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Reposted by Mike Spencer Chapman

Wellcome Sanger Institute @sangerinstitute.bsky.social · Apr 10

The abnormal gene which causes chronic myeloid leukaemia has a very strong ability to drive rapid growth of the cancer, research has revealed 🧬

Scientists were able to track the evolution of this gene to study the rate at which the cancer cells expand: bit.ly/42riKOk

Image shows chromosome pairs with abnormal, stunted, chromosome 22 which causes chronic myeloid leukaemia. Credit: Nangalia Research Group.

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Mike Spencer Chapman @mikespencerchapman.bsky.social · Apr 2

Lovely piece from @s-j-aitken.bsky.social and Claudia Arnedo Pec discussing our recent paper in @nature.com on persistent mutagenic DNA lesions... Love the title!

Puts it in the context of their beautiful previous work on lesion segregation

Sarah Aitken @s-j-aitken.bsky.social · Apr 2

🧩DNA Lesions Piece Together Impossible Trees🧩

This was a fun piece to write (and illustrate!) with Dr Claudia Arnedo Pac about @mikespencerchapman.bsky.social and co’s recent @nature.com paper. Thank you for the invitation, Maria @cp-trendsgenetics.bsky.social

authors.elsevier.com/sd/article/S...

A person made up of jigsaw pieces representing the millions and millions of unique cells with unique genomes, which build a picture of our lifetime of cellular experiences.
Four panels, anticlockwise from top left, highlight key findings. (i) Phylogeny-violating variants (PVVs) caused by persistent DNA lesions explain otherwise ‘impossible’ trees. (ii) An estimate (in chronological time) of when lesions were acquired and for how long they persist. (iii) Demonstration in vivo that individual DNA lesions can give rise to both single nucleotide variants (SNVs) and small insertions or deletions (indels) in different cell cycles; this is a form of multiallelic variation, which more commonly relates to two alternate SNVs at the same site. (iv) Identification of lesion segregation of APOBEC mutagenesis, implicating that genome-wide mutagenesis occurred within a single cell cycle and that lesion segregation could explain the strand coordination of clustered APOBEC mutations commonly seen in cancer genomes.

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Reposted by Mike Spencer Chapman

Leif S. Ludwig @leifludwig.bsky.social · Jan 31

Interested in 'Mitochondrial single cell-multi-omics for lineage tracing and genetics'? Apply for our free workshop in Berlin following our #ISCO2025 conference!

www.isco-conference.eu

www.mdc-berlin.de/news/events/...

Mitochondrial single cell-multi-omics for lineage tracing and genetics

www.mdc-berlin.de

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Reposted by Mike Spencer Chapman

mchasselluhn.bsky.social @mchasselluhn.bsky.social · Jan 31

Is hypothesis generation a hindrance to Night Science? @itaiyanai.bsky.social and @stearnslab.bsky.social demonstrated how easy we fall into pattern recognition, missing the “Gorilla” in our own data. Today’s seminar was all about identifying new strategies to stay curious about our own data.

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Reposted by Mike Spencer Chapman

Sarah Aitken @s-j-aitken.bsky.social · Jan 15

🌟NEW PREPRINT ALERT!🌟

We are very pleased to introduce #StrainDifferences: “Genetic background sets the trajectory of cancer evolution”

www.biorxiv.org/content/10.1...

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Genetic background sets the trajectory of cancer evolution

Human cancers are heterogeneous. Their genomes evolve from genetically diverse germlines in complex and dynamic environments, including exposure to potential carcinogens. This heterogeneity of humans,...

www.biorxiv.org

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Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 17

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

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Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 16

Thank you!

Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 16

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!

Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 16

Thanks for sharing! And apologies for the cheap kitten meme..

Wellcome Sanger Institute @sangerinstitute.bsky.social · Jan 16

Check out @mikespencerchapman.bsky.social's thread below to find out more about his latest @nature.com paper on DNA damage ⤵️

Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 15

In science, we often see weird blips in the data. The question: is it artefact (usually!), or something new & exciting? We don’t always have time to dig deep.

Our paper in @nature.com today came from just such a blip. So don’t ignore the weird stuff. Pull on that thread...

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Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 16

Thank you Maria!

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Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 16

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

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Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 16

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

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Reposted by Mike Spencer Chapman

Barts Cancer Institute (Queen Mary University of London) @qmbci.bsky.social · Jan 15

📰 Some forms of DNA damage linger unrepaired in healthy cells for years, according to a @nature.com study led by Dr Mike Spencer Chapman @mikespencerchapman.bsky.social at BCI and @sangerinstitute.bsky.social.

The findings could inform our understanding of #cancer development. 🧪 #medsky

Discovery of lingering DNA damage could change our understanding of cancer development - Barts Cancer Institute - Queen Mary University of London

Dr Michael Spencer Chapman and team have uncovered forms of DNA damage in healthy cells that can persist unrepaired for years.

bit.ly

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Reposted by Mike Spencer Chapman

Trevor Graham @trevorgraham.bsky.social · Jan 15

This is a cool paper about the surprisingly long-term persistence of DNA lesions (single stranded DNA errors) in the human body. Exquisitely meticulous work from conception through to execution. Congratulations @mikespencerchapman.bsky.social

Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 15

So pleased to have the paper out, available here: www.nature.com/articles/s41586-024-08423-8
For me this was discovery science as I had always hoped it would be. A lot of fun, and some proper detective work with plenty of twists & turns on the way. Brief thread below

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Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 15

Yes! @s-j-aitken.bsky.social your fantastic work on lesion segregation really was the foundation for this.. gave us early confidence that some lesions were able to persist through multiple cell divisions & that our theory was viable

Sarah Aitken @s-j-aitken.bsky.social · Jan 15

Building on our discovery of #LesionSegregation, @mikespencerchapman.bsky.social and colleagues from @sangerinstitute.bsky.social find that some DNA lesions can persist in humans for months or years!

"Prolonged persistence of mutagenic DNA lesions in somatic cells"
www.nature.com/articles/s41...

Prolonged persistence of mutagenic DNA lesions in somatic cells - Nature

Persistent DNA lesions can occur throughout the human lifespan and can remain in the genome of affected cells for several years and generate a substantial proportion of the mutational burden.

www.nature.com

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Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 15

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.

a close up of a statue of yoda with the words `` thank you wise one '' written below him .

ALT: a close up of a statue of yoda with the words `` thank you wise one '' written below him .

media.tenor.com

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Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 15

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.

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Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 15

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

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Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 15

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.

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Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 15

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.

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Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 15

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’)

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Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 15

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’).

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Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 15

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.

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Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 15

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).

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Mike Spencer Chapman @mikespencerchapman.bsky.social · Jan 15

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.

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