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Nicholas Mancuso @nmancuso.bsky.social · 6d ago

genoio got bumped to 0.4.0. Most of the changes were refactoring the Rust backend, but the biggest change was to make read_blocks a proper context-managed resource; Previously genoio would open/close/reopen for read_blocks, which is SLOW; It now scans in-place.

How should we apply linear mixed models to populations under stabilizing selection? The first paper I wrote with my grad school advisor is published in Genetics. academic.oup.com/genetics/adv... 1/n

Genoio has a v0.2.0 release. Performance is better across the board, beating most other libraries or matching highly performance ones (but with a single interface in Python now). Check it out mancusolab.github.io/genoio/

Excited to see @jonj-udd.bsky.social's fantastic work out @genetics-gsa.bsky.social. Selection in _heterozygotes_ is the primary force shaping allele frequencies of loss-of-function mutations in humans, even in genes only associated with purely recessive diseases. 🧪🧬 doi.org/10.1093/gene...

Allele Frequencies at Recessive Disease Genes are Mainly Determined by Pleiotropic Effects in Heterozygotes

Abstract. The classic theory of mutation-selection balance predicts the equilibrium frequency of genetic variation under negative selection. The model pred

doi.org

I wrote about AI in academia. "PhD-level thinking", LLM bias, grunt work, alignment, AGI, data center water use, AI politics -- something for everyone.

Thoughts on AI in academia

PhD-level thinking, LLM bias, alignment, AGI, data centers, and AI politics

open.substack.com

Super excited to see this out! Fantastic collaboration with Luke O'Connor and trainees Amber Shen and Xinran Wang. Thread with details will come soon, but linear ARG provide a HIGHLY efficient representation of genotype data that can be treated as a linear operator www.biorxiv.org/content/10.6...

Thrilled to see this out. What started out as a chat several years back with @drfejzo.bsky.social about leveraging publicly available data on hyperemesis gravidarum GWAS turned into a wonderful collaboration with April Shu, @mvaudel.bsky.social, @xwww.bsky.social and many others! rdcu.be/fdl9k

Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting

Nature Genetics - Multi-ancestry GWAS meta-analysis identifies risk loci for severe nausea and vomiting of pregnancy. Downstream analyses explore maternal and fetal contributions of these loci and...

rdcu.be

If you use dim. reduction, you may be interested in two recent preprints we've posted on contrastive PCA: The Rayleigh Quotient and Contrastive Principal Component Analysis I & II w/ Maria Carilli & Kayla Jackson. They cover a lot of ground from theory to practice. 1/🧵

Very proud to share our new work on General, orders-of-magnitude faster whole-genome analysis with genotype representation graphs (GRG). We topped ourselves in this one 🚀 and made GRG a practical foundation for biobank-scale population and statistical genetics. www.biorxiv.org/content/10.6...

Another preprint from our group @mdanderson.bsky.social led by talented postdoc @seantbres.bsky.social! Joint with @jonhuang.bsky.social, exploring the intersection of environmental toxins, maternal/fetal health, and placental txomics. Tweet thread below!

Sean Bresnahan@seantbres.bsky.social · 4mo ago

🧬Another new preprint with @jonhuang.bsky.social @uhmanoa.bsky.social & @arjunbhattac.bsky.social @mdanderson.bsky.social ! We used variation in how PFAS cross the placenta to dissect the transcriptional architecture of effects on birthweight & gestational age🧵 www.biorxiv.org/content/10.6...

I used a combination of claude and codex, as well as the excellent base code from our jaxQTL project, to drive glmax. glmax is a jax-based GLM framework that is jit-compiled and end-to-end differentiable. It leverages implicit function theorem for improved autodiff. mancusolab.github.io/glmax/

Here's our R package for interacting with WGS derived GWAS summary statistics with many rare variants (from e.g. UKB or AofUs). It uses duckdb underneath so it's fast. Includes some helpful tie ins to Open Targets / Encode Screen / Ensembl APIs for annotation. weinstocklab.github.io/gwasplot/ind...

I used my JAX-based skills for codex to port the excellent Python3 LDSC spec to JAX and Polars. My intent here was to stress test my JAX skill definitions and find how I could improve rules and contexts--NOT to develop a replacement github.com/mancusolab/j...

GitHub - mancusolab/jax_ldsc

Contribute to mancusolab/jax_ldsc development by creating an account on GitHub.

github.com

Been trying my hand with agents with varying degrees of success and placed some definitions into a repo. Feel free to fork/pull-req for improvements. I want to get a skill in there to generate code -> latex (and vice versa) for validation soon. github.com/quattro/jax-...

hijack def adds fear of flying…very good show

Happy to share our new preprint from @sashagusevposts.bsky.social and @nmancuso.bsky.social labs! We introduce Mr. PEG, a framework integrating perturbational screens, eQTL, and GWAS data to identify mediating genes for complex traits. (1/n) www.medrxiv.org/content/10.6...

Integrating perturbational screens, eQTL, and GWAS data identifies mediating genes for complex traits

Most current GWAS-eQTL approaches prioritize genes whose mediating effects on complex traits act through cis-regulation, while trans-acting genes remain largely underexplored. Recent perturbational sc...

medrxiv.org

www.biorxiv.org/content/10.1... We finally submitted the earlier preprint to a journal after massive restructuring. We've expanded the REML section for those interested in the method. We clarify that ARG-LMM estimates mutational variance and not additive variance.

Genetic prediction with ARG-powered linear algebra

Ancestral recombination graphs (ARGs) are an attractive means for quantitative genetic analysis of complex traits because they encode the realized genetic relatedness between a sample of individuals i...

biorxiv.org

@hakha.bsky.social and I wrote a Research Briefing (with a lay summary + "behind the scenes") of our paper on how genes are prioritized by GWAS and rare variant burden tests. 🧬🧪 www.nature.com/articles/d41...

How do genetic association studies rank genes?

Genome-wide association studies and rare-variant burden tests reveal complementary aspects of trait biology.

nature.com

Looking forward to presenting our work on characterizing eqtl architecture across ancestors and cells tomorrow at the Evolgenome seminar! Huge thanks for the invite @lindakachuri.bsky.social

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...

Specificity, length and luck drive gene rankings in association studies - Nature

Genetic association tests prioritize candidate genes based on different criteria.

nature.com

Very proud of you @tszfung.bsky.social for so many achievements!! 🎊

Nicholas Mancuso @nmancuso.bsky.social · 9mo ago

Huge congratulations to @tszfung.bsky.social on successfully defending his PhD! (Co-advised with @charleston.bsky.social ) Plenty of cool insights and methods detailed in his dissertation, "Inferring genetic architecture of complex traits in admixed populations"

Why do complex traits differ in their genetic architecture? In our new PLOS Biology paper, we will try to convince you that two simple scaling laws drive differences in the number, effect sizes and frequencies of causal variants affecting complex traits. Thread: journals.plos.org/plosbiology/...

Simple scaling laws control the genetic architectures of human complex traits

Genome-wide association studies have revealed that the genetic architectures of complex traits vary widely. This study shows that differences in architectures of highly polygenic traits arise mainly f...

journals.plos.org

5 YEARS of HGG Advances! Mike, Jessica, Sara, and so many others have done such a fantastic job in shaping and expanding the journal. Please consider submitting your work in genetics/genomics with us!

Human Genetics and Genomics Advances@hggadvances.bsky.social · 10mo ago

Our October issue is online! Check out the amazing cover from @comfortandadam.bsky.social to commemorate 5 YEARS of HGG Advances! www.cell.com/hgg-advances...

I'm hiring a computational biologist interested in complex trait genetics using deep learning approaches. Reach out to me, if interested.

We are excited to share GPN-Star, a cost-effective, biologically grounded genomic language modeling framework that achieves state-of-the-art performance across a wide range of variant effect prediction tasks relevant to human genetics. www.biorxiv.org/content/10.1... (1/n)

SINGER, our ARG inference method, is finally published and freely available online: doi.org/10.1038/s415... It was a long journey – 16 months from initial submission to acceptance. Is it just me, or has peer review gotten more arduous lately? 4+ rounds of review isn't so unusual these days...

Robust and accurate Bayesian inference of genome-wide genealogies for hundreds of genomes - Nature Genetics

SINGER is a method for creating ancestral recombination graphs to understand the genealogical history of genomes. The method has increased speed, and thus scalability, without sacrificing accuracy.

doi.org

Excited to share our latest manuscript, "Exposure accumulation drives age-dependent disease architectures and polygenic risk scores," led by Xilin Jiang: www.medrxiv.org/content/10.1... I am attempting an explainer thread for the first time here: (I am usually too exhausted to post one)

Exposure accumulation drives age-dependent disease architectures and polygenic risk scores

Our understanding of the dependence of the genetic and environmental architecture of common diseases on age is incomplete. Here, we use longitudinal data to quantify age-dependent genetic and environm...

medrxiv.org

Please consider applying to be HGG new EiC! HGG is a fantastic avenue for publishing work in genetics and genomics, striving for fast turnaround and is committed to open access.

Human Genetics and Genomics Advances@hggadvances.bsky.social · last yr.

We're seeking our next EiC! Are you passionate about human genetics & open science? Apply at apply.ashg.org/a/page/hgga-...

📣Online NOW! 📄Estimation of demography and mutation rates from one million haploid genomes 🧑‍🤝‍🧑 @jgschraiber.bsky.social @jeffspence.github.io @docedge.bsky.social

Estimation of demography and mutation rates from one million haploid genomes

Samples of millions of genomes provide substantial information about recent demography and mutation, but standard population-genetic methods make assumptions not met in these data. We introduce DR EVI...

cell.com

Huge congrats Roshni! Couldn’t wait to see what comes next in the new role!!

Roshni Patel@roshnipatel.bsky.social · 12mo ago

Bittersweet to be leaving @docedge.bsky.social after a wonderful postdoc, but excited to share that I'm joining @uoregon.bsky.social next month as an Assistant Professor in the Department of Data Science.