Untargeted mutation of the maternally derived mouse hypervariable minisatellite allele in F-1 mice born to irradiated spermatozoa

Length change mutation at the Ms6hm hypervariable mouse minisatellite locus was analyzed in C57BL/6N x C3H/HeN F-1 mice and the F-1 of the reciprocal cross born to irradiated male parents. Spontaneous mutant frequencies were 8.4% and 9.8% for the paternally derived and maternally derived C3H/HeN all eles, respectively. The mutant frequencies for the paternally derived allel e increased to 22% and 19% when the male parents were irradiated with 6 Gy at the postmeiotic spermatozoa stage and the spermatogonia stage, respectiv ely. These increases in the mutant frequency were at least 10 to 100 times higher than those expected from the frequency of hits to the 3- to 4-kb all ele, suggesting that the length change mutation at this minisatellite locus was not a targeted event due directly to DNA damage in the region. Further analysis demonstrated that the mutant frequency increased also at the mate rnally derived C3H/HeN allele to 20% when the male parents were irradiated at the spermatozoa stage. This increase in the maternal allele mutation was not observed in F-1 born to irradiated spermatogonia, The present study su ggests that introduction of DNA damage by irradiated sperm triggers genomic instability in zygotes and in embryos of subsequent developmental stages, and this genomic instability induces untargeted mutation in cis at the pate rnally derived minisatellite allele and in trans at the maternally derived unirradiated allele. Untargeted mutation revealed in the present study defi nes a previously unnoticed genetic hazard to the maternally derived genome by the paternally introduced DNA damage.