Hi everyone! I'm excited to announce that our lab at UW will soon be recruiting a postdoc to work on DNA methylation signatures in rare disease. This will be a mostly computational position. Please share and reach out if interested! millerlaboratory.com

📣 Out now @naturemedicine.bsky.social 🧬🤖 👉 rdcu.be/fqasl Our automated reanalysis tool Talos enables broad adoption and delivers timely + equitable #raredisease #diagnosis at scale! ♻️ Runs monthly on >10K datasets 🎯High specificity 💰Low running costs 🤗Open source @dgmacarthur.bsky.social

After 4 years, it's rather nice to finally present our work on genetic's model trait, height, in >1.4M WES/WGS samples (826k discovery; led by Adam Locke & Goncalo Abecasis where we found (amongst many other things) 207 genes (P<1.75e-9). A thread of findings below⬇️ www.medrxiv.org/content/10.6...

Excited to share our new preprint, "Inference of elevated mutation rates and variant effects using 700k exomes"! - www.biorxiv.org/content/10.6... Using gnomAD v4, we estimate per-variant missense selection coefficients, and find loss-of-function (LoF) mutations with enhanced mutation rates.

Inference of elevated mutation rates and variant effects using 700k exomes

Genomic sequencing is now widely accessible for genetic diagnostics and is emerging as a component of newborn screening. This technological development generates the need to characterize incoming muta...

biorxiv.org

Attend the Leena Peltonen Award lecture now at #eshg2026 with Nicola Whiffin from Oxford University and learn About her recent discovieries in rare diseases and the broader inclusion of non-coding variants in clinical genetic testing that led to the Leena Peltonen Award. Congratulations!

👏👏👏 fantastic to see @nickywhiffin.bsky.social win the Leena Peltonen award at #eshg2026 @eshg.bsky.social 👏👏👏

Excited to be at #ESHG2026 in the beautiful Gothenburg! For those of you attending and up for an extra game, check out the bingo cards 👇

Alex Hoischen@ahoischen.bsky.social · 2mo ago

To all attending #eshg2026: if you are ready to spent extra attention to detail throughout the entire conference, I recommend the informal ESHG bingo card. Brought by our great postdoc @lydiasagath.bsky.social @eshg.bsky.social First bingo gets a kanelbullar from me… tinyurl.com/eshgbingo2026

We are excited to share our gnomAD v4.1.1 release gnomad.broadinstitute.org/news/2026-03... Major changes: * Constraint scores on X and Y * Improved coverage correction * LOFTEE fix * Guidance on constraint cut-offs * New quality flag for low coverage/mappability genes @gnomad-project.bsky.social

To nominate disease genes, we introduce two discovery scores: ΔPEPPER flags genes where biological features predicts clinical impact beyond whats published, and DisPo highlights genes under strong constraint with limited literature. Together they prioritize hundreds of candidate genes for follow-up

We train a new model trained on biomedical literature (PEPPER_XGB). Mix LOEUF and PEPPER to make an OMELET, which outperforms either each individual model in identifying disease genes

We introduce LOEUF-MIS, combining pLoF and top 1% predicted deleterious missense constraint. This captures not just LoF but also gain-of-function and dominant-negative signals.

gnomAD v4's 5x sample increase benefits both common and rare disease: more common variants observed across ancestries improve diagnostic filtering, while more rare variants strengthen constraint metrics for disease gene detection

Excited to share our new preprint on gnomAD v4! We present the full analysis of 730,947 exomes — new constraint metrics, improved LoF annotation (LOFTEE-2), LLM-based literature curation, and a unified framework for gene discovery and rare disease diagnosis. www.medrxiv.org/content/10.6...

Integrating 730,947 exome sequences with clinical literature improves gene discovery

Accurate estimates of allele frequencies aid in genetic discovery, including rare disease diagnosis, common disease investigations, and population genetics. Here, we present the Genome Aggregation Dat...

medrxiv.org

If you are submitting an NIH grant in February, you will be required to use SciENcv to prepare you biosketch. IT IS MUCH WORSE THAN YOU CAN POSSIBLY IMAGINE. Set aside *at least* 4 hours just to transfer an existing an biosketch into SciENcv.

Why do some individuals defy their polygenic score? In the largest study of its kind (402k UKB individuals; 7 continuous traits + 3 diseases), we asked: If your phenotype deviates from common-variant polygenic score prediction, what's driving that difference? www.medrxiv.org/content/10.6...

Massive single-cell study by Kanai et al (www.medrxiv.org/content/10.1...): - Once statistical power is high, constrained genes have more (though weaker) eQTLs. - Chromatin-QTLs near constrained genes have "normal" effect sizes, colocalize more with disease, but exhibit attenuated peak-gene effects.

New paper on everyone’s favourite topic, QC! We show why you should do genotype-level QC on your WGS data www.biorxiv.org/content/10.1... Very real quotes about this paper - “The most exciting, mind-blowing paper of the year!” “On a par with Fisher 1918” “I read it every night. Just so beautiful”

Genotype-level quality control substantially reduces error rates in population-scale whole-genome sequencing

Population-scale whole-genome sequencing data will contain many individual-level genotype errors, even after allele-level quality control (QC). We establish the need for genotype-level QC using UK Bio...

biorxiv.org

New study of 800K+ genomes from gnomAD reveals most “pathogenic” variants in healthy people aren’t truly disease-tolerant. They are explained by annotation errors, mosaicism, or compensatory variants. 🧬 A big step for precision medicine! www.nature.com/articles/s41...

Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database - Nature Communications

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD),…

nature.com

📃 We’re excited to share our latest work, now published in Nature Communications — a major update to the Genome Aggregation Database (gnomAD) that improves allele frequency resolution for two gnomAD-defined genetic ancestry groups using local ancestry inference (LAI).

Improved allele frequencies in gnomAD through local ancestry inference - Nature Communications

This study incorporates local ancestry into the Genome Aggregation Database (gnomAD) to improve allele frequency estimates for admixed populations, enhancing variant interpretation and enabling more accurate and equitable genomic research and clinical care.

nature.com

Now published! Our paper on: (1) Accurate sequencing of sperm at scale (2) Positive selection of spermatogenesis driver mutations across the exome (3) Offspring disease risks from male reproductive aging [1/n] www.nature.com/articles/s41...

Sperm sequencing reveals extensive positive selection in the male germline - Nature

A combination of whole-genome NanoSeq with deep whole-exome and targeted NanoSeq is used to accurately characterize mutation rates and genes under positive selection in sperm cells.

nature.com

📣 We are recruiting! Please share!! Are you a bioinformatician / computational scientist who wants to apply your skills to understanding regulatory biology and improving rare disease diagnosis and treatment? 🧠 💻 🧬 🩺 We have two roles available 👇 🧵 1/4

Isn't genetics cool??? Within only 145 nucleotides(!) of a non-coding RNA (RNU4-2) - different variants in distinct regions / structures cause three distinct disorders!!! (all discovered within the last 18 months) 🤯🤓🧬❤️

@alexblakes.bsky.social · 12mo ago

Importantly, most of the mutations potentially responsible for this condition fall outside of the #ReNU syndrome critical region – they cluster in other parts of the U4 structure which make contacts with other RNAs and proteins, or within U4 itself.

🗣️ Quote of #ESHG2025 (so far) "Who licks bone !?!" 🦴 - Johannes Krause Anyone have that on your bingo card? Well apparently archeologists do, to distinguish bone from stones and it causes problems in DNA sequencing. 🤔

We are just wrapping up day 1 at #ESGH2025 in beautiful Milan. For those who want some extra fun while listening to the great science, you can play bingo.👇 I know multiple of these have already occurred.

Alex Hoischen@ahoischen.bsky.social · last yr.

Getting ready for #eshg2025 …and our postdoc @lydiasagath.bsky.social made a nice BINGO card again. Paying a lot of attention to the entire event will pay off!

Buongiorno Milano! Ready for a great day 1 of #eshg2025? Packed program of excellent science 8.30am-8.00pm - plus networking event till 9.30pm to meet many friends, colleagues and collaborators! …andiamo @eshg.bsky.social @eshgyoung.bsky.social

🤗 Hugely excited to share our work on automating iterative reanalysis in #raredisease, preprint out: www.medrxiv.org/content/10.1... 🤖🧬 github.com/populationge... A superb collaboration with @dgmacarthur.bsky.social @cassimons.bsky.social @heidirehm.bsky.social @ksamocha.bsky.social and many more!

Scalable automated reanalysis of genomic data in research and clinical rare disease cohorts

Reanalysis of genomic data in rare disease is highly effective in increasing diagnostic yields but remains limited by manual approaches. Automation and optimization for high specificity will be necess...

medrxiv.org

Human Developmental Cell Atlas (HDCA) expression data is now displayed. Expression is displayed in 12 sections of a 6-7 post-conception week human embryo, alongside a sagittal view which displays the region of the embryo represented by each section @mhaniffa.bsky.social

A few weeks ago, I had an incredibly emotional call with James Coney, a writer for the Sunday Times whose son Charlie was in the @genomicsengland.bsky.social 100k project and was recently diagnosed with ReNU syndrome. This beautiful article tells their story ❤️ www.thetimes.com/article/0bcc...

My son Charlie — and the breakthrough that changed our lives

James Coney and his wife, Sarah, struggled not knowing why their 12-year-old was born with a severe learning disability. In their darkest moments, they blamed themselves. Then, out of the blue, came a...

thetimes.com

Join leading experts working in #RareDisease research at our #GRD25 conference. 📅 Dates: 9-11 April 2025 💭 Share insights in person Explore the latest #genomics advances accelerating improvements in clinical care for rare disorders, globally. ⏰Secure your place by 11 March: bit.ly/3BpAe44

Recently out on #bioRxiv: our updated approach to identify regional variability in missense mutation intolerance (“constraint”) in protein-coding genes using the gnomAD database. www.biorxiv.org/content/10.1... 1/10