Development of Congenic Rat Strains for Alcohol Consumption Derived from the Alcohol-Preferring and Nonpreferring Rats

Abstract

A genome scan of the F2 generation from an inbred alcohol-preferring (iP) and inbred alcohol-nonpreferring (iNP) rat cross identified a significant quantitative trait locus (QTL) on chromosome 4 with a lod score of 9.2. To confirm this QTL and to create animals for fine mapping of the QTL region, chromosome 4 reciprocal congenic strains were developed by transferring the chromosome 4 QTL interval into the respective iP or iNP backgrounds. The iP strain was crossed with the iNP strain to create iPiNP F1 animals, which were backcrossed to either iNP or iP animals to produce the N2 generation. Using marker-assisted selection, 10 generations of backcrossing were performed. The selection was followed by an intercross between the N10 animals to produce homozygous animals (N10F1), resulting in the finished congenic strains. Congenic strains in which the iP chromosome 4 QTL interval was transferred to the iNP (NP.P) and the iNP chromosome 4 QTL was transferred to the iP (P.NP) exhibited the expected effect on alcohol consumption of the donor strain. Development of these congenic strains further indicates that the chromosome 4 QTL region is, in part, responsible for the disparate alcohol consumption observed between the iP and iNP rats. These congenic animals will be an invaluable resource for fine mapping the QTL region and for the identification of the gene(s) that influences the drinking behavior of the iP and iNP rats.

Identification of Candidate Genes for Alcohol Preference by Expression Profiling of Congenic Rat Strains

“…The NP.P strain, with the iP Chr 4 QTL interval introgressed onto the iNP background, exhibits the expected increase in alcohol consumption compared with the iNP littermates (Carr et al, 2006). By examining gene expression in this congenic strain, we limited the differences expected to those originating from genetic variation within the QTL region shown to affect the phenotype of alcohol preference.…”

“…Creation of the NP.P congenic strain has been described previously (Carr et al, 2006). Briefly, the NP.P congenic strain was initiated by crossing 1 male rat from the iP5 strain with 1 female rat from the iNP1 strain to create iPiNP F1 animals, which were backcrossed to the iNP1 strain to produce the N2 generation.…”

“…Owing to the strong association between the chromosome 4 QTL region and alcohol preference, this approximately 25 cM region is likely to harbor at least 1 gene that directly contributes to alcohol preference. Reciprocal congenic strains in which the iP chromosome 4 QTL interval was transferred to the iNP (NP.P) and the iNP chromosome 4 QTL interval was transferred to the iP (P.NP) exhibited the expected effect on alcohol consumption of the strain that donated the chromosome 4 QTL interval (Carr et al, 2006). This indicates that the chromosome 4 QTL region is, in part, responsible for the disparate alcohol consumption observed between the iP and iNP rats.…”

Gut-brain peptides in corticostriatal-limbic circuitry and alcohol use disorders

“…Consistently, genetic linkage studies of P and NP rats identified a QTL on chromosome 4 that was linked to differences alcohol consumption levels and included the NPY gene (Carr et al, 1998). Later, congenic strains created from inbreeding P and NP lines of rats confirmed that the identified QTL from P rats partially explained their increased alcohol consumption and reduced NPY levels (Carr et al, 2006; Liang et al, 2010). These studies suggest that NPY signaling regulates alcohol-related behaviors, especially in the amygdala and cortex.…”

Selective Genotyping and Phenotyping Strategies in a Complex Trait Context

“…Experimental studies appear to be divided over this issue. Some studies have reported epistasis in selectively genotyped samples (Ohno et al 2000;Abasht and Lamont 2007) while others failed to detect it (Carr et al 2006), citing concerns about loss of power. Thus, the generality of these experimental observations requires further theoretical exploration.…”