According to the latest “Nature” paper, researchers from the Sanger Institute and other institutions have found in the genetic analysis of more than 20,000 families.12 children have abnormally high frequency mutations, about 2-7 times that of ordinary people. Surprisingly,Most of these hypermutations may be related to increased mutations in the father’s sperm.
Mutations like this that occur in parental germ cells, especially during meiosis, and are passed on to the next generation are also calledde novo mutation,which isNew mutations that parents don’t have. 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 copying error.
Random mutations in sperm or eggs cannot be completely avoided, while de novo mutations are around 60-70. This mutation usually does not affect the health of the child, but in rare cases it can still cause rare diseases.
One of the factors affecting the incidence of this de novo mutation is the age of the parents,2 additional de novo mutations per year older for fathers and 0.5 for mothers. But this was not enough to explain the several-fold higher mutation frequency in the 12 newborns.
Since the analysis data comes from more than 20,000 British families, the proportion of 12 children is not too high. Therefore, this condition is unlikely to be due to common factors such as parental smoking, environmental pollution, etc.
In a follow-up analysis, the researchers found that eight children had significantly more de novo mutations from their fathers than expected, suggesting that theySperm provided by father apparently caused hypermutation in children, these fathers may have shared characteristics or experiences.
Through background data investigations, they identified possible causes of increased sperm mutation and offspring hypermutation.Most of these fathers had chemotherapy before trying to conceive, 3 children had platinum-based chemotherapy-related mutational patterns in their DNA, and 2 other children had fathers who had been treated with antitumor alkylating agents.
These fathers all had different types of cancer before giving birth,The chemotherapy drugs they received also damaged DNA in different forms. Platinum-based chemotherapy drugs can destroy covalent modifications of DNA and affect base interactions. Of course these errors can be repaired by nucleotide excision, but it is easy to cause single base mutations.
These somatic mutations may ultimately further increase the mutation rate of germ cells, leading to hypermutation in offspring. The study pointed out that the probability of serious genetic diseases caused by new mutations is about 1/300, but once hypermutation occurs,For example, if the new mutation increases by 4 times, the probability of children suffering from genetic diseases has become more than 1 in 100.. Once it happens, it is a serious blow to any family.
Dr John Danesh, of the University of Cambridge, UK, said: “Hypermutation in children is uncommon, but it can increase the risk of genetic diseases. The new findings have important implications for some medical decisions.” For example, fathers may be able to freeze sperm before undergoing chemotherapy. , to reduce the impact of treatment on children.
However, the study also pointed out that due to the small sample size,Chemo seems to have affected sperm in only a very small number of men, and many parents who had children after chemotherapy did not develop hypermutations.
The study’s corresponding author, Professor Matthew Hurles, said they needed to further determine whether there was a causal link between chemotherapy and sperm mutations, and to identify which chemotherapy was more likely to have such effects. This is of great significance for pregnancy guidance and the birth of countless healthy new lives.