I started working on genetic therapies for Mendelian disease in 2000 - and in the subsequent 25 years have never seen a disease where the molecular aetiology has undergone as giant an "OH WOW" moment as this. www.cell.com/cell/fulltex... - ThreadSky

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urnov.bsky.social • 42 days ago

I started working on genetic therapies for Mendelian disease in 2000 - and in the subsequent 25 years have never seen a disease where the molecular aetiology has undergone as giant an "OH WOW" moment as this.
https://www.cell.com/cell/fulltext/S0092-8674(24)01379-5

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stvngrbr.bsky.social•41 days ago

Loved reading through the methods section. Just smart procedure after smart procedure given the technologies available. Thanks for sharing!

pjie2.bsky.social•41 days ago

Amazing paper! I love this specific little nugget that was included almost as a throwaway. Such an elegant biophysical hypothesis for the tipping point of the catastrophe curve.

pjie2.bsky.social•41 days ago

Potentially there could be in vitro experiments to test this - take synthetic DNAs with different length tracts, denature/reanneal and then detect the mispaired segments. If the presence of nucleosomes stabilises the slip-out structures, that’s a smoking gun.

pjie2.bsky.social•41 days ago

More wild speculation - some sort of drug molecule that selectively destabilises the interaction between CAG repeat DNA and nucleosomes, preventing the ‘blocker’ nucleosomes from assembling on the repeat tract. It wouldn’t fully prevent the tracts expanding, but it might keep it at the slow rate?

gemistosplethon.bsky.social•41 days ago

Very nice article indeed. Very hard to approach therapeutically but shows the way. Focusing therapies on downstream cell biological approaches most likely to fail.

schoppik.com•42 days ago

I hear you! But staring at 2E, I just don't see the "armadillo." 😆

pjie2.bsky.social•41 days ago

Trying to visualise it - suspect it may be clearer with a log x axis

schoppik.com•41 days ago

100% agree, but I get why they went linear here.

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