Assessing conservation of alternative splicing with evolutionary splicing graphs.
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ABSTRACT:
SUBMITTER: Zea DJ
PROVIDER: S-EPMC8327911 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Alternative splicing represents a source of great diversity for regulating protein expression and function. It has been estimated that one-third to two-thirds of mammalian genes are alternatively spliced. With the sequencing of the chicken genome and analysis of transcripts expressed in chicken tissues, we are now in a position to address evolutionary conservation of alternative splicing events in chicken and mammals. Here, we compare chicken and mammalian transcript sequences of 41 alternatively-spliced genes and 50 frequently accessed genes. Our results support a high frequency of splicing events in chicken, similar to that observed in mammals.
| S-EPMC3726401 | biostudies-literature
Project description:The evolution of eukaryotes is accompanied by the increased complexity of alternative splicing which greatly expands genome information. One of the greatest challenges in the post-genome era is a complete revelation of human transcriptome with consideration of alternative splicing. Here, we introduce a comparative genomics approach to systemically identify alternative splicing events based on the differential evolutionary conservation between exons and introns and the high-quality annotation of the ENCODE regions. Specifically, we focus on exons that are included in some transcripts but are completely spliced out for others and we call them conditional exons. First, we characterize distinguishing features among conditional exons, constitutive exons and introns. One of the most important features is the position-specific conservation score. There are dramatic differences in conservation scores between conditional exons and constitutive exons. More importantly, the differences are position-specific. For flanking intronic regions, the differences between conditional exons and constitutive exons are also position-specific. Using the Random Forests algorithm, we can classify conditional exons with high specificities (97% for the identification of conditional exons from intron regions and 95% for the classification of known exons) and fair sensitivities (64% and 32% respectively). We applied the method to the human genome and identified 39,640 introns that actually contain conditional exons and classified 8,813 conditional exons from the current RefSeq exon list. Among those, 31,673 introns containing conditional exons and 5,294 conditional exons classified from known exons cannot be inferred from RefSeq, UCSC or Ensembl annotations. Some of these de novo predictions were experimentally verified.
| S-EPMC2467489 | biostudies-literature
Project description:Alternative splicing is an important mechanism for fine tuning of gene expression at the post-transcriptional level. SR proteins govern splice site selection and spliceosome assembly. The Arabidopsis genome encodes 19 SR proteins, several of which have no orthologues in metazoan. Three of the plant specific subfamilies are characterized by the presence of a relatively long alternatively spliced intron located in their first RNA recognition motif, which potentially results in an extremely truncated protein. In atRSZ33, a member of the RS2Z subfamily, this alternative splicing event was shown to be autoregulated. Here we show that atRSp31, a member of the RS subfamily, does not autoregulate alternative splicing of its similarly positioned intron. Interestingly, this alternative splicing event is regulated by atRSZ33. We demonstrate that the positions of these long introns and their capability for alternative splicing are conserved from green algae to flowering plants. Moreover, in particular alternative splicing events the splicing signals are embedded into highly conserved sequences. In different taxa, these conserved sequences occur in at least one gene within a subfamily. The evolutionary preservation of alternative splice forms together with highly conserved intron features argues for additional functions hidden in the genes of these plant-specific SR proteins.
| S-EPMC1636356 | biostudies-literature
Project description:BackgroundRNA editing and alternative splicing play an important role in expanding protein diversity and this is well illustrated in studies of nicotinic acetylcholine receptors (nAChRs).ResultsHere, we compare the RNA editing and alternative splicing of the nAChR alpha6 subunit genes from different insects spanning ~300 million years of evolution- Drosophila melanogaster, Anopheles gambiae, Bombyx mori, Tribolium castaneum and Apis mellifera. The conserved and species-specific A-to-I RNA editing occurred across all species except A. gambiae, which displayed extraordinarily short flanking intronic sequences. Interestingly, some A-to-I editing sites were a genomically encoded G in other species. A combination of the experimental data and computational analysis of orthologous alpha6 genes from different species indicated that RNA editing and alternative splicing predated at least the radiation of insect orders spanning ~300 million years of evolution; however, they might have been lost in some species during subsequent evolution. The occurrence of alternative splicing was found to be regulated in distinct modes and, in some cases, even correlated with RNA editing.ConclusionOn the basis of comparative analysis of orthologous nAChR alpha6 genes from different insects spanning ~300 million years of evolution, we have documented the existence, evolutionary conservation and divergence, and also regulation of RNA editing and alternative splicing. Phylogenetic analysis of RNA editing and alternative splicing, which can create a multitude of functionally distinct protein isoforms, might have a crucial role in the evolution of complex organisms beyond nucleotide and protein sequences.
| S-EPMC1919356 | biostudies-literature
Project description:MotivationAlternative splicing and other processes that allow for different transcripts to be derived from the same gene are significant forces in the eukaryotic cell. RNA-Seq is a promising technology for analyzing alternative transcripts, as it does not require prior knowledge of transcript structures or genome sequences. However, analysis of RNA-Seq data in the presence of genes with large numbers of alternative transcripts is currently challenging due to efficiency, identifiability and representation issues.ResultsWe present RNA-Seq models and associated inference algorithms based on the concept of probabilistic splice graphs, which alleviate these issues. We prove that our models are often identifiable and demonstrate that our inference methods for quantification and differential processing detection are efficient and accurate.AvailabilitySoftware implementing our methods is available at http://deweylab.biostat.wisc.edu/psginfer.Contactcdewey@biostat.wisc.eduSupplementary informationSupplementary data are available at Bioinformatics online.
| S-EPMC3753571 | biostudies-literature
Project description:KEY POINTS:Sodium channels are critical for supporting fast action potentials in neurons; even mutations which cause small changes in sodium channel activity can have devastating consequences for the function of the nervous system. Alternative splicing also changes the activity of sodium channels, and while it is highly conserved, it is not known whether the functional role of this splicing is also conserved. Our data reveal that splicing has a highly conserved impact on the availability of sodium channels during trains of rapid stimulations, and suggest that in one mammalian channel, Nav1.1 encoded by SCN1A, the increased availability of one splice variant is detrimental. A model reproducing the effects of splicing on channel behaviour suggests that the voltage sensor in the first domain is a rate limiting step for release of the inactivation domain, and highlights the functional specialization of channel domains. ABSTRACT:Voltage-gated sodium channels are critical for neuronal activity, and highly intolerant to variation. Even mutations that cause subtle changes in the activity these channels are sufficient to cause devastating inherited neurological diseases, such as epilepsy and pain. However, these channels do vary in healthy tissue. Alternative splicing modifies sodium channels, but the functional relevance and adaptive significance of this splicing remain poorly understood. Here we use a conserved alternate exon encoding part of the first domain of sodium channels to compare how splicing modifies different channels, and to ask whether the functional consequences of this splicing have been preserved in different genes. Although the splicing event is highly conserved, one splice variant has been selectively removed from Nav1.1 in multiple mammalian species, suggesting that the functional variation in Nav1.1 is less well tolerated. We show for three human channels (Nav1.1, Nav1.2 and Nav1.7) that splicing modifies the return from inactivated to deactivated states, and the differences between splice variants are occluded by antiepileptic drugs that bind to and stabilize inactivated states. A model based on structural data can replicate these changes, and indicates that splicing may exploit a distinct role of the first domain to change channel availability, and that the first domain of all three sodium channels plays a role in determining the rate at which the inactivation domain dissociates. Taken together, our data suggest that the stability of inactivated states is under tight evolutionary control, but that in Nav1.1 faster recovery from inactivation is associated with negative selection in mammals.
| S-EPMC5811987 | biostudies-literature
Project description:Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze the intracellular second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP). The cAMP-specific PDE family 4 (PDE4) is widely expressed in vertebrates. Each of the four PDE4 gene isoforms (PDE4 A-D) undergo extensive alternative splicing via alternative transcription initiation sites, producing unique amino termini and yielding multiple splice variant forms from each gene isoform termed long, short, super-short and truncated super-short. Many species across the vertebrate lineage contain multiple splice variants of each gene type, which are characterized by length and amino termini.A phylogenetic approach was used to visualize splice variant form genesis and identify conserved splice variants (genome conservation with EST support) across the vertebrate taxa. Bayesian and maximum likelihood phylogenetic inference indicated PDE4 gene duplication occurred at the base of the vertebrate lineage and reveals additional gene duplications specific to the teleost lineage. Phylogenetic inference and PDE4 splice variant presence, or absence as determined by EST screens, were further supported by the genomic analysis of select vertebrate taxa. Two conserved PDE4 long form splice variants were found in each of the PDE4A, PDE4B, and PDE4C genes, and eight conserved long forms from the PDE4 D gene. Conserved short and super-short splice variants were found from each of the PDE4A, PDE4B, and PDE4 D genes, while truncated super-short variants were found from the PDE4C and PDE4 D genes. PDE4 long form splice variants were found in all taxa sampled (invertebrate through mammals); short, super-short, and truncated super-short are detected primarily in tetrapods and mammals, indicating an increasing complexity in both alternative splicing and cAMP metabolism through vertebrate evolution.There was a progressive independent incorporation of multiple PDE4 splice variant forms and amino termini, increasing PDE4 proteome complexity from primitive vertebrates to humans. While PDE4 gene isoform duplicates with limited alternative splicing were found in teleosts, an expansion of both PDE4 splice variant forms, and alternatively spliced amino termini predominantly occurs in mammals. Since amino termini have been linked to intracellular targeting of the PDE4 enzymes, the conservation of amino termini in PDE4 splice variants in evolution highlights the importance of compartmentalization of PDE4-mediated cAMP hydrolysis.
| S-EPMC2929239 | biostudies-literature
Project description:The gene encoding the hormone secretin has been isolated and structurally characterized. The transcriptional unit is divided into four exons spanning 813 nucleotides. Comparison of the rat secretin gene to the other members of the glucagon-secretin gene family reveals that similarities are restricted to the exons encoding the biologically active peptides. Analysis of RNA from porcine intestine indicates that at least two transcripts are generated from the porcine secretin gene as a result of differential splicing. The longer and more abundant transcript appears to be identical to a previously isolated cDNA, which encodes a precursor that includes a 72-amino acid C-terminal extension peptide. The shorter transcript does not contain the third exon and, as a result, encodes only 44 residues beyond the C terminus of secretin. The amino acid sequence deduced from the shorter transcript is identical to a precursor form of secretin recently isolated from porcine duodenum [Gafvelin, G., Jornvall, H. & Mutt, V. (1990) Proc. Natl. Acad. Sci. USA 87, 6781-6785]. Developmental studies reveal that both secretin mRNA and peptide levels in the intestine are highest just before birth, prior to the onset of gastric acid secretion and feeding. This observation implies that secretin biosynthesis in developing animals is controlled independently of the principal factors known to regulate secretin release in adult animals.
| S-EPMC51867 | biostudies-other
Project description:Alternative splicing (AS) generates extensive transcriptomic and proteomic complexity. However, the functions of species- and lineage-specific splice variants are largely unknown. Here, we show that mammalian-specific skipping of exon 9 of PTBP1 alters its splicing regulatory activities and affects the inclusion levels of numerous exons. During neurogenesis, skipping of exon 9 reduces PTBP1 repressive activity so as to facilitate activation of a brain-specific AS program. Engineered skipping of the orthologous exon in chicken cells induces a large number of mammalian-like AS changes in PTBP1 target exons. These results thus reveal that a single exon skipping event in an RNA binding regulator directs numerous AS changes between species. The results further suggest that these changes contributed to evolutionary differences in the formation of vertebrate nervous systems. This study contains two sets of samples: (Set 1) mRNA profiling of human 293 cells subjected to four different conditions in two biological replicates: non-targetting control siRNA, PTBP1 and PTBP2 siRNA, PTBP1 and PTBP2 siRNA with overexpression of full-length human PTBP1, PTBP1 and PTBP2 siRNA with overexpression of exon-excluded human PTBP1. (Set 2) mRNA profiling of chicken DT40 cells with 3 genotypes in two bioligcal replicates: wildtype cells, cells with PTBP1 exon 8 (orthologous to human PTBP1 exon 9) deleted in one allele, and cells with PTBP1 exon 8 deleted in both alleles.
2015-09-01 | E-GEOD-69656 | biostudies-arrayexpress
Project description:Among polyploid species with complex genomic architecture, variations in the regulation of alternative splicing (AS) provide opportunities for transcriptional and proteomic plasticity and the potential for generating trait diversities. However, the evolution of AS and its influence on grain development in diploid grass and valuable polyploid wheat crops are poorly understood. To address this knowledge gap, we developed a pipeline for the analysis of alternatively spliced transcript isoforms, which takes the high sequence similarity among polyploid wheat subgenomes into account. Through analysis of synteny and detection of collinearity of homoeologous subgenomes, conserved and specific AS events across five wheat and grass species were identified. A global analysis of the regulation of AS in diploid grass and polyploid wheat grains revealed diversity in AS events not only between the endosperm, pericarp and embryo overdevelopment, but also between subgenomes. Analysis of AS in homoeologous triads of polyploid wheats revealed evolutionary divergence between gene-level and transcript-level regulation of embryogenesis. Evolutionary age analysis indicated that the generation of novel transcript isoforms has occurred in young genes at a more rapid rate than in ancient genes. These findings, together with the development of comprehensive AS resources for wheat and grass species, advance understanding of the evolution of regulatory features of AS during embryogenesis and grain development in wheat.
| S-EPMC8384600 | biostudies-literature