/* * Jalview - A Sequence Alignment Editor and Viewer ($$Version-Rel$$) * Copyright (C) $$Year-Rel$$ The Jalview Authors * * This file is part of Jalview. * * Jalview is free software: you can redistribute it and/or * modify it under the terms of the GNU General Public License * as published by the Free Software Foundation, either version 3 * of the License, or (at your option) any later version. * * Jalview is distributed in the hope that it will be useful, but * WITHOUT ANY WARRANTY; without even the implied warranty * of MERCHANTABILITY or FITNESS FOR A PARTICULAR * PURPOSE. See the GNU General Public License for more details. * * You should have received a copy of the GNU General Public License * along with Jalview. If not, see . * The Jalview Authors are detailed in the 'AUTHORS' file. */ package jalview.ext.ensembl; import jalview.api.FeatureColourI; import jalview.api.FeatureSettingsModelI; import jalview.datamodel.AlignmentI; import jalview.datamodel.GeneLociI; import jalview.datamodel.Sequence; import jalview.datamodel.SequenceFeature; import jalview.datamodel.SequenceI; import jalview.datamodel.features.SequenceFeatures; import jalview.io.gff.SequenceOntologyFactory; import jalview.io.gff.SequenceOntologyI; import jalview.schemes.FeatureColour; import jalview.schemes.FeatureSettingsAdapter; import jalview.util.MapList; import jalview.util.Platform; import java.awt.Color; import java.io.UnsupportedEncodingException; import java.net.URLDecoder; import java.util.ArrayList; import java.util.Arrays; import java.util.List; import com.stevesoft.pat.Regex; /** * A class that fetches genomic sequence and all transcripts for an Ensembl gene * * @author gmcarstairs */ public class EnsemblGene extends EnsemblSeqProxy { /* * accepts anything as we will attempt lookup of gene or * transcript id or gene name */ private static final Regex ACCESSION_REGEX = new Regex(".*"); private static final EnsemblFeatureType[] FEATURES_TO_FETCH = { EnsemblFeatureType.gene, EnsemblFeatureType.transcript, EnsemblFeatureType.exon, EnsemblFeatureType.cds, EnsemblFeatureType.variation }; private static final String CHROMOSOME = "chromosome"; /** * Default constructor (to use rest.ensembl.org) */ public EnsemblGene() { super(); } /** * Constructor given the target domain to fetch data from * * @param d */ public EnsemblGene(String d) { super(d); } @Override public String getDbName() { return "ENSEMBL"; } @Override protected EnsemblFeatureType[] getFeaturesToFetch() { return FEATURES_TO_FETCH; } @Override protected EnsemblSeqType getSourceEnsemblType() { return EnsemblSeqType.GENOMIC; } @Override protected String getObjectType() { return OBJECT_TYPE_GENE; } /** * Returns an alignment containing the gene(s) for the given gene or * transcript identifier, or external identifier (e.g. Uniprot id). If given a * gene name or external identifier, returns any related gene sequences found * for model organisms. If only a single gene is queried for, then its * transcripts are also retrieved and added to the alignment.
* Method: * * * @param query * a single gene or transcript identifier or gene name * @return an alignment containing a gene, and possibly transcripts, or null */ @Override public AlignmentI getSequenceRecords(String query) throws Exception { /* * convert to a non-duplicated list of gene identifiers */ List geneIds = getGeneIds(query); AlignmentI al = null; for (String geneId : geneIds) { /* * fetch the gene sequence(s) with features and xrefs */ AlignmentI geneAlignment = super.getSequenceRecords(geneId); if (geneAlignment == null) { continue; } if (geneAlignment.getHeight() == 1) { // ensure id has 'correct' case for the Ensembl identifier geneId = geneAlignment.getSequenceAt(0).getName(); findGeneLoci(geneAlignment.getSequenceAt(0), geneId); getTranscripts(geneAlignment, geneId); } if (al == null) { al = geneAlignment; } else { al.append(geneAlignment); } } return al; } /** * Calls the /lookup/id REST service, parses the response for gene * coordinates, and if successful, adds these to the sequence. If this fails, * fall back on trying to parse the sequence description in case it is in * Ensembl-gene format e.g. chromosome:GRCh38:17:45051610:45109016:1. * * @param seq * @param geneId */ void findGeneLoci(SequenceI seq, String geneId) { GeneLociI geneLoci = new EnsemblLookup(getDomain()).getGeneLoci(geneId); if (geneLoci != null) { seq.setGeneLoci(geneLoci.getSpeciesId(), geneLoci.getAssemblyId(), geneLoci.getChromosomeId(), geneLoci.getMapping()); } else { parseChromosomeLocations(seq); } } /** * Parses and saves fields of an Ensembl-style description e.g. * chromosome:GRCh38:17:45051610:45109016:1 * * @param seq */ boolean parseChromosomeLocations(SequenceI seq) { String description = seq.getDescription(); if (description == null) { return false; } String[] tokens = description.split(":"); if (tokens.length == 6 && tokens[0].startsWith(CHROMOSOME)) { String ref = tokens[1]; String chrom = tokens[2]; try { int chStart = Integer.parseInt(tokens[3]); int chEnd = Integer.parseInt(tokens[4]); boolean forwardStrand = "1".equals(tokens[5]); String species = ""; // not known here int[] from = new int[] { seq.getStart(), seq.getEnd() }; int[] to = new int[] { forwardStrand ? chStart : chEnd, forwardStrand ? chEnd : chStart }; MapList map = new MapList(from, to, 1, 1); seq.setGeneLoci(species, ref, chrom, map); return true; } catch (NumberFormatException e) { jalview.bin.Console.errPrintln("Bad integers in description " + description); } } return false; } /** * Converts a query, which may contain one or more gene, transcript, or * external (to Ensembl) identifiers, into a non-redundant list of gene * identifiers. * * @param accessions * @return */ List getGeneIds(String accessions) { List geneIds = new ArrayList<>(); for (String acc : accessions.split(getAccessionSeparator())) { /* * First try lookup as an Ensembl (gene or transcript) identifier */ String geneId = new EnsemblLookup(getDomain()).getGeneId(acc); if (geneId != null) { if (!geneIds.contains(geneId)) { geneIds.add(geneId); } } else { /* * if given a gene or other external name, lookup and fetch * the corresponding gene for all model organisms */ List ids = new EnsemblSymbol(getDomain(), getDbSource(), getDbVersion()).getGeneIds(acc); for (String id : ids) { if (!geneIds.contains(id)) { geneIds.add(id); } } } } return geneIds; } /** * Constructs all transcripts for the gene, as identified by "transcript" * features whose Parent is the requested gene. The coding transcript * sequences (i.e. with introns omitted) are added to the alignment. * * @param al * @param accId * @throws Exception */ protected void getTranscripts(AlignmentI al, String accId) throws Exception { SequenceI gene = al.getSequenceAt(0); List transcriptFeatures = getTranscriptFeatures(accId, gene); for (SequenceFeature transcriptFeature : transcriptFeatures) { makeTranscript(transcriptFeature, al, gene); } clearGeneFeatures(gene); } /** * Remove unwanted features (transcript, exon, CDS) from the gene sequence * after we have used them to derive transcripts and transfer features * * @param gene */ protected void clearGeneFeatures(SequenceI gene) { /* * Note we include NMD_transcript_variant here because it behaves like * 'transcript' in Ensembl, although strictly speaking it is not * (it is a sub-type of sequence_variant) */ String[] soTerms = new String[] { SequenceOntologyI.NMD_TRANSCRIPT_VARIANT, SequenceOntologyI.TRANSCRIPT, SequenceOntologyI.EXON, SequenceOntologyI.CDS }; List sfs = gene.getFeatures() .getFeaturesByOntology(soTerms); for (SequenceFeature sf : sfs) { gene.deleteFeature(sf); } } /** * Constructs a spliced transcript sequence by finding 'exon' features for the * given id (or failing that 'CDS'). Copies features on to the new sequence. * 'Aligns' the new sequence against the gene sequence by padding with gaps, * and adds it to the alignment. * * @param transcriptFeature * @param al * the alignment to which to add the new sequence * @param gene * the parent gene sequence, with features * @return */ SequenceI makeTranscript(SequenceFeature transcriptFeature, AlignmentI al, SequenceI gene) { String accId = getTranscriptId(transcriptFeature); if (accId == null) { return null; } /* * NB we are mapping from gene sequence (not genome), so do not * need to check for reverse strand (gene and transcript sequences * are in forward sense) */ /* * make a gene-length sequence filled with gaps * we will fill in the bases for transcript regions */ char[] seqChars = new char[gene.getLength()]; Arrays.fill(seqChars, al.getGapCharacter()); /* * look for exon features of the transcript, failing that for CDS * (for example ENSG00000124610 has 1 CDS but no exon features) */ String parentId = accId; List splices = findFeatures(gene, SequenceOntologyI.EXON, parentId); if (splices.isEmpty()) { splices = findFeatures(gene, SequenceOntologyI.CDS, parentId); } SequenceFeatures.sortFeatures(splices, true); int transcriptLength = 0; final char[] geneChars = gene.getSequence(); int offset = gene.getStart(); // to convert to 0-based positions List mappedFrom = new ArrayList<>(); for (SequenceFeature sf : splices) { int start = sf.getBegin() - offset; int end = sf.getEnd() - offset; int spliceLength = end - start + 1; System.arraycopy(geneChars, start, seqChars, start, spliceLength); transcriptLength += spliceLength; mappedFrom.add(new int[] { sf.getBegin(), sf.getEnd() }); } Sequence transcript = new Sequence(accId, seqChars, 1, transcriptLength); /* * Ensembl has gene name as transcript Name * EnsemblGenomes doesn't, but has a url-encoded description field */ String description = transcriptFeature.getDescription(); if (description == null) { description = (String) transcriptFeature.getValue(DESCRIPTION); } if (description != null) { try { transcript.setDescription(URLDecoder.decode(description, "UTF-8")); } catch (UnsupportedEncodingException e) { e.printStackTrace(); // as if } } transcript.createDatasetSequence(); al.addSequence(transcript); /* * transfer features to the new sequence; we use EnsemblCdna to do this, * to filter out unwanted features types (see method retainFeature) */ List mapTo = new ArrayList<>(); mapTo.add(new int[] { 1, transcriptLength }); MapList mapping = new MapList(mappedFrom, mapTo, 1, 1); EnsemblCdna cdna = new EnsemblCdna(getDomain()); cdna.transferFeatures(gene.getFeatures().getPositionalFeatures(), transcript.getDatasetSequence(), mapping, parentId); mapTranscriptToChromosome(transcript, gene, mapping); /* * fetch and save cross-references */ cdna.getCrossReferences(transcript); /* * and finally fetch the protein product and save as a cross-reference */ cdna.addProteinProduct(transcript); return transcript; } /** * If the gene has a mapping to chromosome coordinates, derive the transcript * chromosome regions and save on the transcript sequence * * @param transcript * @param gene * @param mapping * the mapping from gene to transcript positions */ protected void mapTranscriptToChromosome(SequenceI transcript, SequenceI gene, MapList mapping) { GeneLociI loci = gene.getGeneLoci(); if (loci == null) { return; } MapList geneMapping = loci.getMapping(); List exons = mapping.getFromRanges(); List transcriptLoci = new ArrayList<>(); for (int[] exon : exons) { transcriptLoci.add(geneMapping.locateInTo(exon[0], exon[1])); } List transcriptRange = Arrays .asList(new int[] { transcript.getStart(), transcript.getEnd() }); MapList mapList = new MapList(transcriptRange, transcriptLoci, 1, 1); transcript.setGeneLoci(loci.getSpeciesId(), loci.getAssemblyId(), loci.getChromosomeId(), mapList); } /** * Returns the 'transcript_id' property of the sequence feature (or null) * * @param feature * @return */ protected String getTranscriptId(SequenceFeature feature) { return (String) feature.getValue(JSON_ID); } /** * Returns a list of the transcript features on the sequence whose Parent is * the gene for the accession id. *

* Transcript features are those of type "transcript", or any of its sub-types * in the Sequence Ontology e.g. "mRNA", "processed_transcript". We also * include "NMD_transcript_variant", because this type behaves like a * transcript identifier in Ensembl, although strictly speaking it is not in * the SO. * * @param accId * @param geneSequence * @return */ protected List getTranscriptFeatures(String accId, SequenceI geneSequence) { List transcriptFeatures = new ArrayList<>(); String parentIdentifier = accId; List sfs = geneSequence.getFeatures() .getFeaturesByOntology(SequenceOntologyI.TRANSCRIPT); sfs.addAll(geneSequence.getFeatures().getPositionalFeatures( SequenceOntologyI.NMD_TRANSCRIPT_VARIANT)); for (SequenceFeature sf : sfs) { String parent = (String) sf.getValue(PARENT); if (parentIdentifier.equalsIgnoreCase(parent)) { transcriptFeatures.add(sf); } } return transcriptFeatures; } @Override public String getDescription() { return "Fetches all transcripts and variant features for a gene or transcript"; } /** * Default test query is a gene id (can also enter a transcript id) */ @Override public String getTestQuery() { return Platform.isJS() ? "ENSG00000123569" : "ENSG00000157764"; // ENSG00000123569 // H2BFWT histone, 2 transcripts, reverse strand // ENSG00000157764 // BRAF, 5 transcripts, reverse strand // ENSG00000090266 // NDUFB2, 15 transcripts, forward strand // ENSG00000101812 // H2BFM histone, 3 transcripts, forward strand } /** * Answers a list of sequence features (if any) whose type is 'gene' (or a * subtype of gene in the Sequence Ontology), and whose ID is the accession we * are retrieving */ @Override protected List getIdentifyingFeatures(SequenceI seq, String accId) { List result = new ArrayList<>(); List sfs = seq.getFeatures() .getFeaturesByOntology(SequenceOntologyI.GENE); for (SequenceFeature sf : sfs) { String id = (String) sf.getValue(JSON_ID); if (accId.equalsIgnoreCase(id)) { result.add(sf); } } return result; } /** * Answers true unless feature type is 'gene', or 'transcript' with a parent * which is a different gene. We need the gene features to identify the range, * but it is redundant information on the gene sequence. Checking the parent * allows us to drop transcript features which belong to different * (overlapping) genes. */ @Override protected boolean retainFeature(SequenceFeature sf, String accessionId) { SequenceOntologyI so = SequenceOntologyFactory.getInstance(); String type = sf.getType(); if (so.isA(type, SequenceOntologyI.GENE)) { return false; } if (isTranscript(type)) { String parent = (String) sf.getValue(PARENT); if (!accessionId.equalsIgnoreCase(parent)) { return false; } } return true; } /** * Override to do nothing as Ensembl doesn't return a protein sequence for a * gene identifier */ @Override protected void addProteinProduct(SequenceI querySeq) { } @Override public Regex getAccessionValidator() { return ACCESSION_REGEX; } /** * Returns a descriptor for suitable feature display settings with *

    *
  • only exon or sequence_variant features (or their subtypes in the * Sequence Ontology) visible
  • *
  • variant features coloured red
  • *
  • exon features coloured by label (exon name)
  • *
  • variants displayed above (on top of) exons
  • *
*/ @Override public FeatureSettingsModelI getFeatureColourScheme() { return new FeatureSettingsAdapter() { SequenceOntologyI so = SequenceOntologyFactory.getInstance(); @Override public boolean isFeatureHidden(String type) { return (!so.isA(type, SequenceOntologyI.EXON) && !so.isA(type, SequenceOntologyI.SEQUENCE_VARIANT)); } @Override public FeatureColourI getFeatureColour(String type) { if (so.isA(type, SequenceOntologyI.EXON)) { return new FeatureColour() { @Override public boolean isColourByLabel() { return true; } }; } if (so.isA(type, SequenceOntologyI.SEQUENCE_VARIANT)) { return new FeatureColour() { @Override public Color getColour() { return Color.RED; } }; } return null; } /** * order to render sequence_variant after exon after the rest */ @Override public int compare(String feature1, String feature2) { if (so.isA(feature1, SequenceOntologyI.SEQUENCE_VARIANT)) { return +1; } if (so.isA(feature2, SequenceOntologyI.SEQUENCE_VARIANT)) { return -1; } if (so.isA(feature1, SequenceOntologyI.EXON)) { return +1; } if (so.isA(feature2, SequenceOntologyI.EXON)) { return -1; } return 0; } }; } }