Regulatory Divergence of Transcript Isoforms in a Mammalian Model System
Abstract
Phenotypic differences between species are driven by changes in gene expression and, by extension, by modifications in the regulation of the transcriptome. Investigation of mammalian transcriptome divergence has been restricted to analysis of bulk gene expression levels and gene-internal splicing. Using allele-specific expression analysis in inter-strain hybrids of Mus musculus, we determined the contribution of multiple cellular regulatory systems to transcriptome divergence, including: alternative promoter usage, transcription start site selection, cassette exon usage, alternative last exon usage, and alternative polyadenylation site choice. Between mouse strains, a fifth of genes have variations in isoform usage that contribute to transcriptomic changes, half of which alter encoded amino acid sequence. Virtually all divergence in isoform usage altered the post-transcriptional regulatory instructions in gene UTRs. Furthermore, most genes with isoform differences between strains contain changes originating from multiple regulatory systems. This result indicates widespread cross-talk and coordination exists among different regulatory systems. Overall, isoform usage diverges in parallel with and independently to gene expression evolution, and the cis and trans regulatory contribution to each differs significantly.
Additional Information
© 2015 Leigh-Brown et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: June 9, 2015; Accepted: August 15, 2015; Published: September 4, 2015. Funding: This work was supported by the European Research Council (DTO) (http://erc.europa.eu/); EMBO Young Investigators Program (DTO) (http://www.embo.org/funding-awards/young-investigators); Hutchinson Whampoa (DTO) (http://www.hutchisonwhampoa. com/en/global/home.php); Cancer Research UK (DTO, SLB, KS, SW) (http://www.cancerresearchuk.org/); University of Cambridge (SLB, KS, DTO, AG) (http://www.cam.ac.uk/); European Molecular Biology Laboratory (AG, DT, AB, PF, JCM) (http://www.embl.org/); Wellcome Trust WT095908 and WT098051 (DT, PF, DTO) (http://www.wellcome.ac.uk/); and FP7 HEALTH grant from the European Commission GEUVADIS grant agreement 261123 (AG, AB) (http://www.geuvadis.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Since performing the experimental work and writing this manuscript, SLB has taken paid employment at Abcam, a Biotech firm selling reagents to research scientists. Abcam had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Since performing the experimental work and writing this manuscript, SLB has taken paid employment at Abcam, a Biotech firm selling reagents to research scientists. Abcam have no interest in the submitted manuscript and NO Abcam products were used for this experimental work. The authors do not consider this to be a competing interest, and the authors declare it here so that the reviewers may be fully informed. We thank CRUK-CI Genomics, Bioinformatics and Biological Resources Facilities plus Barts and The London Genome Centre for their expertise and involvement in this study. We are grateful to David Adams (Wellcome Trust Sanger Institute) for prior access to the genome and transcriptome sequences for the mouse strains used in this study. We also acknowledge helpful comments and suggestions from Ernest Turro, Simon Anders, Wolfgang Huber, Jenny Tung, Luis Barreiro, Athma Pai, Yoav Gilad, and members of the Marioni, Odom, Flicek, and Brazma groups. Author Contributions: Conceived and designed the experiments: DTO JCM SLB AG KS DT. Performed the experiments: SLB SW. Analyzed the data: AG JCM DT SLB AB. Contributed reagents/materials/analysis tools: PF DT KS AB. Wrote the paper: SLB AG JCM DTO. Provided Castaneus genome: PF. Generated Castaneus transcriptome: DT.Attached Files
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Additional details
- PMCID
- PMC4560434
- Eprint ID
- 60506
- Resolver ID
- CaltechAUTHORS:20150925-085736543
- European Research Council (ERC)
- European Molecular Biology Organization (EMBO)
- Hutchinson Whampoa
- Cancer Research UK
- University of Cambridge
- European Molecular Biology Laboratory (EMBL)
- WT095908
- Wellcome Trust
- WT098051
- Wellcome Trust
- 261123
- European Research Council (ERC)
- Created
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2015-09-25Created from EPrint's datestamp field
- Updated
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2023-06-01Created from EPrint's last_modified field