Leandros Boukas

Higher eQTL power reveals signals that boost GWAS colocalization Expression quantitative trait locus (eQTL) studies in human cohorts typically detect at least one regulatory signal per gene, and have been proposed as a way to explain mechanisms of genetic liability...

Excited to share this preprint from first author Jon Rosen, a postdoctoral fellow in the @klmohlke.bsky.social lab and my lab. We examine eQTL study sample size and how this affects signal discovery and rates of colocalization with GWAS.

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

It's publication day, and Cold Spring Harbor Laboratory Press is running a promotion bundling the hard cover and e-book, and other offers:
cshlpress.com/default.tpl?...

#EpigeneticsBook

A challenge faced by many families undergoing genetic testing is that it's not feasible to collect samples from both biological parents. Hoping duoNovo can help address this.

Identification of de novo variants from parent-proband duos via long-read sequencing While de novo variants cause many Mendelian disorders, their detection currently requires sequencing of the proband and both biological parents. This is not feasible when only one parent is available,...

Looking forward to presenting duoNovo at ASHG this week.

We use long-read sequencing to detect de novo variants without having to sequence both parents. It's conceptually straightforward, and performs very accurately among variants likely to be clinically relevant.

www.medrxiv.org/content/10.1...

Thanks, John. Hope this ends up being useful!

YouTube video by InfiniteHistoryProject MIT David Baltimore

One of the greats of 20th century biology. What a life.

www.youtube.com/watch?v=v9Em...

yeah it's a very vanilla setting

That's amusing for sure. But still, the approach is imo quite interesting and there's interesting results, e.g. the lower MAE for dispersion.

Negative binomial regression and inference using a pre-trained transformer Negative binomial regression is essential for analyzing over-dispersed count data in in comparative studies, but parameter estimation becomes computationally challenging in large screens requiring mil...

This looks like a creative use of transformers. Looking forward to diving into this.
arxiv.org/abs/2508.04111

My book Epigenetics: History, Molecules and Diseases will be published in exactly one month (September 2).

Finalizing cover (looks great), probably going to printer this week.

Nervous anticipation is the mood right now.

#apaperaday is back from holiday. Yuzu is still with the birbsitter so a holiday picture it is. Today's pick is from @nejm.org by Musunuru et al on an N=1 case (patient with severe metabolic disease) treated by base editing (CRISPR therapy). DOI: 10.1056/NEJMoa2504747 Very good way to restart!

Multiple headlines about the first CRISPR 2.0 personalized genome editing and photo of the baby treated

This week's genome editing triumph is a big deal.
Here's why
erictopol.substack.com/p/the-first-...

Reminded of Ed Yong’s response to this question:

“If I cover a preprint, I talk to 2-3 experts to get their views before writing the story.

That’s exactly what I do if I cover a journal article…”

Looking forward to this next week

Beautiful combination of population-scale genetic analyses and mouse work. Damaging variants in a highly constrained chromatin remodeler (CHD1) are better tolerated in males, with mouse experiments indicating a protective effect of androgens.

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...
🧵

Check this out - the company I co-founded is trying to figure out how to make this super easy product.synthesize.bio (and we have beta models out to AI generate new expression data based on experimental design!)

+1 Anshul

Part of this means reviewers not ripping on manuscripts that explicitly mention limitations *for those limitations*

Just a gentle reminder that deceptive hyping in scientific publications (which includes preprints) is actually antithetical to the core mission of the scientific process. We can stay grounded, truthful, humble while being ambitious. Revealing caveats, pitfalls & limitations speeds up progress.

Great new review @natrevgenet.bsky.social by @sedlazeck.bsky.social @timp0.bsky.social and @yileifu.bsky.social! 👇highlighting both the promise of long read DNA methylation analysis and remaining challenges such as the difficulty to benchmark 5hmC and non-CG 5mC given their low abundance👏

Beyond Mechanism—Extending Our Concepts of Causation in Neuroscience The search for neural mechanisms of behaviour often relies on a synchronic, driving view of causation, where neural activity drives more neural activity, which eventually drives behaviour. The real c...

This is really a fantastic piece on causality in biological systems, and relevant beyond neuroscience
onlinelibrary.wiley.com/doi/10.1111/...

Cohesin as an essential disruptor of chromosome organization Cohesin is a multi-subunit molecular machine that is able to create lateral chromatin loops within a linear chromosome fiber. Despite intense study, a…

Plenty of work required to rigorously test the proposed hypothesis but my initial thoughts are this perspective by Adrian Bird in @cp-molcell.bsky.social may well be the most significant conceptual advance in the 3D genome organisation field in years:
www.sciencedirect.com/science/arti...

I just the word epigenetics; it has so many meanings that it's next to useless. I prefer less ambigous terms: Epigenomic data for chromatin-related data (including methylation); gene regulatory mechanisms for the general phenomenon of how genes are regulated, etc.

Protein degradation and growth dependent dilution substantially shape mammalian proteomes Cellular protein concentrations are maintained through a balance of synthesis and clearance. Clearance occurs through both protein degradation and growth-dependent dilution. At slow growth, clearance ...

Remember the role of regulation by degradation.

Research often focusses on the regulation of synthesis rates.

Here, @andrewleduc.bsky.social and I show that degradation can be just as influential in shaping protein abundance variation.

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

The analogy of omics data normalization and cooking:
some processing is usually necessary, overcooking makes it bland, highly over-processed foods are unhealthy, and the quality of the ingredients matters.

Important to mention that duoNovo was developed and tested using sequencing data from the NIH-funded @gregor-research.bsky.social consortium

Feedback and comments are especially welcome - as I mentioned earlier, we really hope that duoNovo can be broadly useful (n/n)

In the preprint we show that this simple approach performs very well in practice. Among rare variants - which are of course the most likely to be disease-causing - duoNovo has perfect accuracy in our evaluations (7/n)

Then, using just one parent, we can tell whether the haplotype containing a given variant of interest was inherited from the available parent. If that's the case, then the variant must be de novo - we don't need to look at the other parent. (6/n)

Our method solves this problem using a simple idea. We first reconstruct haplotypes using read-backed phasing enabled by long read sequencing. This allows us to phase variants that we want to test for de novo status (which isn't possible with non-read-backed phasing approaches). (5/n)

Which is why de novo status is used as a strong criterion of variant pathogenicity.

However, to identify a variant as de novo, both biological parents have to be sequenced. For millions of families, this is impossible for a variety of reasons. (4/n)