Transgenic mice are now routinely generated either by direct pronuclear injection of
exogenous DNA into fertilized zygotes I or by injection of genetically engineered embryonal
stem (ES) cells into the mouse blastocyst. 2 Direct pronuclear injection results in random
integration of the injected DNA into the genome and relies on the dominant nature of the
transgene to give a useful phenotype (eg, the expression of a foreign protein or of a mutated
version of an endogenous gene). Manipulation of endogenous genes (gene targeting) has …