RNA-Seq Analysis of Genetic and Transcriptome Network Effects of Dual-Trait Selection for Ethanol Preference and...

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Genetic factors play a significant role in alcohol consumption and withdrawal severity.
• Opposing genetic predispositions for high alcohol consumption and severe withdrawal exist, even in naive animals.

Purpose of the Study:

• To investigate the genetic underpinnings of differential alcohol consumption and withdrawal responses.
• To identify gene expression differences in mouse lines selectively bred for opposing alcohol-related phenotypes.

Main Methods:

• Selective breeding of mice for high alcohol consumption/low withdrawal (SOT) and low alcohol consumption/high withdrawal (NOT) phenotypes.
• RNA sequencing (RNA-Seq) to analyze genome-wide gene expression in the ventral striatum of S4 generation mice.
• MegaMUGA array for genome-wide genotypic analysis and weighted gene co-expression network analysis.

Main Results:

• 1,816 transcripts were differentially expressed between the SOT and NOT lines.
• Genes highly expressed in the SOT line were enriched for cell adhesion, synapse organization, and postsynaptic membrane functions.
• Genes highly expressed in the NOT line were enriched in mitochondrial function pathways, with several acting as module hub nodes.

Conclusions:

• Selective breeding markedly impacted gene expression in the distinct mouse lines.
• The SOT line exhibited gene expression patterns related to cell adhesion and synaptic plasticity, consistent with high alcohol consumption.
• The NOT line showed enrichment of mitochondrial function-related genes, associated with low alcohol consumption and potentially higher withdrawal severity.