Mutations caused by exposure to ionizing radiation in blood progenitor cells and their skewed growth

What is it about?

We examined mutations caused by exposure to whole-body X-ray irradiation in blood progenitor cells of the mouse by decoding the base sequences of DNA in their entire genome. One-base changes, small deletions, and insertions in the sequences were the most common types of mutations, and they increased up to two- to three-fold by the exposure. The types of one-base changes increased by the exposure implied that they were caused mainly by DNA base damages due to chemicals containing hyperactive oxygen, which were generated by X-rays. Small deletions in the cells from non-exposed mice were found mostly inside tandem-repeat sequences, that is, shrinkages of the repeats, but the exposure caused a large number of small deletions outside the tandem repeats. The exposure also caused a large number of multiple mutations within short sequence segments, and large-scale mutations such as deletions, insertions, and erroneous joining of different chromosomes. We also found that large fractions of blood progenitor cells after the recovery from the radiation exposure were descendants of a single progenitor cell that survived the irradiation. They grew up to the extent that blood cells produced from the progenitor cell occupied the majority of bone marrow and spleen, which are major blood-cell producing organs, demonstrating dominant and skewed growth of descendant cells of a single particular progenitor cell.

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Photo by Sangharsh Lohakare on Unsplash

Photo by Sangharsh Lohakare on Unsplash

Why is it important?

Increased risks of leukemia and cancers are major late adverse effects of exposure to ionizing radiation, and widely believed to be consequences of mutations caused by DNA damages due to the radiation. However, genome-wide features of mutations caused by radiation, or mechanisms by which leukemia and cancers develop many years after the exposure have not been clarified. This study showed sequence features and frequencies of all types of mutations in mouse blood progenitor cells caused by whole-body X-ray irradiation. We thereby determined which type of mutations is prone to occur due to radiation exposure, and determined signatures of mutations by radiation. Further, we showed that large fractions of blood progenitor cells after the recovery from the exposure are descendants of a single progenitor that survived the irradiation. These findings should provide important clues to clarify detailed mechanisms of the late adverse effects of radiation exposure such as development of leukemia and cancers, and to develop novel methods to estimate the amount of past radiation exposure throughout life and thereby evaluate individual risks of leukemia and cancers due to radiation exposure.

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