The rate of denovo genetic mutations in the children of parents exposed to Chernobyl radiation.

[NNadir]

The paper I'll discuss in this post is this one: Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident M. Yeager et al., Science 10.1126/science.abg2365 (2021).

This week marks the 34th anniversary of the steam explosion at the Chernobyl Nuclear Power Plant. The graphite moderator in plant burned for weeks and much of the inventory of volatile fission products was released into the environment, and detected in easily measurable amounts all across Europe, as far away as Scotland.

This event garnered huge attention at the time and still garners significant attention.

It is reported that about six to seven million people die each year from air pollution, meaning that about 200-250 million people have died from air pollution since the explosion of the nuclear reactor, proving in the minds of many that nuclear power is "too dangerous," while apparently the combustive use of fossil fuels and biomass, responsible for these 200-250 million deaths, is not "too dangerous." Neither is climate change "too dangerous." These facts, deaths from air pollution, and the acceleration of climate change despite endless talk about and expenditures on so called "renewable energy," unlike Chernobyl do not garner huge attention.

Go figure.

From the introduction to the paper:

Nearly all inherited genetic variation is present in the germline DNA of at least one parent; however, a small number of transmitted variants are unique, having arisen due to random mutations in gametes (sperm and oocytes), and are known as de novo mutations (DNMs). DNMs are critical building blocks of evolution and the only class of genomic variation that has not undergone extensive evolutionary purifying selection (purging of highly deleterious but non-lethal variants), making DNMs a unique form of inherited variation different from the genetic variation investigated in mapping complex traits and diseases (1). DNMs have been of intense interest because of their role in human disease, particularly neurodevelopmental disorders (2, 3).

Only recently has it been feasible to comprehensively investigate DNMs genome-wide at the population level in humans by whole-genome sequencing (WGS) of mother/father/child trios. Recent reports of human DNMs characterized by WGS of trios estimate between 50 and 100 new mutations arise per individual per generation (2, 4–8), consistent with the population genetic estimate that the human mutation rate for single-nucleotide variants (SNVs) is approximately 1×10?8 per site per generation (9, 10). The strongest predictor of DNMs per individual is paternal age at conception (2–6, 8) with an increase of 0.64-1.51 per one-year increase in paternal age (6, 8, 11) while a maternal effect of approximately 0.35 per one-year increase in age was observed (6, 8, 12). Transgenerational studies of radiation exposure have primarily focused on disease (cancer, reproductive, and developmental) outcomes and have reported inconclusive results (13, 14).

Exposure to ionizing radiation is known to increase DNA mutagenesis above background rates (15, 16). Animal and cellular studies suggest high doses of ionizing radiation can lead to DNMs in offspring, particularly through double-stranded breaks (13, 17). Human studies have sought a biomarker of prior radiation injury (13, 18, 19), but have examined a small number of minisatellites and microsatellites, yielding inconclusive results (20–23). A WGS study of three trios from survivors of the atomic bomb in Nagasaki did not reveal a high load of DNMs (20), while a single-nucleotide polymorphism (SNP) array study of 12 families exposed to low doses of Caesium-137 from the Goiania accident in Brazil reported an increase in large de novo copy-number variants (24). No large comprehensive effort has explored DNMs genome-wide in children born from parents exposed to moderately high amounts of ionizing radiation yet possible genetic effects have remained a concern for radiation-exposed populations, such as the Fukushima evacuees (25).

Herein, we examine whether rates of germline DNMs were elevated in children born to parents exposed to ionizing radiation from the 1986 Chernobyl (Chornobyl in Ukrainian) disaster, where levels of exposure have been rigorously reconstructed and well-documented (26). Our study focused on children born of enlisted cleanup workers (“liquidators”) and evacuees from the town of Pripyat or other settlements within the 70-km zone around Chernobyl Nuclear Power Plant in Ukraine (27) after the meltdown, some of whom had extremely high levels of radiation exposure and several of whom experienced acute radiation syndrome. We performed Illumina paired-end WGS (average coverage 80X), SNP microarray analysis, and relative telomere length assessment on available samples from 130 children from 105 mother-father pairs. The parents had varying combinations of elevated gonadal ionizing radiation exposure from the accident (tables S1 to S3), and included a combination of exposed fathers, exposed mothers, both parents exposed and neither parent exposed (27)...

Some figures from the paper:



The caption:

Fig. 1 Detected DNMs per genome based on distributions of parental age at conception.
Analyses are presented by increasing paternal and maternal age at conception, paternal and maternal dose, birth year of child, and paternal and maternal smoking at conception. All plots are univariate and do not account for other potentially correlated variables (for example, maternal age does not account for high correlation with paternal age).

The caption:

Fig. 2 Distribution of de novo SNVs by type of nucleotide change across six studies.
n = number of children sequenced (adapted from (39)). Liftover was used to convert coordinates to hg38 for all studies and the reference for CpG sites were defined with respect to that reference sequence. Only autosomes were included. Error bars show binomial 95% confidence intervals. Studies included Kong (2); Wong (8); Francioli (4); Michaelson (3); Jónsson (6); and Chernobyl (present study).

Some additional text:

Although it is reassuring that no transgenerational effects of ionizing radiation were observed in adult children of Chernobyl cleanup workers and evacuees in the current study, additional investigation is needed to address the effects of acute high-dose parental gonadal exposure closer to conception. The upper 95% confidence bound suggests the largest effect consistent with our data is less than 1 DNM per 100 mGy from paternal or maternal exposure (Table 3 and tables S8 and S9). Previously, Dubrova et al. (22, 29) reported a two-fold increase in mini-satellite mutations in children born to parents living in a highly exposed region of Belarus. Weinberg et al. (34) reported an increase in the mutation rate at microsatellite loci among children born to cleanup workers. Subsequent small studies have not reported an increased mini-satellite or microsatellite mutation rate in children of cleanup workers, including those with low doses (0.09-0.23 Gy) (21, 30, 35) or in children of the atomic-bomb survivors of Hiroshima or Nagasaki (31).

Our study evaluated peripheral blood from adult children conceived months or years after the Chernobyl accident, which limited the ability to assess exposure closer to conception; however, there was no evidence of notable differences in DNMs in children born the following year (1987). Since these families were recruited several decades after the accident, we acknowledge potential survivor bias among sampled children, although this is unlikely since there is no consistent demonstration in humans of sustained clinical effects of preconception ionizing radiation exposure (36)...

....Although it is reassuring that no transgenerational effects of ionizing radiation were observed in adult children of Chernobyl cleanup workers and evacuees in the current study, additional investigation is needed to address the effects of acute high-dose parental gonadal exposure closer to conception. The upper 95% confidence bound suggests the largest effect consistent with our data is 1 Gy), but lower maternal dose was not associated with elevated DNMs, consistent with animal studies (13). Furthermore, our analysis of 130 adult children from 105 couples using 80X coverage of short-read technology suggests that if such effects on human germline DNA occur, they are uncommon or of small magnitude. This is one of the first studies to systematically evaluate alterations in human mutation rates in response to a man-made disaster, such as accidental radiation exposure. Investigation of trios drawn from survivors of the Hiroshima atomic bomb could shed further light on this public health question

For the record, I am an older father, and therefore there is a higher probability that my sons have DNM's than there may be to the children of men who were younger than I was before coming a father. If so these were happy mutations, since my sons are better men than I was at their age. I love my mutant boys.

Have a nice day tomorrow.