APPRIS: selecting functionally important isoforms.
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ABSTRACT:
SUBMITTER: Rodriguez JM
PROVIDER: S-EPMC8728124 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Here, we present APPRIS (http://appris.bioinfo.cnio.es), a database that houses annotations of human splice isoforms. APPRIS has been designed to provide value to manual annotations of the human genome by adding reliable protein structural and functional data and information from cross-species conservation. The visual representation of the annotations provided by APPRIS for each gene allows annotators and researchers alike to easily identify functional changes brought about by splicing events. In addition to collecting, integrating and analyzing reliable predictions of the effect of splicing events, APPRIS also selects a single reference sequence for each gene, here termed the principal isoform, based on the annotations of structure, function and conservation for each transcript. APPRIS identifies a principal isoform for 85% of the protein-coding genes in the GENCODE 7 release for ENSEMBL. Analysis of the APPRIS data shows that at least 70% of the alternative (non-principal) variants would lose important functional or structural information relative to the principal isoform.
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Project description:The APPRIS database (http://appris-tools.org) uses protein structural and functional features and information from cross-species conservation to annotate splice isoforms in protein-coding genes. APPRIS selects a single protein isoform, the 'principal' isoform, as the reference for each gene based on these annotations. A single main splice isoform reflects the biological reality for most protein coding genes and APPRIS principal isoforms are the best predictors of these main proteins isoforms. Here, we present the updates to the database, new developments that include the addition of three new species (chimpanzee, Drosophila melangaster and Caenorhabditis elegans), the expansion of APPRIS to cover the RefSeq gene set and the UniProtKB proteome for six species and refinements in the core methods that make up the annotation pipeline. In addition APPRIS now provides a measure of reliability for individual principal isoforms and updates with each release of the GENCODE/Ensembl and RefSeq reference sets. The individual GENCODE/Ensembl, RefSeq and UniProtKB reference gene sets for six organisms have been merged to produce common sets of splice variants.
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Project description:MotivationSelecting the splice variant that best represents a coding gene is a crucial first step in many experimental analyses, and vital for mapping clinically relevant variants. This study compares the longest isoforms, MANE Select transcripts, APPRIS principal isoforms, and expression data, and aims to determine which method is best for selecting biological important reference splice variants for large-scale analyses.ResultsProteomics analyses and human genetic variation data suggest that most coding genes have a single main protein isoform. We show that APPRIS principal isoforms and MANE Select transcripts best describe these main cellular isoforms, and find that using the longest splice variant as the representative is a poor strategy. Exons unique to the longest splice isoforms are not under selective pressure, and so are unlikely to be functionally relevant. Expression data are also a poor means of selecting the main splice variant. APPRIS principal and MANE Select exons are under purifying selection, while exons specific to alternative transcripts are not. There are MANE and APPRIS representatives for almost 95% of genes, and where they agree they are particularly effective, coinciding with the main proteomics isoform for over 98.2% of genes.Availability and implementationAPPRIS principal isoforms for human, mouse and other model species can be downloaded from the APPRIS database (https://appris.bioinfo.cnio.es), GENCODE genes (https://www.gencodegenes.org/) and the Ensembl website (https://www.ensembl.org). MANE Select transcripts for the human reference set are available from the Ensembl, GENCODE and RefSeq databases (https://www.ncbi.nlm.nih.gov/refseq/). Lists of splice variants where MANE and APPRIS coincide are available from the APPRIS database.Supplementary informationSupplementary data are available at Bioinformatics online.
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Project description:This paper introduces the APPRIS WebServer (http://appris.bioinfo.cnio.es) and WebServices (http://apprisws.bioinfo.cnio.es). Both the web servers and the web services are based around the APPRIS Database, a database that presently houses annotations of splice isoforms for five different vertebrate genomes. The APPRIS WebServer and WebServices provide access to the computational methods implemented in the APPRIS Database, while the APPRIS WebServices also allows retrieval of the annotations. The APPRIS WebServer and WebServices annotate splice isoforms with protein structural and functional features, and with data from cross-species alignments. In addition they can use the annotations of structure, function and conservation to select a single reference isoform for each protein-coding gene (the principal protein isoform). APPRIS principal isoforms have been shown to agree overwhelmingly with the main protein isoform detected in proteomics experiments. The APPRIS WebServer allows for the annotation of splice isoforms for individual genes, and provides a range of visual representations and tools to allow researchers to identify the likely effect of splicing events. The APPRIS WebServices permit users to generate annotations automatically in high throughput mode and to interrogate the annotations in the APPRIS Database. The APPRIS WebServices have been implemented using REST architecture to be flexible, modular and automatic.
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