No evidence of increased mutations in the germline of a group of British nuclear test veterans.

Reference: Moorhouse et al (2022). No evidence of increased mutations in the germline of a group of British nuclear test veterans. Scientific Reports, 12, 10830.

Background to research

A population of (potentially) radiation exposed individuals are veterans of the British nuclear testing programme whereby it is estimated that over 20,000 UK servicemen attended at least one test site through the 1950s and 60s. Questions as to whether veterans could have received sufficient radiation exposure to cause harm and, worry about potential (inherited) legacy in descendants of any historical radiation exposure, remain. The Genetic and Cytogenetic Family trio (GCFT) study was undertaken to, in part, address these concerns.

DNA mutations arise throughout our life in all cells of our bodies, including in our germ (sperm and egg) cells. Advances in whole-genome sequencing technologies are allowing the number, type, distribution and consequences of these newly arising or de novo mutations in our germline to be measured. From this, the number of new DNA mutations per individual per generation which are expected to occur can be found. Exposure to ionizing radiation is known to increase the burden or amount of DNA mutations. The question of whether the amount of de novo germline mutations is the same or higher as would be expected in unexposed children born to radiation exposed parent/s is ongoing in a number of differently exposed populations.

What was the aim of this research?

To measure the amount and type of de novo germline DNA mutations in families of British veterans of nuclear tests (NTV cohort) and to compare this with families of British military personnel not present at nuclear tests (control cohort).

What did the research involve?

A population of 30 test and 30 control veteran family trios (veteran father, mother, child) who were recruited as part of the Genetic and Cytogenetic Family Trio (GCFT) study, were studied. Information on service history and other potential exposures were gathered and blood samples received. For more information please refer to Rake et al., 2022.

DNA was extracted from the blood samples and the DNA code sequenced using whole-genome sequencing tools. Specialist software programs enabled the identification of new DNA mutations in the child which were not present in either parent. Identified mutations were verified using a number of established techniques and categorized into defined mutation types. All of this analysis was performed blind to test/control family status and enabled the amount (or frequency) and type of de novo mutations to be determined for each family. After completion of analysis, the families were decoded to allow a comparison between test veteran and control family groups.

What did we find?

When compared to the published literature, we find our data to be consistent with those of larger studies examining germline mutations in the general population.

Our data also support the expectation that the amount of de novo mutations increases with increasing age of parent at time of conception.

When we compared the total number of de novo mutations, of any mutation sub-type, among the offspring of nuclear test veterans to those of control personnel, we find no difference.

We did observe an increase in a particular pattern of mutations, known as mutation signature SBS16, in a subset of NTV offspring. We carried out two different statistical methods to examine this in more depth and cannot rule out with sufficient confidence that this represents a random finding.

What does this mean?

Our study shows no significant increases in the amount or type of newly arising DNA mutations in the offspring to nuclear test veteran fathers sampled here. This likely reflects the very low doses thought to have been received by the majority of test veterans and should reassure this community there is no evidence for a genetic legacy of test participation in the families sampled here.

The meaning, if any, of the increased mutation SBS signature 16 in a small number of NT offspring is not clear at this stage and does require further investigation.

What is next?

Work on the GCFT study continues. We are finalising a chromosomal examination of veterans to assess for historical radiation exposure and, we are carrying out additional chromosomal analysis to look for genetic alterations in their adult children. We anticipate that upon completion of these chromosomal analyses, we will be able to undertake a holistic evaluation of all findings thus far generated from across all parts of this study.

Who did this research?

This study was carried out by researchers at the University of Leicester, London School of Hygiene and Tropical Medicine and Brunel University London.
This work was, in part, supported by the Nuclear Community Charity Fund (NCCF) through funds received by The Armed Forces Covenant Fund Trust under the Aged Veterans Fund Grant AVF16 and Brunel University London.