while the phenotypic consequences of knocking out a gene will depend upon the function of that gene.

GENE EXPRESSION

Animal welfare problems also can arise because of poorly controlled expression of the introduced gene (Chapter 2). Many transgenic animals either do not express the inserted gene, or show variable or uncontrolled expression (Seamark, 1993; Eyestone, 1999; Niemann et al., 1999), although the percentage of inappropriate expression might be decreasing as transgenic technologies are refined. It must be noted that earlier experiments with transgenic growth hormone in pigs used metalothionine promoters. Current approaches use more appropriate promoters with greatly reduced abnormalities, although with methods of pronuclear injection, there are still problems and variability.

The most frequently cited example of welfare problems arising from inappropriate transgene expression is that of the so-called Beltsville pigs, which were engineered with a gene for human growth hormone in an attempt to improve growth rate and decrease carcass fat content (Pursel et al., 1987). Backfat thickness was reduced and feed efficiency was improved, although growth rate was not increased. However, the pigs were plagued by a variety of physical problems, including diarrhea, mammary development in males, lethargy, arthritis, lameness, skin and eye problems, loss of libido, and disruption of estrous cycles. Of the 19 pigs expressing the transgene, 17 died within the first year. Two were stillborn and four died as neonates, while the remainder died between two and twelve months of age. The main causes of death were pneumonia, pericarditis, and peptic ulcers. Several pigs died during or immediately after confinement in a restraint device (a metabolism stall), demonstrating an increased susceptibility to stress. Similar problems are seen in mice transgenic for human growth hormone (Berlanga et al., 1993).

Problems due to growth hormone expression also can be seen when the inserted gene comes from the same, or a closely related, species. For example, sheep in which ovine growth hormone inappropriately is expressed are lean but diabetic (Nancarrow et al., 1991; Rexroad, 1994). In salmonids transgenic for fish growth hormone (Devlin et al., 1995a), the largest transgenic fish have growth abnormalities of the head and jaw. Fish with the highest early growth performance are affected the most and have difficulty eating. As a result, growth of these fish is retarded relative to other transgenics at 15 months of age, and they die prior to maturation. Thus, the severity of morphologic abnormalities is correlated with initial growth rate, although not all transgenic fish display abnormalities. Devlin et al. (1995b) also observed that transgenic coho salmon exhibit cranial deformities and opercular overgrowth. After one year of development, the overgrowth of cartilage in the cranial and opercular



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