Longer Genes May Be More Disrupted than Shorter Genes by Random DNA Damage Occuring with Age
Random mutational damage to nuclear DNA occurs constantly. While near all of it is restored by the highly efficient suite of DNA repair mechanisms present in the cell, some is not. This damage accumulates over time. Fortunately, near all of it occurs in DNA that is unused in that cell type, or occurs in genes that are not all that important, or occurs in somatic cells that have few replications remaining before hitting the Hayflick limit. In other words, most DNA damage isn't all that important, and even where it sticks, it will be cleared from the body via the normal processes of replacement of cells in a tissue.
How does DNA damage contribute to aging? Firstly, cancer risk: an unlikely combination of mutations occurring in any cell can give rise to a cancerous cell capable of unfettered replication. It is a risk throughout life, but that risk grows as the immune system ages and as the aged, ever more inflammatory tissue environment becomes more hospitable to the growth of a nascent cancer. Beyond cancer, it is likely that damage to stem cells is the primary problem, as lingering mutations in stem cells can spread throughout tissues to form patterns of overlapping mutational damage called somatic mosaicism. A minor loss of function in one cell is not a disaster. A minor loss of function in half of an organ may be a meaningful contribution to degenerative aging.
Is DNA damage really random in its effects on genes, however? Today's open access paper is one of a number to point out that longer genes are more vulnerable, and that an examination of changes in gene expression shows a greater loss of expression of longer DNA sequences than shorter DNA sequences. It is interesting to speculate on the degree to which this shapes the details of changes in cell behavior observed in aging, as compared to the contributions of the many other issues resulting from forms of damage. It is hard to do much more than speculate, however. Metabolism is ferociously complex, and the best way forward to answer any question is to repair a specific form of damage and see what happens as a result. Repair random mutational damage on a cell by cell basis is not a near term prospect, however, given the present state of genetic engineering.
It is worth noting that a different group of researchers has suggested that a reduction in the expression of longer DNA sequences with advancing age is the result of age-related changes in regulation of transcription, not DNA damage. It will be interesting to see how this debate over mechanisms progresses as more data emerges.
DNA damage has long been proposed as a primary molecular driver of aging. Aging has also been associated with a series of transcriptional changes, most of which are highly tissue- and cell type-specific. Even though the search for a global aging signature has been the goal of much research, meta-analyses have shown that very few genes are consistently upregulated or downregulated with aging across different tissues. It appears that, at the mRNA level, aging signatures are not defined by the overexpression of particular sets of genes, but rather an overall decay in transcription.
Genetic material is constantly challenged throughout the lifespan of the organism, both by endogenous and environmental genotoxins. Some of this damage happens in the form of transcription-blocking lesions (TBLs), which impede transcriptional elongation. Accumulation of TBLs provokes a genome-wide shutdown of transcription, which also affects undamaged genes through poorly understood mechanism. Assuming a constant TBL incidence, meaning that any base pair in the genome has a similar probability of suffering damage that results in a lesion, a greater accumulation of TBLs is to be expected in longer genes. In fact, a gene length-dependent accumulation of other forms of genetic damage, like somatic mutations, has already been reported in conditions like Alzheimer's disease. Hence, TBLs, just like somatic mutations are expected to accumulate with aging, and their accumulation should be dependent on gene length. However, unlike somatic mutations, TBLs have a strong and direct impact on mRNA production, and their gene length-dependent effects are likely to be measurable from RNA sequencing data of aged tissues.
So far, a potential relationship between age-related transcriptional changes and gene length has received relatively little attention. Here, we aimed to extend these early observations, which were based on bulk microarray and RNA sequencing data to the existing aging datasets based on single cell RNA sequencing technology. We also extended our gene length analyses to mouse and human datasets of lifestyle-induced genotoxic exposure (UV, smoke) and progeroid syndromes (Cockayne syndrome and trichothiodystrophy).
We found a pervasive age-associated length-dependent underexpression of genes across species, tissues, and cell types. Furthermore, we observed length-dependent underexpression associated with UV-radiation and smoke exposure, and in progeroid diseases, Cockayne syndrome, and trichothiodystrophy. Finally, we studied published gene sets showing global age-related changes. Genes underexpressed with aging were significantly longer than overexpressed genes. These data highlight a previously undetected hallmark of aging.