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Findlay Lab | Developing novel genome editing methods to test human genetic variants at scale

Greg Findlay @gregfindlay.bsky.social · 7d

🚨 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

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Reposted by Greg Findlay

The Francis Crick Institute @crick.ac.uk · 7d

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...

The Crick's clinical PhD programme.

crick.wd3.myworkdayjobs.com

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Greg Findlay @gregfindlay.bsky.social · Sep 8

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.

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Greg Findlay @gregfindlay.bsky.social · Sep 5

Congrats, Mike!

€1.5 million to uncover disease risk hiding in non-coding DNA

Greg Findlay @gregfindlay.bsky.social · Sep 4

Many thanks!

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Greg Findlay @gregfindlay.bsky.social · Sep 4

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 · Sep 4

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...

Greg 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...

This link will take you to a page that’s not on LinkedIn

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Reposted by Greg Findlay

Wei-Ting Lu @weitinglu.bsky.social · Aug 19

I am delighted to announce that I am starting my lab next month in @oncology.ox.ac.uk @ox.ac.uk It is such a privilege to be a part of this storied institution!
Also, we are hiring - if chromosomal instability and cancer biology excite you, come join the fun!
Job Specification: lnkd.in/e8-3hyfr

lnkd.in

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Greg Findlay @gregfindlay.bsky.social · Aug 18

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 · Aug 18

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

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) ...

www.medrxiv.org

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Reposted by Greg Findlay

alexblakes.bsky.social @alexblakes.bsky.social · Aug 18

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

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) ...

www.medrxiv.org

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Greg Findlay @gregfindlay.bsky.social · Aug 18

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

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Greg Findlay @gregfindlay.bsky.social · Aug 18

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

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

Greg Findlay @gregfindlay.bsky.social · Aug 18

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

Greg Findlay @gregfindlay.bsky.social · Aug 18

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

Greg Findlay @gregfindlay.bsky.social · Aug 18

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

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

Greg Findlay @gregfindlay.bsky.social · Aug 18

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

Greg Findlay @gregfindlay.bsky.social · Aug 18

@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

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Greg Findlay @gregfindlay.bsky.social · Aug 18

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

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Greg Findlay @gregfindlay.bsky.social · Aug 18

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

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

Greg Findlay @gregfindlay.bsky.social · Aug 18

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

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

Greg Findlay @gregfindlay.bsky.social · Aug 18

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

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

Greg Findlay @gregfindlay.bsky.social · Aug 18

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

schematic of a new SGE assay in human mammary epithelial cells

distribution of function scores for variants in BRCA1 tested in HMECs

Greg Findlay @gregfindlay.bsky.social · Aug 18

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

effects of variants measured across the BRCA1 gene

Greg Findlay @gregfindlay.bsky.social · Aug 18

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

Greg Findlay @gregfindlay.bsky.social · Aug 18

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

A sequence-function map of variants in BRCA1 produced in 2018 using saturation genome editing.