Recent studies reveal that a large proportion of cells in cloned blastocysts are aneuploid or polyploid (Nolen et al., 2005; Booth et al., 2003; Shi et al., 2004). Thus, although a large proportion of cloned constructs can attain blastocyst stage and be used to generate ESCs, the genetic integrity of the ESCs obtained must initially be suspect. This places obvious restrictions and requirements on plans to employ clone-derived ESCs for therapy.
When does this aneuploidy arise? We might argue that this most likely occurs during the early cleavage divisions of the cloned constructs, on the premise that the somatic cells should initially be predominantly euploid. In a recent study of aneuploid in cloned bovine embryos, completely euploid constructs comprised only 22% of the total blastocyst population based on the analysis of two chromosomes; the remaining embryos were either polyploid or mixoploid (Booth et al., 2003). A significant rate of polyploidy/aneuploidy was also observed in mouse cloned blastocysts, although less than the rate seen in the bovine study (Nolen et al.,
2005). If we assume that at most only a small fraction of somatic cells would be aneuploid or polyploid, then these results suggest that aneuploidy/polyploidy in cloned embryos likely arises due to mitotic errors during cleavage.
It has been suggested that cloning in primate species may be hindered by the removal of proteins associated with the SCC (Simerly et al., 2003, 2004). Studies in mice reveal spindle defects in SCNT embryos (Miyara et al.,
2006). Other studies reveal that removal of the SCC likely depletes the embryo of factors that otherwise could modulate its phenotypes (i.e., tetraploid constructs prepared by SCNT without SCC removal appear more like fertilized embryos than do diploid clones) (Gao and Latham, 2004).
It is also possible that aneuploidy in clones is the result of aneuploidy in the donor cells. In a study of developing brain, one-third of neuroblasts were aneuploid (Rehen et al., 2001). Aneuploidy was also detectable in adult neurons, which displayed more than 1% aneuploidy for sex chromosomes.
With respect to producing ESCs for therapy, it appears likely that a stringent selection may operate, such that clones with a greater degree of aneuploidy/polyploidy tend to have smaller numbers of cells (Booth et al., 2003), and thus may be less likely to form a healthy inner cell mass from which to derive an ESC line. This may account for why the one clone-derived human ESC line is euploid (Hwang et al., 2004), despite evidence from bovine clones of a high rate of aneuploidy.
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