GREGoR: accelerating genomics for rare diseases - Nature The GREGoR consortium provides foundational resources and substrates for the future of rare disease genomics.

New in @nature.com! “GREGoR: Accelerating Genomics for Rare Diseases” highlights how the GREGoR Consortium is advancing rare disease discovery through data sharing, multi-omics, and next-gen sequencing across 7,500+ individuals in 3,000+ families.

🧬 www.nature.com/articles/s41...

Specificity, length and luck drive gene rankings in association studies - Nature Genetic association tests prioritize candidate genes based on different criteria.

How do GWAS and rare variant burden tests rank gene signals?

In new work @nature.com with @hakha.bsky.social, @jkpritch.bsky.social, and our wonderful coauthors we find that the key factors are what we call Specificity, Length, and Luck!

🧬🧪🧵

www.nature.com/articles/s41...

Using SpliceAI to triage splice-altering variants in 7,220 individuals with rare conditions highlights limitations of the precomputed scores Background: SpliceAI is a deep learning algorithm that predicts whether genetic variants are likely to affect splicing. Precomputed spliceAI predictions for all theoretical SNVs and small indels were ...

I am super proud to present our new manuscript “Using SpliceAI to triage splice-altering variants in 7,220 individuals with rare conditions highlights limitations of the precomputed scores”
www.medrxiv.org/content/10.1...

Happy to see this online!

Having an extra sex chromosome really challenge the binary definition of sex based on XX and XY. So it is not only a medical, but also an important societal question.

Have you worked with human genetics data? Consider taking this short survey to help us better understand how folks are using population descriptors! 🧬💻🧪

Roshni is one of the best people to work with, academia is so lucky to have her as a professor!

You've never seen anything like this before. Come see for yourself! mitnano.mit.edu/events/studi...

Have you worked with human genetics data? Consider taking this short survey to help us better understand how folks are using population descriptors! 🧬💻🧪

It's officially online, learn more about the interplay between the X-chromosome, rare variants, sex, and gene expression! 🧬💻🧪

Standard methods are equivalent to a flashlight, looking at each gene independently. We combine signals from multiple genes, turning a floodlight onto the genome.

Excited to share my first PhD paper in the @sbmontgom.bsky.social lab with @tamigj.bsky.social (www.biorxiv.org/content/10.1...)! Standard QTL methods treat each gene independently. But what if a single variant regulates multiple nearby genes at once - what we call “allelic proxitropy”? 🧵 ⬇️

This survey was put together by several fellow trainees and friends who are dedicated to the ethical conduct of human genetics research. Tagging some below! @christacaggiano.bsky.social @roshnipatel.bsky.social @raungar.bsky.social @dianexue.bsky.social @jpflores.rbind.io

Are you an early-career researcher working on the computational analysis of population-level human genetics data? We want to hear from you about if, how, and why you use population descriptors in your research! Fill out our short survey: forms.gle/SCiNUq71wgi5... 🧬💻🧪

I wrote a thing.

I am eternally grateful for my editor, who took the original draft and helped me narrow down my key points into a more effective piece with a broader reach.

Also, thanks to the editorial & legal teams, who maintained the message while protecting us in this fraught moment.

Happy to share our work characterizing functional rare SVs in rare diseases with long-read genome sequencing and transcriptomic outlier data: genome.cshlp.org/content/earl...

Mapping the regulatory effects of common and rare non-coding variants across cellular and developmental contexts in the brain and heart Whole genome sequencing has identified over a billion non-coding variants in humans, while GWAS has revealed the non-coding genome as a significant contributor to disease. However, prioritizing causal...

New preprint w/ @soumyakundu.bsky.social @sbmontgom.bsky.social @anshulkundaje.bsky.social !

Using deep learning & scATAC-seq, we studied context-specific variants in disease & evolution, and introduce FLARE for de novo mutations—w/ application to autism-affected families.

doi.org/10.1101/2025...

are you an irb cuz i want to spend the next 8 months of my life gaining your approval. it then says, will you be our lab valentine? with a fake irb below, and the choice to approve or decline.

a fake IRB form with the titel: a proposal for mutual affection and lab valentine's. this describes background and rationale, objectives, study design, potential risks, benefits, confidentiality, and consent

explaining why scbe should be the montgomery's lab valentine through the 4 principles of bioethics

there's no one elsi like you, i need some guidelines for navigating these feelings, scBE mine

The Stanford Center for Biomedical Ethics was asked to be the Montgomery Lab's valentine this year via an IRB, and we delightfully approved their request!

Are you a scientist interested in science communication but don’t know where to start? Ever wonder how a graduate student has time for outreach projects?

Check out SCOPE! An org @vangeliqueallen.bsky.social and I created! First panel on creating children’s books and podcasts is today at 1pm ET 😊🧪

This was the first project I started when I joined the Montgomery lab over five years ago, and I really grew up scientifically with this project. I am extra lucky that Stephen developed this project specifically with my personal scientific interests in mind.

Many thanks to my second author Taibo Li, who was wonderful to work with and even helped finish this project even after returning to the MD side of his MD-PhD. I am also grateful for the mentorship of @sbmontgom.bsky.social throughout this project.

We saw that many of these sex-biased variants were enriched for being in motifs that recruited transcription factors with known sex biases.

We show these sex-biased variants are enriched for being in pharmacogenes with adverse-drug reactions, including those with known sex-biased adverse drug reactions. To my knowledge no study had previously looked at pharmacogenetic implications of sex-biased rare variants.

Sex differences are often overstated, so I want to be clear. Males and females are more similar than they are different. We identified just 0.04% of total rare variants to have a difference by sex.

We (Taibo Li) then trained a Bayesian model to predict variants with different functional effects by sex. We identified 753 variants with a predicted sex bias across 464 genes.

We then wanted to understand the functional impact of rare variants, both with and without sex-stratification. In males, but not females, we found that rare variants had a stronger functional impact when on the X-chromosome as compared to the autosomes.

For an individual-gene pair the z-score in the within-sex group (male or female) as compared to the between-sex group. The individual-gene pair points are colored by their sex. Three examples are highlighted above, G6PC2, IL1RAPL2, and FAM9C. Figure 2B of https://www.biorxiv.org/content/10.1101/2025.01.23.634570v1

This project actually started as one trying to understand the impact of sex-stratification on expression outlier discovery. We saw a small change (0.1-0.2% genes changed outlier status), but one that indicated a reduction in false outliers.

Functional impact of rare variants and sex across the X-chromosome and autosomes The human X-chromosome contains hundreds of genes and has well-established impacts on sex differences and traits. However, the X-chromosome is often excluded from many genetic analyses, limiting broad...

Interested in rare variants, the X-chromosome, sex-differences, pharmacogenetics, or transcription factors? You might be interested in our new manuscript where we identified >700 functional rare variants with a difference in effect by sex in GTEx! bit.ly/x_rv_sex #genomics #multiomics 💻🧬

What do you mean when you say that you've #shared your #data broadly? @jonathanmoreno.bsky.social and I published a new data sharing framework in @naturegenet.bsky.social along with #bioethics challenges for #genomics in the #ai era. www.nature.com/articles/s41... @pennmedresearch.bsky.social

Beyond XX and XY: The Extraordinary Complexity of Sex Determination A host of factors figure into whether someone is female, male or somewhere in between

If anyone happens to need it this week for...reasons...this is the best graphic on the complexity of human sex determination I've ever seen. I use it in an undergrad course on gene regulatory mechanisms. Shoutout to @unamandita.bsky.social!

www.scientificamerican.com/article/beyo...

For legal documents and physical spaces the new administration is changing things to be “designated by sex and not identity”. This of course has loads of ethical, legal, and social implications.

~1% of people do not have all four of these categories match in the traditional binary way, they are intersex. This means you know someone who is intersex, and you yourself might be intersex and not know it. Many folks do not find out until they are having fertility issues, or might never find out.