Coordinated dysregulation of modular gene activity in human neuropathologies
- 1University of California, San Francisco
Abstract
Understanding which genes are reproducibly dysregulated in which cell types is foundational knowledge for efforts to slow or reverse pathologies. For neuropathologies, such efforts rely primarily on differential expression analysis of single-nucleus RNA-seq (snRNA-seq) data. However, this strategy suffers from experimental and statistical challenges that limit marker gene reproducibility. We describe a novel strategy called Covariation Projection Analysis (CoPA) that combines the power of bulk sampling with the precision of single-cell methods. By projecting bulk gene coexpression modules onto pseudobulked snRNA-seq cell types, CoPA reveals the cellular origins of highly reproducible genomic programs and their relative importance among cell types. By comparing CoPA projection patterns between normal and pathological human brain samples using differential CoPA (dCoPA), we identify gene coexpression modules that are uniformly and reproducibly dysregulated in specific neocortical cell types in Alzheimers disease or schizophrenia. We share our findings through a novel web application called CoPA Cabana (https://oldhamlab.shinyapps.io/copacabana/).
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BibTeX
@misc{kang2026coordinated,
title = {{Coordinated dysregulation of modular gene activity in human neuropathologies}},
author = {G. Kang and M. C. Oldham},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.25.747130},
url = {https://www.biorxiv.org/content/10.64898/2026.08.25.747130v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Coordinated dysregulation of modular gene activity in human neuropathologies
AU - G. Kang
AU - M. C. Oldham
PY - 2026
DA - 2026/08/25
PB - bioRxiv
DO - 10.64898/2026.08.25.747130
UR - https://www.biorxiv.org/content/10.64898/2026.08.25.747130v1
AB - Understanding which genes are reproducibly dysregulated in which cell types is foundational knowledge for efforts to slow or reverse pathologies. For neuropathologies, such efforts rely primarily on differential expression analysis of single-nucleus RNA-seq (snRNA-seq) data. However, this strategy suffers from experimental and statistical challenges that limit marker gene reproducibility. We describe a novel strategy called Covariation Projection Analysis (CoPA) that combines the power of bulk sampling with the precision of single-cell methods. By projecting bulk gene coexpression modules onto pseudobulked snRNA-seq cell types, CoPA reveals the cellular origins of highly reproducible genomic programs and their relative importance among cell types. By comparing CoPA projection patterns between normal and pathological human brain samples using differential CoPA (dCoPA), we identify gene coexpression modules that are uniformly and reproducibly dysregulated in specific neocortical cell types in Alzheimers disease or schizophrenia. We share our findings through a novel web application called CoPA Cabana (https://oldhamlab.shinyapps.io/copacabana/).
ER -