Long-read transcriptomics of purified human cortical cell types exposes glial isoform complexity and disease-relevant transcript architecture

Journal article

Andy Yang, Miguel Rodríguez de los Santos, A. Kozlenkov, R. Vadukapuram, Yasmin L. Hurd, Stella Dracheva, J. Humphrey, Michael S. Breen
bioRxiv, 2026

Semantic Scholar DOI PubMedCentral PubMed

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APA Click to copy
Yang, A., de los Santos, M. R., Kozlenkov, A., Vadukapuram, R., Hurd, Y. L., Dracheva, S., … Breen, M. S. (2026). Long-read transcriptomics of purified human cortical cell types exposes glial isoform complexity and disease-relevant transcript architecture. BioRxiv.

Chicago/Turabian Click to copy
Yang, Andy, Miguel Rodríguez de los Santos, A. Kozlenkov, R. Vadukapuram, Yasmin L. Hurd, Stella Dracheva, J. Humphrey, and Michael S. Breen. “Long-Read Transcriptomics of Purified Human Cortical Cell Types Exposes Glial Isoform Complexity and Disease-Relevant Transcript Architecture.” bioRxiv (2026).

MLA Click to copy
Yang, Andy, et al. “Long-Read Transcriptomics of Purified Human Cortical Cell Types Exposes Glial Isoform Complexity and Disease-Relevant Transcript Architecture.” BioRxiv, 2026.

BibTeX Click to copy

@article{andy2026a,
  title = {Long-read transcriptomics of purified human cortical cell types exposes glial isoform complexity and disease-relevant transcript architecture},
  year = {2026},
  journal = {bioRxiv},
  author = {Yang, Andy and de los Santos, Miguel Rodríguez and Kozlenkov, A. and Vadukapuram, R. and Hurd, Yasmin L. and Dracheva, Stella and Humphrey, J. and Breen, Michael S.}
}

Abstract

Alternative splicing generates extraordinary transcriptomic complexity in the human brain, yet the full-length isoform landscape across human cortical cell types remains uncharted. Combining fluorescence-activated nuclei sorting with long- and short-read RNA sequencing, we generated isoform-resolved transcriptomes for five major lineages of the adult human prefrontal and orbitofrontal cortex: GABAergic neurons, glutamatergic neurons, oligodendrocytes, astrocytes, and microglia. We cataloged over 220,000 full-length isoforms, ∼35-56% previously unannotated; novel transcripts were longer, more exon-rich, and predominantly protein-coding. Contrary to the neuron-centric view of cortical complexity, glial lineages, particularly oligodendrocytes and microglia, emerged as the most isoform-diverse populations in the cortex. Differential transcript usage and dominant isoform switching defined cell identity, with ∼59-62% of differentially regulated transcripts absent from current annotations. Critically, pathogenic variants were enriched >2-fold at novel splice boundaries within disease genes including POGZ, TARDBP, and PLP1, establishing isoform selection as a primary axis of cortical identity and exposing a layer of pathogenic variation invisible to canonical gene annotations.