Mechanisum of radiation induction of genomic instability

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Induction of genomic instability was investigated by analyzing length change mutation of mouse minisatellite locus, Pc-1, in F1 mice born to irradiated male mice. Mutant frequency of the paternally derived as well as the maternally derived allele of the locus among F1 born to unirradiated males were around 10%. The paternally derived allele of the locus exhibited a higher frequency of mutation when the male parents were irradiated at the spermatogonia, spermatid and spermatozoa stages. The mutant frequency was highest when the mice were irradiated at the spermatid stage. The mutant frequency at the dose of 1 Gy to spermatid stage was around 22%. Therefore, the excess mutant frequency is over 10% which is too high to be due to the direct consequence of radiation induced DNA in the genome. This suggests that the length change mutation is the secondary effect of genomic instability induced by radiation. In order to prove the indirect nature of the mutation induction, male mice were irradi … More ated at the spermatozoa stage and F1 mice were studied for the mutation at the maternally derived locus. Investigation of more than 100 F1 mice revealed that the mutant frequency of the maternally derived allele in F1 born to 6 Gy irradiated males was elevated to 20%, which is similar to that of the paternally derived allele. This value was statistically significant. This indicates that the DNA damage introduced into oocyte by irradiated sperm inflict genomic instability, which act in cis on the paternal genome as well as in trans on the maternal genome to mutate the Pc-1 locus. In addition to mouse minisatellite, the reversion of the white-ivory mutation at the maternally derived white locus of Drosophilla melanogaster was studied in F1 flies born to spermatozoa irradiated male with the white mutation. In this system, the reversion frequency at the maternally derived allele was also elevated by irradiation of spermatozoa. Thus, the present investigations demonstrate that radiation mutates minisatellite sequences indirectly through induced genomic instability in oocytes and in cells of early stage embryos. Less