Jeff Spence
@jeffspence.github.io
assistant professor at ucsf interested in genetics, statistics, etc…
jeffspence.github.io
jeffspence.github.io
Pinned
Jeff Spence
@jeffspence.github.io
· Nov 7
Specificity, length and luck drive gene rankings in association studies - Nature
Genetic association tests prioritize candidate genes based on different criteria.
www.nature.com
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...
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...
Reposted by Jeff Spence
Buscamos una/un postdoc entusiasta y motivada para unirse al grupo de Paleogenómica y Biología Evolutiva en @liigh-unam.bsky.social para liderar un proyecto enfocado a muestras humanas prehispánicas. Interesadxs por favor enviar CV y carta de intención a [email protected]. Por favor #RT.
January 27, 2026 at 11:00 PM
Buscamos una/un postdoc entusiasta y motivada para unirse al grupo de Paleogenómica y Biología Evolutiva en @liigh-unam.bsky.social para liderar un proyecto enfocado a muestras humanas prehispánicas. Interesadxs por favor enviar CV y carta de intención a [email protected]. Por favor #RT.
Reposted by Jeff Spence
(Observation 3) Qualitative trends of portability can depend on the measure of prediction accuracy used. For some traits our measure of group-level prediction accuracy often drops where at the individual level, it increases.
(19/27)
(19/27)
January 26, 2026 at 11:20 PM
(Observation 3) Qualitative trends of portability can depend on the measure of prediction accuracy used. For some traits our measure of group-level prediction accuracy often drops where at the individual level, it increases.
(19/27)
(19/27)
Reposted by Jeff Spence
Relatedly, some cool recent work from @roshnipatel.bsky.social, Jeffrey Spence, @jkpritch.bsky.social et al. dives deep into expectations, based on models of natural selection, for allele frequency in a group B conditional on allele frequency in group A.
academic.oup.com/genetics/art...
(16/27)
academic.oup.com/genetics/art...
(16/27)
January 26, 2026 at 11:20 PM
Relatedly, some cool recent work from @roshnipatel.bsky.social, Jeffrey Spence, @jkpritch.bsky.social et al. dives deep into expectations, based on models of natural selection, for allele frequency in a group B conditional on allele frequency in group A.
academic.oup.com/genetics/art...
(16/27)
academic.oup.com/genetics/art...
(16/27)
Reposted by Jeff Spence
(Observation 1) Previous work suggested genetic distance from the GWAS sample largely explains variation in PGS performance. However, what we see empirically is that prediction accuracy is extremely noisy at the individual level.
(5/27)
(5/27)
January 26, 2026 at 11:20 PM
(Observation 1) Previous work suggested genetic distance from the GWAS sample largely explains variation in PGS performance. However, what we see empirically is that prediction accuracy is extremely noisy at the individual level.
(5/27)
(5/27)
Reposted by Jeff Spence
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
(1/27)
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
(1/27)
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...
rdcu.be
January 26, 2026 at 11:20 PM
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
(1/27)
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
(1/27)
Reposted by Jeff Spence
The number of people arguing, following the #NeurIPS2025 case, that a bit of systematically bad scholarship and borderline academic misconduct is OK because doing things the right way is tedious and time-consuming is concerning.
Yes, doing things well might be boring. But doing them badly is... bad
Yes, doing things well might be boring. But doing them badly is... bad
January 24, 2026 at 10:25 PM
The number of people arguing, following the #NeurIPS2025 case, that a bit of systematically bad scholarship and borderline academic misconduct is OK because doing things the right way is tedious and time-consuming is concerning.
Yes, doing things well might be boring. But doing them badly is... bad
Yes, doing things well might be boring. But doing them badly is... bad
Reposted by Jeff Spence
1/ Our new study, led by Jingwen Ding, examines the role of transcription factors during human neurogenesis to identify gene regulatory networks influencing cell fate, maturation, and subtype specification
www.nature.com/articles/s41...
www.nature.com/articles/s41...
Dissecting gene regulatory networks governing human cortical cell fate - Nature
Systematic screening of transcription factors reveals conserved mechanisms governing cortical radial glia lineage progression across primates and provides a framework for functional dissecti...
www.nature.com
January 23, 2026 at 1:16 AM
1/ Our new study, led by Jingwen Ding, examines the role of transcription factors during human neurogenesis to identify gene regulatory networks influencing cell fate, maturation, and subtype specification
www.nature.com/articles/s41...
www.nature.com/articles/s41...
Reposted by Jeff Spence
Choice of phenotype scale is critical in biobank-based GxE tests https://www.biorxiv.org/content/10.64898/2026.01.20.694695v1
January 21, 2026 at 11:31 AM
Choice of phenotype scale is critical in biobank-based GxE tests https://www.biorxiv.org/content/10.64898/2026.01.20.694695v1
Reposted by Jeff Spence
Balancing selection maintains some remarkable biological diversity, but detecting it from genomic data alone can be tricky. This may bias our view of its true prevalence. We investigated what makes balancing selection more or less detectable in genomic scans. + in thread & preprint!
A new preprint from the lab, with postdoc @deboraycb.bsky.social and collaborators @aidaandres.bsky.social and Tim Connallon:
“Characterising the detectable and invisible fractions of genomic loci under balancing selection”
www.biorxiv.org/content/10.6...
“Characterising the detectable and invisible fractions of genomic loci under balancing selection”
www.biorxiv.org/content/10.6...
www.biorxiv.org
January 21, 2026 at 4:10 PM
Balancing selection maintains some remarkable biological diversity, but detecting it from genomic data alone can be tricky. This may bias our view of its true prevalence. We investigated what makes balancing selection more or less detectable in genomic scans. + in thread & preprint!
Reposted by Jeff Spence
Pregnancy loss is common in humans, and chromosomal abnormalities are the leading cause. Using genetic data from ~140,000 IVF embryos, we show that maternal variation in meiosis genes influences recombination and aneuploidy risk.
First authors: @saracarioscia.bsky.social & @aabiddanda.github.io
First authors: @saracarioscia.bsky.social & @aabiddanda.github.io
Common variation in meiosis genes shapes human recombination and aneuploidy - Nature
Analysis of data from pre-implantation genetic testing sheds light on the genetic basis of meiotic-origin aneuploidy, the leading cause of human pregnancy loss, identifying common genetic variants ass...
www.nature.com
January 21, 2026 at 9:14 PM
Pregnancy loss is common in humans, and chromosomal abnormalities are the leading cause. Using genetic data from ~140,000 IVF embryos, we show that maternal variation in meiosis genes influences recombination and aneuploidy risk.
First authors: @saracarioscia.bsky.social & @aabiddanda.github.io
First authors: @saracarioscia.bsky.social & @aabiddanda.github.io
Reposted by Jeff Spence
General moment closure for the neutral two-locus Wright-Fisher dynamics https://www.biorxiv.org/content/10.64898/2026.01.16.700021v1
January 21, 2026 at 2:32 AM
General moment closure for the neutral two-locus Wright-Fisher dynamics https://www.biorxiv.org/content/10.64898/2026.01.16.700021v1
Reposted by Jeff Spence
We invite you to join our seminar at UCSF Mission Bay campus with @odedrechavi.bsky.social from Tel Aviv University
humangenetics.ucsf.edu/ihg-seminar-...
humangenetics.ucsf.edu/ihg-seminar-...
January 16, 2026 at 6:07 PM
We invite you to join our seminar at UCSF Mission Bay campus with @odedrechavi.bsky.social from Tel Aviv University
humangenetics.ucsf.edu/ihg-seminar-...
humangenetics.ucsf.edu/ihg-seminar-...
Reposted by Jeff Spence
New preprint! and my first single-author paper, so bear with me.
www.biorxiv.org/content/10.6...
Malaria population genetic studies have found some puzzling patterns: Ne estimates spanning orders of magnitude, genome-wide negative Tajima's D, and over a quarter of genes with πN/πS >1
1/n
www.biorxiv.org/content/10.6...
Malaria population genetic studies have found some puzzling patterns: Ne estimates spanning orders of magnitude, genome-wide negative Tajima's D, and over a quarter of genes with πN/πS >1
1/n
Rare variation in malaria parasites biases population-genetic inference
Understanding how pathogens evolve is fundamental to disease control and is a basic question in evolutionary biology, yet pathogens with complex life cycles violate assumptions of classic evolutionary...
www.biorxiv.org
January 14, 2026 at 10:03 PM
New preprint! and my first single-author paper, so bear with me.
www.biorxiv.org/content/10.6...
Malaria population genetic studies have found some puzzling patterns: Ne estimates spanning orders of magnitude, genome-wide negative Tajima's D, and over a quarter of genes with πN/πS >1
1/n
www.biorxiv.org/content/10.6...
Malaria population genetic studies have found some puzzling patterns: Ne estimates spanning orders of magnitude, genome-wide negative Tajima's D, and over a quarter of genes with πN/πS >1
1/n
Reposted by Jeff Spence
But once again, the same trait can show very different sign bias across biobanks. Example: we estimate 72% of rare minor alleles (sign bias of 0.44) increase risk of type 2 diabetes in All of Us, while ~all increase risk in UK Biobank. Why? (11/21)
January 14, 2026 at 7:07 PM
But once again, the same trait can show very different sign bias across biobanks. Example: we estimate 72% of rare minor alleles (sign bias of 0.44) increase risk of type 2 diabetes in All of Us, while ~all increase risk in UK Biobank. Why? (11/21)
Reposted by Jeff Spence
Excited to share our new preprint from the @arbelharpak.bsky.social Lab!
How do recruitment into genetic studies and study characteristics impact what we infer about the genetic bases of traits, and what are the consequences? (1/21)
www.biorxiv.org/content/10.6...
How do recruitment into genetic studies and study characteristics impact what we infer about the genetic bases of traits, and what are the consequences? (1/21)
www.biorxiv.org/content/10.6...
Representation in genetic studies affects inference about genetic architecture
Knowledge of a trait's "genetic architecture," namely the joint distribution of allele frequencies of causal variants and the direction and magnitude of their effects, is essential to understanding it...
www.biorxiv.org
January 14, 2026 at 7:07 PM
Excited to share our new preprint from the @arbelharpak.bsky.social Lab!
How do recruitment into genetic studies and study characteristics impact what we infer about the genetic bases of traits, and what are the consequences? (1/21)
www.biorxiv.org/content/10.6...
How do recruitment into genetic studies and study characteristics impact what we infer about the genetic bases of traits, and what are the consequences? (1/21)
www.biorxiv.org/content/10.6...
Reposted by Jeff Spence
We (with Fanny Pouyet and Brian Charlesworth) provide a theoretical perspective on rescaling forward simulations in population genetics, along with some guidelines:
arxiv.org/abs/2601.05367
arxiv.org/abs/2601.05367
The rights and wrongs of rescaling in population genetics simulations
Computer simulations of complex population genetic models are an essential tool for making sense of the large-scale datasets of multiple genome sequences from a single species that are becoming increa...
arxiv.org
January 12, 2026 at 9:38 PM
We (with Fanny Pouyet and Brian Charlesworth) provide a theoretical perspective on rescaling forward simulations in population genetics, along with some guidelines:
arxiv.org/abs/2601.05367
arxiv.org/abs/2601.05367
Reposted by Jeff Spence
Excited to see this out www.nature.com/articles/s41...! Nonparametric kernel-based tests for spatially variable isoform usage in spatial transcriptomics. So many interesting examples in the CNS and cancer, we're only scratching the surface!
Mapping isoforms and regulatory mechanisms from spatial transcriptomics data with SPLISOSM - Nature Biotechnology
Differential isoform usage is identified with high statistical power from spatial transcriptomics data.
www.nature.com
January 6, 2026 at 7:12 PM
Excited to see this out www.nature.com/articles/s41...! Nonparametric kernel-based tests for spatially variable isoform usage in spatial transcriptomics. So many interesting examples in the CNS and cancer, we're only scratching the surface!
Reposted by Jeff Spence
Clever use of proteomic data to stress-test TWAS and QTL colocalization methods, revealing a high false sign rate. This hypothesis about high-LD and cross-tissue confounding is particularly interesting:
January 6, 2026 at 5:52 PM
Clever use of proteomic data to stress-test TWAS and QTL colocalization methods, revealing a high false sign rate. This hypothesis about high-LD and cross-tissue confounding is particularly interesting:
Reposted by Jeff Spence
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...
www.medrxiv.org
January 5, 2026 at 10:27 PM
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...
Reposted by Jeff Spence
“Integrating perturbational screens, eQTL, and GWAS data identifies mediating genes for complex traits”
Very nice @medrxivpreprint.bsky.social study by @zeyunlu.bsky.social @sashagusevposts.bsky.social & colleagues 🧪🧬
www.medrxiv.org/content/10.6...
Very nice @medrxivpreprint.bsky.social study by @zeyunlu.bsky.social @sashagusevposts.bsky.social & colleagues 🧪🧬
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...
www.medrxiv.org
January 6, 2026 at 7:24 AM
“Integrating perturbational screens, eQTL, and GWAS data identifies mediating genes for complex traits”
Very nice @medrxivpreprint.bsky.social study by @zeyunlu.bsky.social @sashagusevposts.bsky.social & colleagues 🧪🧬
www.medrxiv.org/content/10.6...
Very nice @medrxivpreprint.bsky.social study by @zeyunlu.bsky.social @sashagusevposts.bsky.social & colleagues 🧪🧬
www.medrxiv.org/content/10.6...
Reposted by Jeff Spence
How well does TWAS estimate a gene’s direction of effect on a trait? We think of this as an important stress-test for the accuracy of TWAS.
In a new pre-print, we find that TWAS gets the sign wrong around 20-30% of the time!
doi.org/10.64898/202...
1/n
In a new pre-print, we find that TWAS gets the sign wrong around 20-30% of the time!
doi.org/10.64898/202...
1/n
High false sign rates in transcriptome-wide association studies
Transcriptome-wide association studies (TWAS) are widely used to identify genes involved in complex traits and to infer the direction of gene effects on traits. However, despite their popularity, it r...
doi.org
January 6, 2026 at 2:30 AM
How well does TWAS estimate a gene’s direction of effect on a trait? We think of this as an important stress-test for the accuracy of TWAS.
In a new pre-print, we find that TWAS gets the sign wrong around 20-30% of the time!
doi.org/10.64898/202...
1/n
In a new pre-print, we find that TWAS gets the sign wrong around 20-30% of the time!
doi.org/10.64898/202...
1/n
Reposted by Jeff Spence
New preprint alert: we use sign errors as a test of how well TWAS works.
Very worryingly we find that TWAS gets the sign wrong around 1/3 of the time (compared to 50% for pure guessing). You can read more about our analysis here, and what we think is going on 👇
Very worryingly we find that TWAS gets the sign wrong around 1/3 of the time (compared to 50% for pure guessing). You can read more about our analysis here, and what we think is going on 👇
How well does TWAS estimate a gene’s direction of effect on a trait? We think of this as an important stress-test for the accuracy of TWAS.
In a new pre-print, we find that TWAS gets the sign wrong around 20-30% of the time!
doi.org/10.64898/202...
1/n
In a new pre-print, we find that TWAS gets the sign wrong around 20-30% of the time!
doi.org/10.64898/202...
1/n
High false sign rates in transcriptome-wide association studies
Transcriptome-wide association studies (TWAS) are widely used to identify genes involved in complex traits and to infer the direction of gene effects on traits. However, despite their popularity, it r...
doi.org
January 6, 2026 at 2:48 AM
New preprint alert: we use sign errors as a test of how well TWAS works.
Very worryingly we find that TWAS gets the sign wrong around 1/3 of the time (compared to 50% for pure guessing). You can read more about our analysis here, and what we think is going on 👇
Very worryingly we find that TWAS gets the sign wrong around 1/3 of the time (compared to 50% for pure guessing). You can read more about our analysis here, and what we think is going on 👇
Reposted by Jeff Spence
Furthermore, Ron explored how perturbation outcomes grouped regulators that act coherently on transcriptional programs. Several known programs emerge, but the real magic is the context specificity: many programs and their regulators change drastically across different stimulation conditions.
January 5, 2026 at 6:42 PM
Furthermore, Ron explored how perturbation outcomes grouped regulators that act coherently on transcriptional programs. Several known programs emerge, but the real magic is the context specificity: many programs and their regulators change drastically across different stimulation conditions.
Reposted by Jeff Spence
Together with @ronghuizhu.bsky.social, we are thrilled to present our new perturb-seq study of 22M primary CD4+ T cells, across donors and timepoints – the result of a decade-long collaboration between the Marson @marsonlab.bsky.social and Pritchard @jkpritch.bsky.social labs 🧵 tinyurl.com/gwt2025
Genome-scale perturb-seq in primary human CD4+ T cells maps context-specific regulators of T cell programs and human immune traits
Gene regulatory networks encode the fundamental logic of cellular functions, but systematic network mapping remains challenging, especially in cell states relevant to human biology and disease. Here, ...
tinyurl.com
January 5, 2026 at 6:42 PM
Together with @ronghuizhu.bsky.social, we are thrilled to present our new perturb-seq study of 22M primary CD4+ T cells, across donors and timepoints – the result of a decade-long collaboration between the Marson @marsonlab.bsky.social and Pritchard @jkpritch.bsky.social labs 🧵 tinyurl.com/gwt2025
Reposted by Jeff Spence
Interesting to search for works with “Genetics” in the title in Anthropic Works List Lookup to see what was stolen and ingested.
#Genetics #AI #Anthropic
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#Genetics #AI #Anthropic
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December 26, 2025 at 12:50 PM
Interesting to search for works with “Genetics” in the title in Anthropic Works List Lookup to see what was stolen and ingested.
#Genetics #AI #Anthropic
secure.anthropiccopyrightsettlement.com/lookup
#Genetics #AI #Anthropic
secure.anthropiccopyrightsettlement.com/lookup