, the same three loci, on chr 1, 3, and 8, explained much of the phenotypic variance. One of these intervals, on chr 1, also contains one of 15 genes with significant differences in expression between ILS and ISS in cerebellum (MacLaren et al, 2006) and ventral tegmentum (M. Miles, personal communication). X-ray repair complementing defective repair in Chinese hamster cells (Xrcc5) has a 2.5-fold higher expression in ISS strain and a human ortholog in a genomic region linked to ethanol sensitivity in humans.…”

Molecular Targets of Alcohol Action

“…Gene expression profiles derived from microarray analysis can be compared across recombinant inbred strains or other genetic tools, and genes from QTLs with differential expression are likely to provide promising candidate genes in this endeavor (6, 109). Indeed, this was recently obtained for the alcohol-induced loss of righting reflex, as well as for alcohol preference and acute functional tolerance (110, 111). Several mouse candidate genes are also located in human alcohol sensitivity-associated QTLs (110).…”

“…Indeed, this was recently obtained for the alcohol-induced loss of righting reflex, as well as for alcohol preference and acute functional tolerance (110, 111). Several mouse candidate genes are also located in human alcohol sensitivity-associated QTLs (110). The behavioral, gene expression and gene-sequence differences among recombinant inbred strains are being cumulatively added to online databases as strains are being tested for different phenotypes.…”