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Thursday, February 9, 2023

Older fathers pass on more mutations and diseases to Children compared to mothers – Scientists 

In a new study, researchers have described why older male fruit flies are more likely to pass on mutations to their offspring, which may shed light on the risk of inherited disease in humans. The male reproductive system serves as a hotspot for the emergence of new genes. Perhaps this explains why more new mutations are inherited from fathers than from mothers.

However, this does not explain why older fathers pass on more mutations and diseases to children than younger ones. The mechanisms that might underlie these well-documented trends have long remained a mystery, the study said.

Scientists at Rockefeller University in the US studied mutations that occur during the production of sperm from germ cells, known as spermatogenesis. They found that mutations are common in the testes of both young and old fruit flies, but are more abundant from the start in older flies.

The findings were published in the journal Nature Ecology & Evolution.

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Moreover, many of these mutations appear to be removed in younger fruit flies during spermatogenesis by the body’s genome repair mechanisms—but fail to be fixed in the testes of older flies.

“We sought to test whether the older germline is less efficient at repairing mutations, or whether the older germline begins to mutate more,” said first author Evan Witt.

“Our results suggest that it is actually both. At each stage of spermatogenesis, there are more mutations per RNA molecule in older flies than in younger flies,” Witt said.

Genomes are kept in order by several repair mechanisms.

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When it comes to testicles, they have to work overtime; the testis has the highest level of gene expression of any organ. Additionally, genes that are highly expressed in spermatogenesis tend to have fewer mutations than those that are not.

It sounds counterintuitive, but according to the study, it makes sense. One theory to explain why the testes express so many genes posits that it could be a kind of genome surveillance mechanism — a way to detect and then remove problematic mutations, the study said.

But when it comes to older sperm, the researchers found that the weed apparently sizzles. Previous research suggests that a faulty repair mechanism associated with transcription, which only fixes transcribed genes, could be to blame.

To get these results, the researchers performed single-cell sequencing of RNA from the testes of about 300 fruit flies, about half of which were young (48 hours old) and half old (25 days old), advancing a line of inquiry they began in 2019, according to studies.

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To understand whether the mutations they detected were somatic, or inherited from the flies’ parents, or de novo — arising in the germline of individual flies — they then sequenced each fly’s genome, the study said.

They were able to document that each mutation was a true original.

“We can directly say that this mutation was not present in the DNA of the same fly in its somatic cells,” Witt said. “We know it’s a de novo mutation.”

This unconventional approach—inferring genomic mutations from single-cell RNA sequencing and comparing them to genomic data—allowed researchers to match mutations to the type of cell in which they occurred.

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“It’s a good way to compare mutational load between cell types because you can track them during spermatogenesis,” Witt said.

The next step is to extend the analysis to more age groups of flies and test whether or not this mechanism of transcriptional repair can emerge — and if so, identify the pathways responsible, Witt said.

“What genes really drive the difference between old and young flies in terms of mutation repair?” Witt asked.

Because fruit flies have a high reproductive rate, examining their mutational patterns may offer new insights into the effect of new mutations on human health and evolution, the study said.

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“It is largely unknown whether the more mutated male germline is more or less fertile than the less mutated.

“There hasn’t been a lot of research on this, except at the population level. And if people inherit more mutations from aging fathers, it increases the likelihood of de novo genetic disorders or certain types of cancer,” Witt said.

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