Thanks Trevor! I remember this was the PhD chapter that probably sparked the most viva discussion.. ☺️

Thank you!

Ha.. yeah, the big question! Not really unfortunately. We think it is probably structurally non-bulky so as not to substantially stall the replication machinery. And may relate to the hypoxic niche of HSCs. I know others have also speculated that aldehydes may be involved.. Any theories welcome!

Thank you Maria!

Thanks Andrew. Yeah, an exciting discovery is rarely the end result! But great when it is

Ha! Love it.. need to get a copy of that for my wall

A huge thank you to Peter Campbell, my supervisor whose insights were vital to getting this study started. When I showed him the 1st unexpected mutation he said (typically) ‘I wondered if this might happen..’ Also, thanks to @imartincorena.bsky.social & @timcoorens.bsky.social for valuable advice.

Also, the whole idea of these persistent lesions builds on the concept of 'lesion segregation' observed (again, unexpectedly) and developed by
@s-j-aitken.bsky.social , Martin Taylor, Duncan Odom & team.

This discovery science is only possible thanks to the large-scale somatic phylogeny datasets re-analysed here, generated by Emily Mitchell, Stan Ng, Matthias Wilk,Kenichi Yoshida,Jyoti Nangalia+others, funded by @cancerresearchuk.org @sangerinstitute.bsky.social @wellcometrust.bsky.social + others

Intriguingly, blood stem cells had a particular type of very long-lasting damage (~2-3 years), leading to 15-20% of their mutations – some contributing to cancer. This damage wasn’t evident in other tissues. We have theories, but we don’t yet know why.

It was these patterns of unusual mutation inheritance, or multiple different mutations at the same site in closely related cells that was the key to recognizing & characterizing these unusual types of long-lasting damage.

If the base is partially recognizable, the DNA copying machinery may flip between copying it right, and copying it wrong in one specific way. This will only cause 1 mutation, but the pattern of inheritance will not fit a single acquisition event (a ‘phylogeny-violating variant’)

But what if it’s not? If the DNA damage sticks around through multiple rounds of cell division & DNA replication it may be misread in different ways in each round. This will lead to different mistakes at the same position (a ‘multi-allelic variant’).

If the damaged base is present during DNA replication it may be misread, resulting in permanent mutations that can contribute to cancer development. However, the DNA damage itself is usually recognized and mended quickly by repair mechanisms in our cells.

How did we work this out?

DNA damage is distinct from a mutation. While a mutation is one of the 4 standard DNA bases (A, G, T or C) in the wrong place (like a spelling mistake), DNA damage is chemically altered DNA (more like some illegible writing).

After ‘pulling the thread’ we found the explanation. Some specific types of DNA damage persist unrepaired through multiple cell divisions, in some cases for years. This goes against the usual idea that damage is efficiently repaired by the cell’s DNA repair machinery.