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      A comprehensive survey of non-canonical splice sites in the human transcriptome

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          Abstract

          We uncovered the diversity of non-canonical splice sites at the human transcriptome using deep transcriptome profiling. We mapped a total of 3.7 billion human RNA-seq reads and developed a set of stringent filters to avoid false non-canonical splice site detections. We identified 184 splice sites with non-canonical dinucleotides and U2/U12-like consensus sequences. We selected 10 of the herein identified U2/U12-like non-canonical splice site events and successfully validated 9 of them via reverse transcriptase-polymerase chain reaction and Sanger sequencing. Analyses of the 184 U2/U12-like non-canonical splice sites indicate that 51% of them are not annotated in GENCODE. In addition, 28% of them are conserved in mouse and 76% are involved in alternative splicing events, some of them with tissue-specific alternative splicing patterns. Interestingly, our analysis identified some U2/U12-like non-canonical splice sites that are converted into canonical splice sites by RNA A-to-I editing. Moreover, the U2/U12-like non-canonical splice sites have a differential distribution of splicing regulatory sequences, which may contribute to their recognition and regulation. Our analysis provides a high-confidence group of U2/U12-like non-canonical splice sites, which exhibit distinctive features among the total human splice sites.

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          Most cited references53

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          Understanding alternative splicing: towards a cellular code.

          In violation of the 'one gene, one polypeptide' rule, alternative splicing allows individual genes to produce multiple protein isoforms - thereby playing a central part in generating complex proteomes. Alternative splicing also has a largely hidden function in quantitative gene control, by targeting RNAs for nonsense-mediated decay. Traditional gene-by-gene investigations of alternative splicing mechanisms are now being complemented by global approaches. These promise to reveal details of the nature and operation of cellular codes that are constituted by combinations of regulatory elements in pre-mRNA substrates and by cellular complements of splicing regulators, which together determine regulated splicing pathways.
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            Predictive identification of exonic splicing enhancers in human genes.

            Specific short oligonucleotide sequences that enhance pre-mRNA splicing when present in exons, termed exonic splicing enhancers (ESEs), play important roles in constitutive and alternative splicing. A computational method, RESCUE-ESE, was developed that predicts which sequences have ESE activity by statistical analysis of exon-intron and splice site composition. When large data sets of human gene sequences were used, this method identified 10 predicted ESE motifs. Representatives of all 10 motifs were found to display enhancer activity in vivo, whereas point mutants of these sequences exhibited sharply reduced activity. The motifs identified enable prediction of the splicing phenotypes of exonic mutations in human genes.
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              Update on activities at the Universal Protein Resource (UniProt) in 2013

              The mission of the Universal Protein Resource (UniProt) (http://www.uniprot.org) is to support biological research by providing a freely accessible, stable, comprehensive, fully classified, richly and accurately annotated protein sequence knowledgebase. It integrates, interprets and standardizes data from numerous resources to achieve the most comprehensive catalogue of protein sequences and functional annotation. UniProt comprises four major components, each optimized for different uses, the UniProt Archive, the UniProt Knowledgebase, the UniProt Reference Clusters and the UniProt Metagenomic and Environmental Sequence Database. UniProt is produced by the UniProt Consortium, which consists of groups from the European Bioinformatics Institute (EBI), the SIB Swiss Institute of Bioinformatics (SIB) and the Protein Information Resource (PIR). UniProt is updated and distributed every 4 weeks and can be accessed online for searches or downloads.
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                Author and article information

                Journal
                Nucleic Acids Res
                Nucleic Acids Res
                nar
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                15 September 2014
                14 August 2014
                14 August 2014
                : 42
                : 16
                : 10564-10578
                Affiliations
                Nucleus Millennium in Stress and Addiction, Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile
                Author notes
                [* ]To whom correspondence should be addressed. Tel: +562 23542654; Fax: +562 23542660; Email: kgysling@ 123456bio.puc.cl
                Correspondence may also be addressed to Roberto Munita. Tel: +562 23542657; Fax: +562 23542660; Email: rnmunita@ 123456uc.cl
                [†]

                The authors wish it to be known that, in their opinion, the first two authors should be regarded as Joint First Authors.

                Article
                10.1093/nar/gku744
                4176328
                25123659
                9d0f6b80-393d-49d1-8adf-ec68263986a5
                © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 01 August 2014
                : 31 July 2014
                : 11 June 2014
                Page count
                Pages: 15
                Categories
                Genomics
                Custom metadata
                15 September 2014

                Genetics
                Genetics

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