Abstract
DNA variants that affect alternative splicing and the relative quantities of different gene transcripts have been shown to be risk alleles for some Mendelian diseases. However, for complex traits characterized by a low odds ratio for any single contributing variant, very few studies have investigated the contribution of splicing variants. The overarching goal of this study is to discover and characterize the role that variants affecting alternative splicing may play in the genetic etiology of complex traits, which include a significant number of the common human diseases. Specifically, we hypothesize that single nucleotide polymorphisms (SNPs) in splicing regulatory elements can be characterized in silico to identify variants affecting splicing, and that these variants may contribute to the etiology of complex diseases as well as the inter-individual variability in the ratios of alternative transcripts. We leverage high-throughput expression profiling to 1) experimentally validate our in silico predictions of skipped exons and 2) characterize the molecular role of intronic genetic variations in alternative splicing events in the context of complex human traits and diseases. We propose that intronic SNPs play a role as genetic regulators within splicing regulatory elements and show that their associated exon skipping events can affect protein domains and structure. We find that SNPs we would predict to affect exon skipping are enriched among the set of SNPs reported to be associated with complex human traits.
Highlights
Alternative Splicing (AS) is a eukaryotic-specific cellular mechanism that increases the diversity of mRNA and allows for the production of multiple proteins from one gene
Alternative splicing is a common eukaryotic cellular mechanism that allows for the production of multiple proteins from one gene and occurs in 40%–90% of all human genes
We evaluate their enrichment among established diseaseassociated variations
Summary
Alternative Splicing (AS) is a eukaryotic-specific cellular mechanism that increases the diversity of mRNA and allows for the production of multiple proteins from one gene. AS is a biological system that leads to the production of tissue-specific and disease-specific expressed mRNA isoforms and may be a contributing factor to differences in normal and pathological physiology [2,7,8]. Intronic splicing enhancers (ISE), exonic splicing enhancers (ESE), intronic splicing silencers (ISS), and exonic splicing silencers (ESS) regulate the intron excision process by assisting in the recognition of the correct splice site to generate in the correct combination of exons in the final mRNA. Genetic variation in cis-acting splicing regulatory elements (SREs: ISE, ESE, ISS, and ESS) may lead to aberrant intron excision [9], resulting in exon skipping and varying protein products. Exon skipping interventions have been developed as potential molecular therapies for Duchenne Muscular Dystrophy [16,17,18] and effects of statins on alternative splicing have been suggested to contribute to efficacy variation in cardiovascular disease treatment [19]
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