Document Type
Article
Publication Date
4-3-2023
Original Citation
Karlebach G,
Carmody L,
Sundaramurthi J,
Casiraghi E,
Hansen P,
Reese J,
Mungall C,
Valentini G,
Robinson P.
An expectation-maximization framework for comprehensive prediction of isoform-specific functions. Bioinformatics. 2023;39(4):btad132.
Keywords
JGM, Humans, Motivation, Protein Isoforms, Software, Alternative Splicing, Sequence Analysis, RNA
JAX Source
Bioinformatics. 2023;39(4):btad132.
ISSN
1367-4811
PMID
36929917
DOI
https://doi.org/10.1093/bioinformatics/btad132
Grant
This work was supported by internal funding of the Jackson Laboratory.
Abstract
MOTIVATION: Advances in RNA sequencing technologies have achieved an unprecedented accuracy in the quantification of mRNA isoforms, but our knowledge of isoform-specific functions has lagged behind. There is a need to understand the functional consequences of differential splicing, which could be supported by the generation of accurate and comprehensive isoform-specific gene ontology annotations.
RESULTS: We present isoform interpretation, a method that uses expectation-maximization to infer isoform-specific functions based on the relationship between sequence and functional isoform similarity. We predicted isoform-specific functional annotations for 85 617 isoforms of 17 900 protein-coding human genes spanning a range of 17 430 distinct gene ontology terms. Comparison with a gold-standard corpus of manually annotated human isoform functions showed that isoform interpretation significantly outperforms state-of-the-art competing methods. We provide experimental evidence that functionally related isoforms predicted by isoform interpretation show a higher degree of domain sharing and expression correlation than functionally related genes. We also show that isoform sequence similarity correlates better with inferred isoform function than with gene-level function.
AVAILABILITY AND IMPLEMENTATION: Source code, documentation, and resource files are freely available under a GNU3 license at https://github.com/TheJacksonLaboratory/isopretEM and https://zenodo.org/record/7594321.
Comments
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.