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Detection of de novo single nucleotide variants in offspring of atomic-bomb survivors close to the hypocenter by whole-genome sequencing

Journal of Human Geneticsvolume 63pages357363 (2018) | Download Citation


Ionizing radiation released by the atomic bombs at Hiroshima and Nagasaki, Japan, in 1945 caused many long-term illnesses, including increased risks of malignancies such as leukemia and solid tumours. Radiation has demonstrated genetic effects in animal models, leading to concerns over the potential hereditary effects of atomic bomb-related radiation. However, no direct analyses of whole DNA have yet been reported. We therefore investigated de novo variants in offspring of atomic-bomb survivors by whole-genome sequencing (WGS). We collected peripheral blood from three trios, each comprising a father (atomic-bomb survivor with acute radiation symptoms), a non-exposed mother, and their child, none of whom had any past history of haematological disorders. One trio of non-exposed individuals was included as a control. DNA was extracted and the numbers of de novo single nucleotide variants in the children were counted by WGS with sequencing confirmation. Gross structural variants were also analysed. Written informed consent was obtained from all participants prior to the study. There were 62, 81, and 42 de novo single nucleotide variants in the children of atomic-bomb survivors, compared with 48 in the control trio. There were no gross structural variants in any trio. These findings are in accord with previously published results that also showed no significant genetic effects of atomic-bomb radiation on second-generation survivors.

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  1. 1.

    Kamiya K, Ozasa K, Akiba S, Niwa O, Kodama K, Takamura N, et al. Long-term effects of radiation exposure on health. Lancet. 2015;386:469–78.

  2. 2.

    Hsu WL, Preston DL, Soda M, Sugiyama H, Funamoto S, Kodama K, et al. The incidence of leukemia, lymphoma and multiple myeloma among atomic bomb survivors: 1950–2001. Radiat Res. 2013;179:361–82.

  3. 3.

    Preston DL, Ron E, Tokuoka S, Funamoto S, Nishi N, Soda M, et al. Solid cancer incidence in atomic bomb survivors: 1958–98. Radiat Res. 2007;168:1–64.

  4. 4.

    Muller HJ. Artificial transmission in the gene. Science. 1927;66:84–87.

  5. 5.

    Russell WL, Russell LB, Kelly EM. Radiation dose rate and mutation frequency. Science. 1958;128:1546–50.

  6. 6.

    Otake M, Schull WJ, Neel JV. Congenital malformations, stillbirths, and early mortality among the children of atomic bomb survivors: a reanalysis. Radiat Res. 1990;122:1–11.

  7. 7.

    Neel JV, Satoh C, Goriki K, et al. Search for mutations altering protein charge and/or function in children of atomic bomb survivors: final report. Am J Hum Genet. 1988;42:663–76.

  8. 8.

    Kodaira M, Izumi S, Takahashi N, Nakamura N. No evidence of radiation effect on mutation rates at hypervariable minisatellite loci in the germ cells of atomic bomb survivors. Radiat Res. 2004;162:350–6.

  9. 9.

    Kodaira M, Ryo H, Kamada N, Furukawa K, Takahashi N, Nakajima H, et al. No evidence of increased mutation rates at microsatellite loci in offspring of A-bomb survivors. Radiat Res. 2010;173:205–13.

  10. 10.

    Grant EJ, Furukawa K, Sakata R, Sugiyama H, Sadakane A, Takahashi I, et al. Risk of death among children of atomic bomb survivors after 62 years of follow-up: a cohort study. Lancet Oncol. 2015;16:1316–23.

  11. 11.

    Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012;488:471–5.

  12. 12.

    Kent WJ. BLAT-The BLAST-Like Alignment Tool. Genome Res. 2002;12:656–64.

  13. 13.

    McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–303.

  14. 14.

    DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43:391–8.

  15. 15.

    Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, del Angel G, Levy-Moonshine A, et al. From FastQ data to high-confidence variant calls: the genome analysis toolkit best practices pipeline. Curr Protoc Bioinforma. 2013;43:10.1–33.

  16. 16.

    Smit AFA, Hubley R, Green P. RepeatMasker Open-3.0. 1996–2010.

  17. 17.

    Bailey JA, Gu Z, Clark RA, Reinert K, Samonte RV, Schwartz S, et al. Recent segmental duplications in the human genome. Science. 2002;297:1003–7.

  18. 18.

    Harrow J, Frankish A, Gonzalez JM, Tapanari E, Diekhans M, Kokocinski F, et al. GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res. 2012;22:1760–74.

  19. 19.

    Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010;26:841–2.

  20. 20.

    R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2013.

  21. 21.

    Wickham H. ggplot2: Elegant graphics for data analyses. New York: Springer-Verlag; 2009.

  22. 22.

    Li H, Durbin R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics. 2009;25:1754–60.

  23. 23.

    Yang L, Luquette LJ, Gehlenborg N, Xi R, Haseley PS, Hsieh C-H, et al. Diverse mechanisms of somatic structural variations in human cancer genomes. Cell. 2013;153:919–29.

  24. 24.

    Batzer MA, Deininger PL, Hellmann Blumberg U, Jurka J, Labuda D, Rubin CM, et al. Standardized nomenclature for Alu repeats. J Mol Evol. 1996;42:3RepeatMasker Open-4.0, 2013-2015.6.

  25. 25.

    Smit AFA, Hubley R, Green P. RepeatMasker Open-4.0, 2013–2015.

  26. 26.

    Untergasser A, Cutcutache I, Koressaar T, Ye J, Faircloth BC, Remm M, et al. Primer3 -- new capabilities and interfaces. Nucleic Acids Res. 2012;40:e115.

  27. 27.

    Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, et al. The human genome browser at UCSC. Genome Res. 2002;12:996–1006.

  28. 28.

    Gilbert ES, Ohara JL. Analysis of the DS86 atomic bomb radiation dosimetry methods using data on severe epilation. Radiat Res. 1984;100:124–38.

  29. 29.

    Young RW, Kerr GD, editors. Reassessment of the atomic bomb radiation dosimetry for Hiroshima and Nagasaki-Dosimetry System 2002. The Radiation Effect Research Foundation, Hiroshima 732-0815, Japan, 2005.

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This work was partly supported by the Program of the Network-type Joint Usage/Research Centre for Radiation Disaster Medical Science of Hiroshima University, Nagasaki University and Fukushima Medical University, and Takeda Science Foundation.

Author contributions

MH, YN, TM, and TH approached subjects, and collected data and samples. CH, AK, and K-iY performed sample preparation. MH, SS, DI, YI, KT, KY, and YM analysed the laboratory data. HM, AK, and K-iY analysed the genome data. YM and K-iY planned and organised the project. YM and K-iY wrote the manuscript.

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  1. Department of Hematology, Nagasaki University Graduate School of Biomedical Sciences, Atomic Bomb Disease Institute, Nagasaki, Japan

    • Makiko Horai
    • , Shinya Sato
    • , Daisuke Imanishi
    • , Yoshitaka Imaizumi
    • , Tomoko Hata
    •  & Yasushi Miyazaki
  2. Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Atomic Bomb Disease Institute, Nagasaki, Japan

    • Hiroyuki Mishima
    • , Chisa Hayashida
    • , Akira Kinoshita
    •  & Koh-ichiro Yoshiura
  3. Health Management Center, Nagasaki Atomic Bomb Casualty Council, Nagasaki, Japan

    • Yoshibumi Nakane
    •  & Tatsuki Matsuo
  4. Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    • Kazuto Tsuruda
    •  & Katsunori Yanagihara


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The authors declare that they have no competing interests.

Corresponding authors

Correspondence to Yasushi Miyazaki or Koh-ichiro Yoshiura.

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