One important point to be considered here is the goal of transgenic studies in the first place – which has not always been expressed particularly explicitly. In most of these early studies the goal was to determine (or perhaps confirm) the site of action of drugs of abuse by eliminating the initial targets using homozygous knockout mice. As models of human genetic variation, these transgenic models are consequently rather poor because it is rare for deletion of entire genes to occur in humans. If the goal is to model human genetic variation then other approaches are necessary, depending on the nature of the human genetic variants to be modeled. Heterozygous knockout mice, generally expressing 50% of the usual RNA and protein levels, may in fact be better models of the range of human variation, but this has not always been done, perhaps because this was not the intended goal of most studies. One problem, overall, with each genetic manipulation, particularly if heterozygous mice are to be studied, is whether a single manipulation can produce a large enough effect to be
