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Most People With Hypermutated Genome Obtain Excess Mutations from Father, Study Finds

NEW YORK – While the human germline appears to be relatively impervious to acquiring many mutations, some genetic vulnerabilities or paternal exposure to chemotherapy can prompt pronounced de novo mutations, new research has found.

"Our results suggest that the germline is well protected from mutagenic effects, hypermutation is rare, the number of excess mutations is relatively modest, and most individuals with a hypermutated genome will not have a genetic disease," senior author Matthew Hurles, a researcher at the Wellcome Sanger Institute, and his colleagues wrote in Nature on Wednesday.

Following prior studies in mice with specific DNA repair mutations or mutagenic exposures, the team set out to search for signs of hypermutation in the human germline, where far less is known about individuals at the high end of the germline mutation spectrum.

Using exome or whole-genome sequence data for nearly 21,900 parent-child sets from the 100,000 Genomes Project or the Deciphering Developmental Disorders project — including families with children suspected of having rare genetic conditions — the researchers found a dozen participants who had up to seven times as many de novo single-base mutations in their germline than the median of other individuals.

In nine of the 12 individuals, the team traced the hypermutation back to their fathers. In some families, individuals carried damaging alterations affecting DNA repair genes, while others had germline mutation signatures linked to platinum-based chemotherapy, including children born to fathers who went through cancer treatment prior to conceiving children.

When the investigators explored the latter results further using data for dozens of parents from the 100,000 Genomes Project who had a history of cancer treatment, they found germline hypermutation in children born to two of 27 fathers treated for cancer. They also detected a nominal increase in de novo single-nucleotide changes in children born to mothers with a cancer treatment history, though the women also tended to be older than unaffected mothers when their children were born.

Among other implications, the results suggest that there may be a benefit for male cancer patients to preserve sperm prior to chemotherapy treatment, particularly for men who wish to have children in the future. At the moment, measures are typically offered to protect against chemotherapy-related infertility.

"Clinically, patients receiving chemotherapy who might want to go on to have children in the future are often offered the opportunity to freeze sperm prior to treatment as part of standard of care in the UK," Hurles explained in an email, adding that "it is not just cancer patients that receive mutagenic chemotherapies; these drugs are also given for non-cancer conditions, for example for immune suppression in some auto-immune disorders."

Although the evidence available so far suggests that the germline "generally appears to be well protected from large increases in mutation rate," the authors wrote, Hurles and his colleagues called for additional studies that include individuals exposed to a broader set of potential mutagens, and their family members, to find more modest germline mutation signatures and ties between genes and other environment factors.

"I anticipate that the publication of our study will trigger a range of future studies looking into the germline effects of a range of mutagens, including many chemotherapies," Hurles wrote. "I also think that more studies will identify genetic causes of hypermutation, and through these studies, we will learn more about the differences between the soma and the germline in terms of how mutations are minimized."