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Alternative isoform regulation in human tissue transcriptomes
Open accessAbstract
Through alternative processing of pre-messenger RNAs, individual mammalian genes often produce multiple mRNA and protein isoforms that may have related, distinct or even opposing functions. Here we report an in-depth analysis of 15 diverse human tissue and cell line transcriptomes on the basis of deep sequencing of complementary DNA fragments, yielding a digital inventory of gene and mRNA isoform expression. Analyses in which sequence reads are mapped to exon-exon junctions indicated that 92-94% of human genes undergo alternative splicing, 86% with a minor isoform frequency of 15% or more. Differences in isoform-specific read densities indicated that most alternative splicing and alternative cleavage and polyadenylation events vary between tissues, whereas variation between individuals was approximately twofold to threefold less common. Extreme or 'switch-like' regulation of splicing between tissues was associated with increased sequence conservation in regulatory regions and with generation of full-length open reading frames. Patterns of alternative splicing and alternative cleavage and polyadenylation were strongly correlated across tissues, suggesting coordinated regulation of these processes, and sequence conservation of a subset of known regulatory motifs in both alternative introns and 3' untranslated regions suggested common involvement of specific factors in tissue-level regulation of both splicing and polyadenylation.
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“Direct sequencing of RNA libraries also provides the opportunity to explore alternative splicing, a key mechanism that contributes to transcriptome diversity (Pan et al., 2008;Wang et al., 2008).”
From An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex (2014) · cites this paper as Wang et al., 2008
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“RNA sequencing (RNA-seq) studies indicate that ~93% of human genes undergo alternative splicing and about 86% have a minor isoform frequency above 15% (ref. 11).”
From How many human proteoforms are there? (2018) · cites this paper as [11]
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“RNA sequencing (RNA-seq) studies indicate that ~93% of human genes undergo alternative splicing and about 86% have a minor isoform frequency above 15% (ref. 11).”
From How many human proteoforms are there? (2018) · cites this paper as [11]
In the citing paper
“RNA-seq experiments have discovered over 100,000 AS transcripts in the human genome (Pan et al., 2008; Wang et al., 2008)”
From Splice-Junction-Based Mapping of Alternative Isoforms in the Human Proteome (2019) · cites this paper as Wang et al., 2008
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“Transcripts from ∼95% of multi-exon human genes are alternatively spliced (Pan et al., 2008, Wang et al., 2008).”
From Impact of Alternative Splicing on the Human Proteome (2017) · cites this paper as Wang et al., 2008
In the citing paper
“Several recent findingspropose that Rbfox can also regulate alternative polyadenylation (Wang et al., 2008) and mRNA stability (Ray et al., 2013), based on analysis of Rbfox motif sites in 3′ UTRs that are correlated with transcript abundance in different tissues.”
From HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism (2014) · cites this paper as Wang et al., 2008
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Metadata
- Authors
- Wang, E. T., Sandberg, R., Luo, S., Khrebtukova, I., Zhang, L., Mayr, C., Kingsmore, S. F., Schroth, G. P., & Burge, C. B.
- Affiliations
- Massachusetts Institute of Technology (US)
- Karolinska Institutet (SE)
- Illumina (United States) (US)
- Whitehead Institute for Biomedical Research (US)
- National Center for Genome Resources (US)
- Corresponding author
- Burge, Christopher B.
- ORCID
- Venue
- Nature
- Published
- 2008-11
- Volume
- 456
- Issue
- 7221
- Pages
- 470-476
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2593745
- OpenAlex
- W2155804510
- Cited by
- 5,181
- References
- 41
- Citations by year
- 2026: 172 · 2025: 222 · 2024: 253 · 2023: 254 · 2022: 317 · 2021: 364 · 2020: 294 · 2019: 304 · 2018: 266 · 2017: 262 · 2016: 294 · 2015: 316 · 2014: 345 · 2013: 347 · 2012: 376
- FWCI
- 108.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Human Genome Research Institute (R01HG002439)
- National Cancer Institute (P30CA008748)
- National Institute of General Medical Sciences (R01GM085319)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- alternative splicing, mRNA isoforms, tissue-specific gene expression, exon-exon junctions, sequence conservation, 3' untranslated region, human transcriptome, human cell lines, splicing regulation
- MeSH terms
- RNA Splicing Factors, Base Sequence, Cell Line, Exons, Humans, Organ Specificity, Repressor Proteins, RNA, Messenger, Open Reading Frames, RNA-Binding Proteins, Alternative Splicing, Protein Isoforms, Gene Expression Profiling, Polyadenylation
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