virus (HIV) can be used to efficiently insert genes into the germline of mice, and that genes inserted in this way are not subject to silencing following germline transmission (Lois et al., 2002; Pfeiffer et al., 2002). Such vectors promise to yield more efficient and reliable means of generating transgenic animals of many species. Similar vector systems based on the distantly related feline immunodeficiency virus (FIV) and bovine immunodeficiency virus (BIV) also are being developed (Curran et al., 2000; Berkowitz et al., 2001). Again, methylation-induced shutoff of gene expression is an issue affecting the strategy and efficiency of production of transgenic animals, much less their safety as producers of useful products.

Necessity for Selection

As the discussion above indicates, germline modification remains a hit-or-miss technology and, with most techniques, only a very small fraction of the progeny obtained has the desired properties of expression, copy number, and lack of genetic damage. Thus, large numbers of animals must be screened for the presence and copy number of the inserted sequence, for its properly regulated expression, for the ability of this expression to survive transmission through the germline and, finally, for the desired phenotypic characteristics and absence of unintended genetic side effects (see below and Chapter 6). Such screening could require several generations of breeding before one can be confident of the absence of recessive genetic damage, and the failure rate of the overall process is very high. As nuclear transfer technology improves, techniques requiring direct introduction of DNA into the animal germline followed by extensive screening of progeny are likely to be replaced by much simpler manipulation and selection of cells in culture, followed by recreation of animals with the desired properties directly from the nuclei of the manipulated cells (Brink et al., 2000).

CONCERNS RELATED TO GERMLINE TECHNOLOGY

There are a number of safety issues that arise as a consequence of manipulation of the germline. These can be divided into several levels of concern: from the animal (or group of animals); to the human handler, recipient, or user of the animal or its products; to the human population as a whole; and the environment. All of these levels are discussed here in the context of the technology used; many are presented in more detail in the following chapters.



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