Random Mutations in Nuclear DNA are Prevalent in Old Tissues

Evolution requires happenstance mutation in order to progress, but too much of this random mutation leads to cancer or other forms of dysfunction sufficient to reduce reproductive fitness. The result is our present balance: enough mutation to make cancer a major cause of death, to ensure that mitochondria contribute to aging via mutation of mitochondrial DNA, and to produce some level of general dysfunction in aged tissues due to the accumulated mutational burden. The research noted here is one representative example of a range of research that seeks to quantify the degree to which our cells exhibit random mutational damage as we age. You might compare it with another set of results published recently on competition between mutations in skin, and how this paradoxically manages to suppress cancer risk.

Every person accumulates genetic changes, or mutations, throughout their lifetime. These mutations in normal tissue, called somatic mutations, are key to understanding the first steps to cancer and likely contribute towards ageing, but are uncharted territory due to technical limitations. For the first time, scientists have uncovered that on average, healthy cells in the oesophagus carry at least several hundred mutations per cell in people in their twenties, rising to over 2,000 mutations per cell later in life. Only mutations in a dozen or so genes seem to matter however, as these give the cells a competitive advantage allowing them to take over the tissue and form a dense patchwork of mutations.

The team used targeted and whole-genome sequencing to map groups of mutant cells in normal oesophageal tissue from nine individuals aged 20 to 75 years. The individuals' oesophageal tissues were considered healthy as none of the donors had a known history of oesophageal cancer, nor were taking medication for problems relating to the oesophagus. The study also casts new light on the mutations that are found in the squamous kind of oesophageal cancers. One mutated gene, TP53, which is found in almost all oesophageal cancers is already mutated in 5-10 per cent of normal cells, suggesting that cancer develops from this minority of cells.

In contrast, mutations in the NOTCH1 gene, known to control cell division, were found in nearly half of all cells of normal oesophagus by middle age, being several times more common in normal tissue than cancer. This observation suggests that researchers need to reconsider the role of some genes recurrently mutated in cancer in the light of mutations in normal tissue, and raises the possibility that the NOTCH1 mutation may even protect cells against cancer development. "This study shows that some genetic changes linked to cancer are present in surprisingly large numbers of normal cells. We still have a long way to go to fully understand the implications of these new findings, but as cancer researchers, we can't underestimate the importance of studying healthy tissue."

Link: https://www.sanger.ac.uk/news/view/mutant-cells-colonise-our-tissues-over-our-lifetime

Comments

Does this mean that SENS is sunk?

Posted by: Jim at October 23rd, 2018 6:28 AM

@Jim: Old tissues have more mutation. The question has always been does this have a significant effect on metabolism over the present human life span, beyond cancer risk. The evidence meanders back and forth, and at present the consensus seems to be that there is enough of an issue not to just put it off. Fixes will be technically challenging, of course. That doesn't remove the benefits or the necessity for all the portions of SENS unrelated to numclear DNA damage.

Whether nuclear DNA damage should be tackled now or whether it is best put off into SENS version 2 is an interesting topic for debate.

Posted by: Reason at October 23rd, 2018 7:03 AM

Several hundred by age 20? This brings up the question of whether it is possible to have a full genome done on cord blood, which we have banked for our daughter.

Posted by: Tom Schaefer at October 23rd, 2018 7:27 AM

@Reason The real question here is what kind of mutations did they find? We know some kind of mutations are harmless and they doesn't state that.

Posted by: Moses at October 23rd, 2018 8:23 AM

Also it doesn't tell us how many of these mutated cells are senescent.
It was much more informative if they made single cell transcriptome analysis

Posted by: Moses at October 23rd, 2018 9:11 AM

A good question is whether these nuclear mutations cause detectable changes in the cell membrane that could be located by the Oisin technology. Badly mutated cells could be destroyed and repopulated with stem cell grafts.

Posted by: Morpheus at October 24th, 2018 12:35 AM

The obvious solution to nuclear DNA damage is some kind of stem-cell based regeneration. I don't understand why people think nuclear DNA damage is some kind of show-stopper that cannot be overcome.

Posted by: Abelard Lindsey at October 26th, 2018 1:30 PM
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