Highly accurate isoform identification for the human transcriptome
Open accessPreprint — published as 10.7554/elife.82556 · Paper page
Abstract
We explore a new hypothesis in genome annotation, namely whether computationally predicted protein structures can help to identify which of multiple possible gene isoforms represents a functional protein product. Guided by structure predictions, we evaluated over 140,000 isoforms of human protein-coding genes assembled from over 10,000 RNA sequencing experiments across many human tissues. We illustrate our new method with examples where structure provides a guide to function in combination with expression and evolutionary evidence. Additionally, we provide the complete set of structures as a resource to better understand the function of human genes and their isoforms. These results demonstrate the promise of protein structure prediction as a genome annotation tool, allowing us to refine even the most highly-curated catalog of human proteins. One-Sentence Summary: We describe the use of 3D protein structures on a genome-wide scale to evaluate human protein isoforms for biological functionality.
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Varabyou, A., Sommer, M. J., Erdogdu, B., Shinder, I., Minkin, I., Chao, K.-H., Park, S., Heinz, J., Pockrandt, C., Shumate, A., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24465127
Self-citationVarabyou, A., Sommer, M. J., Erdogdu, B., Shinder, I., Minkin, I., Chao, K.-H., Park, S., Heinz, J., Pockrandt, C., Shumate, A., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26634009
Self-citationVarabyou, A., Sommer, M. J., Erdogdu, B., Shinder, I., Minkin, I., Chao, K.-H., Park, S., Heinz, J., Pockrandt, C., Shumate, A., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26634012
Self-citationVarabyou, A., Sommer, M. J., Erdogdu, B., Shinder, I., Minkin, I., Chao, K.-H., Park, S., Heinz, J., Pockrandt, C., Shumate, A., et al. (2024) · Figshare · doi:10.6084/m9.figshare.24465317
Self-citationIsoforms in action: The impact of transcript diversity in phenotype
Mamede, I., Mata-Machado, C., Reis, C. R., Amaral, P., & Franco, G. R. (2026) · Genetics and Molecular Biology · doi:10.1590/1678-4685-gmb-2025-0220
Systematic evaluation of MANE Plus Clinical transcripts: implications for genomic diagnosticsPreprint
Pagnamenta, A. T., Cannon, S. J., & Wright, C. F. (2026) · Research Square · doi:10.21203/rs.3.rs-9680068/v1
A structure-aware generative AI framework for revealing functional relationships in protein families
Shukla, D., Martin, J., Morcos, F., & Potoyan, D. A. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2536965123
- Authors
- Sommer, M. J., Cha, S., Varabyou, A., Rincon, N., Park, S., Minkin, I., Pertea, M., Steinegger, M., & Salzberg, S. L.
- Affiliations
- Johns Hopkins University (US)
- Seoul National University (KR)
- Corresponding author
- Sommer, Markus J.
- Steinegger, Martin
- Salzberg, Steven L.
- ORCID
- Venue
- eLife
- Publisher
- openRxiv
- Published
- 2022-06-09
- Volume
- 11
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC9812405
- OpenAlex
- W4311579410
- Cited by
- 40
- References
- 57
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 10 · 2023: 9 · 2022: 3
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- National Science Foundation (R01-HG006677, 1759518)
- National Research Foundation (2021-R1C1-C102065)
- Seoul National University
- National Research Foundation of Korea (2021-R1C1-C102065, 2021-M3A9-I4021220, 2020M3‐A9G7‐103933, 2019R1-A6A1-A10073437)
- National Institutes of Health
- National Institute of Mental Health (R01MH123567)
- National Human Genome Research Institute (R01HG006677)
- National Institute of General Medical Sciences (R35GM130151)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- protein isoforms, protein structure prediction, human transcriptome, genome annotation, gene function prediction, evolutionary conservation
- MeSH terms
- Humans, Genome, Sequence Analysis, RNA, Protein Isoforms, Molecular Sequence Annotation, Transcriptome
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