Skip to content
DraconiticResearch
Search Sources API
203,234 studies31 sourcesUpdated 44 min ago
Peer-reviewedCC BYGenome biology

Perplexity as a metric for isoform diversity in the human transcriptome

  • Megan D. Schertzer1,2
  • S H Park2
  • Jiayu Su3
  • Fairlie Reese4,5
  • Gloria M. Sheynkman5,6,7,8,2
  • David A. Knowles8,1,3,2
8 affiliations
  1. 1Department of Computer Science, Columbia University, New York, NY
  2. 2New York Genome Center, New York, NY
  3. 3Department of Systems Biology, Columbia University, New York, NY
  4. 4Life Sciences Department, Barcelona Supercomputing Center (BSC), Barcelona, Catalonia
  5. 5Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA
  6. 6Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA
  7. 7UVA Comprehensive Cancer Center, University of Virginia, Charlottesville, VA
  8. 8Data Science Institute, Columbia University, New York, NY
Open at sourceDOICite

Abstract

-an interpretable measure derived from entropy-that quantifies the effective number of isoforms per gene based on the full, unfiltered isoform ratio distribution. Calculating perplexity for 124 ENCODE4 PacBio LRS datasets spanning 55 human cell types, we show that it provides intuitive assessments of isoform diversity and captures uncertainty across genes with varying complexity. Perplexity can be calculated at multiple gene regulatory levels-from transcript to protein-to compare how isoform diversity is reduced across stages of gene expression. On average, genes have an ORF-level perplexity of 2.1, indicating production of two distinct protein isoforms. We extended this analysis to evaluate expression variation across tissues and identified 4,593 ORFs across 3,102 genes with moderate to extreme tissue-specificity. We propose perplexity as a consistent, quantitative metric for interpreting isoform diversity across genes, cell types, and disease states. All results are compiled into a community resource to enable cross-study comparisons of novel isoforms.

Related

  1. Whole-transcriptome-scale isoform-resolved spatial imaging of single cells in tissues
    Limor Cohen, Aaron R. Halpern, Timothy R. Blosser +3
    CellPeer-reviewedCC BY15 citedMolecular biology & gene regulationOpenAlex
  2. Gene body architecture predicts isoform diversity across eukaryotic genomes
    Quinton Brohart, Arvind Mer
    BMC GenomicsPeer-reviewedCC BY-NC-ND 4.0Molecular biology & gene regulationCrossref
  3. scTHREAD: a cell-resolved long-read transcriptome database with linked isoform, poly(A), junction, and allelic evidence
    Zhi-Can Fu, Yelian Yan, Chunchun Wu +12
    Nucleic Acids ResearchPeer-reviewedCC BY-NC 4.0Full textMolecular biology & gene regulationCrossref
  4. HIF1A-AS2 Regulates Hypoxia-Driven HIF Isoform Switching in Human Endothelial Cells
    A. Barton, A. Wiech-Walow, P. Czechowicz +4
    bioRxivPreprintCC BY-NC-NDFull textMolecular biology & gene regulationbioRxiv
  5. Methylglyoxal hampers the angiogenic capacity of human retinal endothelial cells modifying cell transcriptome with the contribution of NRSF/REST
    Marianna Aprile, Cecilia Nigro, Caterina Perfetto +9
    Frontiers in cell and developmental biologyPeer-reviewedCC BYFull textGeneral biochemistryEurope PMC

Cite

BibTeXRIS
BibTeX
@article{schertzer2026perplexity,
  title = {{Perplexity as a metric for isoform diversity in the human transcriptome}},
  author = {Megan D. Schertzer and S H Park and Jiayu Su and Fairlie Reese and Gloria M. Sheynkman and David A. Knowles},
  journal = {Genome biology},
  year = {2026},
  month = sep,
  doi = {10.1186/s13059-026-04260-2},
  url = {https://doi.org/10.1186/s13059-026-04260-2},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Perplexity as a metric for isoform diversity in the human transcriptome
AU  - Megan D. Schertzer
AU  - S H Park
AU  - Jiayu Su
AU  - Fairlie Reese
AU  - Gloria M. Sheynkman
AU  - David A. Knowles
PY  - 2026
DA  - 2026/09/02
JO  - Genome biology
DO  - 10.1186/s13059-026-04260-2
UR  - https://doi.org/10.1186/s13059-026-04260-2
AB  - -an interpretable measure derived from entropy-that quantifies the effective number of isoforms per gene based on the full, unfiltered isoform ratio distribution. Calculating perplexity for 124 ENCODE4 PacBio LRS datasets spanning 55 human cell types, we show that it provides intuitive assessments of isoform diversity and captures uncertainty across genes with varying complexity. Perplexity can be calculated at multiple gene regulatory levels-from transcript to protein-to compare how isoform diversity is reduced across stages of gene expression. On average, genes have an ORF-level perplexity of 2.1, indicating production of two distinct protein isoforms. We extended this analysis to evaluate expression variation across tissues and identified 4,593 ORFs across 3,102 genes with moderate to extreme tissue-specificity. We propose perplexity as a consistent, quantitative metric for interpreting isoform diversity across genes, cell types, and disease states. All results are compiled into a community resource to enable cross-study comparisons of novel isoforms.
SN  - 1465-6906
SN  - 1465-6914
SN  - 1474-7596
SN  - 1474-760X
ER  -