The Problem of Passenger Genes in Transgenic Mice

Abstract

Gene targeted or transgenic mice are frequently created on one genetic background and the mutation then transferred to a second genetic background by a series of backcrosses, with selection for the mutation at each generation. This is the same experimental design as that used in the production of classical congenic strains in which a genomic region from a “donor” strain is transferred to the background of a “recipient” strain by backcrossing and selection for ten or more generations. While the strategy largely results in the replacement of the donor background with the recipient background, the region flanking the selected gene remains of donor origin. Thus, the genes in this flanking region are “passengers” that travel with the selected gene, and when comparing transgenic (or knockout) mice with non-transgenic littermates, allelic differences in the passenger genes can conceivably influence the traits of interest. It now appears that this passenger gene effect may be an important confounder in studies of cardiovascular and metabolic traits that are influenced by dozens of common variations present among inbred mouse strains. Here, we discuss the problem and some approaches to avoid it.