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, 10 (1), 37

Characteristics of Induced Mutations in Offspring Derived From Irradiated Mouse Spermatogonia and Mature Oocytes

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Characteristics of Induced Mutations in Offspring Derived From Irradiated Mouse Spermatogonia and Mature Oocytes

Yasunari Satoh et al. Sci Rep.

Abstract

The exposure of germ cells to radiation introduces mutations in the genomes of offspring, and a previous whole-genome sequencing study indicated that the irradiation of mouse sperm induces insertions/deletions (indels) and multisite mutations (clustered single nucleotide variants and indels). However, the current knowledge on the mutation spectra is limited, and the effects of radiation exposure on germ cells at stages other than the sperm stage remain unknown. Here, we performed whole-genome sequencing experiments to investigate the exposure of spermatogonia and mature oocytes. We compared de novo mutations in a total of 24 F1 mice conceived before and after the irradiation of their parents. The results indicated that radiation exposure, 4 Gy of gamma rays, induced 9.6 indels and 2.5 multisite mutations in spermatogonia and 4.7 indels and 3.1 multisite mutations in mature oocytes in the autosomal regions of each F1 individual. Notably, we found two types of deletions, namely, small deletions (mainly 1~12 nucleotides) in non-repeat sequences, many of which showed microhomology at the breakpoint junction, and single-nucleotide deletions in mononucleotide repeat sequences. The results suggest that these deletions and multisite mutations could be a typical signature of mutations induced by parental irradiation in mammals.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Experimental design of parental exposure. (a) Time scheme of the spermatogonia exposure experiment. A male mouse was mated with a female 16 weeks after irradiation. It takes approximately 5 weeks for spermatogonia to develop into sperm during the spermatogenesis process. Thus, the F1 mice born to the exposed father were derived from irradiated spermatogonia. (b) Time scheme of the mature oocyte exposure experiment. A female mouse was mated with a male just after irradiation, and thus, the F1 mice born to the exposed mother were derived from irradiated mature oocytes.
Figure 2
Figure 2
De novo multisite mutations detected in this study. The sequences of multisite mutations (Alt) compared with the reference sequence (ref.) are shown in red. The dashed lines show deletions. There is no strain difference of the sequences between B6 and C3H where multisite mutations were occurred. n.d., the parental alleles were not determined due to lack of the neighbouring polymorphism between B6 and C3H.
Figure 3
Figure 3
Size distribution of de novo indel mutations in F1 mice. The “size of indels” (insertions and deletions) indicates the number of nucleotides inserted (negative values represent deletions). (a) Before the exposure of spermatogonia to radiation. (b) Before the exposure of mature oocytes to radiation. (c) After the exposure of spermatogonia to radiation. (d) After the exposure of mature oocytes to radiation. The blue bar shows the number of indels occurring in repeat sequences, and the red bar shows the number of indels occurring in non-repeat sequences. The shaded red bar shows the number of non-repeat sequence indels having microhomology at the breakpoint junction.
Figure 4
Figure 4
Profile of spontaneous SNVs and nucleotide substitutions present within multisite mutations. We used SNVs observed in a total of 12 F1 mice whose parents were mated at 8 weeks of age as a reference for spontaneous germline SNVs. For multiple sites, we used nucleotide substitutions within the multisite mutations detected in a total of 12 F1 mice born after parental irradiation. The significance of the differences was estimated using a two-tailed Fisher’s exact test. Error bars, binomial 95% CI. P values were obtained after Bonferroni correction.

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