Spectra and characteristics of somatic mutations induced by ionizing radiation in hematopoietic stem cells

Matsuda, Yukiko; Uchimura, Arikuni; Satoh, Yasunari; Kato, Naohiro; Toshishige, Masaaki; Kajimura, Junko; Hamasaki, Kanya; Yoshida, Kengo; Hayashi, Tomonori; Noda, Asao; Tanabe, Osamu

doi:10.1073/pnas.2216550120

Title: Spectra and characteristics of somatic mutations induced by ionizing radiation in hematopoietic stem cells

Journal Article · 05 April 2023 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.2216550120 · OSTI ID:1968514

^[1];

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^[2]; Kato, Naohiro ^[2];

^[2]; Kajimura, Junko ^[2]; Hamasaki, Kanya ^[2]; Yoshida, Kengo ^[2];

^[2];

^[2]

Radiation Effects Research Foundation (RERF), Hiroshima (Japan); Hiroshima Univ. (Japan)
Radiation Effects Research Foundation (RERF), Hiroshima (Japan)

Spectra and frequencies of spontaneous and X-ray-induced somatic mutations were revealed with mouse long-term hematopoietic stem cells (LT-HSCs) by whole-genome sequencing of clonal cell populations propagated in vitro from single isolated LT-HSCs. SNVs and small indels were the most common types of somatic mutations, and increased up to twofold to threefold by whole-body X-irradiation. Base substitution patterns in the SNVs suggested a role of reactive oxygen species in radiation mutagenesis, and signature analysis of single base substitutions (SBS) revealed a dose-dependent increase of SBS40. Most of spontaneous small deletions were shrinkage of tandem repeats, and X-irradiation specifically induced small deletions out of tandem repeats (non-repeat deletions). Presence of microhomology sequences in non-repeat deletions suggested involvement of microhomology mediated end-joining repair mechanisms as well as nonhomologous end-joining in radiation-induced DNA damages. We also identified multisite mutations and structural variants (SV), i.e., large indels, inversions, reciprocal translocations, and complex variants. The radiation-specificity of each mutation type was evaluated from the spontaneous mutation rate and the per-Gy mutation rate estimated by linear regression, and was highest with non-repeat deletions without microhomology, followed by those with microhomology, SV except retroelement insertions, and multisite mutations; these types were thus revealed as mutational signatures of ionizing radiation. Further analysis of somatic mutations in multiple LT-HSCs indicated that large fractions of postirradiation LT-HSCs originated from single LT-HSCs that survived the irradiation and then expanded in vivo to confer marked clonality to the entire hematopoietic system, with varying clonal expansion and dynamics depending on radiation dose and fractionation.

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Research Organization:: Radiation Effects Research Foundation (RERF), Hiroshima (Japan)

Sponsoring Organization:: USDOE; Japan Society for the Promotion of Science (JSPS); Grants-in-Aid for Scientific Research (KAKENHI); Ministry of Education, Culture, Sports, Science and Technology (MEXT)

Grant/Contract Number:: RP-P3-19; 19K12338; 22K12388; Not applicable

OSTI ID:: 1968514

Alternate ID(s):: OSTI ID: 2424610

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 120, Issue 15; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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