Engineering mouse chromosomes with Cre-loxP: Range, efficiency, and somatic applications

Chromosomal rearrangements are important resources for genetic studies. Rec ently, a Cre-loxP-based method to introduce defined chromosomal rearrangeme nts (deletions, duplications, and inversions) into the mouse genome (chromo some engineering) has been established. To explore the limits of this techn ology systematically, we have evaluated this strategy on mouse chromosome 1 1, Although the efficiency of Cre-loxP-mediated recombination decreases wit h increasing genetic distance when the two endpoints are on the same chromo some, the efficiency is not limiting even when the genetic distance is maxi mized, Rearrangements encompassing up to three quarters of chromosome 11 ha ve been constructed in mouse embryonic stem (ES) cells. While larger deleti ons may Lead to ES cell lethality, smaller deletions can be produced very e fficiently both in ES cells and in vivo in a tissue- or cell-type-specific manner. We conclude that any chromosomal rearrangement can be made in ES ce lls with the Cre-loxP strategy provided that it does not affect cell viabil ity, In vivo chromosome engineering can be potentially used to achieve soma tic losses of heterozygosity in creating mouse models of human cancers.