Why older fathers might pass on more mutations to offspring, new study reveals

In a new study, scientists explain why older male fruit flies are more likely to transfer mutations onto their progeny, perhaps providing light on the danger of genetic illness in people.

The male reproductive system acts as a breeding ground for new genes.

Perhaps this explains why dads inherit more new mutations than moms. This does not explain why older dads pass on more mutations than younger fathers.

According to the study, the processes that may underpin these well-documented patterns have long been a mystery. Rockefeller University in the United States examined mutations that develop during the creation of sperm from germline cells, a process known as spermatogenesis.

They discovered that both young and old fruit flies have mutations in their testes, but that older flies have more mutations overall. 

The research results were released in the journal Nature Ecology & Evolution. Furthermore, many of these mutations appear to be fixed by the body's genomic repair mechanisms during spermatogenesis in younger fruit flies, but not in the testes of older flies. 

According to first author Evan Witt, "We were trying to test whether the older germline is less efficient at mutation repair, or whether the older germline just starts out more mutated." "Our findings show that it's really both. Older flies have more mutations per RNA molecule than younger flies at every stage of spermatogenesis. 

Genomes keep themselves tidy using a handful of repair mechanisms. When it comes to testes, they have to work overtime; testes have the highest rate of gene expression of any organ. Moreover, genes that are highly expressed in spermatogenesis tend to have fewer mutations than those that are not. This sounds counterintuitive, but it makes sense, according to the study. 

One theory to explain why the testes express so many genes holds that it might be a sort of genomic surveillance mechanism - a way to reveal, and then weed out, problematic mutations, the study said. But when it comes to older sperm, the researchers found, the weed-whacker apparently sputters out. 

Previous research suggests that a faulty transcription-coupled repair mechanism, which only fixes transcribed genes, could be to blame. 

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

In order to understand whether the mutations they detected were somatic, or inherited from the flies' parents, or de novo - arising in the individual fly's germline - they then sequenced the genome of each fly, the study said. They were able to document that each mutation was a true original. 

"We can directly say this mutation was not present in the DNA of that same fly in its somatic cells," said Witt. "We know that it's a de novo mutation." This unconventional approach - inferring genomic mutations from single-cell RNA sequencing and then comparing them to the genomic data - allowed the researchers to match mutations to the cell type in which they occurred. "It's a good way to compare mutational load between cell types, because you can follow them throughout spermatogenesis," said Witt. 

The next step is to expand the analysis to more age groups of flies and test whether or not this transcription repair mechanism can occur - and if it does, identify the pathways responsibly, Witt said. "What genes are really driving the difference between old and young flies in terms of mutation repair?" asked Witt. Because fruit flies have a high reproductive rate, investigating their mutation patterns can offer new insights into the effect of new mutations on human health and evolution, said the study. 

"It's largely unknown whether a more mutated male germline is more or less fertile than a less mutated one. "There's not been very much research on it except for at a population level. And if people inherit more mutations from aging fathers, that increases the odds of de novo genetic disorders or certain types of cancers," said Witt.