Bill Mowrey

Missense variants in TUBA4A cause myo-tubulinopathies #RareDisease #Genetics #morbidgene #newphenotype academic.oup.com/brain/advanc...

✨ A new star allele was born! Excited to share our first in vivo pharmacokinetic recall study involving 114 participants from @ESTbiobank with previously uncharacterised variants in CYP2C19 and CYP2D6:
www.nature.com/articles/s41... #Pharmacogenomics @pharmvar.org @clinpgx.org

Our paper is (finally) out in Cell today!

CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis
www.cell.com/cell/fulltex...

Great collaborative effort - read more from first author @asamelson.bsky.social below:

Three open questions in polygenic score portability Nature Communications - Genetic predictors of health outcomes often drop in accuracy when applied to people dissimilar to participants of large genetic studies. Here, the authors investigate the...

Our work on the generalizability of polygenic scores (PGS) from the @arbelharpak.bsky.social Lab is now officially out!

We examine the accuracy of PGS predictions at the individual level. We make 3 observations that expose gaps in our understanding of PGS “portability.”

rdcu.be/e0LAr

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Figure from: Joint modelling of whole genome sequence data for human height via approximate message passing

A new algorithm can jointly analyze tens of millions of genetic variants at once in whole genome sequence data. Applied to human height in UK Biobank, it reveals rare variants and achieves 46% prediction accuracy.

https://www.biorxiv.org/content/10.1101/2023.09.14.557703

Welcome to rv rv - A fast, declarative, R package manager

rv. like uv, but for #Rstats a2-ai.github.io/rv-docs/

I'm just delighted to announce our new preprint on genome-scale perturb-seq in CD4+ T cells. We learned both general lessons about the power of perturb-seq, and specific lessons about T cell biology.

Led by amazing postdocs Emma Dann and Ronghui Zhu, with my wonderful collaborator Alex Marson.

Heterozygous Loss of OSR2 Can Cause Radio-Ulnar Synostosis with Ancillary Skeletal Manifestations #RareDisease #Genetics #morbidgene www.sciencedirect.com:5037/science/arti...

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.

How do ARRB1 loss-of-function variants alter GLP-1R internalization and cAMP signaling, and do GLP1R Gly168Ser carriers show distinct weight-loss responses? Can polygenic models integrating GLP1R and ARRB1 predict long-term GLP-1RA efficacy across ancestries?

We are thrilled to announce the first official release (v0.1.8) of #𝗯𝗲𝗱𝗱𝗲𝗿, the successor to one of our flagship tool, #𝗯𝗲𝗱𝘁𝗼𝗼𝗹𝘀! Based on ideas we conceived of long ago (!), this was achieved thanks to the dedication of Brent Pedersen.

1/n

Determining the value of genomics in healthcare - Nature Medicine Assessing the value of genomics is key to informing evidence-based policies; this Review outlines how current approaches to health technology assessment, implementation and data management can be adap...

In this Nature Medicine paper, we draw from our experiences in evaluating and implementing #genomics in Australia, Canada, England, Hong Kong and the US

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

Editing stem cell genomes at scale to measure variant effects in diverse cell and genetic contexts Multiplexed assays of variant effect (MAVEs) systematically measure variant function but have been limited to cancer cell lines rather than disease-relevant cell types. We developed saturation genome ...

The effects of genetic variants primarily occur in differentiated cells meaning we need to access these cell types to measure variant effects for most disease genes. We developed saturation genome editing in stem cells (iPSC-SGE) to enable phenotyping in diverse genetic and cell contexts at scale!

The missing heritability question is now (mostly) answered Not with a bang but with a whimper

I wrote a little bit about the "missing heritability" question and several recent studies that have brought it to a close. A short 🧵

The amazing @shawnfayer.bsky.social has developed a saturation genome editing method in iPSCs enabling MAVEs in differentiated cell types and diploid contexts. Please check it out!
And, for some lucky department, Shawn is on the faculty job market!

🚨Big News!🚨
Our keynote lineup for the ASHG Genetic Diagnosis & Rare Disease Virtual Symposium is here!
Dec 2: @ahrensnicklas.bsky.social & @kiranmusunuru.bsky.social
Dec. 3: Helene Cederroth & Eric Klee
You won't want to miss their insights shaping rare disease genetics: bit.ly/3WVd6l2 #ASHG

Estimation and mapping of the missing heritability of human phenotypes - Nature WGS data were used from 347,630 individuals with European ancestry in the UK Biobank to obtain high-precision estimates of coding and non-coding rare variant heritability for 34 co...

First time on Bsky and first big announcement!

I am excited to announce that our new study explaining the missing heritability of many phenotypes using WGS data from ~347,000 UK Biobank participants has just been published in @Nature.

Our manuscript is here: 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...

📍Pinned Post: Welcome to the papers with code feed!
bsky.app/profile/did:...

Papers from PubMed, bioRxiv, Bature, PLoS, etc, with links to GitHub will be included here. Anyone can post to this feed.

See also: blog.stephenturner.us

Partial STX11 deficiency due to a hypomorphic variant—self-limiting inflammatory disease preceding HLH onset | Journal of Human Immunity | Rockefeller University Press Recently developed in vitro technology was used to define the function of a previously uncharacterized STX11 mutation L135P present in a patient with atypi

Noori, Banday, Voskoboinik et al use recently developed in vitro technology to define the function of a previously uncharacterized STX11 mutation L135P in a patient w/ atypical familial hemophagocytic lymphohistiocytosis. rupress.org/jhi/article/...

🎥 See a video summary: youtu.be/cYSBIU0lh6U

Designing allosteric modulators to change GPCR G protein subtype selectivity - Nature Studies of the G-protein-coupled receptor NTSR1 show that the G protein selectivity of this receptor can be modified by small molecules, enabling the design of drugs that work by switching receptor su...

Now online @nature.com!

Want to change the consequences of receptor activation?

Small molecules binding the GPCR-transducer interface change G protein subtype preference in predictable ways, enabling rational drug design 💥

So many new possibilities! 🧪🧠🟦

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

🧵👇

“Cellular Olympics” our catalog of freeky ultra fast cellular superhero’s is freely available “Ann Rev of microbiology”

www.annualreviews.org/content/jour...

This is a compilation of world’s fastest single cell organisms - enjoy this buffet of rare delightful protists with mind bending speeds. 🧪

Cracking the code of the non-coding genome via allele-specific genomics?
Can we link non-coding elements—like lncRNAs and enhancers—to their protein-coding target genes, and in doing so, connect overlapping non-coding disease variants to their protein-coding counterparts?

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...

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/...

Headline from NYT referring to a “lasting piece”

Lasting piece of what?

A bar chart of the distribution of rare disease categories in the U.K. Biobank cohort.

Analyses of U.K. Biobank and clinical cohorts show that rare genetic diseases can be misdiagnosed as common diseases, which may have implications for clinical trials as well as for diagnosis and treatment. Full study results: nej.md/3Jk1MvD

#MedSky #Genetics

@biorxivpreprint.bsky.social Precision targeting of autoreactive B cells in systemic lupus erythematosus using anti-9G4 idiotope synthetic immune receptor T cells
www.biorxiv.org/content/10.1...
Great work @maxkonigmd.bsky.social

It was fun writing this essay, about bottom-up neuroscience and how we might simulate entire brains, using data collected via new technologies (expansion microscopy, optogenetics, whole brain voltage imaging, and more), with @kordinglab.bsky.social!

It’s not the thought that counts: Allostasis at the core of brain function The authors review evidence that the primary function of the brain, supported by distributed neural systems, is the predictive regulation of physiology (i.e., allostasis). An example from Alzheimer’s ...

A paradigm shift in our understanding of the brain.

www.cell.com/neuron/fullt...

Comprehensive benchmarking of somatic single-nucleotide variant and indel detection at ultra-low allele fractions using short- and long-read data Mosaic mutations in normal tissues occur at low variant allele fractions (VAFs), complicating detection. To benchmark strategies, the SMaHT Network created a cell-line mixture (1:49) and produced…

Comprehensive benchmarking of somatic single-nucleotide variant and indel detection at ultra-low allele fractions using short- and long-read data. #SNV #UltraLowFrequencyVariants #ShortRead #LongRead #Sequencing #Bioinformatics @biorxiv-bioinfo.bsky.social 🧬 🖥️
www.biorxiv.org/content/10.1...