Selective breeding, congenic strains, and other classical genetic approaches to the analysis of alcohol-related polygenic pleiotropisms.

Dimensions of behavioral sensitivities to alcohol in mice are under control of polygenic systems of relatively small size. The mode of inheritance of these phenotypes is frequently additive, with no evidence of dominance, epistasis, or sex linkage. The utility of classical breeding methodologies, such as selection, for assessment of genetic correlations is reviewed. A distinction is drawn between pleiotropisms in these polygenic systems, and the statistical concept of a genetic correlation. Development of congenic strains is argued to be a powerful alternative methodology, heretofore unused in alcohol pharmacogenetics. Using the phenotype of behavioral activation produced by a low dose of ethanol, we describe the production of an activated congenic strain on the non-activated background of the C57BL/6 mouse strain. Through five generations of repeated backcrossing, from a genetically heterogenous stock, "activational" alleles are being successfully transferred to the C57BL/6 background. Theoretical issues in the creation of congenic strains in potentially polygenic systems are covered, including number of effective loci and heritability.