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. Clusteredde novomutations (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 isolatedde novomutations, which cause the majority of genetic disorders. We found that the number of isolatedde novomutations 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 clusteredde novomutations represent a transgenerational biomarker for paternal exposure to ionizing radiation.
