**：infoxmed
Aging is a complex biological process accompanied by changes in gene expression and mutational burden. In many species, including humans, older fathers pass on more de novo mutations from the paternal line;However, the cellular basis and cell types that drive this pattern remain unclear.
On January 12, 2023, Li Zhao's team at Rockefeller University published a study titled "Transcriptional and mutational signatures of the Drosophila ageing germline" in Nature Ecology & Evolution** The study found that the early germ cells of old and young Drosophila had a similar mutational load when they entered the spermatogenesis process, but the elderly Drosophila had a poor ability to remove mutations during spermatogenesis.
Mutations in old cells may also increase during sperm formation. The data show that old and young fruit flies have a clear tendency to mutate. Many species of genes show increased post-meiotic expression in the germline of aged Drosophila. The late spermatogenesis bias gene has a higher DN DS (ratio of non-synonymous substitutions to synonymous substitutions) than the early spermatogenesis bias genes, which supports the hypothesis that late spermatogenesis is an evolutionary innovation**. Surprisingly, genes biased in young germ cells showed higher DN DS than genes biased in older germ cells. The study provides new insights into the role of germline in de novo mutations.
In animals, aging is a process that is accompanied by phenotypic changes. These phenotypic changes include both observable traits and intermediate traits such as gene expression. Aging affects not only the health of future generations, but also evolution. As they age, they may pass on more de novo mutations to their offspring. Most new mutations are inherited from the paternal germline, and the number of mutations inherited increases with paternal age. Some studies attribute too many paternal mutations to the increase in the number of cell**s that sperm stem cells experience over the course of a man's lifetime. Conversely, other reports have found that too many cells** are not associated with the ratio of maternal to paternal mutations during aging, suggesting that lifestyle, chemicals, and environmental factors may contribute to this difference. Previous studies on the effect of age on paternal genetic mutations have inferred de novo mutations through sequencing of parents and offspring. These methods are very useful, but they can only capture nascent mutations that evade the repair mechanism and eventually enter viable gametes, fertilizing the egg and producing viable embryos. Little is known about mutations and repair dynamics within the male germline.
One study found that mutations occurred least frequently in human spermatogonia. However, in previous studies, it was found that the mutational load was highest in the early stages of spermatogenesis. These results suggest that most mutations occur prior to germline stem cell (GSC) differentiation and are removed during spermatogenesis. Are these mutations replicating in origin?If this is the case, germline stem cells from older fruit flies are more susceptible to mutations than germline stem cells from young fruit flies. In addition to these mutational effects, senescence is known to lead to other germ cell phenotypes, such as a decrease in the number of germ cells and a decrease in the ability of germ cell stem cells to proliferate. The GSC microenvironment also undergoes chemical changes associated with reduced fecundity. In fact, these phenotypic consequences may be associated with mutations, as germline mutation rates in young people correlate with lifespan. Therefore, the germline mutation rate has an impact on both the organism and its offspring.
The proportion of mutant cells and the mutational load span young and old flies across cell types (Figure from Nature Ecology & Evolution).
In a previous study, researchers used single-cell RNA sequencing (scrna-seq) to track germline mutations during spermatogenesis in Drosophila and found evidence that the abundance of germline mutations decreased during spermatogenesis. Some germline genomic maintenance genes have also been found to be more expressive in GSCs and early spermatogonia (the earliest male germ cells). This result is consistent with the idea that active DNA repair plays a role in the male germline. The study showed that the germline of older flies was less capable of removing de novo mutations than the germline of young flies. Throughout spermatogenesis, germ cells from aged Drosophila were observed to have more mutations per RNA molecule than their congeners from younger Drosophila. This finding provides a new explanation for the still controversial mechanism behind the age-dependent mutational burden increase in the male germline.
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