The male reproductive system has been identified as a hub for the appearance of novel genes, which might account for the greater number of new mutations that are transmitted by fathers as opposed to mothers. However, the explanation behind why elderly fathers tend to pass on more mutations compared to younger ones has been elusive.
A study recently published in Nature Ecology & Evolution by researchers from Rockefeller University sheds some light on this issue. The study examines why male fruit flies that are older are more prone to passing on mutations to their offspring. The findings of this research could bring us closer to understanding the likelihood of inheriting diseases in humans.
Scientists working in Li Zhao's laboratory investigated mutations that take place during the formation of sperm from germline cells, called spermatogenesis. They discovered that mutations are prevalent in the testes of both young and old fruit flies, but are more plentiful in older flies from the beginning. Additionally, the body's genomic repair mechanisms appear to eliminate many of these mutations during spermatogenesis in younger fruit flies, but they remain unfixed in the testes of older flies.
Determining Aging Germline and Mutations
According to Evan Witt, the first author of the study and a computational biologist at BioMarin Pharmaceuticals, the objective of the research was to determine if the aging germline is less effective at fixing mutations or if it simply starts with more mutations. The results showed that it is a combination of both factors. At every stage of sperm production, there are higher levels of mutations per RNA molecule in older fruit flies compared to younger ones.
The genomes maintain their integrity by using several repair mechanisms. In the case of testes, they have to perform at an increased rate due to the high expression of genes in this organ. Additionally, genes that are highly expressed during sperm production tend to have fewer mutations compared to those that are not. Although this may seem counter intuitive, it is logical as one theory suggests that the high expression of genes in testes might serve as a monitoring system for identifying and eliminating harmful mutations, as reported by SciTech Daily.
However, the study found that when it comes to older sperm, the mechanism for eliminating mutations seems to become ineffective. Previous research has indicated that a defective transcription-coupled repair system, which only repairs genes that are transcribed, could be the cause of this issue. The researchers in the Laboratory of Evolutionary Genetics and Genomics arrived at these conclusions by conducting single-cell sequencing on the RNA from the testes of approximately 300 fruit flies. Half of these fruit flies were young (48 hours old) and half were old (25 days old). They continued the research they started in 2019.
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Dominant Mutations
To determine whether the mutations they detected were somatic, inherited from the parent flies, or de novo (occurring in the individual fly's germline), they sequenced the genome of each fly. They were able to confirm that each mutation was a new occurrence. According to Witt, they were able to state directly that the mutation was not present in the DNA of the same fly in its somatic cells and that it was a de novo mutation. This innovative approach of inferring genomic mutations from single-cell RNA sequencing and then comparing them to the genomic data allowed the researchers to link mutations to the specific cell type in which they took place.
Witt explains that this is a useful method for comparing the mutational load between different cell types as it enables tracking of mutations throughout the sperm production process. The next step for the research is to expand the analysis to include more age groups of fruit flies and investigate if the transcription repair mechanism can occur and identify the responsible pathways. Witt is curious to know, "What genes are actually behind the difference between old and young flies in terms of mutation repair?"
According to Zhao, the high reproductive rate of fruit flies makes them a valuable model for studying mutation patterns and the impact of new mutations on human health and evolution. Witt states that there has been limited research on whether a more mutated male reproductive system is more or less fertile compared to a less mutated one, mostly at a population level. If individuals inherit more mutations from aging fathers, it increases the likelihood of developing genetic disorders or specific types of cancers.
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