Under the Shadow: Old-biased Genes Are Subject to Weak Purifying Selection at Both the Tissue- and Cell Type-Specific Levels.

The mutation accumulation hypothesis suggests that weakened purifying selection at old age leads to the accumulation of late-acting deleterious variants in the gene pool, which may contribute to the evolution of ageing. In accordance with this model, others and we have shown that sequence conservation among old-biased genes (with higher expression in old vs. young adults) is weaker than among young-biased genes across several mammalian and insect species. However, it has remained unclear whether the observed patterns were driven by tissue and cell type composition shifts or by cell-autonomous expression changes during ageing. How wide this trend would extend to nonmammalian metazoan ageing was also uncertain. Here we analyzed bulk tissue as well as cell type-specific RNA sequencing data from diverse animal taxa across six different datasets from five species. We show that the previously reported age-related decrease in transcriptome conservation is commonly found in ageing tissues of nonmammalian species, including nonmammalian vertebrates (chicken brain, killifish liver and skin) and invertebrates (fruit fly brain). Analyzing cell type-specific transcriptomes of adult mice, we further detect the same age-related decrease in transcriptome conservation trend at the single-cell type level. Old-biased genes are less conserved across most cell types analyzed in the lung, brain, liver, muscle, kidney, and skin, and these include both tissue-specific cell types, and also ubiquitous immune cell types. Our results support the notion that ageing in metazoan tissues is shaped by the mutation accumulation process.