Abstract
BackgroundVariation in pre-mRNA splicing is common and in some cases caused by genetic variants in intronic splicing motifs. Recent studies into the insulin gene (INS) discovered a polymorphism in a 5′ non-coding intron that influences the likelihood of intron retention in the final mRNA, extending the 5′ untranslated region and maintaining protein quality. Retention was also associated with increased insulin levels, suggesting that such variants - splice translational efficiency polymorphisms (STEPs) - may relate to disease phenotypes through differential protein expression. We set out to explore the prevalence of STEPs in the human genome and validate this new category of protein quantitative trait loci (pQTL) using publicly available data.Methodology/Principal FindingsGene transcript and variant data were collected and mined for candidate STEPs in motif regions. Sequences from transcripts containing potential STEPs were analysed for evidence of splice site recognition and an effect in expressed sequence tags (ESTs). 16 publicly released genome-wide association data sets of common diseases were searched for association to candidate polymorphisms with HapMap frequency data. Our study found 3324 candidate STEPs lying in motif sequences of 5′ non-coding introns and further mining revealed 170 with transcript evidence of intron retention. 21 potential STEPs had EST evidence of intron retention or exon extension, as well as population frequency data for comparison.Conclusions/SignificanceResults suggest that the insulin STEP was not a unique example and that many STEPs may occur genome-wide with potentially causal effects in complex disease. An online database of STEPs is freely accessible at http://dbstep.genes.org.uk/.
Highlights
Alternative splicing of pre-mRNA is common in human and other species [1]
We further examined candidate splice translational efficiency polymorphisms (STEPs) in silico for splice site recognition using sequences containing each SNP allele and for expressed sequence tag (EST) evidence of intron retention where possible
The fewest number of variants appears in the shortest intronic motif, the 39 acceptor splice site (39ss), with 326 variants (248 SNPs, 78 INDELs)
Summary
Alternative splicing of pre-mRNA is common in human and other species [1]. Alternative splicing events have been recognised for their effects on protein coding sequences, because most exons contain protein coding sequence which may be present or absent in the translation product, altering the qualities of the protein produced [2]. Alternative protein versions may subserve different functions, a classic example being calcitonin expressed from thyroid C cells versus CGRP as a neurotransmitter produced by some nerve cells [3]. Such pre-mRNA splicing may be tissue-specific and is equivalent between all individuals in a population, but some is individual-specific because the alleles of a polymorphism differentially affect splicing through their presence in or effect on splicing sequence motifs. Retention was associated with increased insulin levels, suggesting that such variants - splice translational efficiency polymorphisms (STEPs) - may relate to disease phenotypes through differential protein expression. We set out to explore the prevalence of STEPs in the human genome and validate this new category of protein quantitative trait loci (pQTL) using publicly available data
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