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iGEMS: an integrated model for identification of alternative exon usage events

Sood, Sanjana; Szkop, Krzysztof J.; Nakhuda, Asif; Gallagher, Iain J.; Murie, Carl; Brogan, Robert J.; Kaprio, Jaakko; Kainulainen, Heikki; Atherton, Philip J.; Kujala, Urho M.; Gustafsson, Thomas; Larsson, Ola; Timmons, James A.

iGEMS: an integrated model for identification of alternative exon usage events Thumbnail


Authors

Sanjana Sood

Krzysztof J. Szkop

Asif Nakhuda

Iain J. Gallagher

Carl Murie

Robert J. Brogan

Jaakko Kaprio

Heikki Kainulainen

PHILIP ATHERTON philip.atherton@nottingham.ac.uk
Professor of Clinical, metabolic & Molecular Physiology

Urho M. Kujala

Thomas Gustafsson

Ola Larsson

James A. Timmons



Abstract

DNA microarrays and RNAseq are complementary methods for studying RNA molecules. Current computational methods to determine alternative exon usage (AEU) using such data require impractical visual inspection and still yield high false-positive rates. Integrated Gene and Exon Model of Splicing (iGEMS) adapts a gene-level residuals model with a gene size adjusted false discovery rate and exon-level analysis to circumvent these limitations. iGEMS was applied to two new DNA microarray datasets, including the high coverage Human Transcriptome Arrays 2.0 and performance was validated using RT-qPCR. First, AEU was studied in adipocytes treated with (n = 9) or without (n = 8) the anti-diabetes drug, rosiglitazone. iGEMS identified 555 genes with AEU, and robust verification by RT-qPCR (∼90%). Second, in a three-way human tissue comparison (muscle, adipose and blood, n = 41) iGEMS identified 4421 genes with at least one AEU event, with excellent RT-qPCR
verification (95%, n = 22). Importantly, iGEMS identified a variety of AEU events, including 3 UTR extension, as well as exon inclusion/exclusion impacting on protein kinase and extracellular matrix domains. In conclusion, iGEMS is a robust method for identification of AEU while the variety of exon usage between human tissues is 5–10 times more prevalent than reported by the Genotype-Tissue Expression consortium using RNA sequencing.

Citation

Sood, S., Szkop, K. J., Nakhuda, A., Gallagher, I. J., Murie, C., Brogan, R. J., …Timmons, J. A. (2016). iGEMS: an integrated model for identification of alternative exon usage events. Nucleic Acids Research, 44(11), e109. https://doi.org/10.1093/nar/gkw263

Journal Article Type Article
Acceptance Date Apr 2, 2016
Online Publication Date Apr 19, 2016
Publication Date Jun 20, 2016
Deposit Date Sep 6, 2018
Publicly Available Date May 6, 2020
Journal Nucleic Acids Research
Print ISSN 0305-1048
Electronic ISSN 1362-4962
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 44
Issue 11
Pages e109
DOI https://doi.org/10.1093/nar/gkw263
Public URL https://nottingham-repository.worktribe.com/output/1117694
Publisher URL https://academic.oup.com/nar/article/44/11/e109/2468305
PMID 27095197

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