This is a really cool paper

In the December issue of #GENETICS, @jeremyjberg.bsky.social et al. introduce an evolutionary model of complex disease susceptibility, identifying how diseases are shaped by selection acting on other pleiotropically related traits. buff.ly/QTZPpYQ

How much better is an ancestral recombination graph (ARG) than a site frequency spectrum (SFS)? For recovering mutation rate history, we can answer fairly precisely because both ARG and SFS are linear transforms of mutation rate history. This blog post uses spectral analysis to clarify the picture.

In fact, they appear to be eerily similar. The per generation mutation rate seems to lay between 10-9 and 10-8 per bp in all animal taxa surveyed to date–despite vast differences in environments, life histories, and three orders of magnitude variation in the generation time: 4/n

Happy to highlight an essay I wrote together with @marcdemanuel.bsky.social, @natanaels.bsky.social and Anastasia Stolyarova, trying to think through what sets the mutation rate of a cell type in an animal species: www.biorxiv.org/content/10.6... 1/n

No contest. Just read the first two sentences of the abstract. www.nature.com/articles/s41...

This paper by Celentano et al. on scalable simulation under the birth death is one of my favourites for the year! It introduces some elegant thinning that has been sorely needed. Fantastic to pave the way forward for future simulation-heavy inference, including neural Bayes! doi.org/10.1073/pnas...

I guess the preprint came out in 2024 but it was published this year so I'll say this paper from @jeffspence.github.io and @hakha.bsky.social which is probably the paper that pleiotropy-pilled me the most. Really got me to think about what GWAS means www.nature.com/articles/s41...

All right it’s time for the annual “please tell us about one (or a few if you are ambitious) paper from 2025 that really impressed you and why we should all read it“! Go! If you tell us how it changed your view of the world and what makes it so powerful and consequential It would be excellent.

High false sign rates in transcriptome-wide association studies https://www.biorxiv.org/content/10.64898/2025.12.19.695550v1

But if each gene is doing multiple jobs, then every phenotypical trait is controlled by multiple genes. Even homozygous deleterious mutations are doing something else when in heterozygous form: doi.org/10.64898/202... Complexity is the norm, more complexity than what fits in the human imagination

This is a good time to talk about the TRUE genetics revolution brought in by sequencing the human genome: The genetic underpinning of traits is not simple, will never be simple. Complex gene-gene interactions are the rule, not the exception 🧵 www.nature.com/articles/d41...

Published online on Jan 2, 2025 and just appeared in the December 2025 issue!

A heads up for people using scipy.sparse.linalg.expm_multiply to solve linear ODEs -- the function appears to have some randomness that is not documented, but appears to be fixable by setting numpy.random.seed beforehand. github.com/scipy/scipy/issues/24188

Happy to share my work with my advisor Zachary Szpiech! Why are associations between ROH & complex traits inconsistent across studies? We use realistic simulations to show how demographic history and genetic architecture interact to shape the phenotypic impact of ROH. www.biorxiv.org/content/10.6...

While stories of singular DNA changes that drove evolution of human brain/behaviour remain seductive, advances across multiple fields of biology cast doubt on such simplistic narratives of our origins. A new paper from my lab shows how biobanks may speak to this fundamental question.🧪 Explainer🧵👇1/n

Grateful to share our paper on gene-specific selective sweeps in human gut microbiomes, now out in Nature! It has been a joy to work with @rwolff.bsky.social, whose insights and hard work made this possible. www.nature.com/articles/s41...

Have you ever wondered: just how strong *is* the evidence for Muller's ratchet on mtDNA? Well, wonder no more! (Project led by Yu Mo, with @smishra677.bsky.social and @yadirapga.bsky.social) "No molecular evidence for Muller's ratchet in mitochondrial genomes" www.biorxiv.org/content/10.6...

I'm hiring a postdoc with a flexible start date (any time in 2026). Come work with us on topics at the interface of machine learning, biophysics, a nonequilibrium statistical mechanics. If interested, send me a CV and a short summary of why you think you'd be a good fit. statmech.stanford.edu

"Together, these results suggest that most selection experienced by pathogenic mutations in recessive disease genes may be due to stabilizing selection in heterozygotes [due to pleiotropy]. We conclude that very few human genes follow the classic model of recessive mutation-selection balance."

Well well. The standard model for how frequencies of recessive disease genes are established doesn't work. And that seems to be because recessive variants are visible to selection due to pleiotropy. (But still we teach Mendelian genetics...) www.biorxiv.org/content/10.6...

Preprint online right before the holidays! Excited to share the first piece of work from the Zhang Lab, led by my absolutely stellar postdoc Michelle Kim! In this work, we ask how admixture, selection and demography shape complex trait genetics and GWAS performance www.biorxiv.org/content/10.6...

Congratulations to the winners of the 2025 Genomic History Inference Strategies Tournament challenges! Among the 9 challenges, we had five winners: @alwaysrong.bsky.social, @adaigle.bsky.social, @andrewhvaughn.bsky.social, @thymelicus.bsky.social, @rgollnisch.bsky.social

Important piece thinking through what eugenics actually is and how this qualifies. It's not lost on me that these companies are primarily men telling women how to responsibly reproduce. The marketing/examples are telling. It's part of a larger movement around control & should be treated seriously.

Updated job posting description for our postdoc recruitment to include interest in immuno-oncology

As a (to me very enjoyable) part of this paper, we worked out what mutation-selection balance looks like in finite populations with varying degrees of inbreeding.

I wrote about the bizarre case of Herasight, the embryo selection company going all in on eugenics.

But when Jon started exploring this model in real data for human recessive disease genes (frequencies from gnomAD), he got this striking result: Almost no annotated human recessive genes are compatible with recessive mutation-selection balance!

Yes: deleterious recessives aren’t completely recessive! An important study confirming intuitions from at least some of us.

Now TWO great new papers on why frequencies of disease genes rarely match expectations Here was the first: www.nature.com/articles/s41...

Our latest preprint revisits the classic model of mutation-selection balance. Do human recessive genes fit Haldane's 100-year old model? This work is by the wonderful @jonj-udd.bsky.social, and co-mentored by @jeffspence.github.io www.biorxiv.org/content/10.6...

Over the past 5+ years I've had the honor of working with @wsdewitt.github.io @victora.bsky.social and many others on a project to "replay" affinity maturation evolution from a fixed starting point. matsen.group/general/2025...

Nature research paper: Causal modelling of gene effects from regulators to programs to traits go.nature.com/3MRSE2y

GWAS has been an incredible discovery tool for human genetics: it regularly identifies *causal* links from 1000s of SNPs to any given trait. But mechanistic interpretation is usually difficult. Our latest work on causal models for this is out yesterday: www.nature.com/articles/s41... A short🧵:

Thank you Alex! Excited to see our paper published in @nature.com ! Huge thanks to @jeffspence.github.io , @tkyzeng.bsky.social , @emmamarydann.bsky.social, @nikhilmilind.dev, @marsonlab.bsky.social, @jkpritch.bsky.social, and all the members of the Pritchard and Marson labs for your enormous help!

Our latest collaboration with @jkpritch.bsky.social – led by joint post-doc Mineto Ota – is in @nature.com today: www.nature.com/articles/s41...

We are hiring a PhD intern for Summer 2026 in ML for regulatory genomics at ReLU/BRAID/Genentech! Work on DNA sequence models for the noncoding genome (e.g. DNA design, models of MPRA and genetic variants)! 🥳

*A new pre-print on increasing gene expression!* 🧬📈 doi.org/10.64898/202...

Allele Frequencies at Recessive Disease Genes are Mainly Determined by Pleiotropic Effects in Heterozygotes https://www.biorxiv.org/content/10.64898/2025.12.05.692665v1

The Sudmant Lab & Wilsterman Lab are hiring a postdoc! Come work on the genetics and evolution of the placenta and dissecting genetic adaptations to altitude in deer mice! Check out more details here: evol.mcmaster.ca/brian/evoldi... www.sudmantlab.org www.thewilstermanlab.com Please Share!

Faculty at OHSU, UIowa, UCSF, UW–Madison, and VCU: Your next amazing mentee could be one 10‑minute conversation away. PROPEL Virtual Matchmaking Event is Jan 30: 9–1 PT. Faculty registration deadline extended to 5pm PT on Wed Dec 10: propelscholars.org/matchmaking-...

I rounded up some of the missing heritability discussions from the past few weeks and got the last word in (for now).

Popgen folks, Jiseon, Nate, and Andy, along with Yuxin Ning and Franz Baumdicker, just released a really cool new method for simulation based inference (think ABC) using normalizing flows. It seems to work really well! full joint posteriors ftw! www.biorxiv.org/content/10.6...

It's with heavy hearts that we share that Claude, our beloved albino alligator, has passed away at the age of 30. Claude brought joy to millions of people at the Academy and across the world during his 17 year tenure. We will miss him dearly. 🤍

Oh no!!!!

It was a total pleasure to work with @roshnipatel.bsky.social on this, who really led the charge in all respects. Anyone interested in learning about the intersection of population genetics and statistical genetics should check out her new lab in Oregon!

Excited about AI for Biology? At NeurIPS? Come say hi to the Biohub (née EvolutionaryScale) folks in the exhibit hall! Keep me company: Tue 12-3 Wed 3-6 Or stop by any time for a chance to meet my incredible colleagues: roshanrao.bsky.social, ebetica.bsky.social, rsmolina.bsky.social et al.

As promised, a longer thread on what I consider to be some of the most interesting and important contributions of this paper (1/10)

Excited to share work from my postdoc with @docedge.bsky.social and collaborators Matt Pennell and @jgschraiber.bsky.social, newly out over the weekend: www.biorxiv.org/content/10.1... (1/6)

This was a super fun project to do my small part on. @roshnipatel.bsky.social really helped me understand what we're doing when we're trying to "control for genetics" when assessing associations between interventions and outcomes, and how a lot of the standard ways to do so are simply inadequate.