/* * 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.analysis; import jalview.datamodel.AlignedCodonFrame; import jalview.datamodel.Alignment; import jalview.datamodel.AlignmentI; import jalview.datamodel.DBRefEntry; import jalview.datamodel.Mapping; import jalview.datamodel.Sequence; import jalview.datamodel.SequenceFeature; import jalview.datamodel.SequenceI; import jalview.util.DBRefUtils; import jalview.util.MapList; import jalview.ws.SequenceFetcherFactory; import jalview.ws.seqfetcher.ASequenceFetcher; import java.util.ArrayList; import java.util.Iterator; import java.util.List; /** * Functions for cross-referencing sequence databases. * * @author JimP * */ public class CrossRef { /* * the dataset of the alignment for which we are searching for * cross-references; in some cases we may resolve xrefs by * searching in the dataset */ private AlignmentI dataset; /* * the sequences for which we are seeking cross-references */ private SequenceI[] fromSeqs; /** * matcher built from dataset */ SequenceIdMatcher matcher; /** * sequences found by cross-ref searches to fromSeqs */ List rseqs; /** * Constructor * * @param seqs * the sequences for which we are seeking cross-references * @param ds * the containing alignment dataset (may be searched to resolve * cross-references) */ public CrossRef(SequenceI[] seqs, AlignmentI ds) { fromSeqs = seqs; dataset = ds.getDataset() == null ? ds : ds.getDataset(); } /** * Returns a list of distinct database sources for which sequences have either * * * @param dna * - when true, cross-references *from* dna returned. When false, * cross-references *from* protein are returned * @return */ public List findXrefSourcesForSequences(boolean dna) { List sources = new ArrayList(); for (SequenceI seq : fromSeqs) { if (seq != null) { findXrefSourcesForSequence(seq, dna, sources); } } return sources; } /** * Returns a list of distinct database sources for which a sequence has either *
    *
  • a (dna-to-protein or protein-to-dna) cross-reference
  • *
  • an indirect cross-reference - a (dna-to-protein or protein-to-dna) * reference from another sequence in the dataset which has a cross-reference * to a direct DBRefEntry on the given sequence
  • *
* * @param seq * the sequence whose dbrefs we are searching against * @param fromDna * when true, context is DNA - so sources identifying protein * products will be returned. * @param sources * a list of sources to add matches to */ void findXrefSourcesForSequence(SequenceI seq, boolean fromDna, List sources) { /* * first find seq's xrefs (dna-to-peptide or peptide-to-dna) */ DBRefEntry[] rfs = DBRefUtils.selectDbRefs(!fromDna, seq.getDBRefs()); addXrefsToSources(rfs, sources); if (dataset != null) { /* * find sequence's direct (dna-to-dna, peptide-to-peptide) xrefs */ DBRefEntry[] lrfs = DBRefUtils.selectDbRefs(fromDna, seq.getDBRefs()); List foundSeqs = new ArrayList(); /* * find sequences in the alignment which xref one of these DBRefs * i.e. is xref-ed to a common sequence identifier */ searchDatasetXrefs(fromDna, seq, lrfs, foundSeqs, null); /* * add those sequences' (dna-to-peptide or peptide-to-dna) dbref sources */ for (SequenceI rs : foundSeqs) { DBRefEntry[] xrs = DBRefUtils .selectDbRefs(!fromDna, rs.getDBRefs()); addXrefsToSources(xrs, sources); } } } /** * Helper method that adds the source identifiers of some cross-references to * a (non-redundant) list of database sources * * @param xrefs * @param sources */ void addXrefsToSources(DBRefEntry[] xrefs, List sources) { if (xrefs != null) { for (DBRefEntry ref : xrefs) { /* * avoid duplication e.g. ENSEMBL and Ensembl */ String source = DBRefUtils.getCanonicalName(ref.getSource()); if (!sources.contains(source)) { sources.add(source); } } } } /** * Attempts to find cross-references from the sequences provided in the * constructor to the given source database. Cross-references may be found *
    *
  • in dbrefs on the sequence which hold a mapping to a sequence *
      *
    • provided with a fetched sequence (e.g. ENA translation), or
    • *
    • populated previously after getting cross-references
    • *
    *
  • as other sequences in the alignment which share a dbref identifier with * the sequence
  • *
  • by fetching from the remote database
  • *
* The cross-referenced sequences, and mappings to them, are added to the * alignment dataset. * * @param source * @return cross-referenced sequences (as dataset sequences) */ public Alignment findXrefSequences(String source, boolean fromDna) { rseqs = new ArrayList(); AlignedCodonFrame cf = new AlignedCodonFrame(); matcher = new SequenceIdMatcher( dataset.getSequences()); for (SequenceI seq : fromSeqs) { SequenceI dss = seq; while (dss.getDatasetSequence() != null) { dss = dss.getDatasetSequence(); } boolean found = false; DBRefEntry[] xrfs = DBRefUtils .selectDbRefs(!fromDna, dss.getDBRefs()); // ENST & ENSP comes in to both Protein and nucleotide, so we need to // filter them // out later. if ((xrfs == null || xrfs.length == 0) && dataset != null) { /* * found no suitable dbrefs on sequence - look for sequences in the * alignment which share a dbref with this one */ DBRefEntry[] lrfs = DBRefUtils.selectDbRefs(fromDna, seq.getDBRefs()); /* * find sequences (except this one!), of complementary type, * which have a dbref to an accession id for this sequence, * and add them to the results */ found = searchDatasetXrefs(fromDna, dss, lrfs, rseqs, cf); } if (xrfs == null && !found) { /* * no dbref to source on this sequence or matched * complementary sequence in the dataset */ continue; } List sourceRefs = DBRefUtils.searchRefsForSource(xrfs, source); Iterator refIterator = sourceRefs.iterator(); // At this point, if we are retrieving Ensembl, we still don't filter out // ENST when looking for protein crossrefs. while (refIterator.hasNext()) { DBRefEntry xref = refIterator.next(); found = false; // we're only interested in coding cross-references, not // locus->transcript if (xref.hasMap() && xref.getMap().getMap().isTripletMap()) { SequenceI mappedTo = xref.getMap().getTo(); if (mappedTo != null) { /* * dbref contains the sequence it maps to; add it to the * results unless we have done so already (could happen if * fetching xrefs for sequences which have xrefs in common) * for example: UNIPROT {P0CE19, P0CE20} -> EMBL {J03321, X06707} */ found = true; /* * problem: matcher.findIdMatch() is lenient - returns a sequence * with a dbref to the search arg e.g. ENST for ENSP - wrong * but findInDataset() matches ENSP when looking for Uniprot... */ SequenceI matchInDataset = findInDataset(xref); if (matchInDataset != null && xref.getMap().getTo() != null && matchInDataset != xref.getMap().getTo()) { System.err .println("Implementation problem (reopen JAL-2154): CrossRef.findInDataset seems to have recovered a different sequence than the one explicitly mapped for xref." + "Found:" + matchInDataset + "\nExpected:" + xref.getMap().getTo() + "\nFor xref:" + xref); } /*matcher.findIdMatch(mappedTo);*/ if (matchInDataset != null) { if (!rseqs.contains(matchInDataset)) { rseqs.add(matchInDataset); // need to try harder to only add unique mappings if (xref.getMap().getMap().isTripletMap() && dataset.getMapping(seq, matchInDataset) == null && cf.getMappingBetween(seq, matchInDataset) == null) { // materialise a mapping for highlighting between these sequences if (fromDna) { cf.addMap(dss, matchInDataset, xref.getMap().getMap(), xref.getMap().getMappedFromId()); } else { cf.addMap(matchInDataset, dss, xref.getMap().getMap().getInverse(), xref.getMap().getMappedFromId()); } } } refIterator.remove(); continue; } // TODO: need to determine if this should be a deriveSequence SequenceI rsq = new Sequence(mappedTo); rseqs.add(rsq); if (xref.getMap().getMap().isTripletMap()) { // get sense of map correct for adding to product alignment. if (fromDna) { // map is from dna seq to a protein product cf.addMap(dss, rsq, xref.getMap().getMap(), xref.getMap() .getMappedFromId()); } else { // map should be from protein seq to its coding dna cf.addMap(rsq, dss, xref.getMap().getMap().getInverse(), xref.getMap().getMappedFromId()); } } } } if (!found) { SequenceI matchedSeq = matcher.findIdMatch(xref.getSource() + "|" + xref.getAccessionId()); // if there was a match, check it's at least the right type of // molecule! if (matchedSeq != null && matchedSeq.isProtein() == fromDna) { if (constructMapping(seq, matchedSeq, xref, cf, fromDna)) { found = true; } } } if (!found) { // do a bit more work - search for sequences with references matching // xrefs on this sequence. found = searchDataset(fromDna, dss, xref, rseqs, cf, false); } if (found) { refIterator.remove(); } } /* * fetch from source database any dbrefs we haven't resolved up to here */ if (!sourceRefs.isEmpty()) { retrieveCrossRef(sourceRefs, seq, xrfs, fromDna, cf); } } Alignment ral = null; if (rseqs.size() > 0) { ral = new Alignment(rseqs.toArray(new SequenceI[rseqs.size()])); if (!cf.isEmpty()) { dataset.addCodonFrame(cf); } } return ral; } private void retrieveCrossRef(List sourceRefs, SequenceI seq, DBRefEntry[] xrfs, boolean fromDna, AlignedCodonFrame cf) { ASequenceFetcher sftch = SequenceFetcherFactory.getSequenceFetcher(); SequenceI[] retrieved = null; SequenceI dss = seq.getDatasetSequence() == null ? seq : seq .getDatasetSequence(); try { retrieved = sftch.getSequences(sourceRefs, !fromDna); } catch (Exception e) { System.err .println("Problem whilst retrieving cross references for Sequence : " + seq.getName()); e.printStackTrace(); } if (retrieved != null) { updateDbrefMappings(seq, xrfs, retrieved, cf, fromDna); for (SequenceI retrievedSequence : retrieved) { // dataset gets contaminated ccwith non-ds sequences. why ??! // try: Ensembl -> Nuc->Ensembl, Nuc->Uniprot-->Protein->EMBL-> SequenceI retrievedDss = retrievedSequence.getDatasetSequence() == null ? retrievedSequence : retrievedSequence.getDatasetSequence(); DBRefEntry[] dbr = retrievedSequence.getDBRefs(); if (dbr != null) { for (DBRefEntry dbref : dbr) { // find any entry where we should put in the sequence being // cross-referenced into the map Mapping map = dbref.getMap(); if (map != null) { if (map.getTo() != null && map.getMap() != null) { // TODO findInDataset requires exact sequence match but // 'congruent' test is only for the mapped part // maybe not a problem in practice since only ENA provide a // mapping and it is to the full protein translation of CDS SequenceI matched = findInDataset(dbref); // matcher.findIdMatch(map.getTo()); if (matched != null) { /* * already got an xref to this sequence; update this * map to point to the same sequence, and add * any new dbrefs to it */ DBRefEntry[] toRefs = map.getTo().getDBRefs(); if (toRefs != null) { for (DBRefEntry ref : toRefs) { matched.addDBRef(ref); // add or update mapping } } map.setTo(matched); } else { if (dataset.findIndex(map.getTo()) == -1) { dataset.addSequence(map.getTo()); matcher.add(map.getTo()); } } try { // compare ms with dss and replace with dss in mapping // if map is congruent SequenceI ms = map.getTo(); int sf = map.getMap().getToLowest(); int st = map.getMap().getToHighest(); SequenceI mappedrg = ms.getSubSequence(sf, st); // SequenceI loc = dss.getSubSequence(sf, st); if (mappedrg.getLength() > 0 && ms.getSequenceAsString().equals( dss.getSequenceAsString())) // && mappedrg.getSequenceAsString().equals( // loc.getSequenceAsString())) { String msg = "Mapping updated from " + ms.getName() + " to retrieved crossreference " + dss.getName(); System.out.println(msg); map.setTo(dss); /* * give the reverse reference the inverse mapping * (if it doesn't have one already) */ setReverseMapping(dss, dbref, cf); /* * copy sequence features as well, avoiding * duplication (e.g. same variation from two * transcripts) */ SequenceFeature[] sfs = ms.getSequenceFeatures(); if (sfs != null) { for (SequenceFeature feat : sfs) { /* * make a flyweight feature object which ignores Parent * attribute in equality test; this avoids creating many * otherwise duplicate exon features on genomic sequence */ SequenceFeature newFeature = new SequenceFeature( feat) { @Override public boolean equals(Object o) { return super.equals(o, true); } }; dss.addSequenceFeature(newFeature); } } } cf.addMap(retrievedDss, map.getTo(), map.getMap()); } catch (Exception e) { System.err .println("Exception when consolidating Mapped sequence set..."); e.printStackTrace(System.err); } } } } } retrievedSequence.updatePDBIds(); rseqs.add(retrievedDss); if (dataset.findIndex(retrievedDss) == -1) { dataset.addSequence(retrievedDss); matcher.add(retrievedDss); } } } } /** * Sets the inverse sequence mapping in the corresponding dbref of the mapped * to sequence (if any). This is used after fetching a cross-referenced * sequence, if the fetched sequence has a mapping to the original sequence, * to set the mapping in the original sequence's dbref. * * @param mapFrom * the sequence mapped from * @param dbref * @param mappings */ void setReverseMapping(SequenceI mapFrom, DBRefEntry dbref, AlignedCodonFrame mappings) { SequenceI mapTo = dbref.getMap().getTo(); if (mapTo == null) { return; } DBRefEntry[] dbrefs = mapTo.getDBRefs(); if (dbrefs == null) { return; } for (DBRefEntry toRef : dbrefs) { if (toRef.hasMap() && mapFrom == toRef.getMap().getTo()) { /* * found the reverse dbref; update its mapping if null */ if (toRef.getMap().getMap() == null) { MapList inverse = dbref.getMap().getMap().getInverse(); toRef.getMap().setMap(inverse); mappings.addMap(mapTo, mapFrom, inverse); } } } } /** * Returns the first identical sequence in the dataset if any, else null * * @param xref * @return */ SequenceI findInDataset(DBRefEntry xref) { if (xref == null || !xref.hasMap() || xref.getMap().getTo() == null) { return null; } SequenceI mapsTo = xref.getMap().getTo(); String name = xref.getAccessionId(); String name2 = xref.getSource() + "|" + name; SequenceI dss = mapsTo.getDatasetSequence() == null ? mapsTo : mapsTo .getDatasetSequence(); for (SequenceI seq : dataset.getSequences()) { /* * clumsy alternative to using SequenceIdMatcher which currently * returns sequences with a dbref to the matched accession id * which we don't want */ if (name.equals(seq.getName()) || seq.getName().startsWith(name2)) { if (sameSequence(seq, dss)) { return seq; } } } return null; } /** * Answers true if seq1 and seq2 contain exactly the same characters (ignoring * case), else false. This method compares the lengths, then each character in * turn, in order to 'fail fast'. For case-sensitive comparison, it would be * possible to use Arrays.equals(seq1.getSequence(), seq2.getSequence()). * * @param seq1 * @param seq2 * @return */ // TODO move to Sequence / SequenceI static boolean sameSequence(SequenceI seq1, SequenceI seq2) { if (seq1 == seq2) { return true; } if (seq1 == null || seq2 == null) { return false; } char[] c1 = seq1.getSequence(); char[] c2 = seq2.getSequence(); if (c1.length != c2.length) { return false; } for (int i = 0; i < c1.length; i++) { int diff = c1[i] - c2[i]; /* * same char or differ in case only ('a'-'A' == 32) */ if (diff != 0 && diff != 32 && diff != -32) { return false; } } return true; } /** * Updates any empty mappings in the cross-references with one to a compatible * retrieved sequence if found, and adds any new mappings to the * AlignedCodonFrame * * @param mapFrom * @param xrefs * @param retrieved * @param acf */ void updateDbrefMappings(SequenceI mapFrom, DBRefEntry[] xrefs, SequenceI[] retrieved, AlignedCodonFrame acf, boolean fromDna) { SequenceIdMatcher idMatcher = new SequenceIdMatcher(retrieved); for (DBRefEntry xref : xrefs) { if (!xref.hasMap()) { String targetSeqName = xref.getSource() + "|" + xref.getAccessionId(); SequenceI[] matches = idMatcher.findAllIdMatches(targetSeqName); if (matches == null) { return; } for (SequenceI seq : matches) { constructMapping(mapFrom, seq, xref, acf, fromDna); } } } } /** * Tries to make a mapping between sequences. If successful, adds the mapping * to the dbref and the mappings collection and answers true, otherwise * answers false. The following methods of making are mapping are tried in * turn: *
    *
  • if 'mapTo' holds a mapping to 'mapFrom', take the inverse; this is, for * example, the case after fetching EMBL cross-references for a Uniprot * sequence
  • *
  • else check if the dna translates exactly to the protein (give or take * start and stop codons>
  • *
  • else try to map based on CDS features on the dna sequence
  • *
* * @param mapFrom * @param mapTo * @param xref * @param mappings * @return */ boolean constructMapping(SequenceI mapFrom, SequenceI mapTo, DBRefEntry xref, AlignedCodonFrame mappings, boolean fromDna) { MapList mapping = null; SequenceI dsmapFrom = mapFrom.getDatasetSequence() == null ? mapFrom : mapFrom.getDatasetSequence(); SequenceI dsmapTo = mapTo.getDatasetSequence() == null ? mapTo : mapTo.getDatasetSequence(); /* * look for a reverse mapping, if found make its inverse. * Note - we do this on dataset sequences only. */ if (dsmapTo.getDBRefs() != null) { for (DBRefEntry dbref : dsmapTo.getDBRefs()) { String name = dbref.getSource() + "|" + dbref.getAccessionId(); if (dbref.hasMap() && dsmapFrom.getName().startsWith(name)) { /* * looks like we've found a map from 'mapTo' to 'mapFrom' * - invert it to make the mapping the other way */ MapList reverse = dbref.getMap().getMap().getInverse(); xref.setMap(new Mapping(dsmapTo, reverse)); mappings.addMap(mapFrom, dsmapTo, reverse); return true; } } } if (fromDna) { mapping = AlignmentUtils.mapCdnaToProtein(mapTo, mapFrom); } else { mapping = AlignmentUtils.mapCdnaToProtein(mapFrom, mapTo); if (mapping != null) { mapping = mapping.getInverse(); } } if (mapping == null) { return false; } xref.setMap(new Mapping(mapTo, mapping)); /* * and add a reverse DbRef with the inverse mapping */ if (mapFrom.getDatasetSequence() != null && false) // && mapFrom.getDatasetSequence().getSourceDBRef() != null) { // possible need to search primary references... except, why doesn't xref // == getSourceDBRef ?? // DBRefEntry dbref = new DBRefEntry(mapFrom.getDatasetSequence() // .getSourceDBRef()); // dbref.setMap(new Mapping(mapFrom.getDatasetSequence(), mapping // .getInverse())); // mapTo.addDBRef(dbref); } if (fromDna) { AlignmentUtils.computeProteinFeatures(mapFrom, mapTo, mapping); mappings.addMap(mapFrom, mapTo, mapping); } else { mappings.addMap(mapTo, mapFrom, mapping.getInverse()); } return true; } /** * find references to lrfs in the cross-reference set of each sequence in * dataset (that is not equal to sequenceI) Identifies matching DBRefEntry * based on source and accession string only - Map and Version are nulled. * * @param fromDna * - true if context was searching from Dna sequences, false if * context was searching from Protein sequences * @param sequenceI * @param lrfs * @param foundSeqs * @return true if matches were found. */ private boolean searchDatasetXrefs(boolean fromDna, SequenceI sequenceI, DBRefEntry[] lrfs, List foundSeqs, AlignedCodonFrame cf) { boolean found = false; if (lrfs == null) { return false; } for (int i = 0; i < lrfs.length; i++) { DBRefEntry xref = new DBRefEntry(lrfs[i]); // add in wildcards xref.setVersion(null); xref.setMap(null); found |= searchDataset(fromDna, sequenceI, xref, foundSeqs, cf, false); } return found; } /** * Searches dataset for DBRefEntrys matching the given one (xrf) and adds the * associated sequence to rseqs * * @param fromDna * true if context was searching for refs *from* dna sequence, false * if context was searching for refs *from* protein sequence * @param fromSeq * a sequence to ignore (start point of search) * @param xrf * a cross-reference to try to match * @param foundSeqs * result list to add to * @param mappings * a set of sequence mappings to add to * @param direct * - indicates the type of relationship between returned sequences, * xrf, and sequenceI that is required. *
    *
  • direct implies xrf is a primary reference for sequenceI AND * the sequences to be located (eg a uniprot ID for a protein * sequence, and a uniprot ref on a transcript sequence).
  • *
  • indirect means xrf is a cross reference with respect to * sequenceI or all the returned sequences (eg a genomic reference * associated with a locus and one or more transcripts)
  • *
* @return true if relationship found and sequence added. */ boolean searchDataset(boolean fromDna, SequenceI fromSeq, DBRefEntry xrf, List foundSeqs, AlignedCodonFrame mappings, boolean direct) { boolean found = false; if (dataset == null) { return false; } if (dataset.getSequences() == null) { System.err.println("Empty dataset sequence set - NO VECTOR"); return false; } List ds; synchronized (ds = dataset.getSequences()) { for (SequenceI nxt : ds) { if (nxt != null) { if (nxt.getDatasetSequence() != null) { System.err .println("Implementation warning: CrossRef initialised with a dataset alignment with non-dataset sequences in it! (" + nxt.getDisplayId(true) + " has ds reference " + nxt.getDatasetSequence().getDisplayId(true) + ")"); } if (nxt == fromSeq || nxt == fromSeq.getDatasetSequence()) { continue; } /* * only look at same molecule type if 'direct', or * complementary type if !direct */ { boolean isDna = !nxt.isProtein(); if (direct ? (isDna != fromDna) : (isDna == fromDna)) { // skip this sequence because it is wrong molecule type continue; } } // look for direct or indirect references in common DBRefEntry[] poss = nxt.getDBRefs(); List cands = null; // todo: indirect specifies we select either direct references to nxt // that match xrf which is indirect to sequenceI, or indirect // references to nxt that match xrf which is direct to sequenceI cands = DBRefUtils.searchRefs(poss, xrf); // else // { // poss = DBRefUtils.selectDbRefs(nxt.isProtein()!fromDna, poss); // cands = DBRefUtils.searchRefs(poss, xrf); // } if (!cands.isEmpty()) { if (!foundSeqs.contains(nxt)) { found = true; foundSeqs.add(nxt); if (mappings != null && !direct) { /* * if the matched sequence has mapped dbrefs to * protein product / cdna, add equivalent mappings to * our source sequence */ for (DBRefEntry candidate : cands) { Mapping mapping = candidate.getMap(); if (mapping != null) { MapList map = mapping.getMap(); if (mapping.getTo() != null && map.getFromRatio() != map.getToRatio()) { /* * add a mapping, as from dna to peptide sequence */ if (map.getFromRatio() == 3) { mappings.addMap(nxt, fromSeq, map); } else { mappings.addMap(nxt, fromSeq, map.getInverse()); } } } } } } } } } } return found; } }