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Mechanisum of radiation induction of genomic instability

辐射诱导基因组不稳定性的机制

基本信息

批准号：
09680523
负责人：
NIWA Ohtsura
金额：
$ 2.24万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

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

通过分析受辐射雄性小鼠所生F1小鼠小卫星基因座Pc-1的长度变化突变，研究了基因组不稳定性的诱导。突变频率的父系衍生以及母系衍生的等位基因的基因座之间的F1出生的未照射的男性约10%。当父本在精原细胞、精子细胞和精子期受到辐射时，该位点的父系来源等位基因表现出较高的突变频率。在精细胞期照射小鼠，突变频率最高。在精子细胞期接受1戈伊的剂量时，突变频率约为22%。因此，过量突变频率超过10%，这太高而不是由于基因组中辐射诱导的DNA的直接后果。这表明，长度变化突变是辐射诱导的基因组不稳定性的继发效应。为了证明突变诱导的间接性质，雄性小鼠被irradi ...更多信息在精子期和F1小鼠中进行了母源性基因座突变的研究。对100多只F1代小鼠的研究表明，6戈伊照射雄性小鼠所生F1代小鼠的母系来源的等位基因突变频率升高至20%，这与父系来源的等位基因的突变频率相似。该值具有统计学显著性。这表明辐照精子引入卵母细胞的DNA损伤造成基因组不稳定性，其以顺式作用于父本基因组以及反式作用于母本基因组以使Pc-1位点突变。除了小鼠小卫星，白象牙突变的恢复在母系来源的白色基因座的果蝇进行了研究，在F1果蝇出生的精子照射男性与白色突变。在这个系统中，在母系来源的等位基因的回复频率也提高了照射精子。因此，目前的调查表明，辐射突变小卫星序列间接通过诱导基因组不稳定性的卵母细胞和早期胚胎的细胞。少