Aging is a complex biological process involving gene expression and changes in mutation load. 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 at Rockefeller University are investigating the root causes of this phenomenon. To do this, they studied mutations that occur during the production of sperm from germline cells, known as spermatogenesis. They found that young and old fruit flies have mutations in their testes, but older flies generally have more mutations. In addition, 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 tried to test whether the older germline is less efficient at repairing mutations or whether the older germline is starting to become more mutated. Our results indicate that it is both. At each 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 level of gene expression of any organ, so they have to work extra hard. In addition, high-expressing spermatogenesis genes typically have fewer mutations than low-expressing genes. Despite what may seem strange, this makes sense: According to one theory, the high gene expression of the testes could be a kind of genomic surveillance mechanism that identifies and eliminates deleterious mutations.

However, when it comes to older sperm, the weed killer sputters out, scientists have found.

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

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

“This unconventional approach – deriving 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 is a good way to reduce the mutation load between cell types. compare, because you can follow them throughout the entire spermatogenesis.”

Scientists further plan to expand this research to more age groups of flies and test whether or not this transcription repair mechanism can occur — and if so, responsibly identify the pathways.

Magazine reference:

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