Revisiting Next Generation Effects of Ionizing Radiation
Creators: name: Mathews, John D.
Publisher: name: Zenodo
Year: 2021
Subjects: medical radiation
de novo mutations
parental radiation

description: We have long wondered whether ionizing radiation to parents, before conception, can cause gene mutations leading to adverse effects in the next generations<sup>1</sup>. Animal experiments suggest that de novo gene mutations (DNM) occur with a doubling dose of about one Gy.<sup>1</sup> To address this question in humans, Yeager and colleagues<sup>2</sup> used whole genome sequencing (WGS) to study DNM in children of parents exposed to Chernobyl radiation before conception. The DNMs detected were predominantly single nucleotide variants (SNV), which did not increase in frequency with estimated parental radiation doses. These negative results were consistent with earlier studies in humans<sup>3,4</sup> and mice<sup>5</sup>. However, the exoneration of SNV as mediators of transgenerational radiation effects does not show that such effects do not exist. Indeed, it is much more plausible that radiation would mediate its mutational effect through gene deletions and other copy number variants (CNV), as these are the mutational signatures of ionizing radiation<sup>4,5</sup>. (SNV seem to be generated by replication errors). Although de novo CNV are less frequent than SNV<sup>6</sup>, they are much larger, ranging up to many Mb in size<sup>7</sup> and they contribute much more genetic variation than de novo SNV. De novo CNV, especially if large, are much more likely to be expressed as dominants with adverse phenotypic effects<sup>7</sup>, including autism, congenital heart disease and cancer, to be subject to negative (purifying) selection, and to be eliminated from the gene pool within one or a few generations. In comparison, SNV tend to be selectively neutral when heterozygous. The Yeager study was unable to report on CNV, so that a definitive test of the CNV hypothesis will require a larger study using array technologies. Such a study will be of particular salience for public health if deleterious CNV prove to be caused by low dose radiation from medical X-rays and scans. In the meantime, we can bypass the genetics in a national epidemiological study to link parental records of medical radiation to the health outcomes of their children, allowing a direct test of the hypothesis that parental radiation doses, before conception, predict adverse outcomes in their offspring. Estimates of the magnitude of any next generation burden will allow us to assess the scope for prevention (e.g. by reducing medical radiation exposures for persons who may yet still reproduce).
description: License: Creative Commons Attribution Non Commercial No Derivatives 2.5 Generic Grants: I would like to leave it blank.
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