A transgenerational mutational signature from ionizing radiation exposure.

Effects of accidental radiation exposure on the human germline remain a topic of medical interest. Sequencing technology now allows the accurate analysis of the entire human genome in potentially exposed cohorts to search for possible signatures of ionizing radiation exposure. Clustered de novo mutations (cDNMs), that are multiple DNA lesions within 20 bp of each other, have been hypothesized to be a signature for paternal exposure to ionizing radiation. We analyzed whole genome trio data of 240 children and their likely exposed parents as well as 1,275 offspring from unexposed families. The cohort of exposed children consists of 130 offspring of Chernobyl cleanup workers (CRU, exposure range = 0-4,080 mSv) and 110 offspring of former soldiers from both German armies which have likely been irradiated during their service (Radar cohort, exposure range = 0-353 mSv). For the Radar cohort, a retrospective dosage estimation was conducted based on the service records from each soldier, but it remains a challenging task to retrospectively estimate received dose accurately. In agreement with previous epidemiological data, no transgenerational effects could be detected for the class of isolated de novo mutations, which cause the majority of genetic disorders. We found that the number of isolated de novo mutations increases by 2% per year of age of the father at conception, which is also in line with previous works. On average, we observed 2.65 cDNMs per offspring in the CRU cohort, 1.48 in the Radar cohort and 0.88 in the control cohort, with a median of two clustered mutations per genome in offspring of irradiated fathers. This is a significant increase (p < 0.005) in the number of cDNMs compared to a set of age-matched controls. Furthermore, we show that the cDNM rates scale with paternal exposure to ionizing radiation (p\ <\ 0.001). Our findings corroborate that clustered de novo mutations represent a transgenerational biomarker for paternal exposure to ionizing radiation. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Funding for the sequencing and analysis of the Radar cohort was provided by the Federal Office of Bundeswehr Equipment, Information Technology and In-Service Support (Bundesamt fuer Ausruestung, Informationstechnik und Nutzung der Bundeswehr, BAAINBw) under contract E/U2AD/HD004/HF554 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All participants of the radarstudy were of legal age at time of recruitment and consented to the use of their data for research purposes. Ethics approval was granted by the Ethikkommission der Medizinischen Fakultät Bonn (Ethics committee of the medical faculty Bonn). All identifiers were pseudonymized prior to publication and the reidentification based on identifiers mentioned in the manuscript or supplemental material is only possible by members of the research group. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at EGA with Study ID EGAS00001007321.