What have we learnt from the Genetic and Cytogenetic Family trio study so far?

The Genetic and Cytogenetic Family trio (GCFT) study is the first study to obtain blood samples from a group of British nuclear test veterans and their families. The overall aim is to look into whether there is a genetic legacy associated with being a UK nuclear test veteran: whether exposure to radiation at nuclear test sites in the 1950s and 60s has resulted in DNA damage, and if so, whether this is observed as being passed down to the next generation.

Progress, like many research studies, has been negatively impacted by covid-19 however, over the preceding months we have seen the publication of the first of our expected research outputs and, the open access (free to all) sharing of these scientific publications with accompanying lay summaries through our and, veterans’ organisations’, websites https://chrc4veterans.uk/articles/peer-reviewed-articles/

These publications are just the beginning however do inform on two major elements of work undertaken (see Figure). This article aims to provide an overview of these, highlighting what can and what can’t be learnt from the work published to date and, what work remains ongoing.

Study population
Firstly, Rake et al., 2022 is a descriptive paper of the approach we took to recruit veterans to take part in the study. Our aim was to select those nuclear test veterans with the highest potential for exposure to radiation and to compare them to a control group of veterans not present at test sites. Key challenges at this stage of the study included the time which had elapsed since the nuclear tests, the age of the veterans, the limited records on exposure history or dose which were available, the data protection laws which protect confidentiality, the need to recruit family trios (veteran father, mother and adult child) and also, the need to gain blood samples from all. 

Surviving test veterans, aged 82 or younger, who had attended multiple military operations and/or who had participated in certain activities with the potential to result in exposure, comprised our long list of 1,459 veterans to invite to participate in the study. This number was reduced to 908 after feedback from the NHS mainly due to death, diagnosis of cancer or not having GP contact details. As shown in Rake etal., invitations were sent to GPs with requests to forward our study packs to veterans if medically appropriate and thence subsequently, to their partners and children. Rake et al., describes how our study population of 49 test veteran and 42 control families, representing veteran servicemen from the Army, Royal Navy and RAF, reflects those veterans and their families who responded and who were eligible to take part.  

Rake et al., also provides a general description of the study population who was recruited and shows some of the characteristics of the two (test and control veteran) family groupings. For instance, as part of the recruitment interview process, information on a range of other potential exposures and health conditions in families were gathered.

The paper shows similar proportions of nuclear test and control families reporting ever smoking, drinking alcohol regularly, having X-rays, CT scans or other medical scans involving radiation. Differences were seen between the groups, however, with a higher proportion of nuclear test veterans reporting at least one of their children or grandchildren being born with a congenital anomaly, sometimes known as a birth defect, and, a higher proportion of control veterans reporting chemical or radiation exposure through their jobs. The paper discusses how these reports may, or may not, be representative of the entire test and non-test veteran population in the UK and highlights the demands of this study, including the requirement to provide blood samples, which may have led families with a particular interest to be more likely to participate. For instance, nuclear test veterans may have been more likely to take part in the study if they thought their family had been adversely affected, whereas other servicemen may have been more likely to participate if they were concerned about their chemical or radiation exposures. 

Rake et al., doesn’t include any results of the genetic analysis undertaken meaning the information presented on family health concerns does not provide a link between exposure and genetic health outcome. All of the information gathered and presented in Rake et al., will however be used in further evaluations of the GCFT study as outlined below.

Germline DNA mutations
The second publication to arise from the GCFT study describes the genetic analysis to look for new (de novo) DNA mutations in the germline of veterans (Moorhouse et al.,). DNA de novo mutations in the germline are variations in the DNA of the child but which are not present in either of the parents’ own genomes. The aim of this part of the GCFT study was to ask if more than expected de novo mutations were detected in the germline of nuclear test veterans compared with families whose veteran fathers did not attend nuclear test sites. 

Moorhouse et al., describes how the de novo germline DNA mutations were measured in the sample of 30 test veteran and 30 control veteran families. The paper also shows the comparison between families in the nuclear test group with families of military personnel not present at nuclear tests (control group).

This comparison shows there to be no difference in the total amount of de novo DNA mutations in the germline between the two veteran family groups. DNA variations can also be categorised based on their type. Again, when the amount of the different types of DNA mutation were compared between the 30 families in each group, no difference was found.

The paper compares its results with those carried out by other research groups in different human populations, and shows similar findings to that of Yeager et al., 2021 who studied those exposed as a consequence of the Chernobyl accident. Further, the results published in Moorhouse et al., are consistent with studies examining germline mutations in general (non-exposed) populations. The main conclusion drawn in Moorhouse et al., is that the lack of any observable difference in the amount or type of de novo DNA mutations in the descendants of nuclear test veterans compared to control veteran families likely reflects the very low doses thought to have been received by the majority of test veterans. This finding should offer reassurance that as a population, we find no evidence for a genetic legacy of test participation in the 30 families sampled here. 

One difference was detected, however, in a small number of test veteran families. An increase in the amount of a particular pattern of DNA mutation, known as mutation signature SBS16, was identified. Moorhouse et al., stresses that based on our research so far, we cannot rule out that this could be a random or chance observation. Further, the paper highlights that the meaning, if any, of the increased mutation SBS signature 16 observed in a small number of nuclear test offspring is not clear at this stage and does require further investigation. This investigation will involve a deeper analysis of the data thus far generated. 

Accordingly, until we understand more, it would be wrong for any associations to be drawn between this finding and, any relevance to health.

What is next?
Work on the GCFT study continues. We are finalising a chromosomal examination of veterans to give some insight into their previous radiation exposure and, we are carrying out additional chromosomal analysis to look for genetic alterations in their adult children. As above, we shall compare all families within the test veteran group with all families within the control family group to look for any differences between these two populations. We anticipate that upon completion of these chromosomal analyses, we will additionally be able to undertake a holistic evaluation of all findings thus far generated from across all parts of the GCFT study to enable further study within each population. This part of the work remains ongoing however we hope we will be in a position to submit further papers for peer-review leading to publication, later this year.

• Whole genome sequence (WGS) analysis is a laboratory process that is used to determine the genetic sequence (or code) of nearly all of an individual’s complete DNA sequence. Changes to this DNA structure can arise naturally due to DNA damage. These changes, which can be identified by WGS analysis, are known as DNA mutations and they contribute to normal variation between individuals.

• A new DNA mutation that arises in a germ cell (egg or sperm) of one of the parents and which is then transmitted to the child or children, or in a fertilized egg cell itself, is called a de novo mutation.

• DNA mutations arise throughout our life in all cells of our bodies, including in our germ (sperm and egg) cells. This means that the number of new DNA mutations per individual increase naturally with every generation.

Full Reference:
Christine Rake et al (2022). British nuclear test veteran family trios for the study of genetic risk. Journal of Radiological Protection 42(2), 021528. https://iopscience.iop.org/article/10.1088/1361-6498/ac6e10

Lay summary on CHRC Website: https://chrc4veterans.uk/articles/peer-reviewed-articles/11526-2/

Moorhouse et al (2022). No evidence of increased mutations in the germline of a group of British nuclear test veterans. Scientific Reports. 12, 10830. https://www.nature.com/articles/s41598-022-14999-w#citeasac6e10

Lay summary on CHRC Website: https://chrc4veterans.uk/articles/peer-reviewed-articles/11545-2/

Yeager M, et al., (2021) Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident.
Science 372 (6543), 725-729.
https://www.science.org/doi/10.1126/science.abg2365?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

Lay summary on CHRC Website: https://chrc4veterans.uk/lay-summaries/yeager-and-co-workers-explained/

Collett, G., Martin, W., Young, W. R., & Anderson, R. M. (2022). “Is that a coincidence?”: Exploring health perceptions and the causal attributions of physical health conditions in British nuclear test veterans. SSM-Qualitative Research in Health, 100127.

Lay Summary on CHRC Website:  https://chrc4veterans.uk/articles/peer-reviewed-articles/is-that-a-coincidence-exploring-health-perceptions-and-the-causal-attributions-of-physical-health-conditions-in-british-nuclear-test-veterans/