Selfish sperm cause older fathers to pass on more disease-causing mutations

The risk of older parents passing disease-causing mutations to their children is higher than we thought. Genome sequencing revealed that among men in their early 30s, about one in 50 sperm have a disease-causing mutation, which rises to nearly 1 in 20 by the age of 70.

“The study clearly shows that older parents have a greater risk of transmitting more disease-causing mutations,” the study says. Rahila Rahbari At the Wellcome Sanger Institute in the United Kingdom.

Prospective parents may want to take this into consideration, says the team member Matthew Nevilleand also at the Sanger Institute. “It’s something families need to take into consideration when making their own decisions.” For example, younger men can consider sperm freezing if they think they are unlikely to have children until they are much older, while older men who are planning to start a family can consider the different screening techniques available.

Recent studies have shown that each of us has about 70 new mutations that neither parent has in most cells in our body, with 80% of these mutations arising in the fathers’ testes (this is not counting extensive chromosomal abnormalities, which are more common in the mother’s eggs). It was thought that the number of mutations in sperm rose steadily as men aged, due to random mutations. But some genetic conditions, including achondroplasia, or dwarfism, are much more common than would be expected from random mutations.

In 2003, Anne Gorelli Researchers at Oxford University realized that this might be the result of some stem cells causing sperm to become selfish. This means that some mutations can cause these stem cells to reproduce more than normal, so the percentage of sperm carrying these mutations rises dramatically as men age, rather than at a constant rate. Gorrelli went on to show that mutations in several different genes could make sperm stem cells selfish, but she suspected there was more.

Now, Rahbari, Neville and their colleagues have sequenced more than 100,000 sperm from 81 men of various ages, along with their blood cells. With standard sequencing methods, the error rate is too high to reliably identify mutations in single DNA molecules, but the team used a new technique that involves sequencing both strands of the double helix – if a mutation is found on both strands, it is unlikely to be an error.

This approach allowed them to identify a wide range of mutations in more than 40 genes that make sperm stem cells selfish. “The magnitude of the effect across the genome was much higher than any of us thought,” Neville says.

While these selfish mutations represent only a small percentage of all mutations, their impact is very large. This is because Most of our genomes are junkWhich means that most random mutations have no effect.

In contrast, selfish mutations affect key genes and can therefore have large effects. “Most of the time, these are fairly severe neurodevelopmental disorders,” Neville says. With at least two of the 40 genes present, these conditions include autism, while some mutations significantly increase the risk of cancer.

She says it’s a very interesting study Robin Arslan at Witten University in Germany, who highlighted the finding that these selfish mutations increase nonlinearly. One way to look at this, he says, is that one extra year of paternal life when you’re young is less harmful than one year when you’re old.

It’s a good study that requires a lot of effort, Gorelli says. “We’ve known for a long time that being an older parent is not a good idea,” she says. “The focus was already tied to the mother. Now we understand that both parents contribute to the health of their children.”

In men’s blood samples, the overall burden of mutations was much higher in men who smoked, drank heavily, or were obese. But the mutations accumulated eight times slower in sperm, and there was no link to smoking, drinking or obesity. This suggests that the body has a way of protecting the testicles from environmental factors such as these.

In a separate study by a team including Rahberry and Neville, the new sequencing technology was applied to skin cells in the mouth, revealing a similar pattern of growth-promoting mutations that increase the proportion of certain stem cell lineages.

“It appears that these patterns of selection are not something exclusive to sperm cells,” Rahbari says. She says that while growth-promoting mutations are a step towards cells becoming cancerous, they can cause problems even if the cells do not become cancerous, and may even contribute to the aging process.

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