Martinho Lab

Have you seen this paper in @Nature ? doi.org/10.1038/s41586-022-0… I’m very skeptical about the idea that accumulation of somatic mutations could be the cause of aging. However, in this study authors demonstrated how strikingly accurate rate of mutations accumulation between species correlate (inversely) with species lifespan. Also note, that absolute number of mutations per genome is extremely low in naked-mole rats compared to mice. (Does it mean that NMRs have more faithful DNA polymerase?) But my skepticism still holds. Without mechanistical evidence I would say that accumulation of somatic mutations is rather consequence of aging, than its driver. Again, look at the data. Animals ultimately accumulate around 4,000 mutations per genome. But more than 90% of our genome does not code proteins. Hence we might say that only 400 of these mutations target genes. But out of 20,000 genes in our genome one type of cell uses less than half of them. Thus, we have now only 200 plausibly detrimental mutations. However, not all mutations are missense: decrease the number again. Next, our genome is diploid and for vast majority of genes one functional copy is more than enough. What’s the probability that among these 150 mutations you will hit one of those rare genes, for which the loss of a single copy results in a strong phenotype? Or what’s the probability that among these 150 mutations you hit both copies of one gene? Finally, many proteins have isoforms with partially or even fully overlapping functions. Moreover, in this study authors used intestinal cells, a tissue known for one of the highest rate of mutations in the organism. However, I’m not the specialist in genomics and maybe I’m totally wrong. If the answers to my doubts are already given I would be happy to hear them! For example, I know that @VijgJan lab have data on a strong correlation between increased number of mutations in the cell and augmentation of transcriptional noise. Another argument coming to my mind is that untranslated regions of genome are less susceptible to DNA damage just because of passive protection with histones and thus mutations might target the actively translated (and hence pivotal for a cell function) regions of genome with higher probability.