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Fuzzy splicing in precursor-mRNA sequences: prediction of aberrant splice-junctions in viral DNA context  [PDF]
Perambur S. Neelakanta, Sharmistha Chatterjee, Mirjana Pavlovic, Abijit Pandya, Dolores de Groff
Journal of Biomedical Science and Engineering (JBiSE) , 2011, DOI: 10.4236/jbise.2011.44037
Abstract: RNA splicing normally generates stable splice- junction sequences in viruses that are important in the context of virus mimicry. Potential variability in envelop proteins may occur with point-mutations inducing cryptic splice-junctions, which would remain unrecognized by T-memory cells of higher organisms in vaccine trials. Such aberrant splice- junctions result from evolution-specific non-conser- vation of actual splice-junction sites due to mutations; as such, locations of splice-junctions in a test DNA sequence could only be imprecisely specified. Such impreciseness of splice-junction locations (or cryptic sites) in a sequence is evaluated in this study via “noisy” attributes (with associated stochastics) to the mutated subspace; and, relevant fuzzy considerations are invoked with membership attributes expressed in terms of a spatial signal-to-noise ratio (SSNR). That is, SSNR adopted as a membership function expresses the belongingness of a site-region to exon/intron subspaces. An illustrative example with actual (Dengue 1 viral) DNA data is furnished demonstrating the pursuit developed in predicting aberrant splice-junctions at cryptic sites in the test sequence.
A comprehensive survey of human polymorphisms at conserved splice dinucleotides and its evolutionary relationship with alternative splicing
Makoto K Shimada, Yosuke Hayakawa, Jun-ichi Takeda, Takashi Gojobori, Tadashi Imanishi
BMC Evolutionary Biology , 2010, DOI: 10.1186/1471-2148-10-122
Abstract: We found 212 validated SNPs at splice dinucleotides (sdSNPs); these were confirmed to be consistent with the GT-AG rule at either allele. Moreover, 53 of them were observed to neighbor ASEs (AE dinucleotides). No significant differences were observed between sdSNPs at AE dinucleotides and those at constitutive exons (CE dinucleotides) in SNP properties including average heterozygosity, SNP density, ratio of predicted alleles consistent with the GT-AG rule, and scores of splice sites formed with the predicted allele. We also found that the proportion of non-conserved exons was higher for exons with sdSNPs than for other exons.sdSNPs are found at CE dinucleotides in addition to those at AE dinucleotides, suggesting two possibilities. First, sdSNPs at CE dinucleotides may be robust against sdSNPs because of unknown mechanisms. Second, similar to sdSNPs at AE dinucleotides, those at CE dinucleotides cause differences in AS patterns because of the arbitrariness in the classification of exons into alternative and constitutive type that varies according to the dataset. Taking into account the absence of differences in sdSNP properties between those at AE and CE dinucleotides, the increased proportion of non-conserved exons found in exons flanked by sdSNPs suggests the hypothesis that sdSNPs are maintained at the splice dinucleotides of newly generated exons at which negative selection pressure is relaxed.Pre-mRNA splicing of eukaryotes requires three basic signals (splicing motifs) for the recognition of introns. The splicing motifs are the 5' intron end (donor) and the 3' intron end (acceptor), and the branch site. The splicing motifs at the 5' and 3' splice sites, known as "ag|GTragt" ("|" is the splice junction; "r" is a or g) and "(y)12-17nAG|g" ("y" is c or t; "n" is a, t, g or c; and subscript indicates the repeat number) [1,2]. A human expressed sequence tag-based study showed that 99.24% and 0.69% of introns are flanked by GT-AG and GC-AG dinucleotides (splice dinu
Alcoholism and Alternative Splicing of Candidate Genes  [PDF]
Toshikazu Sasabe,Shoichi Ishiura
International Journal of Environmental Research and Public Health , 2010, DOI: 10.3390/ijerph7041448
Abstract: Gene expression studies have shown that expression patterns of several genes have changed during the development of alcoholism. Gene expression is regulated not only at the level of transcription but also through alternative splicing of pre-mRNA. In this review, we discuss some of the evidence suggesting that alternative splicing of candidate genes such as DRD2 (encoding dopamine D2 receptor) may form the basis of the mechanisms underlying the pathophysiology of alcoholism. These reports suggest that aberrant expression of splice variants affects alcohol sensitivities, and alcohol consumption also regulates alternative splicing. Thus, investigations of alternative splicing are essential for understanding the molecular events underlying the development of alcoholism.
Global analysis of aberrant pre-mRNA splicing in glioblastoma using exon expression arrays
Hannah C Cheung, Keith A Baggerly, Spiridon Tsavachidis, Linda L Bachinski, Valerie L Neubauer, Tamara J Nixon, Kenneth D Aldape, Gilbert J Cote, Ralf Krahe
BMC Genomics , 2008, DOI: 10.1186/1471-2164-9-216
Abstract: In total, we confirmed 14 genes with glioma-specific splicing; seven were novel events identified by the exon expression array (A2BP1, BCAS1, CACNA1G, CLTA, KCNC2, SNCB, and TPD52L2). Our data indicate that large changes (> 5-fold) in alternative splicing are infrequent in gliomagenesis (< 3% of interrogated RefSeq entries). The lack of splicing changes may derive from the small number of splicing factors observed to be aberrantly expressed.While we observed some tumor-specific alternative splicing, the number of genes showing exclusive tumor-specific isoforms was on the order of tens, rather than the hundreds suggested previously by in silico mining. Given the important role of alternative splicing in neural differentiation, there may be selective pressure to maintain a majority of splicing events in order to retain glial-like characteristics of the tumor cells.In alternative pre-mRNA splicing, multiple transcript isoforms are expressed from a single gene by varying the combination of exons that are included in the mature mRNA. These isoforms may differ in their transcript and protein stabilities and/or in their protein structures and activities, which allows for functional and physiological diversity [1,2]. Alternative splicing affects up to 74% of all genes and may cause epigenetic instability when aberrant [3]. In cancer, two major mechanisms lead to the dysregulation of proper splicing: somatic mutations in splice regulatory cis-elements and mis-expression of trans-acting factors [4,5]. The second phenomenon has been reported in numerous cancers including glioma, ovarian and colon cancer [6-11]. Furthermore, many individual genes have cancer-predominant splicing patterns that contribute to tumorigenesis [5,12,13]. However, it is unclear whether the tumor-specific misexpression of splice factors leads to global aberrant splicing in cancer. Genome-wide attempts to address this have been performed mostly in silico by aligning and comparing EST libraries. Several h
Accumulation of GC donor splice signals in mammals
Alexander Churbanov, Stephen Winters-Hilt, Eugene V Koonin, Igor B Rogozin
Biology Direct , 2008, DOI: 10.1186/1745-6150-3-30
Abstract: This article was reviewed by Jerzy Jurka and Anton Nekrutenko. For the full reviews, please go to the Reviewers' Reports section.In vertebrates, most of the protein-coding genes are interrupted by multiple introns that are removed at the donor and acceptor splice sites so that the adjacent exons are spliced. This process is mediated by an elaborate molecular machine, the spliceosome that consists of 5 snRNPs (small nuclear ribonucleoprotein particles) along with numerous less stably associated proteins, and is conserved throughout the eukaryotic world [1-3]. The U2 spliceosome (the major eukaryotic spliceosome) interacts with specific parts of the intron and the flanking exons to ensure accurate and efficient splicing [4]. The nucleotides at the intron termini and the adjacent nucleotides in the exons are involved in these interactions and comprise the splicing signal. The (A/C)AG|GT(A/G)AGT consensus sequence (the exon|intron boundary is shown by the vertical streak and the first two nucleotides of the intron are underlined) at the donor splice signal is complementary to the 5' end of U1 snRNA, and this interaction is believed to be the major requirement for splicing [5-7].The GT dinucleotide in the first two intron positions is the most conserved element of the U2 donor splice signal. However, in a small fraction of donor sites (<1%), GT is replaced by GC; in these cases, the rest of the nucleotides in the donor signal adhere more closely to the consensus sequence, apparently, compensating for the T to C substitution that is unfavorable for splicing [8-10]. This rare class of donor splice signals has been implicated in alternative splicing [9,11,12]. For example, the conserved C at the +2 position of the 10th intron of the let-2 gene which encodes one of the collagen isoforms is essential for developmentally regulated alternative splicing in the nematode C. elegans. Replacement of the GC donor signal with a moderate or strong GT signal abolishes splicing regulatio
Control of Pre-mRNA Splicing by the General Splicing Factors PUF60 and U2AF65  [PDF]
Michelle L. Hastings, Eric Allemand, Dominik M. Duelli, Michael P. Myers, Adrian R. Krainer
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000538
Abstract: Pre-mRNA splicing is a crucial step in gene expression, and accurate recognition of splice sites is an essential part of this process. Splice sites with weak matches to the consensus sequences are common, though it is not clear how such sites are efficiently utilized. Using an in vitro splicing-complementation approach, we identified PUF60 as a factor that promotes splicing of an intron with a weak 3′ splice-site. PUF60 has homology to U2AF65, a general splicing factor that facilitates 3′ splice-site recognition at the early stages of spliceosome assembly. We demonstrate that PUF60 can functionally substitute for U2AF65 in vitro, but splicing is strongly stimulated by the presence of both proteins. Reduction of either PUF60 or U2AF65 in cells alters the splicing pattern of endogenous transcripts, consistent with the idea that regulation of PUF60 and U2AF65 levels can dictate alternative splicing patterns. Our results indicate that recognition of 3′ splice sites involves different U2AF-like molecules, and that modulation of these general splicing factors can have profound effects on splicing.
Disturbed Expression of Splicing Factors in Renal Cancer Affects Alternative Splicing of Apoptosis Regulators, Oncogenes, and Tumor Suppressors  [PDF]
Agnieszka Piekielko-Witkowska,Hanna Wiszomirska,Anna Wojcicka,Piotr Poplawski,Joanna Boguslawska,Zbigniew Tanski,Alicja Nauman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013690
Abstract: Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer. One of the processes disturbed in this cancer type is alternative splicing, although phenomena underlying these disturbances remain unknown. Alternative splicing consists of selective removal of introns and joining of residual exons of the primary transcript, to produce mRNA molecules of different sequence. Splicing aberrations may lead to tumoral transformation due to synthesis of impaired splice variants with oncogenic potential. In this paper we hypothesized that disturbed alternative splicing in ccRCC may result from improper expression of splicing factors, mediators of splicing reactions.
Ligand-induced sequestering of branchpoint sequence allows conditional control of splicing
Dong-Suk Kim, Veronica Gusti, Kenneth J Dery, Rajesh K Gaur
BMC Molecular Biology , 2008, DOI: 10.1186/1471-2199-9-23
Abstract: We constructed a series of pre-mRNAs in which the BPS was inserted within theophylline aptamer. We show that theophylline-induced sequestering of BPS inhibits pre-mRNA splicing both in vitro and in vivo in a dose-dependent manner. Several lines of evidence suggest that theophylline-dependent inhibition of splicing is highly specific, and thermodynamic stability of RNA-theophylline complex as well as the location of BPS within this complex affects the efficiency of splicing inhibition. Finally, we have constructed an alternative splicing model pre-mRNA substrate in which theophylline caused exon skipping both in vitro and in vivo, suggesting that a small molecule-RNA interaction can modulate alternative splicing.These findings provide the ability to control splicing pattern at will and should have important implications for basic, biotechnological, and biomedical research.Pre-mRNA splicing is a fundamental process that joins exons by catalyzing the removal of intervening sequences (introns) from mRNA precursors. Pre-mRNAs are spliced in a two-step pathway catalyzed by the spliceosome, a dynamic macromolecular machinery consisting of five small nuclear ribonucleoproteins (U1, U2, U4, U5 and U6 snRNPs) and many non-snRNP proteins. In the first step, pre-mRNA is cleaved at the 5' splice site (ss) generating two splicing intermediates: a linear first exon, and an intron-second exon in a lariat configuration. In the second step, the 3'-hydroxyl group of the last nucleotide in first exon makes a nucleophillic attack at the phosphodiester bond separating the intron and the second exon (3' ss), enabling the joining of two exons and release of the intron as a lariat (for review, see references [1-3]).The differential joining of 5' and 3' ss of a single pre-mRNA, a phenomenon known as alternative splicing, can generate variant mRNAs with diverse and often antagonistic functions [4-7]. Alternative splicing of pre-mRNA is now considered to be the most important source of protein
The (In)dependence of Alternative Splicing and Gene Duplication  [PDF]
David Talavera ,Christine Vogel ,Modesto Orozco,Sarah A Teichmann,Xavier de la Cruz
PLOS Computational Biology , 2007, DOI: 10.1371/journal.pcbi.0030033
Abstract: Alternative splicing (AS) and gene duplication (GD) both are processes that diversify the protein repertoire. Recent examples have shown that sequence changes introduced by AS may be comparable to those introduced by GD. In addition, the two processes are inversely correlated at the genomic scale: large gene families are depleted in splice variants and vice versa. All together, these data strongly suggest that both phenomena result in interchangeability between their effects. Here, we tested the extent to which this applies with respect to various protein characteristics. The amounts of AS and GD per gene are anticorrelated even when accounting for different gene functions or degrees of sequence divergence. In contrast, the two processes appear to be independent in their influence on variation in mRNA expression. Further, we conducted a detailed comparison of the effect of sequence changes in both alternative splice variants and gene duplicates on protein structure, in particular the size, location, and types of sequence substitutions and insertions/deletions. We find that, in general, alternative splicing affects protein sequence and structure in a more drastic way than gene duplication and subsequent divergence. Our results reveal an interesting paradox between the anticorrelation of AS and GD at the genomic level, and their impact at the protein level, which shows little or no equivalence in terms of effects on protein sequence, structure, and function. We discuss possible explanations that relate to the order of appearance of AS and GD in a gene family, and to the selection pressure imposed by the environment.
Splicing bioinformatics to biology
Douglas L Black, Brenton R Graveley
Genome Biology , 2006, DOI: 10.1186/gb-2006-7-5-317
Abstract: Alternative splicing affects many aspects of eukaryotic biology and is studied by groups with diverse interests. Geneticists and biochemists have long been interested in understanding the molecular mechanisms that underlie changes in splice-site choice, and the role of splicing regulation in particular biological systems. More recently, computational biologists have entered the field with the goals of defining the products of genomes and understanding the role of alternative splicing in genome evolution. Although their interests broadly overlap, these fields often utilize distinct languages, and there have been relatively few meetings dedicated to bringing the two groups together. Exceptions have been the symposia on alternative transcript diversity organized by the European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI); the second symposium was held in March in Heidelberg. This meeting made clear that the interests of these two groups coincide more than ever, and that combining genomic approaches with mechanistic analyses is leading to significant new understanding of splicing regulation.The combined approach was apparent in the opening talk given by one of us (B.G.) describing the use of comparative genomics in analysis of the splicing of the Dscam locus in Drosophila. This gene is the most complex system of alternative splicing yet described. Dscam contains several large arrays of alternative exons that are used in a mutually exclusive manner where only one exon in each array is spliced into the Dscam mRNA. The mechanisms that enforce the mutually exclusive choice in such a large array are obscure. For one array (exon 6), the comparative sequence analysis identified conserved features that predict base pairing between a docking site in the intron upstream of the array and selector sequences adjacent to each alternative exon. This finding leads to a unique model for the regulation of exon 6 splicing, in which mutually exclusive pairing
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