Somatic mutation as an explanation for epigenetic aging

This is an interesting paper as it looks at the question as to what extent DNA methylation results in DNA mutation which then results in less methylation.

https://www.nature.com/articles/s43587-024-00794-x

Obviously this is potentially a big issue as it implies that genes which are methylated end up being mutated which is harder to fix than methylation which merely needs a TET enzyme.

There is an element to which DNA has forms of check digits in it which can be used to fix mutation. I have not reviewed this in detail, but there clearly is something there.

I have contacted the author of the paper to ask what proportion of methylated sites end up mutated.

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From chatgpt without reviewing for accuracy

Methylated DNA is more prone to mutations, particularly at CpG sites, where cytosine (C) is methylated to 5-methylcytosine (5mC). The most common mutation occurs when 5mC deaminates to thymine (T), leading to a C→T transition.

Proportion of Mutations at Methylated Sites:

  1. CpG sites mutate 10–50 times more frequently than non-methylated sites.

  2. About one-third of all point mutations in the human genome occur at methylated CpG sites.

  3. 80–90% of CpG sites in vertebrates are methylated, making them mutation hotspots.

  4. C→T transitions at CpG sites account for about 25–30% of disease-causing mutations in humans.

In summary, methylation significantly increases the likelihood of mutations, particularly C→T transitions, making CpG sites one of the most mutation-prone regions in the genome.

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