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Jonas Koeppel

@jonaskoeppel.bsky.social
250 followers 293 following 27 posts

Postdoc in the Shendure & Pinglay labs @UW Trying to understand and engineer our wonderfully weird genomes 🧬

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Reposted by Jonas Koeppel
Mike Dorrity @mwdorr.bsky.social · 19/06/2026
First pre-print from the lab, a collaborative effort led by Jess Bourn @bournsupremacy.bsky.social, a fantastic PhD in my group. We resolve a key problem in development + evolution: how do we quantify heterochrony and link temporal variation to phenotype? www.biorxiv.org/content/10.6...
biorxiv.org
Quantitative mapping of heterochrony to species-specific phenotypes
The genetic program of animal development is conserved, but its rate of execution varies across species. Heterochrony, shifts in the relative timing of developmental events, generates phenotypic varia...
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Jonas Koeppel @jonaskoeppel.bsky.social · 06/06/2026
It’s a great question. I’m not sure if they are enriched or appear enriched because variants in active regions (which are negatively correlated to the inactive regions) are depleted. Would be cool to distinguish those two cases!
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Jonas Koeppel @jonaskoeppel.bsky.social · 06/06/2026
Thank you Adam! 🙏
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Jonas Koeppel @jonaskoeppel.bsky.social · 06/06/2026
Thank you Fillip! Looking forward to catching up again in Heidelberg. Crazy how time flies. Dissecting wing discs in in the practical still feels like yesterday
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
Thank you!!! 😊
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Reposted by Jonas Koeppel
Sudarshan Pinglay @sudpinglay.bsky.social · 04/06/2026
How much of the human genome is essential? Two pieces out today from our lab: 1) a method to map essential genomic intervals at gigabase scale, and 2) an argument that it's time to consider synthesizing a minimal human genome. biorxiv.org/content/10.6... nature.com/articles/d41...
nature.com
Why a synthetic human genome is still worth building
A decade on from the launch of an ambitious project, it’s time to revisit the reasons for constructing a human genome from scratch.
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
22/n On a personal note, I’ll soon start an independent research group in the Genome Biology Unit at EMBL Heidelberg. If you enjoy this type of work and want to engineer genomes at the largest scale, please reach out! jonas-koeppel.github.io/koeppellab/ www.embl.org/groups/koepp...
jonas-koeppel.github.io
Koeppel Lab | Structural Variation and Genome Engineering
Genome engineering research led by Jonas Koeppel, developing scalable technologies to design structural variants and study mammalian genome function.
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
21/n This has been a really fun project to work on. Huge thanks to all co-authors, collaborators, and everyone who helped along the way: @sudpinglay.bsky.social, @jshendure.bsky.social, Aidan Keith, Sam Sgrizzi, Peixi Chen, Riza Daza, Faaiz Quaisar, @eleftasia.bsky.social, Zihao Song
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
20/n Of course, viability in one near-haploid cell line is a narrow definition of essentiality. The exciting next step is to apply Shred-seq across diverse cell types, including pluripotent stem cells and differentiation systems
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
19/n See the fantastic perspective by @sudpinglay.bsky.social, also out today! www.nature.com/articles/d41...
nature.com
Why a synthetic human genome is still worth building
A decade on from the launch of an ambitious project, it’s time to revisit the reasons for constructing a human genome from scratch.
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
18/n Overall, we think Shred-seq opens the door to genome-wide deletion scanning at high resolution. Once we can empirically define which sequences are required for survival in defined contexts, we can design minimal human genomes
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
17/n. We envision that large data sets matching tens of thousands of deletions to viability and expression changes will be ideal to train/benchmark the next generation of genomic AI models, which are currently bottlenecked by the paucity, relatedness, and bias of natural genomes
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
16/n It worked! For example, we recovered an allelic deletion series where some deletions overlap RBM3 while others spare it. In single-cell transcriptomes, only the RBM3-overlapping deletions reduced RBM3 expression, giving a clean genotype-phenotype link
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
15/n Making this work required several tweaks. For example, in situ T7 transcripts are not naturally polyadenylated, so we adapted the workflow to polyadenylate T7-derived transcripts and capture them alongside endogenous mRNAs. Details are in the manuscript
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
14/n A major advantage of phage-promoter genotyping is that the genotype is transcribed into RNA. That means Shred-seq should, in principle, be compatible with single-cell RNA-seq, linking specific deletions to transcriptomes in the same cells
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
13/n Coming back to the original question: How much of the human genome is dispensable for the growth of a haploid cell line? Somewhere between 50-96%! Running Shred-seq at higher coverage should further narrow that empirical bound
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
12/n For example, surviving deletions at this locus are depleted of deletions that intersect WDR3, an essential gene. Generally, Shred-seq lets us identify constrained loci by looking for places where the surviving deletion profile deviates from the expected Cas3 distribution
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
11/n Beyond global trends, deletion scans allow us to look at locus-specific essentiality. If unselected deletions follow a baseline length distribution, then post-selection distortions of that distribution can reveal regions under constraint without relying on prior annotations
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
10/n Is this all just avoidance of essential coding genes? Not entirely. Even when we restricted the analysis to non-coding deletions, surviving deletions were depleted from active chromatin and enriched in inactive chromatin features
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
9/n Surviving deletions are depleted not only for essential protein-coding genes, but also for active, conserved, and mutation-constrained sequences. We even see a signal for lncRNAs (using a dataset generated by @nevillesanjana.bsky.social lab)
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
8/n Because we generate the deletions experimentally, we can compare variants shortly after editing, before strong selection, to variants that survive weeks of growth in culture. This gives a direct way to quantify purifying selection on deletions in coding and non-coding regions
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
7/n After lots of optimizations, we managed to make this really high throughput (gigabase-scale): We induced > 36k deletions between 100bp-500 kb that sum up to 2.55 Gb, and scanned ~14% of the human genome
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
6/n With all the components in place, here is how Shred-seq works: We randomly integrate deletion launch sites ‘beacons’ into the genome, target Cas3 to them, make deletions, and read out the variants using phage promoters on the beacon
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
5/n Making deletions is only half the problem. The harder question is how to read out thousands of unpredictable deletion junctions at high throughput. For this, we took inspiration from phage-promoter-based genotyping developed by @sudpinglay.bsky.social, Xiaoyi Li, and others
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
4/n There is a CRISPR system that does exactly that! CRISPR-Cas3 can be targeted to any DNA sequence using a crRNA. Once there, it starts chewing up DNA, leaving large deletions in its wake! Fantastic pioneering work by the Yan Zhang lab
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
3/n But not just any deletions. Ideally, we wanted deletion scans: many overlapping deletions of different lengths starting from defined sites. Such an allelic series should make it possible to identify where essential genomic regions begin and end with high resolution
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
2/n For two decades, genome-wide screens in human cells overwhelmingly confined themselves to the disruption of protein-coding genes, leaving the remaining non-coding 98% of the genome largely unexplored by direct perturbation
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Jonas Koeppel @jonaskoeppel.bsky.social · 04/06/2026
1/n What fraction of the human genome is essential for cells? Excited to share our preprint that explores this question by combining an unusual CRISPR system, phage promoters, and thousands of deletion launchpads. @sudpinglay.bsky.social @jshendure.bsky.social www.biorxiv.org/content/10.6...
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Reposted by Jonas Koeppel
Jay Shendure @jshendure.bsky.social · 10/04/2026
Latest from Shendure & Qiu labs (@cxqiu.bsky.social) )! We combined a new 4M cell mouse whole embryo scATAC-seq atlas (E10-P0), millions of 'evolutionarily coherent' orthologs from 241 mammalian genomes (Zoonomia), and the CREsted CNN framework (@steinaerts.bsky.social).
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Leopold Parts @leopoldparts.bsky.social · 05/11/2025
New 🧬✂️ pre-print! We show that paired prime editing can efficiently generate large deletions — even >1 Mb — with high precision and at scale. We use this to perform the first pooled prime deletion screen across the human genome. 🔗 biorxiv.org/content/10.1... A short thread (by Juliane Weller)👇
biorxiv.org
Generating long deletions across the genome with pooled paired prime editing screens
Engineered deletions are a powerful probe for studying genome architecture, function, and regulation. Yet, the lack of effective methods to create them in large numbers and at multi-kilobase scale has...
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Reposted by Jonas Koeppel
Daniel Ibrahim @danielibrahim.bsky.social · 16/10/2025
What is a promoter? And how does it work? We very happy to share our latest work trying to understand enhancer-promoter compatibility. I am very excited about the results of @blanka-majchrzycka.bsky.social, which changed the way I think about promoters www.biorxiv.org/content/10.1...
biorxiv.org
Enhancer-promoter compatibility is mediated by the promoter-proximal region
Gene promoters induce transcription in response to distal enhancers. How enhancers specifically activate their target promoter while bypassing other promoters remains unclear. Here, we find that the p...
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Reposted by Jonas Koeppel
Jay Shendure @jshendure.bsky.social · 14/10/2025
Super excited about first Shendure/Baker Lab collaboration & preprint on a multiplex sequencing-based strategy for screening de novo proteome editors in mammalian cells. Kudos to the brilliant Chase Suiter (not here) & @greenahn.bsky.social on the work! Preprint here: www.biorxiv.org/content/10.1...
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Reposted by Jonas Koeppel
Leopold Parts @leopoldparts.bsky.social · 10/02/2025
We're hiring to expand on the work to understand the human genome by engineering it! lnkd.in/da-gitNc
lnkd.in
Wellcome Sanger Institute hiring Postdoctoral Fellow | Generative and Synthetic Genomics in Hinxton, England, United Kingdom | LinkedIn
Posted 2:51:51 PM. Do you want to help us improve human health and understand life on Earth? Make your mark by shaping…See this and similar jobs on LinkedIn.
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Reposted by Jonas Koeppel
Di Jiang @dijiang319.bsky.social · 01/02/2025
@science.org Genome recombination on demand | Science www.science.org/doi/10.1126/... a Perspective by @seczmarta.bsky.social Lars Steinmetz @stanford.edu on two studies bit.ly/4hzFRMg + bit.ly/4jyT4Hf that generate large genome rearrangements in mammalian cells @ unprecedented scale #synbio #genome
science.org
Genome recombination on demand
Large genome rearrangements in mammalian cells can be generated at scale
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Reposted by Jonas Koeppel
Di Jiang @dijiang319.bsky.social · 01/02/2025
🧬@science.org Randomizing the human genome by engineering recombination between repeat elements bit.ly/4jyT4Hf @jonaskoeppel.bsky.social @f-raphael.bsky.social @geochurch.bsky.social @proftomellis.bsky.social @leopoldparts.bsky.social +al. @sangerinstitute.bsky.social @harvardmed.bsky.social #synbio
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Reposted by Jonas Koeppel
Sudarshan Pinglay @sudpinglay.bsky.social · 31/01/2025
If tinkering with genomes - designing, writing, shuffling and augmenting them excites you, come join us! We are hiring at all levels. www.pinglay-lab.com
t.co
https://www.pinglay-lab.com/
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Reposted by Jonas Koeppel
Sudarshan Pinglay @sudpinglay.bsky.social · 31/01/2025
Now out in @science.org w/ @jshendure.bsky.social we present 'Genome-shuffle-seq': a method to shuffle mammalian genomes and characterize the impact of structural variants (SVs) with single-cell resolution in one experiment. www.science.org/doi/10.1126/...
science.org
Multiplex generation and single-cell analysis of structural variants in mammalian genomes
Studying the functional consequences of structural variants (SVs) in mammalian genomes is challenging because (i) SVs arise much less commonly than single-nucleotide variants or small indels and (ii) ...
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Jonas Koeppel @jonaskoeppel.bsky.social · 31/01/2025
Nothing much to add here from my side! It was in fact a very similar situation with @f-raphael.bsky.social and us. We connected for a different reason and figured out we both tried to insert loxP sites into LINE1 and then decided to join forces
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Reposted by Jonas Koeppel
Nature Biotechnology @natbiotech.nature.com · 31/01/2025
Rearranging mammalian genomes with recombinases to study structural variants at scale provides insights into genome organization and dispensability #NBTHighlight www.science.org/doi/10.1126/... and www.science.org/doi/10.1126/...
science.org
Randomizing the human genome by engineering recombination between repeat elements
We lack tools to edit DNA sequences at scales necessary to study 99% of the human genome that is noncoding. To address this gap, we applied CRISPR prime editing to insert recombination handles into re...
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Reposted by Jonas Koeppel
Leopold Parts @leopoldparts.bsky.social · 31/01/2025
We're delighted to share our work on scrambling the human genome using prime editing, repetitive elements, and recombinases in @science.org , led by @jonaskoeppel.bsky.social , @f-raphael.bsky.social , with @proftomellis.bsky.social and George Church. www.science.org/doi/10.1126/...
science.org
Randomizing the human genome by engineering recombination between repeat elements
We lack tools to edit DNA sequences at scales necessary to study 99% of the human genome that is noncoding. To address this gap, we applied CRISPR prime editing to insert recombination handles into re...
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Reposted by Jonas Koeppel
Leopold Parts @leopoldparts.bsky.social · 15/01/2025
We are happy to share our enhancer scramble story, a strategy to create hundreds of stochastic deletions, inversions, and duplications within mammalian gene regulatory regions and associate these new architectures with gene expression levels 🧵 www.biorxiv.org/content/10.1...
Enhancer scrambling strategy
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xinhexue.bsky.social @xinhexue.bsky.social · 28/12/2024
Excited to share my latest preprint on establishing a generalizable toolkit for decoding the gene regulatory landscape using two types of CRISPR screens. Big thanks to my amazing mentor @nevillesanjana.bsky.social for the in-depth thread below. Looking forward to feedback and comments!
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Leopold Parts @leopoldparts.bsky.social · 02/12/2024
Does my mutation have the same impact as yours? Population genetics 🤠 🥸 🤓 🤡 meets single cell CRISPRi ⚡ ! www.biorxiv.org/content/10.1... Led by Claudia Feng, Oliver Stegle, Britta Velten, @sangerinstitute.bsky.social .
lnkd.in
LinkedIn
This link will take you to a page that’s not on LinkedIn
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Leopold Parts @leopoldparts.bsky.social · 16/11/2024
Structural variants are ripe for interrogation using genome engineering. Jonas Koeppel Juliane Weller Thomas Vanderstichele (Wellcome Sanger Institute) and I review technology progress, insights gained to date, and challenges and promise for the road ahead. www.nature.com/articles/s41588-024-01981-7
nature.com
Engineering structural variants to interrogate genome function - Nature Genetics
Structural variations (SVs) impact gene expression, genome stability and disease susceptibility. This Review discusses recent advances in genome-engineering tools that enable precise SV generation and...
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