IsoGraph resolves coordinated transcript choice and gene abundance in the aging human brain
- 1Northwestern University Feinberg School of Medicine
Abstract
Relative transcript usage can change without a corresponding change in total gene expression, but resolving coordinated transcript choice across genes while separating it from abundance remains challenging. We present IsoGraph, a gene-centered framework that represents isoform usage and abundance as paired network channels, identifies gene modules, and quantifies their channel-specific contributions. In synthetic benchmarks, IsoGraph preferentially recovered network structure when coordinated transcript usage carried the planted signal, whereas abundance-based representations were more informative in abundance-dominated and RNA-degradation settings. Applied to BrainSEQ and GTEx adult brain transcriptomes, IsoGraph identified age-associated transcript-usage signals that persisted after conditioning on gene abundance and, in a region-dependent manner, after adjustment for estimated cellular composition. Modules were stable across donor subsets, and frozen module axes retained age associations across cohorts even when exact gene partitions differed. IsoGraph module context captured predictive information about held-out differential transcript usage beyond gene-wise evidence and conventional co-expression. Convergent evidence from structural annotation, short-read junction usage, independent long-read sequencing, and within-donor allelic analyses supported constituent transcript events. Disease colocalization further prioritized candidate isoform events at neurological and psychiatric disease loci, including an alternative terminal-exon event at *PRDM2* associated with amyotrophic lateral sclerosis. Together, these results establish coordinated transcript usage as a reproducible component of transcriptomic organization and provide a framework for resolving its contribution alongside gene abundance and for tracing network-level signals to candidate transcript events.
Related
- Imaging-based spatial isoform transcriptomics resolves transcript diversity at cellular and subcellular resolution
- Re-Analysis on GRCh38 with the MANE Select Transcript Resolves Previously Undetected Biallelic ODAD4 Variants in Primary Ciliary Dyskinesia
- Modulator Resolves Transcript-, Allele-, and Condition-associated RNA Modification Differences from Direct RNA Sequencing
- A human CHRNA6 3' UTR variant alters the molecular environment and microRNA engagement of the adolescent VTA without changing Chrna6 transcript abundance
- On Motivating the Choice of Link Function in Binomial Regression Through A Latent Abundance Process
BibTeX
@misc{bennett2026isograph,
title = {{IsoGraph resolves coordinated transcript choice and gene abundance in the aging human brain}},
author = {A. Bennett and E. K. Johnson and K. J. M. Benjamin},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.04.756439},
url = {https://www.biorxiv.org/content/10.64898/2026.10.04.756439v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - IsoGraph resolves coordinated transcript choice and gene abundance in the aging human brain
AU - A. Bennett
AU - E. K. Johnson
AU - K. J. M. Benjamin
PY - 2026
DA - 2026/10/04
PB - bioRxiv
DO - 10.64898/2026.10.04.756439
UR - https://www.biorxiv.org/content/10.64898/2026.10.04.756439v1
AB - Relative transcript usage can change without a corresponding change in total gene expression, but resolving coordinated transcript choice across genes while separating it from abundance remains challenging. We present IsoGraph, a gene-centered framework that represents isoform usage and abundance as paired network channels, identifies gene modules, and quantifies their channel-specific contributions. In synthetic benchmarks, IsoGraph preferentially recovered network structure when coordinated transcript usage carried the planted signal, whereas abundance-based representations were more informative in abundance-dominated and RNA-degradation settings. Applied to BrainSEQ and GTEx adult brain transcriptomes, IsoGraph identified age-associated transcript-usage signals that persisted after conditioning on gene abundance and, in a region-dependent manner, after adjustment for estimated cellular composition. Modules were stable across donor subsets, and frozen module axes retained age associations across cohorts even when exact gene partitions differed. IsoGraph module context captured predictive information about held-out differential transcript usage beyond gene-wise evidence and conventional co-expression. Convergent evidence from structural annotation, short-read junction usage, independent long-read sequencing, and within-donor allelic analyses supported constituent transcript events. Disease colocalization further prioritized candidate isoform events at neurological and psychiatric disease loci, including an alternative terminal-exon event at *PRDM2* associated with amyotrophic lateral sclerosis. Together, these results establish coordinated transcript usage as a reproducible component of transcriptomic organization and provide a framework for resolving its contribution alongside gene abundance and for tracing network-level signals to candidate transcript events.
ER -