Horai and Co-Workers Explained:

Detection of De Novo Single Nucleotide Variants in Offspring of Atomic-Bomb Survivors Close to the Hypocenter by Whole-Genome Sequencing.

Reference: Horai, M., Mishima, H., Hayashida, C. et al. (2018) Detection of de novo single nucleotide variants in offspring of atomic-bomb survivors close to the hypocenter by whole-genome sequencing. Journal of Human Genetics 63, pp. 357–36.

What was the research question?

In 1945, residents of the Japanese cities of Hiroshima and Nagasaki were exposed to varying doses of ionising radiation from the explosion of atomic bombs. Since then scientists have investigated whether there may be a genetic legacy, i.e. heritable genetic effects among the unexposed offspring of the survivors of these bombs. No conclusive evidence of any genetic effect has been found to date, however, many of the studies performed thus far have tested for DNA mutations in just portions of the genome.

This study uses ‘next generation sequencing’ to analyse the whole human genome to assess whether the atomic bombings have produced heritable genetic effects. The researchers were interested in de novo mutations, defined as mutations which arise in the offspring but which are not present in the parents’ DNA sampled from their blood cells.

The research team were particularly interested in the type of de novo mutations called single nucleotide variants; this is when one nucleotide in a DNA sequence is changed. They were also interested in larger changes to DNA involving tens of thousands of nucleotides, that are referred to as structural changes.

How was the scientific problem approached?

The research team assumed that the higher the dose received by the parents, the greater the probability that the offspring would have genetic alterations. For this reason, the researchers recruited fathers who were estimated to have had received in the region of 2 Gy of radiation. Within each family, the mother was not exposed and the child was born after the time of the bombings. By comparing the child’s DNA with that of their parents it was possible to identify newly arising or de novo mutations. De novo mutations also arise spontaneously in people and so the researchers also recruited control family trios known not to have been exposed to radiation.

What did the research involve?

The researchers recruited a study group of three family trios (exposed father, unexposed mother and their child) and one control family trio. The fathers were judged to have received doses greater than 2 Gy, because they were within 1 mile of the hypocentre (the location on the ground directly below where the bomb exploded) in Nagasaki and they had experienced symptoms of acute radiation sickness, e.g. hair loss.

All of the participants donated blood so that DNA could be extracted from their lymphocytes (white blood cells). The researchers ‘cut’ the DNA into smaller fragments, which they sequenced (determined the sequence of bases) individually and then they used this data to determine the whole genome sequence of each individual with the aid of computer software.

The research team identified possible de novo mutations by comparing the sequenced genomes of the children with that of their parents.

What did they find?

The children of the exposed fathers had a similar number of single nucleotide variant mutations (62, 81 and 42) as the child of the nonexposed father (48). No large structural variant mutations were observed in any of the children. No statistical analysis was carried out due to the small sample size.

How did they interpret their results?

The authors concluded that they had found no evidence that ionising radiation causes heritable genetic change, however, they noted that their study had limitations.

For instance, they had conducted their research using only four family trios, they had only investigated the effects of male (paternal) exposure and, their study had not included any examination for indels (insertions and deletions). Deletions are the most common mutations associated with radiation; however, they did not assess these as the “accuracy” of their DNA sequence reader was “limited”. They stated that the possibility of heritable genetic effects could not be ruled out and recommended that further research is done.

Who did this research?

This work was done by a team of researchers from Nagasaki University and Nagasaki Atomic Bomb Casualty Council.

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