Induced reciprocal translocation in transgenic mice near sites of transgene integration

Transgenic mice (JCP₀ #18), heterozygous for an insertion of approximately 50 copies of the rat peripheral myelin (P₀) protein cDNA, displayed a pattern of reduced litter size that suggested a chromosome rearrangement. Chromosome banding studies of fetal cells disclosed the presence of an apparently balanced translocation between a Chromosome (Chr) 1 and 14 with breakpoints at bands 1H3 and 14C3. In situ hybridization of biotin-labeled P₀ rat cDNA probe to chromosome spreads and detection of specific signal with fluorescein isothiocyanate-conjugated avidin revealed a strong signal on the 1¹⁴ translocation chromosome at the site of the breakpoint. A weaker signal was present near the breakpoint on the 14¹ derivative chromosome. These results suggest an etiologic relationship between the insertion of the transgene and the origin of the translocation. To further elucidate possible mechanisms, we first mapped the endogenous P₀ gene (gene symbol Mpp). As previously reported (You et al., Genomics 9: 751, 1991), we found that Mpp is located on Chr 1 in the region of the translocation breakpoint in JCP₀ mice. Subsequently, we have carried out pulsed-field gel and standard Southern analyses with P₀ gene probes, but found no evidence for a direct involvement of the endogenous P₀ gene in the process that generated the balanced reciprocal translocation. Thus, we favor the hypothesis that, during repair of DNA strand breakage-possibly induced by the microinjection procedure-the transgene copies were ligated to broken ends of Chrs 1 and 14. According to convention, this translocation is designated T(1;14) 1Po. Homozygotes are phenotypically normal and breed well; they will be useful for genetic and physical mapping of Chrs 1 and 14.