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

The mechanisms that might underlie these well-documented trends have long remained a mystery.

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Aging is a complex biological process accompanied by gene expression and mutational load changes. In many species, including humans, older fathers pass on more paternally derived de novo mutations; however, the cellular basis and cell types driving this pattern are still unclear.

Scientists from Rockefeller University explore the root causes of this phenomenon. To do so, they studied mutations occurring during the production of sperm from germline cells, known as spermatogenesis. They discovered that young and old fruit flies have mutations in their testes but that older flies have more mutations overall. Furthermore, many of these mutations appear to be removed by the body’s genomic repair systems during spermatogenesis in younger fruit flies but not in the testes of older flies.

First author Evan Witt, a graduate student in the lab and now a computational biologist at Biomarin Pharmaceuticals said, “We were trying to test whether the older germline is less efficient at mutation repair or whether the older germline starts more mutated. Our results indicate that it’s both. At every stage of spermatogenesis, there are more mutations per RNA molecule in older and younger flies.”

Genomes use numerous repair methods to keep themselves tidy. Testes have the highest rate of gene expression of any organ, thus, they have to work extra hard. Furthermore, spermatogenesis genes with high expression typically have fewer mutations than genes with low expression. Despite what might seem odd, this makes sense: According to one theory, the testes’ high gene expression may be a kind of genomic surveillance mechanism that identifies and eliminates harmful mutations.

However, when it comes to older sperm, the weed-whacker sputters out, found scientists.

To further a line of research they started in 2019, scientists from the Laboratory of Evolutionary Genetics and Genomics used single-cell sequencing on the RNA from the testes of about 300 fruit flies, roughly half of them young (48 hours old) and half of them old (25 days old). They next analyzed the genome of each fly to determine if the mutations they discovered were somatic, inherited from the parents of the flies, or de novo—arising in the particular fly’s germline. They were able to provide proof that every mutation was an authentic original.

Witt said“We can directly say this mutation was not present in the DNA of that same fly in its somatic cells. 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 us 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.”

Scientists are further planning to expand this research 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.

Journal Reference:

  1. Witt, E., Langer, C.B., Svetec, N. et al. Transcriptional and mutational signatures of the Drosophila aging germline. Nat Ecol Evol (2023). DOI: 10.1038/s41559-022-01958-x
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