Genetic Variables That Influence Phenotype

Characterization of genetically engineered mice requires consideration of the gene of interest and the genetic background on which the mutation is maintained. A fundamental prerequisite to deciphering the genetic factors that influence the phenotype of a mutant mouse is an understanding of genetic nomenclature. Mutations and transgenes are often maintained on segregating or mixed backgrounds of often-unspecified origin. Minimizing the importance of strain and substrain differences, especially among 129 strains, can lead to poor experimental design or faulty interpretations of data. Genetic factors that influence phenotype can be categorized as traits that are unique to the background strain, unique to the gene of interest, or an interaction of both the background strain and the gene of interest. The commonly used inbred strains are generally well characterized and understood; however, specific genetic alterations combined with genes unique to the background inbred strain may lead to unexpected results. Genetic background effects can be analyzed and controlled for by using specific targeting and breeding strategies. Selection of appropriate experimental controls is critical. Ideally, mutations or transgenes should be characterized on more than one genetic background and in hybrids of the two progenitor strains. This approach may lead to the identification of novel genetic modifiers of the "gene of interest." Conditional mutagenesis technologies increase the options for controlling genetic background effects in addition to permitting the study of developmental and temporal changes in gene and protein expression and thus phenotype.