Greg Findlay

Variants: the typos turning loss into hope Across the 3 billion ‘letters’ of our DNA, we each carry around 6 million variations. Researchers are unravelling their effects on our lives.

We each carry around six million variations in our DNA.

Henry Scowcroft explores how scientists like @gregfindlay.bsky.social and @carovinuesa.bsky.social are helping unravel the effects of these variants, where even a small change can have a big impact on our lives.
www.crick.ac.uk/news/2025-10...

Doctoral clinical fellows The Crick's clinical PhD programme.

Just a few weeks left to apply for our clinical PhD programme.

We're looking for clinicians who are passionate about research to join the 3-year fully funded programme.

Learn more and see what positions are available ⬇️

www.crick.ac.uk/careers-and-...

Planning your afternoon poster session at #ashg25? Come say hello!

This is an amalgamation of our two recent preprints - working with @gregfindlay.bsky.social , @cassimons.bsky.social , @dgmacarthur.bsky.social and many others to study variation across RNU4-2 and describe a new recessive NDD 🧬

And lastly, come chat with me about Phoebe Dace's latest work on performing saturation genome editing of BRCA1 across cell types at poster 9004T, Thursday 2:30-4:30pm. Or come by just to say hi!

On Friday, @chloeterwagne.bsky.social will present:

“A scalable framework to link rare human variants to disease phenotypes using pooled prime editing”

Friday Oct 17th at 1:40pm, Rm205ABC

You can also catch up with Chloé at her poster, 5002T, Thursday 2:30-4:30

Excited to be presenting our work on "Saturation mutagenesis of 37 human splicing factor genes using pooled prime editing" later today at #ASHG2025 during the Platform Session "RNA Functions Beyond Coding Sequences" (1:30-2:30PM, Room 205ABC).

Tomorrow, October 16 at 2:00 pm,
@magdaarmas.bsky.social presents a new method:

"Modulating gene expression in human cells via high-throughput prime editing of regulatory elements"
[Rm210AB]

Hello Boston! The lab is delighted to be at #ASHG25🧬
Check out our talks over the next few days - all unpublished stories.

Kicking things off is @michaelherger.bsky.social presenting "Saturation mutagenesis of 37 human splicing factor genes with pooled prime editing". Today @2pm, Rm205abc

Also 👇

We're recruiting early career Group Leaders this autumn! I cannot think of a better place to build a lab. Come join us! 👇

Future Leaders in Biomedical Sciences: How to Apply How to apply for a Future Leaders in Biomedical Sciences Scholarship. Open to candidates of Black or mixed Black heritage only.

This year the lab is also participating in the Crick's Future Leaders in Biomedical Sciences scholarship programme, which has opened for candidates of Black or mixed Black heritage.

www.crick.ac.uk/careers-and-...

🚨 Applications to the Crick PhD programme are now open!

We are pleased to be recruiting this year. 👇

www.crick.ac.uk/careers-stud...

Doctoral clinical fellows The Crick's clinical PhD programme.

We're looking for clinicians who are passionate about research to join our 3-year fully funded clinical PhD programme. 🔬🩺

Apply by 14 November 2025. 👇

www.crick.ac.uk/careers-stud...

We now have an open post-doc position in the lab:

crick.wd3.myworkdayjobs.com/External/job...

Please apply if you have a background in functional genomics or a related field and are eager to develop methods to map variant effects at scale.

Congrats, Mike!

Many thanks!

Hugely thankful for this 🙏. We will do our best to make the most of it. @erc.europa.eu!

We recently performed SGE of RNU4-2 and identified functionally impactful variants underlying a new recessive disease. Today, the team led by @rociorius.bsky.social @alexblakes.bsky.social @cassimons.bsky.social & @nickywhiffin.bsky.social provide in-depth analysis of its clinical presentation. 🧵⬇️

Biallelic variants in the non-coding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes Genetic variants in RNU4-2, which encodes U4, a key non-coding small nuclear RNA (snRNA) component of the major spliceosome, were recently shown to cause a prevalent neurodevelopmental disorder (NDD) ...

I am absolutely delighted to share our work describing a new *recessive* condition caused by variants in #RNU4-2. Yes, that #RNU4-2!

tinyurl.com/3j9r56s8
@rociorius.bsky.social @yuyangchen.bsky.social @gregfindlay.bsky.social @dgmacarthur.bsky.social @cassimons.bsky.social @nickywhiffin.bsky.social

This story is the PhD work of Phoebe Dace, who has done remarkably well to bring this all together. Congrats, Phoebe! 👏
Thanks to the lab, Nicole, @lcubes.bsky.social @chloeterwagne.bsky.social and Megan), our great collaborators, and @crick.ac.uk & @cancerresearchuk.org for vital funding. 🙏 END/16

A Sankey plot of functional evidence derived for BRCA1 variants using SGE across cell lines

Rather than confounding clinical interpretation, having data from multiple models is clearly preferable. A path forward to more precisely calibrating the risk caused by individual variants is to integrate functional evidence from multiple experimental data sets generated at scale. 15/n

In summary, this work reveals the extent to which variant effects can be contingent upon the cell model used. As quality functional data from a single cell line often tips the balance of evidence in favour of pathogenicity or benignity, this is critical to recognise. 14/n

We’ve opted to release all function scores now (see Supplementary Tables). While this data hasn't yet been peer reviewed, we hope sharing now speeds up others' research and allows performance to be assessed across diverse cohorts. Please reach out with questions regarding specific variants. 13/n

Mapping function score for BRCA1 variants to evidence codes to support clinical classification.

Finally, we used gold-standard sets of variants to calibrate the strength of evidence provided by scores from each cell line individually and produced ACMG/AMP-style evidence codes, which we anticipate will improve BRCA1 variant classification. 12/n

Phoebe also took care to test p.R1699Q in both lines, a variant known to confer intermediate breast cancer risk (pubmed.ncbi.nlm.nih.gov/22889855/). Indeed, p.R1699Q scored discordantly between HAP1 and HMEC, as did all 7 other variants tested thought to cause intermediate cancer risk. 11/n

@mariazanti.bsky.social‬ and @kmichailidou.bsky.social addressed this by estimating breast cancer risk from case-control data. Variants causing loss-of-function ONLY in HAP1 moderately increased risk (OR=3.3). Yet variants that were loss-of-function in BOTH lines highly increased risk (OR>10). 10/n

All evidence points to variants scoring discordantly between lines as being hypomorphic in cells (i.e. leading to reduced BRCA1 function but not a null allele). Might such variants also cause intermediate cancer risk? 9/n

ROC-AUC cruves for prediction of pathogenic BRCA1 variants using SGE data

Importantly, both the HAP1 and HMEC SGE assays perform well for predicting which BRCA1 variants are pathogenic. Looking at a set of 420 pathogenic and benign variants in ClinVar, it was the HAP1-based assay that performed better overall, with near-perfect accuracy. 8/n

Comparison of SGE function scores in HMECs with and without PARP inhibitor treatment.

To better understand why variants act differently between lines, Phoebe performed more SGE using PARP inhibition and a knock-out HMEC line to reveal context-specific effects. Many variants initially scoring discordantly between HAP1 and HMEC can be reconciled in specific contexts. 7/n

function scores for BRCA1 variants in exons 11 and 12, measured in HAP1 cells and HMEC cells

Comparing how variants impact function across cell lines has proven quite interesting. Nearly half of variants leading to loss-of-function in HAP1 do not have the same effect when introduced to HMECs. Variants with discordant effects are typically missense and splice. Here's an example... 6/n