RNA sequencing reveals the role of splicing polymorphisms in regulating human gene expression
Open accessAbstract
Expression levels of many human genes are under the genetic control of expression quantitative trait loci (eQTLs). Despite technological advances, the precise molecular mechanisms underlying most eQTLs remain elusive. Here, we use deep mRNA sequencing of two CEU individuals to investigate those mechanisms, with particular focus on the role of splicing control loci (sQTLs). We identify a large number of genes that are differentially spliced between the two samples and associate many of those differences with nearby single nucleotide polymorphisms (SNPs). Subsequently, we investigate the potential effect of splicing SNPs on eQTL control in general. We find a significant enrichment of alternative splicing (AS) events within a set of highly confident eQTL targets discovered in previous studies, suggesting a role of AS in regulating overall gene expression levels. Next, we demonstrate high correlation between the levels of mature (exonic) and unprocessed (intronic) RNA, implying that ∼75% of eQTL target variance can be explained by control at the level of transcription, but that the remaining 25% may be regulated co- or post-transcriptionally. We focus on eQTL targets with discordant mRNA and pre-mRNA expression patterns and use four examples: USMG5 , MMAB , MRPL43 , and OAS1 , to dissect the exact downstream effects of the associated genetic variants.
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eQTL analysis shows gene expression and splicing are heavily influenced by common variants, possibly for most transcripts.
“eQTL analysis shows that gene expression and splicing are heavily influenced by common variants, possibly for the majority of transcripts86–88.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [88]
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- Authors
- Lalonde, E., Ha, K. C. H., Wang, Z., Bemmo, A., Kleinman, C. L., Kwan, T., Pastinen, T., & Majewski, J.
- Affiliations
- McGill University and Génome Québec Innovation Centre (CA)
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2010-12-20
- Volume
- 21
- Issue
- 4
- Pages
- 545-554
- ISSN
- 1088-9051 (ISSN-L)
- PMC
- PMC3065702
- OpenAlex
- W2142550096
- Cited by
- 111
- References
- 51
- Citations by year
- 2025: 1 · 2024: 4 · 2023: 4 · 2022: 1 · 2021: 3 · 2020: 6 · 2019: 6 · 2018: 12 · 2017: 8 · 2016: 5 · 2015: 13 · 2014: 12 · 2013: 13 · 2012: 14
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- McGill University
- Genome Canada
- Canada Research Chairs
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- expression quantitative trait loci, splicing quantitative trait loci, alternative splicing, single nucleotide polymorphisms, gene expression regulation, pre-mRNA processing, post-transcriptional regulation, OAS1
- MeSH terms
- Cell Line, Exons, Gene Expression Regulation, Humans, Introns, Membrane Proteins, Polymorphism, Genetic, RNA Splicing, Transcription, Genetic, 2',5'-Oligoadenylate Synthetase, Sequence Analysis, RNA, Alkyl and Aryl Transferases, Gene Order, Mitochondrial Proteins, Quantitative Trait Loci
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