Early Developmental Mutations Due to DNA Rearrangements in Transgenic Mouse Embryos

The integration of exogenous DNA into the genome of a mammalian cell would be expected'-despite l m-ited knowledge of the recombinatorial mechanisms-to have an intrinsic potential for generating change in the donor or host DNA sequences. The changes might entail tandem duplications, deletions, other rearrange-ments, such as inversions or translocations, or even base substitutions. When the recipient cell is the fertilized egg rather than a somatic ell, the consequences of uch a muta-tion may be far-reaching, especially if the change is deleterious. Not only can the new genotype be repli-cated and found in all somatic ells of the animal de-rived from that egg; it can be transmitted to the next generation through the germ cells. A mutation initially present in the heterozygous state could appear in the homozygous form of a percentage of progeny de-scended from a pair of heterozygotes. Thus, a trans-genic individual derived from an egg with integrated exogenous (proviral or recombinant) DNA would have at risk any cell type(s) in which the relevant genetic re-gion is ordinarily expressed, if the mutation is a domi-nant or codominant one, and could generate handi-capped or inviable homozygotes, if the mutation is recessive. There is abundant evidence that DNA that is trans-fected or injected, with or without viral sequences, into cultured mammalian somatic ells undergoes mutation at a high frequency, up to approximately 1 ~ per gene (Lebkowski et al. 1984; Miller et al. 1984; Mounts and Kelly 1984). The mutations are chiefly base substitu-tions and deletions in the donor DNA, but they also include insertions from the host genome. Cotrans-fected DNA species can themselves become covalently linked by homologous recombination or by blunt-end ligation, and may experience rearrangement (Wiglet et