Why older fathers pass on more genetic mutations to their offspring?

The male reproductive system is a hot spot
for the emergence of new genes.
Perhaps this explains why more new mutations are inherited from fathers than from
mothers.
However, it doesn't explain why older fathers pass on more mutations
than younger fathers.

The mechanisms behind these well-documented trends have long been a mystery
.
Now, scientists at Rockefeller University have described why older male fruit flies are more likely to pass on mutations to their offspring, which could provide clues
to the risk of genetic diseases in humans.

Researchers in Li Zhao's lab studied the mutations that occur during the production of sperm by germ cells, the spermatogenesis process
.
They found that mutations were common in the testicles of both young and old fruit flies, but from the beginning, older fruit flies had more mutations in their testicles
.
In addition, many of these mutations appear to be cleared by the body's genomic repair machinery during spermatogenesis in young fruit flies, but they cannot be repaired
in the testicles of old fruit flies.

"We tried to test whether older germ cells were less efficient at mutation repair, or whether older germ cells were more mutant in the first place," said first author Evan Witt.

At every stage of spermatogenesis, older flies had more
mutations in each RNA molecule than young flies.
”

Self-care at the genetic level

The genome maintains itself intact
through a number of repair mechanisms.
When it comes to the testicles, they have to work overtime because the testicles have the highest
gene expression rate of any organ.
In addition, genes that are highly expressed during spermatogenesis tend to have fewer mutations
than those that are not.
It sounds counterintuitive, but it makes sense
.
One theory that explains why the testes express so many genes suggests that this could be a genomic surveillance mechanism, a way to
reveal and weed out problematic mutations.

But the researchers found that this clearance mechanism stopped working
when it came to aging sperm.
Previous research has suggested that the faulty transcriptional coupling repair mechanism (repairing only transcriptional genes) may be the culprit.

Inherited or new mutations?

To get these results, the scientists performed single-cell sequencing of RNA from the testes of about 300 fruit flies, about half of them young flies (48 hours old) and half old flies (25 days old), which advanced a series of studies
they began in 2019.
To understand whether the mutations they detected were somatic, inherited from the flies' parents, or produced de novo in the individual flies' germ cells, they sequenced
each flies' genome.
The researchers proved that each mutation was a true original gene
.
"We can simply say that this mutation is not present in
the somatic DNA of the same fruit fly," Witt said.
We know it's a de novo mutation
.
”

This unconventional method — a method of inferring genomic mutations from single-cell RNA sequencing and then comparing them to genomic data — allows researchers to match mutations to
the cell type in which the mutation occurred.
"It's a great way to compare mutational load between cell types because you can track them
throughout spermatogenesis," Witt said.

Relationship with humans

The next step is to expand the analysis to more age groups of flies and test whether this transcriptional repair mechanism will occur — and if it does, determine the pathway responsible, Witt said
.
"What genes really drive the difference between old and young fruit flies in terms of mutation repair?"

Because fruit flies have a high reproductive rate, studying their mutation patterns could provide new insights
into the impact of new mutations on human health and evolution, Zhao said.

Witt added: "Whether a male germline with more mutations is more or less fertile than a male germline with fewer mutations
is largely unknown.
There are not many
studies on it other than at the population level.
If people inherit more mutations from their aging fathers, it increases the odds
of a newborn genetic disorder or certain types of cancer.
”