Expression profiling identifies novel candidate genes for ethanol sensitivity QTLs.
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, genome-wide 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.
MacLaren
Erik J
EJ
Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80045, USA.
Bennett
Beth
B
Johnson
Thomas E
TE
Sikela
James M
JM
D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D008040:Genetic Linkage; D016678:Genome; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D000072200:Ku Autoantigen; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D020411:Oligonucleotide Array Sequence Analysis; D027701:Organic Cation Transport Proteins; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D027981:Symporters
D034961:Antigens, Nuclear; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006993:Hypnotics and Sedatives; D008565:Membrane Proteins; D027701:Organic Cation Transport Proteins; C491659:Slc22a4 protein, mouse; D027981:Symporters; D000431:Ethanol; C000606512:Xrcc5 protein, mouse; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen