Variants Affecting Exon Skipping Contribute to Complex Traits

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.

The genetic basis for individual differences in mRNA splicing and APOBEC1 editing activity in murine macrophages

“…In the present study, we detected significant linkage between murine genetic variants and AS events for various genes, including Apobec3, Il3ra, Clec7a, and Apobec1, congruent with previous studies that demonstrated association between individual AS events and SNPs in the human genome (Cartegni et al 2002;Narla et al 2005;Lee et al 2012). AS can result in nonfunctional protein isoforms (Lango Allen et al 2010), which may alter cellular physiological states (David et al 2010;Gao and Cooper 2013).…”

“…AS can be due to variations at the splice site (cis) or to polymorphic or differentially expressed splice factors, enhancers, and repressors (trans) Lee et al 2012;Zaphiropoulos 2012). Therefore, based on the distance from the corresponding splice site, the sQTL can be categorized as cis or trans.…”

“…Even though the sequential assembly of the spliceosome (Kornblihtt et al 2013) can occur around any splice site that consists of consensus sequences recognized by the spliceosomal components, splice sites that conform better to a consensus sequence are strongly recognized and favored by the spliceosome complex. Besides the consensus sequences, the selection of optimal splice sites is regulated, in part, by a minimal set of conserved cis-acting GU and AG sequences at the 59 and 39 splice sites, respectively , and sequence elements known as intronic/exonic splicing enhancers and silencers Lee et al 2012). As such, genetic variation at the splice site, in the consensus sequences, or in the intronic/exonic enhancers and repressors may lead to alternative splicing (AS), resulting in alternative transcripts and protein isoforms from a single gene.…”

Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid-β accumulation modifier

“…3B, Right). DNA sequence variation as causative in disease has also been implicated in other studies (27)(28)(29). In summary, the strengths of each approach (model mice with mixed genetic backgrounds and transcriptomics) are synergized, whereas their respective drawbacks are minimized.…”

Co-expression networks reveal the tissue-specific regulation of transcription and splicing

“…However, posttranscriptional modifications, including alternative splicing, are important in creating a transcriptome with diverse biological functions (Matlin et al 2005). Mutations that lead to disruption of splicing play an important role in tissueand disease-specific pathways (López-Bigas et al 2005;Ward and Cooper 2010;Lee et al 2012;DeBoever et al 2015;Li et al 2016c).…”