Cerebellar gene expression profiling and eQTL analysis in inbred mouse strains selected for ethanol sensitivity

Area of Science:

• Neurogenetics
• Behavioral Genetics
• Pharmacogenomics

Background:

• Inbred Long-Sleep (ILS) and Inbred Short-Sleep (ISS) mice display distinct alcohol and drug-related behaviors.
• The cerebellum, a key site for ethanol's central nervous system effects, was analyzed for gene expression differences.
• Over 39,000 transcripts were examined to identify candidate genes underlying these behavioral variations.

Purpose of the Study:

• To identify differentially expressed (DE) genes in the cerebellum of ILS and ISS mice.
• To correlate DE genes and their regulatory regions with known behavioral phenotypes.
• To uncover potential genetic underpinnings of alcohol and drug responses.

Main Methods:

• Oligonucleotide and complementary DNA arrays were used to detect DE genes between mouse strains.
• Sequence alignment and in silico expression quantitative trait loci (eQTL) mapping identified gene locations and regulatory regions.
• The EASE program analyzed overrepresented functional themes, and the Cap1 gene's upstream region was sequenced.

Main Results:

• Nearly 300 genes were found to be differentially expressed in the cerebella of ILS and ISS mice.
• DE genes and their eQTLs mapped to chromosomal regions associated with ethanol preference and cocaine-induced locomotor activation.
• Eight genes were validated, with three single nucleotide polymorphisms (SNPs) identified in the Cap1 gene's upstream region, suggesting a role in ethanol phenotypes.

Conclusions:

• Differentially expressed genes identified are strong candidates for influencing alcohol and drug-related phenotypes.
• Genes mapping to or linked via eQTLs to ethanol-related quantitative trait loci (QTLs) are implicated.
• Overrepresentation of genes involved in calcium ion binding and transcriptional regulation suggests their importance in mediating alcohol behaviors.