This thesis investigates expression instability, focusing on mice carrying a transgene encoding sheep β-lactoglobulin (BLG), the major whey protein BLG transgenes inserted as multicopy arrays within the mouse genome are robustly expressed in mammary epithelium and the product is exported into milk (Simons et al 1987). In two of the three lines studied, milk BLG levels differed markedly between individuals. This was attributed to mosaic expression due to stochastic inactivation of the transgene (Dobie et al 1996), and suggestive of position effect variegation as seen in Drosophila. The highly variegating line, BLG/7, was chosen for further studies. The original line was created on a mixed genetic background. First, to address a possible link between genetic background and variegation, BLG/7 animals were backcrossed to inbred mouse strains CBA and C57BL/6. Transgene expression continued to variegate after 13 backcross generations. However, inbreeding reduced the absolute expression levels: the mean and variance differed significantly from the parental population. Levels were restored by intercrossing inbred strains. Second, homozygous BLG/7 mice were studied. Variegated expression was maintained, but maximum expression levels were indistinguishable from heterozygote levels. Fluorescent in situ hybridisation for nuclear BLG transcription revealed that only one transgene locus is active per cell. This is suggestive of a trans-homology effect for the BLG/7 transgene. Previously, similar events have only been reported in plants and insects. Finally, mosaic expression could reflect clonal expansion of committed progenitor cells. To address this issue, we sought to exploit X-inactivation. A lacZ reporter gene under BLG promoter control was targeted to the X-linked hypoxanthine-xanthine phosophoribosyl transferase (HPRT) gene of ES cells. To date, chimeric animals have been obtained.