Jonas Koeppel

nature.comWhy a synthetic human genome is still worth buildingA decade on from the launch of an ambitious project, it’s time to revisit the reasons for constructing a human genome from scratch.

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...

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...

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

jonas-koeppel.github.ioKoeppel Lab | Structural Variation and Genome EngineeringGenome engineering research led by Jonas Koeppel, developing scalable technologies to design structural variants and study mammalian genome function.

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...

nature.comWhy a synthetic human genome is still worth buildingA decade on from the launch of an ambitious project, it’s time to revisit the reasons for constructing a human genome from scratch.

19/n See the fantastic perspective by @sudpinglay.bsky.social, also out today! www.nature.com/articles/d41...

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

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

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

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

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

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

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

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

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

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)

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

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

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

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

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

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

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

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

Jonas Koeppel reposted

Jay Shendure

@jshendure.bsky.social

10 Apr

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).

Jonas Koeppel reposted

biorxiv.orgGenerating long deletions across the genome with pooled paired prime editing screensEngineered 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...

5 Nov 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)👇

Jonas Koeppel reposted

Daniel Ibrahim

@danielibrahim.bsky.social

16 Oct 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.orgEnhancer-promoter compatibility is mediated by the promoter-proximal regionGene 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...

Jonas Koeppel reposted

Jay Shendure

@jshendure.bsky.social

14 Oct 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...

Jonas Koeppel reposted

lnkd.inWellcome Sanger Institute hiring Postdoctoral Fellow | Generative and Synthetic Genomics in Hinxton, England, United Kingdom | LinkedInPosted 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.

10 Feb 2025

We're hiring to expand on the work to understand the human genome by engineering it! lnkd.in/da-gitNc

Leopold Parts@leopoldparts.bsky.social

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.orgRandomizing the human genome by engineering recombination between repeat elementsWe 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...

Jonas Koeppel reposted

Di Jiang

@dijiang319.bsky.social

1 Feb 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.orgGenome recombination on demandLarge genome rearrangements in mammalian cells can be generated at scale

Jonas Koeppel reposted

Di Jiang

@dijiang319.bsky.social

1 Feb 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

Leopold Parts@leopoldparts.bsky.social

Jonas Koeppel reposted

Sudarshan Pinglay

@sudpinglay.bsky.social

t.cohttps://www.pinglay-lab.com/

Replying to @sudpinglay.bsky.social

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

Jonas Koeppel reposted

Sudarshan Pinglay

@sudpinglay.bsky.social

science.orgMultiplex generation and single-cell analysis of structural variants in mammalian genomesStudying 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) ...

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/...

Jonas Koeppel reposted

Nature Biotechnology

@natbiotech.nature.com

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/...

Jonas Koeppel reposted

Jonas Koeppel reposted

15 Jan 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...

Jonas Koeppel reposted

xinhexue.bsky.social

@xinhexue.bsky.social

28 Dec 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!

Neville Sanjana@nevillesanjana.bsky.social

🎇🎄Some holiday reading: Overdue TWEETORIAL on the latest preprint from our lab 🎇🎄 In this work, superstar postdoc @xinhexue.bsky.social combined 2 kinds of pooled CRISPR screens to pinpoint noncoding regulatory elements and the transcription factors that activate these elements.

Jonas Koeppel reposted

lnkd.inLinkedInThis link will take you to a page that’s not on LinkedIn

2 Dec 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 .

Jonas Koeppel reposted