Congrats to Eva Medico Salsench from our lab for successfully defending her PhD thesis last week: "Precision Medicine for Rare Neurogenetic Disorders: from aquarium to bedside"
#proudPI, #genetics #diseasemodelling @erasmusmc.bsky.social @erasmusuniversity.bsky.social
New international collaborative work (incl us) just out in @natgenet.nature.com showing how dominant variants in RNU genes like RNU4-2 can also cause Retinitis Pigmentosa
Mathieu Quinodoz, Kim Rodenburg, Susanne Roosing, @carlorivolta.bsky.social & many others
www.nature.com/articles/s41...
still time to apply till early January, spread the news!
Some more media attention yesterday in the Dutch press @pzc.bsky.social about our research into causes of hereditary disease hidden in the noncoding genome.
www.pzc.nl/schouwen-dui...
Yesterday I explained on the local radio the added value of DNA diagnostics for rare diseases, and how we are now able to find mutations in the dark matter of the human genome that can cause disease. The interview (in Dutch) is available via:
www.radiosd.nl/nieuwsberich...
We are hiring! Are you looking for a challenging PhD project studying neurodevelopmental disorders related to chromatin dysfunction, using in vitro stem cell based models, multi-omics and functional studies? Then check out the vacancy!
#phd #vacancy
www.werkenbijerasmusmc.nl/en/vacancy/1...
Very grateful to colleagues including @rdexeter.bsky.social, @nihrexeterbrc.bsky.social, @stefanbarakat.bsky.social, the NHS Rare & Inherited Disease Genomic Network of Excellence, and to the patients and families who made this work possible. 🙏
Paper: pubmed.ncbi.nlm.nih.gov/41349538/
Our new study defines a distinct #neurogenetic condition arising from recurrent structural variants at 16p13.3 palindrome.
Individuals show progressive ataxia, cognitive decline, and a characteristic MRI pattern with caudate & cerebellar atrophy.
#Genomics #RareDisease 🧵1/3
another great international collaboration with our friends in UK and Australia to which we could contribute, describing a very unique disease mechanism for a novel neurodegenerative disorder #genetics #raredisease @ajhgnews.bsky.social @jamesfasham.bsky.social @rdexeter.bsky.social
Cool work as usual, @elphegenoralab.bsky.social , congrats!
More international collaborative work:
Single nucleotide variants in UNC13C associated with neurodevelopmental disorders affect ethanol sensitivity in Drosophila #raredisease #morbidgene #genetics #diseasemodelling www.sciencedirect.com/science/arti...
thank you!
🧠🧲 BRAIN-MAGNET: A functional genomics atlas for interpretation of non-coding variants
💡 Fantastic initiative from the Barakat Lab
👀 Great to have a sneak peak at #MDC25
🧬 Predicts enhancer activity from DNA sequence
🕵️♂️ Prioritises functional non-coding variants
👇🧵 Check it out
Onderzoekers van Erasmus MC gebruiken kunstmatige intelligentie om verborgen schakelaars te zoeken in het DNA. Die aanpak kan mensen met een zeldzame genetische aandoening alsnog een diagnose bezorgen. amazingerasmusmc.nl/genetica/ai-...
if you would like to read more on BRAIN-MAGNET in the popular press, have a look at the link below!
thank you Sally!
BRAIN-MAGNET: A functional genomics atlas for interpretation of non-coding variants @cellcellpress.bsky.social
www.cell.com/cell/fulltex... @ruizhideng.bsky.social
happy to see our latest paper finally online!
If you reached till here, and you still find this interesting: soon we will open a position for a computational scientist to continue on some of this work. Feel free to reach out, follow us and spread the news! #functionalgenomics #noncoding #enhancer #STARR-seq
Also grateful to the input of the anonymous reviewers which further improved the work. Particular, Reviewer 1 provided comments whose combined length surpassed that of the manuscript, requiring >100 pages of rebuttal and many additional analysis for which there was no space in the paper.
We started working on this in 2017 when I set-up my lab in Rotterdam. Many involved over the years, but I am particular grateful to both shared first-authors @ruizhideng.bsky.social (dry-lab) and Elena Perenthaler (wet-lab) and our collaborators (@eskeww.bsky.social , @roshchupkin.bsky.social)
Together, our functional atlas and BRAIN-MAGNET AI model bridge experimental and computational genomics, helping decode how the non-coding genome shapes the brain. And importantly, allows us now to move this knowledge into analysis of patient genomes aiming for novel diagnoses
This identified amongst others a novel enhanceropathy, caused by a rare single nucleotide variant in the enhancer of the gene RAB7A, causing a novel type of Charcot-Marie-Tooth disease. We show in cells and zebrafish models how this variant affects RAB7A expression.
Then we moved to the field of rare disease. Making use of the @genomicsengland.bsky.social 100,000 Genomes Project data, genomes from collaborators and from our genetics department @erasmusmc.bsky.social, we use BRAIN-MAGNET to filter for potential non-coding disease causing variants.
We then asked can we apply this model to interpret variants? We first tried on GWAS data 🧩:
BRAIN-MAGNET pinpointed which SNPs at disease loci actually affect enhancer function — correctly prioritizing previously experimentally validated variants for schizophrenia & depression.
Then came the AI. 🤖
We trained a convolutional neural network, BRAIN-MAGNET, directly on our experimental data.
It predicts enhancer activity from DNA sequence alone and highlights key nucleotides required for enhancer activity. Those predictions held up rigorous experimental validation
We then tested the activity of the same regions in embryonic stem cells, a developmentally earlier cell state. Comparing embryonic vs neural stem cells, we found “primed” enhancers: marked early in ESCs, activated later during neural differentiation. Capturing the early wiring of brain gene control
Ranking the functional enhancers according to their activity and linking them to their target genes provided insights into the regulatory grammar of gene regulation, for example showing enrichment of transcription factors at highly active non-coding regulatory elements (NCREs)
First, we used ChIP-STARR-seq to functionally test >148,000 candidate enhancers in human neural stem cells.
This represents one of the largest experimental atlas of quantitatively tested brain regulatory regions to date, providing novel insights in gene regulation during early brain development
Here we developed BRAIN-MAGNET (brain-focused artificial intelligence method to analyze genomes for non-coding regulatory element mutation targets), an AI model trained on functional genomics data to make it more easy to find those needles. How does this work?
