Appendix N. 
389 
differentiation-associated genes that had been transcribed in the 
original donor cell. Inadequate “reprogramming"^ of the donor 
nucleus is most likely the principal reason for developmental failure 
of clones. Since few clones survive to birth, the question remains 
whether survivors are fully normal or merely the least affected 
ammals carrying through to adulthood despite harboring subtle 
abnormalities that originate in faulty reprogramming but that are not 
severe enough to interfere with survival to birth or beyond. 
HI. Reprogramming of the genome during normal development 
and after nuclear transfer 
The fundamental difference between nuclear cloning and normal 
fertilization is that the nucleus used in nuclecir cloning comes from a 
somatic (body) cell that has not undergone the developmental events 
required to produce the egg and sperm. Nuclear cloning involves the 
transplantation of a somatic nucleus into the oocyte from which the 
nucleus has been removed. However, the genes in the somatic 
nucleus are not in the same state as those in the fertilized egg 
because nuclear transplantation short-cuts the complex process of 
egg and sperm maturation which involves extensive 
“reprogramming” of the genome, a process that shuts some genes off 
and leaves others on. Reprogramming during gametogenesis 
prepares the genome of the two mature gametes with the ability to 
activate faithfully the genetic program that ensures normal 
embryonic development when they combine at fertilization (Fig la). 
This reprogramming of the genome begins at gastrulation, when 
primordial germ cells (PGCs) are formed, and continues during 
differentiation into mature gametes resulting, in a radically different 
chromatin configuration of sperm and oocyte (Rideout et al., 2001). 
Experiments have showm that uniparental embryos (embryos 
whose genomes are derived solely from either the maternal or 
paternal parent) do not develop normally. Uniparental embryos first 
seem normal; they direct cleavage (early development to the 
blastocyst stage) despite profound differences in their epigenetic 
organization (Reik et al., 2001). However, uniparental embryos fail 
soon after the implantation of the embryo into the wall of the uterus, 
indicating that both parental genomes are needed and functionally 
complement each other beginning at this later step of 
embryogenesis. Presumably, the different epigenetic organization of 
the two genomes is crucial for achieving normal development. 
Moreover, it has been well established that the imbalance of 
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