fast becoming a practical way to rapidly propagate animals with valuable properties (Polejaeva et al., 2000). The DNA genomes of somatic cell nuclei used for this procedure differ in two important ways from those of germline cells. First, they have shortened telomeres at the ends of the chromosomes, a consequence of multiple rounds of cell division in the absence of telomerase, the enzyme responsible for maintenance of telomere length. Since loss of telomere length is the principal mechanism limiting the lifespan of cells in culture (Urquidi et al., 2000), the lack of appropriate-length telomeres might be expected to reduce the lifespan of the newly generated offspring or their progeny, but, surprisingly, telomere length (and lifespan of cultured cells) are restored to normal values following generation of cattle by somatic cell nuclear transfer (Betts et al., 2001), even when senescent cells are used to donate nuclei (Lanza et al., 2000). Second, the methylation state of the DNA of somatic cells is quite different from that of germline cells (Rideout et al., 2001). Since methylation (at CG sequences) plays a major role in the overall regulation of gene expression, it might be expected that inappropriate methylation states might lead to gross developmental abnormalities in embryos produced by somatic cell nuclear transfer. Indeed, it is possible that the inability of the embryo to properly reprogram methylation and expression is a major cause of the developmental abnormalities often seen in the generation of NT-produced embryos (Rideout et al., 2001). However, the apparently rapid increase in success rate of this procedure with experience, combined with the fact that animals who survive to adulthood are apparently normal (Betthauser et al., 2000), implies that correct methylation can be restored in NT embryos under the proper conditions. “Correct conditions” might involve having the transferred nucleus in the proper stage of the cell cycle (Gibbons et al., 2002), but this point is controversial. Furthermore, in a direct study (Kang et al., 2001), it was found that correct methylation and expression levels of several key genes were restored in pig embryos derived from adult cell nuclei. Thus, although nuclear reprogramming is a significant practical issue in the efficient application of this technology, it does not appear to present as insurmountable a barrier as once thought. Apparently the developmental process has a much more robust error-correction system than believed possible a few years ago.

The committee carefully considered the possible concerns that might be raised by use of somatic cell nuclear transfer technology. A few issues regarding animal welfare could be identified (see Chapter 6), including the possibility of inappropriate gene expression during development due to altered methylation patterns, or other developmental problems, such as oversized fetuses (Young et al., 1998), as well as concerns that the widespread application of this technology might reduce genetic diversity of animal populations. However, the effects of cloning are more difficult to anticipate because competing processes are at issue. On the one hand, cloning by its nature produces identical copies of a particular individual, reducing genetic



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