[Title]
Quantitative and qualitative mutational impact of ionizing radiation on normal cells

[Author]

Jeonghwan Youk,1,21 Hyun Woo Kwon,2,3,21 Joonoh Lim,1,4,21 Eunji Kim,5,6,21 Taewoo Kim,1,21 Ryul Kim,1,4 Seongyeol Park,1,4 Kijong Yi,1,4 Chang Hyun Nam,1 Sara Jeon,7 Yohan An,1 Jinwook Choi,8,9 Hyelin Na,10,20 Eon-Seok Lee,11 Youngwon Cho,2,12 Dong-Wook Min,2,12 HyoJin Kim,11 Yeong-Rok Kang,11 Si Ho Choi,11 Min Ji Bae,11 Chang Geun Lee,11 Joon-Goon Kim,1,13 Young Seo Kim,1,13 Tosol Yu,6,14 Won-Chul Lee,4 Jong-Yeon Shin,4 Dong Soo Lee,2,15 Tae-You Kim,2,12,16 Taeyun Ku,1,13 Su Yeon Kim,1 Joo-Hyeon Lee,8,9 Bon-Kyoung Koo,10 Hyunsook Lee,7 On Vox Yi,17 Eon Chul Han,18 Ji Hyun Chang,6,19,* Kyung Su Kim,6,19,* Tae Gen Son,11,* and Young Seok Ju1,4,22,*

1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
2Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea
3Department of Nuclear Medicine, Korea University College of Medicine, Seoul, Republic of Korea
4Genome Insight, Inc., San Diego, CA 92121, USA
5Department of Radiation Oncology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, 20, Boramae-ro 5 Gil, Dongjak-gu, Seoul 07061, Republic of Korea
6Department of Radiation Oncology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
7Department of Biological Sciences & IMBG, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea 8Wellcome- MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, CB2 0AW Cambridge, UK 9Department of Physiology, Development and Neuroscience, University of Cambridge, CB2 3EL Cambridge, UK
10Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Dr. Bohr-Gasse3, 1030 Vienna, Austria
11Research Center, Dongnam Institute of Radiological and Medical Science, Busan, Republic of Korea
12Cancer Research Institute, Seoul National University, Seoul, Republic of Korea
13KI for Health Science and Technology, KAIST, Daejeon 34141, Republic of Korea
14Department of Radiation Oncology, Dongnam Institute of Radiological and Medical Science, Busan 46033, Republic of Korea
15Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
16Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea
17Department of Breast Surgery, Dongnam Institute of Radiological and Medical Science, Busan, Republic of Korea
18Department of Surgery, Dongnam Institute of Radiological and Medical Science, Busan, Republic of Korea
19Department of Radiation Oncology, Seoul National University Hospital, Seoul, Republic of Korea
20Present address: TONY Investment Co., Ltd., Seoul 06180, Republic of Korea
21These authors contributed equally
22Lead contact
*Correspondence: jh.chang@snu.ac.kr (J.H.C.), kskim.cirt@snu.ac.kr (K.S.K.), tgson@dirams.re.kr (T.G.S.), ysju@kaist.ac.kr (Y.S.J.) https://doi.org/10.1016/j.xgen.2024.100499

[Journal] 

Cell Genomics  VOLUME 4, ISSUE 2, 100499, FEBRUARY 14, 2024


[Abstract]

The comprehensive genomic impact of ionizing radiation (IR), a carcinogen, on healthy somatic cells remains unclear. Using large-scale whole-genome sequencing (WGS) of clones expanded from irradiated murine and human single cells, we revealed that IR induces a characteristic spectrum of short insertions or deletions (indels) and structural variations (SVs), including balanced inversions, translocations, composite SVs (deletion-insertion, deletion-inversion, and deletion-translocation composites), and complex genomic rearrangements (CGRs), including chromoplexy, chromothripsis, and SV by breakage-fusion-bridge cycles. Our findings suggest that 1 Gy IR exposure causes an average of 2.33 mutational events per Gb genome, comprising 2.15 indels, 0.17 SVs, and 0.01 CGRs, despite a high level of inter-cellular stochasticity. The mutational burden was dependent on total irradiation dose, regardless of dose rate or cell type. The findings were further validated in IR-induced secondary cancers and single cells without clonalization. Overall, our study highlights a comprehensive and clear picture of IR effects on normal mammalian genomes.

[Graphical abstract]