Comparative analysis detects dependencies among the 5′ splice-site positions

Carmel, Ido; Tal, Saar; Vig, Ida; Ast, Gil

doi:10.1261/rna.5196404

Cited by 197 publications

(232 citation statements)

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“…1D). This is in agreement with previous studies, which show that splicing requires the minimal number of six base pairs between U1A snRNA and the 59SS (Zhuang and Weiner 1986;Ketterling et al 1999;Carmel et al 2004;Freund et al 2005). Next, we used the same data set of human canonical introns to investigate possible base pairing interactions between the U1A5, U1A6, and U1A7 snRNA variants and 59SS sequences (Fig.…”

Section: Resultssupporting

confidence: 87%

“…This could imply that these variants will not efficiently recognize a canonical 59SS. To investigate this, we first analyzed the U1A snRNA:59SS interaction following the approach of (Carmel et al 2004) using a data set of human 59SS sequences extracted from 252,159 canonical GU-AG introns. A Gaussian-like distribution centered around seven base pairs was observed, and FIGURE 1.…”

Section: Resultsmentioning

confidence: 99%

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U1-like snRNAs lacking complementarity to canonical 5′ splice sites

Kyriakopoulou¹,

Larsson²,

Liu³

et al. 2006

RNA

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We have detected a surprising heterogeneity among human spliceosomal U1 small nuclear RNA (snRNA). Most interestingly, we have identified three U1 snRNA variants that lack complementarity to the canonical 59 splice site (59SS) GU dinucleotide. Furthermore, we have observed heterogeneity among the identified variant U1 snRNA genes caused by single nucleotide polymorphism (SNP). The identified snRNAs were ubiquitously expressed in a variety of human tissues representing different stages of development and displayed features of functional spliceosomal snRNAs, i.e., trimethylated cap structures, association with Sm proteins and presence in nuclear RNA-protein complexes. The unanticipated heterogeneity among spliceosomal snRNAs could contribute to the complexity of vertebrates by expanding the coding capacity of their genomes.

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

U1-like snRNAs lacking complementarity to canonical 5′ splice sites

Kyriakopoulou¹,

Larsson²,

Liu³

et al. 2006

RNA

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“…Based on a preliminary analysis in which we found considerable nucleotide bias between position ‫4מ‬ and 8 (the fourth position upstream of the 5Јss and the eighth position downstream from the 5Јss, respectively), we defined this 12-nucleotide (nt) region as the 5Јss (see also Lim and Burge 2001;Carmel et al 2004). The most striking observation regarding the 5Јss was its varying degrees of conservation (Fig.…”

Section: Varying Degrees Of 5јss Conservationmentioning

confidence: 99%

Large-scale comparative analysis of splicing signals and their corresponding splicing factors in eukaryotes

Schwartz

Silva²,

Burstein³

et al. 2007

Genome Res.

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Introns are among the hallmarks of eukaryotic genes. Splicing of introns is directed by three main splicing signals: the 5Ј splice site (5Јss), the branch site (BS), and the polypyrimdine tract/3Јsplice site (PPT-3Јss). To study the evolution of these splicing signals, we have conducted a systematic comparative analysis of these signals in over 1.2 million introns from 22 eukaryotes. Our analyses suggest that all these signals have dramatically evolved: The PPT is weak among most fungi, intermediate in plants and protozoans, and strongest in metazoans. Within metazoans it shows a gradual strengthening from Caenorhabditis elegans to human. The 5Јss and the BS were found to be degenerate among most organisms, but highly conserved among some fungi. A maximum parsimony-based algorithm for reconstructing ancestral position-specific scoring matrices suggested that the ancestral 5Јss and BS were degenerate, as in metazoans. To shed light on the evolutionary variation in splicing signals, we have analyzed the evolutionary changes in the factors that bind these signals. Our analysis reveals coevolution of splicing signals and their corresponding splicing factors: The strength of the PPT is correlated to changes in key residues in its corresponding splicing factor U2AF2; limited correlation was found between changes in the 5Јss and U1 snRNA that binds it; but not between the BS and U2 snRNA. Thus, although the basic ability of eukaryotes to splice introns has remained conserved throughout evolution, the splicing signals and their corresponding splicing factors have considerably evolved, uniquely shaping the splicing mechanisms of different organisms.[Supplemental material is available online at www.genome.org.]Splicing of pre-mRNA is a key step in eukaryotic gene expression, contributing to gene regulation, protein diversity, and phenotypic complexity. Introns are removed from the pre-mRNA by the spliceosome, which is composed of five snRNPs (small nuclear ribonucleoprotein) (U1, U2, U4, U5, and U6), each containing a small RNA bound by proteins. High-precision recognition of introns is required for correct splicing. This recognition is achieved by the binding of splicing factors to signals of varying specificity that are located both in the intron and its flanking exons (Hastings and Krainer 2001;Black 2003;. In vertebrates, three signals are known to direct splicing: The 5Ј splice site (5Јss) at the 5Ј end of the intron, the polypyrimdine tract/3Ј splice site (PPT-3Јss) at the 3Ј end of the intron, and a branch site (BS) upstream of the PPT-3Јss (Hastings and Krainer 2001;Black 2003). Spliceosome assembly is initiated by the binding of specific splicing factors to these signals: the U1 snRNP to the 5Јss, the protein SF1 to the BS, the U2 snRNP auxiliary factor U2AF large subunit (U2AF2; also known as U2AF65) to the PPT, and the U2AF small subunit (U2AF1; also known as U2AF35) to the 3Јss. In an ensuing reaction, U2 snRNP associates with the pre-mRNA through a base-pairing interaction between U2 snRNA (small nuclear RNA)...

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“…Compared with PWMs, which assume independence between positions within the 5Јss, methods that have considered the dependencies between these positions (Brunak et al 1991;Yeo and Burge 2004) have provided some improvements in predicting 5Јss efficiency (Roca et al 2003(Roca et al , 2005Buratti et al 2007). Such analyses have been previously carried out on smaller data sets (Burge and Karlin 1997;Carmel et al 2004) or implicitly considered in various 5Јss scoring algorithms (Brunak et al 1991;Yeo and Burge 2004;Krawczak et al 2007). …”

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confidence: 99%

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

Roca¹,

Olson²,

Rao³

et al. 2007

Genome Res.

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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.

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Comparative analysis detects dependencies among the 5′ splice-site positions

Cited by 197 publications

References 68 publications

U1-like snRNAs lacking complementarity to canonical 5′ splice sites

U1-like snRNAs lacking complementarity to canonical 5′ splice sites

Large-scale comparative analysis of splicing signals and their corresponding splicing factors in eukaryotes

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

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