Hypermutation, as its name suggests, is a kind of mutation with significantly higher frequency than normal mutation. It usually appears in the form of point mutation. For example, this phenomenon is very common in cancer cells and is also a means for their survival. In the genetic process, some rare cases, newborns may also have hypermutation.
According to the latest paper in nature, researchers from Sanger Institute and other institutions found that 12 children had abnormally high-frequency mutations, about 2-7 times that of ordinary people, in the genetic analysis of more than 20000 families. Surprisingly, most of these hypermutations may be related to the increase of mutations in the father's sperm.
Such mutations that occur in parental germ cells, especially during meiosis, and are passed on to the next generation are also known as neonatal mutations, that is, new mutations that are not available to parents. When the genome is passed from parents to offspring, the replication error rate is actually very low, but it does not mean that there is no genome.
Random mutations in sperm or eggs cannot be completely avoided, while newborn mutations are about 60-70. This mutation usually does not affect children's health, but in rare cases, it may still cause rare diseases.
One of the factors affecting the incidence of this newborn mutation is the age of the parents. For each year older, the father will add 2 newborn mutations and the mother will add 0.5. But this is not enough to explain the multiple mutation frequency in 12 newborns.
Since the analysis data come from more than 20000 British families, the proportion of 12 children is not too high. Therefore, this situation is unlikely to be caused by common factors, such as parental smoking, environmental pollution, etc.
In the follow-up analysis, the researchers found that there were 8 children, and their newborn mutations from their father were significantly higher than expected, suggesting that the sperm provided by their father obviously caused the supermutation of their children, and these fathers may have common characteristics or experiences.
Through the investigation of background data, they found the possible reasons for the increase of sperm mutation and supermutation in offspring. Most of these fathers had received chemotherapy before preparing for pregnancy. There were platinum chemotherapy related mutation patterns in the DNA of three children, and the fathers of two children had been treated with antitumor alkylating agents.
These fathers had suffered from different types of cancer before giving birth, and the chemotherapy drugs they received also damaged DNA in different forms. Platinum chemotherapeutic drugs can destroy the covalent modification of DNA and affect the base interaction. Of course, these errors can be repaired by nucleotide excision, but it is easy to cause single base mutation.
These somatic mutations may eventually further increase the mutation rate of germ cells, resulting in supermutation in offspring. The study pointed out that the probability of serious genetic diseases caused by newborn mutations is about 1 / 300, but once there is a super mutation phenomenon, such as a four fold increase in newborn mutations, the probability of children suffering from genetic diseases will become more than 1 / 100. Once it happens, it will be a serious blow to any family.
Dr John Danesh, of the University of Cambridge, UK, said: "hypermutation is not common in children, but it increases the risk of genetic diseases. The new findings have important guiding significance for some medical decisions." For example, fathers may choose to freeze sperm before receiving chemotherapy to reduce the impact of treatment on their children.
However, the study also pointed out that due to the small number of samples, it seems that chemotherapy has only affected the sperm of a very small number of men, and many parents who have given birth after chemotherapy have no hypermutation in their children.
Professor Matthew Hurles, the corresponding author of the study, said they need to further determine whether there is a causal relationship between chemotherapy and sperm mutations, and identify which chemotherapy is more likely to have such effects. This is of great significance to pregnancy preparation guidance and the birth of countless healthy new lives.