Untargeted mutation of the maternally derived mouse hypervariable minisatellite allele in F_1 mice born to irradiated spermatozoa

摘要

Length change mutation at the Ms6hm hypervariable mouse mini- satellite locus was analyzed in C57BL/6N × C3H/H_eN F_1 mice and the F_1 of the reciprocal cross born to irradiated male parents. Spontaneous mutant frequencies were 8.4/100 and 9.8/100 for the paternally derived and maternally derived C3H/H_eN alleles, re- spectively. The mutant frequencies for the paternally derived allele increased to 22/100 and 19/100 when the male parents were irradiated with 6 Gy at the postmeiotic spermatozoa stage and the spermato- gonia stage, respectively. 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 allele, 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 maternally derived C3H/H_eN allele to 20/100 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 suggests 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 paternally derived minisatellite allele and in trans at the maternally derived unirradiated allele. Untargeted mutation revealed in the present study defines a previously unnoticed genetic hazard to the maternally derived genome by the paternally introduced DNA damage.