Evidence map›Paper›PMID 40259084›Full record

ArticleNature genetics2025

Transcriptome-wide analysis of differential expression in perturbation atlases.

Ajay Nadig, Joseph M Replogle, Angela N Pogson, Mukundh Murthy, Steven A McCarroll, Jonathan S Weissman, Elise B Robinson, Luke J O'Connor

Abstract read
In one paragraph

Article in Nature genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
29citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

29 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Article
  3. Review
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  13. Concordant transcriptional and morphological remodeling revealed bybioRxiv : the preprint server for biology · 2026
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  16. Clinical,medRxiv : the preprint server for health sciences · 2026
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  18. Virtual Cells Need Context, Not Just Scale.bioRxiv : the preprint server for biology · 2026
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

8 authors.

Ajay NadigDepartment of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. anadig@broadinstitute.org.ORCID http://orcid.org/0000-0001-9634-2141
Joseph M ReplogleDepartment of Medicine, Massachusetts General Hospital, Boston, MA, USA. jreplogle@mgh.harvard.edu.ORCID http://orcid.org/0000-0003-1832-919X
Angela N PogsonWhitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
Mukundh MurthyStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0009-0001-7559-2990
Steven A McCarrollStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jonathan S WeissmanWhitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-2445-670X
Elise B RobinsonAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0003-2314-2792
Luke J O'ConnorDepartment of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. loconnor@broadinstitute.org.ORCID http://orcid.org/0000-0003-2730-9668

Funding

Medical Scientist Training ProgramT32GM007753 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI WALENSKY, LOREN DAVID · 1985 to 2021
$50.0M
MEDICAL SCIENTIST TRAINING PROGRAMT32GM007618 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ANDERSON, MARK S · 1985 to 2020
$29.6M
Medical Scientist Training ProgramT32GM144273 · NIGMS · HARVARD MEDICAL SCHOOL · PI David Shumway Jones, Jacqueline A. Lees · 2022 to 2026
$14.7M
The role of TMA7 in mitochondrial dysfunctionF31NS115380 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI REPLOGLE, JOSEPH · 2019 to 2020
$75k
The transcriptome-wide impact of biological perturbationsF31HG013036 · NHGRI · HARVARD MEDICAL SCHOOL · PI NADIG, AJAY · 2023 to 2024
$72k
NHGRI NIH HHS F31 HG013036NIGMS NIH HHS T32 GM144273U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) T32GM007618U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) T32GM007753U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) F31NS115380
6 · The paper itself

Abstract

Single-cell CRISPR screens such as Perturb-seq enable transcriptomic profiling of genetic perturbations at scale. However, the data produced by these screens are noisy, and many effects may go undetected. Here we introduce transcriptome-wide analysis of differential expression (TRADE)-a statistical model for the distribution of true differential expression effects that accounts for estimation error appropriately. TRADE estimates the 'transcriptome-wide impact', which quantifies the total effect of a perturbation across the transcriptome. Analyzing several large Perturb-seq datasets, we show that many transcriptional effects remain undetected in standard analyses but emerge in aggregate using TRADE. A typical gene perturbation affects an estimated 45 genes, whereas a typical essential gene affects over 500. We find moderate consistency of perturbation effects across cell types, identify perturbations where transcriptional responses vary qualitatively across dosage levels and clarify the relationship between genetic and transcriptomic correlations across neuropsychiatric disorders.

Indexed as

Gene Expression ProfilingTranscriptomeCRISPR-Cas SystemsGene Expression RegulationHumansSingle-Cell Analysis

Identifiers

PMID40259084
PMCPMC13063516

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.