Greg Findlay

Our latest story is now on bioRxiv. We present PETRA, a new method for deciphering how sequence variants impact gene regulation at scale. www.biorxiv.org/content/10.1... This work was led by Magdalena Armas Reyes, a @crick.ac.uk PhD student until very recently. Congrats, Dr. Armas! 🧵 1/9

@davidbalchin.bsky.social

Greg Findlay reposted

David Balchin

13 Feb

Join us at the @crick.ac.uk for the 2026 meeting of the UK proteostasis community! We especially encourage students and postdocs to attend and share their work. All talks (except the keynotes) will be selected from abstracts.

Proteostasis UK@proteostasisuk.bsky.social

📣 UK Proteostasis Meeting 2026 – Registration Now Open! I’m delighted to share that registration is now open for the UK Proteostasis Meeting 2026, hosted by The Francis Crick Institute on 20–21 July 2026 . Please register here(lnkd.in/ervXMzWN) and through Eventbrite for payment (lnkd.in/eTxqjnQy)

We hope PETRA’s scalability and flexibility make the method attractive to many labs studying a wide range of genes and cell types, with applications to dissecting the logic of gene regulation, discovering beneficial edits for therapies, and generating data to benchmark and refine AI models. 8/9

Do reach out if interested in establishing PETRA in your system. Thanks for reading, and thanks to our generous funders for all their support. 🙏 @crick.ac.uk @erc.europa.eu END/9

Comparing variant sets between primary T cells and Jurkats reveals highly correlated effects for VAV1, but much less so for IL2RA. 6/9

Lastly, PETRA can be used to assess the performance of state-of-the-art AI models, such as Borzoi and AlphaGenome. Correlations between PETRA scores and model outputs vary highly across the four genes studied, emphasising the need to generate more data in diverse genomic contexts. 7/9

Scoring of random 6-mer insertions in large libraries is highly reproducible, with dozens of variants having relatively large effects (over 2-fold). Effects of insertions across different genes are largely context dependent, reflecting e.g. transcription factor (TF) binding site creation. 4/9

We define TF motifs that modulate expression and engineer alleles with 2+ motifs via combinatorial PE. Expression effects are largely additive. For example, some alleles with multiple MYBL2 motifs express >10-fold more IL2RA RNA. Conversely, CTCF motifs can effectively silence target genes. 5/9

PETRA leverages prime editing to test variants installed downstream of target genes' transcription start sites. This allows RNA-level effects to be quantified in multiplex via amplicon sequencing of DNA and RNA, akin to the strategy of STARR-seq but with the big advantage of endogenous editing. 2/9

The Francis Crick Institute

PETRA affords high scalability and flexibility, as no pre-engineering or elaborate assay optimisation is required. We demonstrate PETRA across four loci in Jurkat cells and two loci in primary T cells, scoring over 14,000 engineered sequences in total. Highlights of our Results are as follows: 3/9

Greg Findlay reposted

@crick.ac.uk

6 Nov 2025

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...

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

Greg Findlay reposted

The Francis Crick Institute

@crick.ac.uk

30 Oct 2025

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-...

crick.ac.ukDoctoral clinical fellowsThe Crick's clinical PhD programme.

Greg Findlay reposted

Nicky Whiffin

@nickywhiffin.bsky.social

16 Oct 2025

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 🧬

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 👇

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

michaelherger.bsky.social

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!

Greg Findlay reposted

@michaelherger.bsky.social

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]

9 Oct 2025

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

The Francis Crick Institute@crick.ac.uk

We're now recruiting early career group leaders at the Crick to lead ambitious research programmes and explore bold scientific questions. Hear our Director, Edith Heard, explain why the Crick is a unique place for curiosity-driven research. Apply now ➡️ www.crick.ac.uk/careers-stud...

crick.ac.ukFindlay Lab | Developing novel genome editing methods to test human genetic variants at scale

1 Oct 2025

🚨 Applications to the Crick PhD programme are now open! We are pleased to be recruiting this year. 👇 www.crick.ac.uk/careers-stud...

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

1 Oct 2025

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-...

Greg Findlay reposted

The Francis Crick Institute

@crick.ac.uk

1 Oct 2025

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...

crick.ac.ukDoctoral clinical fellowsThe Crick's clinical PhD programme.

crick.wd3.myworkdayjobs.comcrick.wd3.myworkdayjobs.com

8 Sept 2025

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.

crick.ac.uk€1.5 million to uncover disease risk hiding in non-coding DNAGreg Findlay, Group Leader of the Genome Function Laboratory at the Francis Crick Institute, has been awarded a Starting Grant from the European Research Council for €1.5 million to take a deep dive i...

4 Sept 2025

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

The Francis Crick Institute@crick.ac.uk

Congratulations to @gregfindlay.bsky.social on being awarded a €1.5 million Starting Grant from the @erc.europa.eu to take a closer look at possible disease variants hiding in the dark genome. www.crick.ac.uk/news/2025-09...

medrxiv.orgBiallelic variants in the non-coding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changesGenetic 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) ...

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. 🧵⬇️

alexblakes.bsky.social@alexblakes.bsky.social

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

Greg Findlay reposted

alexblakes.bsky.social

@alexblakes.bsky.social

medrxiv.orgSaturation genome editing of BRCA1 across cell types accurately resolves cancer riskGermline pathogenic BRCA1 variants predispose women to breast and ovarian cancer. Despite accumulation of functional evidence for variants in BRCA1 , over half of reported single-nucleotide variants (...

Our latest research is out today on ‪@medrxivpreprint.bsky.social: www.medrxiv.org/content/10.1... Saturation genome editing of BRCA1 across cell types accurately resolves cancer risk. Led by the amazing Phoebe Dace. This one’s packed full of data, so check out the paper. Quick highlights… 🧵 1/n

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

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

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

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

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

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

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

@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

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

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

She also engineered a new SGE assay in human mammary epithelial cells (HMECs). 5/n

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

Since, SGE studies of other tumour suppressors have also yielded valuable data, changing how patients with rare variants are managed clinically. Work from the labs of @davidjadams.bsky.social (BAP1, RAD51C), Shyam Sharan (BRCA2), Fergus Couch (BRCA2), Thorsten Stiewe (TP53) and ours (VHL). 3/n

In each of these key studies, effects of variants were measured in only a single cell line. This is what makes Phoebe’s new work so impressive. She not only tested over 4,000 new BRCA1 variants in our optimised HAP1 system… 4/n

In @jshendure.bsky.social lab in 2018, we performed saturation genome editing (SGE) to test 3,893 genetic variants in BRCA1. SGE is a CRISPR method to engineer variants in lab-grown human cells. This work showed that SGE could be used to identify variants that cause high cancer risk in people. 2/n

rdcu.beDetermining variant effects with pooled prime editingNature Reviews Genetics - In this Tools of the Trade article, Christina Kajba and Michael Herger describe their screening platform, based on pooled prime editing, for large-scale functional...

16 June 2025

Check out @ckajba.bsky.social and Michael Herger's concise description of their recent work. Thanks to Nature Reviews Genetics for featuring this. rdcu.be/eraxZ

Greg Findlay reposted

The American Journal of Human Genetics

@ajhgnews.bsky.social

5 June 2025

🚨In this issue🚨 A trio of papers provide key insights for integrating functional data into clinical variant interpretation #MAVE #VUS @dougfowler.bsky.social @clareturnbull.bsky.social @leastarita.bsky.social @gregfindlay.bsky.social @afrubin.bsky.social

cell.comHigh-throughput screening of human genetic variants by pooled prime editingHerger and Kajba et al. introduce a prime editing platform to screen genetic variants for functional effects in haploid human cells. Negative and positive selection screens identify loss-of-function v...

4 June 2025

Big congratulations to our very own Christina Kajba for winning a presentation award at #ESHG25. You can read all about her work here: www.cell.com/cell-genomic...

European Society of Human Genetics@eshg.bsky.social

#ESHG2025 Vienna Medical Academy Award: Best presentation in translational genetic reserach/therapy of genetic diseases. Christina Marie Kajba, London, UK "A pooled prime editing platform in haploid human cells for high throughput variant screening"

Greg Findlay reposted

MaRtiNA Hallegger

@martinahallegger.bsky.social

3 June 2025

Join the Hallegger Lab in Oxford! A post-doc position available to develop neuronal cell models to characterise how TDP-43 aggregation leads to its dysfunction in MND. Highly collaborative project funded by My Name'5 Doddie Foundation @MNDoddie5 Please repost and share widely!

Greg Findlay reposted

kjaganatha.bsky.social

@kjaganatha.bsky.social

29 May 2025

We're thrilled to introduce PromoterAI — a tool for accurately identifying promoter variants that impact gene expression. 🧵 (1/)

Greg Findlay reposted

Isabelle Zane

@isabellease.bsky.social

21 May 2025

Chloe Terwagne at #VariantEffect25