SNPSplicer: systematic analysis of SNP-dependent splicing in genotyped cDNAs

ElSharawy, Abdou; Manaster, Carl; Teuber, Markus; Rosenstiel, Philip; Kwiatkowski, Ruta; Huse, Klaus; Platzer, Matthias; Becker, Albert; Nürnberg, Peter; Schreiber, Stefan; Hampe, Jochen

doi:10.1002/humu.20377

Cited by 40 publications

(28 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There have been a few reports of SNPs that do affect splicing (Shinmura et al 2004;Field et al 2005;Skarratt et al 2005;ElSharawy et al 2006;Kawase et al 2007) but no comprehensive analysis of this phenomenon. In our study, we used the 1260 SNPs at 5Јss (dbSNP) (Smigielski et al 2000) that are confirmed by population data and lie outside of positions +1 and +2.…”

Section: Snps At 5јssmentioning

confidence: 99%

Features of 5′-splice-site efficiency derived from disease-causing mutations and comparative genomics

Roca¹,

Olson²,

Rao³

et al. 2007

Genome Res.

View full text Add to dashboard Cite

Many human diseases, including Fanconi anemia, hemophilia B, neurofibromatosis, and phenylketonuria, can be caused by 5Ј-splice-site (5Јss) mutations that are not predicted to disrupt splicing, according to position weight matrices. By using comparative genomics, we identify pairwise dependencies between 5Јss nucleotides as a conserved feature of the entire set of 5Јss. These dependencies are also conserved in human-mouse pairs of orthologous 5Јss. Many disease-associated 5Јss mutations disrupt these dependencies, as can some human SNPs that appear to alter splicing. The consistency of the evidence signifies the relevance of this approach and suggests that 5Јss SNPs play a role in complex diseases.[Supplemental material is available online at www.genome.org.]The sequenced genomes of a wide range of organisms allow global, comparative analyses of regulatory sequences. The genomic set of splice-site sequences corresponds to a large-scale splicing experiment performed by nature under evolutionary constraints. Here we focus on 5Ј-splice-site (5Јss) sequences of the U2-type GT-AG class, which comprise over 98% of all splice sites, and use disease-causing mutations, human single nucleotide polymorphisms (SNPs), and variations in natural splice sites in the genome (within and between species) to infer properties inherent to 5Јss, with important implications for human genetics.Splice sites are conserved sequences at both ends of an intron that are recognized during the initial steps of splicing (Hastings and Krainer 2001;Brow 2002;Jurica and Moore 2003). Both the 5Јss and the 3Ј splice site (3Јss) conform to degenerate motifs that are recognized by specific splicing factors. The U2-type GT-AG 5Јss, spanning 3 nucleotides (nt) at the 3Ј end of the exon and 6 nt at the 5Ј end of the intron, is initially recognized via base pairing to the 5Ј end of the U1 snRNA (Fig.

show abstract

Section: Snps At 5јssmentioning

confidence: 99%

Features of 5′-splice-site efficiency derived from disease-causing mutations and comparative genomics

Roca¹,

Olson²,

Rao³

et al. 2007

Genome Res.

View full text Add to dashboard Cite

show abstract

“…Previously, Ensembl made its SNP annotation algorithm accessible via the tool “Variant Effect Predictor” [7]. SNP annotation in more specific contexts is furthermore performed by a series of other software tools [8–12]. However, with the rapid spreading of high-throughput sequencing machines, there is a growing need for high-quality assembly and annotation tools to cope efficiently with the massive amount of sequencing data in respect to annotation and speed data analysis and to extend the analysis to indels.…”

Section: Introductionmentioning

confidence: 99%

NovelSNPer: A Fast Tool for the Identification and Characterization of Novel SNPs and InDels

Aßmus

Schmitt

Bortfeldt

et al. 2011

Advances in Bioinformatics

View full text Add to dashboard Cite

Typically, next-generation resequencing projects produce large lists of variants. NovelSNPer is a software tool that permits fast and efficient processing of such output lists. In a first step, NovelSNPer determines if a variant represents a known variant or a previously unknown variant. In a second step, each variant is classified into one of 15 SNP classes or 19 InDel classes. Beside the classes used by Ensembl, we introduce POTENTIAL_START_GAINED and START_LOST as new functional classes and present a classification scheme for InDels. NovelSNPer is based upon the gene structure information stored in Ensembl. It processes two million SNPs in six hours. The tool can be used online or downloaded.

show abstract

“…Mutations that affect splicing appear to be responsible for a large proportion of human genetic diseases (see [5], [6] for reviews) and may even be the largest contributor to human genetic diseases resulting from single point mutations [7]. Researchers investigating the potential functional implications of genetic variants have often tended to ignore splicing effects [5], although, recently, there have been several large-scale studies to identify common genetic variants with an effect on mRNA splicing [4], [8], [9], [10], [11], [12], [13], [14], [15]. These studies parallel efforts to determine the genetic contribution to gene expression variation (for review see [16]).…”

Section: Introductionmentioning

confidence: 99%

Heritability in the Efficiency of Nonsense-Mediated mRNA Decay in Humans

Seoighe

Gehring

2010

PLoS ONE

View full text Add to dashboard Cite

BackgroundIn eukaryotes mRNA transcripts of protein-coding genes in which an intron has been retained in the coding region normally result in premature stop codons and are therefore degraded through the nonsense-mediated mRNA decay (NMD) pathway. There is evidence in the form of selective pressure for in-frame stop codons in introns and a depletion of length three introns that this is an important and conserved quality-control mechanism. Yet recent reports have revealed that the efficiency of NMD varies across tissues and between individuals, with important clinical consequences.Principal FindingsUsing previously published Affymetrix exon microarray data from cell lines genotyped as part of the International HapMap project, we investigated whether there are heritable, inter-individual differences in the abundance of intron-containing transcripts, potentially reflecting differences in the efficiency of NMD. We identified intronic probesets using EST data and report evidence of heritability in the extent of intron expression in 56 HapMap trios. We also used a genome-wide association approach to identify genetic markers associated with intron expression. Among the top candidates was a SNP in the DCP1A gene, which forms part of the decapping complex, involved in NMD.ConclusionsWhile we caution that some of the apparent inter-individual difference in intron expression may be attributable to different handling or treatments of cell lines, we hypothesize that there is significant polymorphism in the process of NMD, resulting in heritable differences in the abundance of intronic mRNA. Part of this phenotype is likely to be due to a polymorphism in a decapping enzyme on human chromosome 3.

show abstract

SNPSplicer: systematic analysis of SNP-dependent splicing in genotyped cDNAs

Cited by 40 publications

References 30 publications

Features of 5′-splice-site efficiency derived from disease-causing mutations and comparative genomics

Features of 5′-splice-site efficiency derived from disease-causing mutations and comparative genomics

NovelSNPer: A Fast Tool for the Identification and Characterization of Novel SNPs and InDels

Heritability in the Efficiency of Nonsense-Mediated mRNA Decay in Humans

Contact Info

Product

Resources

About