Amit Sud

Mendelian randomization of immune cell phenotypes to discover potential drug targets for B-cell malignancy - Blood Cancer Journal Blood Cancer Journal - Mendelian randomization of immune cell phenotypes to discover potential drug targets for B-cell malignancy

We are excited to announce our latest publication in #BloodCancerJournal of our Two-Sample MR analysis to investigate causal relationships between 446 immune cell traits and 6 B-cell malignancies

📄 www.nature.com/articles/s41...

#cancer #genetics #Bcell #bloodcancer #drugdiscovery #MR

It's not all work and no play in the Houlston Lab. We had our annual #Easter taste test! Returning to hot cross buns this year. We went a bit maverick and allowed some more ... unconventional varieties!

#hotcrossbuns #tastetests

📸: @jessicamayh.bsky.social

Design principles of cell-state-specific enhancers in hematopoiesis Screen of minimalistic enhancers in blood progenitor cells demonstrates widespread dual activator-repressor function of transcription factors (TFs) and enables the model-guided design of cell-state-sp...

Out in Cell @cp-cell.bsky.social: Design principles of cell-state-specific enhancers in hematopoiesis
🧬🩸 screen of fully synthetic enhancers in blood progenitors
🤖 AI that creates new cell state specific enhancers
🔍 negative synergies between TFs lead to specificity!
www.cell.com/cell/fulltex...
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Spatial transcriptomics holds great promise to understand biological tissue function, but the assignment of transcripts to cells has been a substantial bottleneck.

For this reason, Elyas Heidari, a student in my lab and in @steglelab.bsky.social built segger.

www.biorxiv.org/content/10.1...

First distributed quantum algorithm brings quantum supercomputers In a milestone that brings quantum computing tangibly closer to large-scale practical use, scientists at Oxford University’s Department of Physics have demonstrated the first instance of distributed

Using a photonic network interface, scientists from Oxford University have successfully linked two separate quantum processors to form a single, fully connected quantum computer, paving the way to tackling computational challenges previously out of reach.

More info ⬇️

Quantifying metabolites using structure-switching aptamers coupled to DNA sequencing Nature Biotechnology - Metabolites can be quantified using a combination of aptamers and DNA barcodes.

Delighted to share our latest paper describing a method to read the levels of hundreds of metabolites or drugs in parallel using DNA sequencing. This method, which we call ‘smol-seq’ (Small MOLecule sequencing), harnesses the power of DNA sequencing for metabolite detection:
rdcu.be/d8xLv (1/6)

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) ...

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/...

Beware! AAV libraries prone to length & homology dependent chimerism! Our latest preprint, from the brilliant @jblalanne.bsky.social‬, was a true surprise as related phenomena are textbook for lentivirus (highly relevant to HIV & Perturb-seq) yet to our reading not known for AAV tinyurl.com/5amc562a

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...

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/...

Efficient count-based models improve power and robustness for large-scale single-cell eQTL mapping Population-scale single-cell transcriptomic technologies (scRNA-seq) enable characterizing variant effects on gene regulation at the cellular level (e.g., single-cell eQTLs; sc-eQTLs). However, existi...

Excited to present our work on developing jaxQTL, a fast single-cell eQTL mapping tool that improves power and robustness in identifying sc-eQTLs using count-based models. See details in threads 🧵
www.medrxiv.org/content/10.1...

I posted a couple days ago about our new paper on building causal graphs from genetic associations + Perturb-seq.

Here I want to expand on the value of using DIRECTIONAL information contained in LoF burden tests.🧵
[work led by @minetoota.bsky.social ]

bsky.app/profile/jkpr...

How population stratification makes environments look like genes. A short 🧵:

The Entertainment World Mourns the ‘Dreamer’ Director David Lynch Lynch’s death inspired tributes from fellow filmmakers, celebrities and past collaborators, who praised his visionary work and singular voice.

The death of the surrealist film and television director David Lynch inspired tributes from fellow filmmakers, celebrities and past collaborators, who praised his visionary work and singular voice.

Massively parallel characterization of transcriptional regulatory elements - Nature Lentivirus-based reporter assays for 680,000 regulatory sequences from three cell lines coupled to machine-learning models lead to insights into the grammar of cis-regulatory elements.

Massively parallel reporter assays (MPRAs) testing >680,000 sequences combined with machine learning to improve regulatory element & variant effect prediction. Amazing work by @vagar.bsky.social, Fumitaka Inoue, @jshendure.bsky.social and many others as part of ENCODE.
www.nature.com/articles/s41...

I've written a lot about polygenic risk scores in DNA testing, which, for at least the time being, are regarded as largely unhelpful (at best). That's because these tests analyze many genes to predict risk of a condition. With our current knowledge of the genome, that's just tough to do.

In science, we often see weird blips in the data. The question: is it artefact (usually!), or something new & exciting? We don’t always have time to dig deep.

Our paper in @nature.com today came from just such a blip. So don’t ignore the weird stuff. Pull on that thread...

Researchers uncover what drives aggressive bone cancer Study identifies a novel mechanism driving osteosarcoma and provides insights to help predict patient outcomes.

Osteosarcoma, an aggressive bone cancer, most commonly affects children and young adults.

New research solves the mystery of what drives the genomic rearrangements causing the aggressive development and evolution of osteosarcoma tumours.

www.ebi.ac.uk/about/news/r...
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We held a great launch meeting at @cpmoxford.bsky.social last week for our award from #RHO to research health #inequalities and #ethnicity in the NHS genomic medicine service. Great discussions from @medesh.bsky.social @bughayleyw.pharmsky.app and many others [apols 4 ltd knowledge bsk addrs] 1/8

Happy New Year! (and first post here 😀) Excited to share the final version of our work where we combine deep mutational scanning, cryo-EM, and molecular dynamics to further resolve the mechanisms of pH sensing in GPCRs.

🧵(1/n)

www.cell.com/cell/fulltex...

Sailing By, by Damon & Naomi from the album A Sky Record

BBC Radio4 is celebrating a hundred years of the Shipping Forecast this New Year’s Day - as loyal listeners, here’s our contribution damonandnaomi.bandcamp.com/track/sailin...

Opinion | America Needs More Jimmy Carters He was a model ex-president and achieved a great deal in office.

From @nytopinion.nytimes.com

Jimmy Carter “described his second career as ‘waging peace.’ That work remains far from finished, and it remains for those who admired Mr. Carter to continue,” the editorial board writes.

And I was viciously mocked!

Contributing factors to the oxidation-induced mutational landscape in human cells - Nature Communications 8-oxoG is a common single-base DNA lesion caused by oxidative stress. Here, authors characterize the mutational signature of potassium bromate (KBrO3) exposure, the chromatin structural determinants o...

Our final paper of 2024 is a great collaborative effort between multiple genome stability groups (Steve Roberts & David Cortez). Kudos to the extremely talented scientists - @tmweaver.bsky.social @k4v1.bsky.social, Justin Ling, and Cameron Cordero.
www.nature.com/articles/s41...

Human DNA polymerase ε is a source of C>T mutations at CpG dinucleotides - Nature Genetics A new method called polymerase error rate sequencing (PER-seq) can measure the nucleotide misincorporation rate of DNA polymerases. DNA polymerase ε mutants produce an excess of CpG<TpG errors duri...

I'm going to repost a #thread here about a recent #paper from my group together with the labs of Marketa Tomkova and Skirmantas Kriaucionis:

nature.com/articles/s41588-024-01945-x

In it, we show that epigenetic DNA methylation causes errors during DNA replication!

#epigenetics #mutations
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Specialized Foundation Models Struggle to Beat Supervised Baselines Following its success for vision and text, the "foundation model" (FM) paradigm -- pretraining large models on massive data, then fine-tuning on target tasks -- has rapidly expanded to domains in the ...

This work finds that costly foundation models are outperformed by CNNs in genomics benchmarks, and are outperformed by *linear* autoregression in time-series benchmarks. 👀

Ultra-long sequencing for contiguous haplotype resolution of the human immunoglobulin heavy chain locus Genetic diversity within the human immunoglobulin heavy chain (IGH) locus influences the expressed antibody repertoire and susceptibility to infectious and autoimmune diseases. However, repetitive seq...

Check out long-read sequencing results in human IGH! HUGE duplications in constant gene regions...and 7 copies of IGHV3-23 on one haplotype! @lossiusandreas.bsky.social @williamlees.bsky.social

www.biorxiv.org/content/10.1...

Specificity, length, and luck: How genes are prioritized by rare and common variant association studies https://www.biorxiv.org/content/10.1101/2024.12.12.628073v1

Prof @alucassen.bsky.social is the new Academic Champion for Public and Community Engagement with Research!👏 With expertise in integrating community engagement into translational research, Prof Anneke will pioneer the 2024-2029 strategy.

Read more 👉 https://buff.ly/4ivFnIj

Central control of dynamic gene circuits governs T cell rest and activation - Nature Resting and activated T cell states are established by context-specific regulators and dynamic gene circuits.

Beautiful work led by Maya Arce from Marson lab reveals a fascinating story about rewiring of a critical gene regulatory circuit in different T cell types: T effectors and Tregs
www.nature.com/articles/s41...