/*
* 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.AlignedCodon;
import jalview.datamodel.AlignedCodonFrame;
import jalview.datamodel.Alignment;
import jalview.datamodel.AlignmentAnnotation;
import jalview.datamodel.AlignmentI;
import jalview.datamodel.DBRefEntry;
import jalview.datamodel.IncompleteCodonException;
import jalview.datamodel.Mapping;
import jalview.datamodel.Sequence;
import jalview.datamodel.SequenceFeature;
import jalview.datamodel.SequenceGroup;
import jalview.datamodel.SequenceI;
import jalview.io.gff.SequenceOntologyFactory;
import jalview.io.gff.SequenceOntologyI;
import jalview.schemes.ResidueProperties;
import jalview.util.Comparison;
import jalview.util.MapList;
import jalview.util.MappingUtils;
import java.io.UnsupportedEncodingException;
import java.net.URLEncoder;
import java.util.ArrayList;
import java.util.Arrays;
import java.util.Collection;
import java.util.Collections;
import java.util.Comparator;
import java.util.HashMap;
import java.util.HashSet;
import java.util.Iterator;
import java.util.LinkedHashMap;
import java.util.List;
import java.util.Map;
import java.util.Map.Entry;
import java.util.NoSuchElementException;
import java.util.Set;
import java.util.TreeMap;
/**
* grab bag of useful alignment manipulation operations Expect these to be
* refactored elsewhere at some point.
*
* @author jimp
*
*/
public class AlignmentUtils
{
private static final String SEQUENCE_VARIANT = "sequence_variant:";
private static final String ID = "ID";
private static final String CLINICAL_SIGNIFICANCE = "clinical_significance";
/**
* A data model to hold the 'normal' base value at a position, and an optional
* sequence variant feature
*/
static class DnaVariant
{
String base;
SequenceFeature variant;
DnaVariant(String nuc)
{
base = nuc;
}
DnaVariant(String nuc, SequenceFeature var)
{
base = nuc;
variant = var;
}
}
/**
* given an existing alignment, create a new alignment including all, or up to
* flankSize additional symbols from each sequence's dataset sequence
*
* @param core
* @param flankSize
* @return AlignmentI
*/
public static AlignmentI expandContext(AlignmentI core, int flankSize)
{
List sq = new ArrayList();
int maxoffset = 0;
for (SequenceI s : core.getSequences())
{
SequenceI newSeq = s.deriveSequence();
final int newSeqStart = newSeq.getStart() - 1;
if (newSeqStart > maxoffset
&& newSeq.getDatasetSequence().getStart() < s.getStart())
{
maxoffset = newSeqStart;
}
sq.add(newSeq);
}
if (flankSize > -1)
{
maxoffset = Math.min(maxoffset, flankSize);
}
/*
* now add offset left and right to create an expanded alignment
*/
for (SequenceI s : sq)
{
SequenceI ds = s;
while (ds.getDatasetSequence() != null)
{
ds = ds.getDatasetSequence();
}
int s_end = s.findPosition(s.getStart() + s.getLength());
// find available flanking residues for sequence
int ustream_ds = s.getStart() - ds.getStart();
int dstream_ds = ds.getEnd() - s_end;
// build new flanked sequence
// compute gap padding to start of flanking sequence
int offset = maxoffset - ustream_ds;
// padding is gapChar x ( maxoffset - min(ustream_ds, flank)
if (flankSize >= 0)
{
if (flankSize < ustream_ds)
{
// take up to flankSize residues
offset = maxoffset - flankSize;
ustream_ds = flankSize;
}
if (flankSize <= dstream_ds)
{
dstream_ds = flankSize - 1;
}
}
// TODO use Character.toLowerCase to avoid creating String objects?
char[] upstream = new String(ds.getSequence(s.getStart() - 1
- ustream_ds, s.getStart() - 1)).toLowerCase().toCharArray();
char[] downstream = new String(ds.getSequence(s_end - 1, s_end
+ dstream_ds)).toLowerCase().toCharArray();
char[] coreseq = s.getSequence();
char[] nseq = new char[offset + upstream.length + downstream.length
+ coreseq.length];
char c = core.getGapCharacter();
int p = 0;
for (; p < offset; p++)
{
nseq[p] = c;
}
System.arraycopy(upstream, 0, nseq, p, upstream.length);
System.arraycopy(coreseq, 0, nseq, p + upstream.length,
coreseq.length);
System.arraycopy(downstream, 0, nseq, p + coreseq.length
+ upstream.length, downstream.length);
s.setSequence(new String(nseq));
s.setStart(s.getStart() - ustream_ds);
s.setEnd(s_end + downstream.length);
}
AlignmentI newAl = new jalview.datamodel.Alignment(
sq.toArray(new SequenceI[0]));
for (SequenceI s : sq)
{
if (s.getAnnotation() != null)
{
for (AlignmentAnnotation aa : s.getAnnotation())
{
aa.adjustForAlignment(); // JAL-1712 fix
newAl.addAnnotation(aa);
}
}
}
newAl.setDataset(core.getDataset());
return newAl;
}
/**
* Returns the index (zero-based position) of a sequence in an alignment, or
* -1 if not found.
*
* @param al
* @param seq
* @return
*/
public static int getSequenceIndex(AlignmentI al, SequenceI seq)
{
int result = -1;
int pos = 0;
for (SequenceI alSeq : al.getSequences())
{
if (alSeq == seq)
{
result = pos;
break;
}
pos++;
}
return result;
}
/**
* Returns a map of lists of sequences in the alignment, keyed by sequence
* name. For use in mapping between different alignment views of the same
* sequences.
*
* @see jalview.datamodel.AlignmentI#getSequencesByName()
*/
public static Map> getSequencesByName(
AlignmentI al)
{
Map> theMap = new LinkedHashMap>();
for (SequenceI seq : al.getSequences())
{
String name = seq.getName();
if (name != null)
{
List seqs = theMap.get(name);
if (seqs == null)
{
seqs = new ArrayList();
theMap.put(name, seqs);
}
seqs.add(seq);
}
}
return theMap;
}
/**
* Build mapping of protein to cDNA alignment. Mappings are made between
* sequences where the cDNA translates to the protein sequence. Any new
* mappings are added to the protein alignment. Returns true if any mappings
* either already exist or were added, else false.
*
* @param proteinAlignment
* @param cdnaAlignment
* @return
*/
public static boolean mapProteinAlignmentToCdna(
final AlignmentI proteinAlignment, final AlignmentI cdnaAlignment)
{
if (proteinAlignment == null || cdnaAlignment == null)
{
return false;
}
Set mappedDna = new HashSet();
Set mappedProtein = new HashSet();
/*
* First pass - map sequences where cross-references exist. This include
* 1-to-many mappings to support, for example, variant cDNA.
*/
boolean mappingPerformed = mapProteinToCdna(proteinAlignment,
cdnaAlignment, mappedDna, mappedProtein, true);
/*
* Second pass - map sequences where no cross-references exist. This only
* does 1-to-1 mappings and assumes corresponding sequences are in the same
* order in the alignments.
*/
mappingPerformed |= mapProteinToCdna(proteinAlignment, cdnaAlignment,
mappedDna, mappedProtein, false);
return mappingPerformed;
}
/**
* Make mappings between compatible sequences (where the cDNA translation
* matches the protein).
*
* @param proteinAlignment
* @param cdnaAlignment
* @param mappedDna
* a set of mapped DNA sequences (to add to)
* @param mappedProtein
* a set of mapped Protein sequences (to add to)
* @param xrefsOnly
* if true, only map sequences where xrefs exist
* @return
*/
protected static boolean mapProteinToCdna(
final AlignmentI proteinAlignment,
final AlignmentI cdnaAlignment, Set mappedDna,
Set mappedProtein, boolean xrefsOnly)
{
boolean mappingExistsOrAdded = false;
List thisSeqs = proteinAlignment.getSequences();
for (SequenceI aaSeq : thisSeqs)
{
boolean proteinMapped = false;
AlignedCodonFrame acf = new AlignedCodonFrame();
for (SequenceI cdnaSeq : cdnaAlignment.getSequences())
{
/*
* Always try to map if sequences have xref to each other; this supports
* variant cDNA or alternative splicing for a protein sequence.
*
* If no xrefs, try to map progressively, assuming that alignments have
* mappable sequences in corresponding order. These are not
* many-to-many, as that would risk mixing species with similar cDNA
* sequences.
*/
if (xrefsOnly && !AlignmentUtils.haveCrossRef(aaSeq, cdnaSeq))
{
continue;
}
/*
* Don't map non-xrefd sequences more than once each. This heuristic
* allows us to pair up similar sequences in ordered alignments.
*/
if (!xrefsOnly
&& (mappedProtein.contains(aaSeq) || mappedDna
.contains(cdnaSeq)))
{
continue;
}
if (mappingExists(proteinAlignment.getCodonFrames(),
aaSeq.getDatasetSequence(), cdnaSeq.getDatasetSequence()))
{
mappingExistsOrAdded = true;
}
else
{
MapList map = mapCdnaToProtein(aaSeq, cdnaSeq);
if (map != null)
{
acf.addMap(cdnaSeq, aaSeq, map);
mappingExistsOrAdded = true;
proteinMapped = true;
mappedDna.add(cdnaSeq);
mappedProtein.add(aaSeq);
}
}
}
if (proteinMapped)
{
proteinAlignment.addCodonFrame(acf);
}
}
return mappingExistsOrAdded;
}
/**
* Answers true if the mappings include one between the given (dataset)
* sequences.
*/
public static boolean mappingExists(List mappings,
SequenceI aaSeq, SequenceI cdnaSeq)
{
if (mappings != null)
{
for (AlignedCodonFrame acf : mappings)
{
if (cdnaSeq == acf.getDnaForAaSeq(aaSeq))
{
return true;
}
}
}
return false;
}
/**
* Builds a mapping (if possible) of a cDNA to a protein sequence.
*
* - first checks if the cdna translates exactly to the protein sequence
* - else checks for translation after removing a STOP codon
* - else checks for translation after removing a START codon
* - if that fails, inspect CDS features on the cDNA sequence
*
* Returns null if no mapping is determined.
*
* @param proteinSeq
* the aligned protein sequence
* @param cdnaSeq
* the aligned cdna sequence
* @return
*/
public static MapList mapCdnaToProtein(SequenceI proteinSeq,
SequenceI cdnaSeq)
{
/*
* Here we handle either dataset sequence set (desktop) or absent (applet).
* Use only the char[] form of the sequence to avoid creating possibly large
* String objects.
*/
final SequenceI proteinDataset = proteinSeq.getDatasetSequence();
char[] aaSeqChars = proteinDataset != null ? proteinDataset
.getSequence() : proteinSeq.getSequence();
final SequenceI cdnaDataset = cdnaSeq.getDatasetSequence();
char[] cdnaSeqChars = cdnaDataset != null ? cdnaDataset.getSequence()
: cdnaSeq.getSequence();
if (aaSeqChars == null || cdnaSeqChars == null)
{
return null;
}
/*
* cdnaStart/End, proteinStartEnd are base 1 (for dataset sequence mapping)
*/
final int mappedLength = 3 * aaSeqChars.length;
int cdnaLength = cdnaSeqChars.length;
int cdnaStart = cdnaSeq.getStart();
int cdnaEnd = cdnaSeq.getEnd();
final int proteinStart = proteinSeq.getStart();
final int proteinEnd = proteinSeq.getEnd();
/*
* If lengths don't match, try ignoring stop codon (if present)
*/
if (cdnaLength != mappedLength && cdnaLength > 2)
{
String lastCodon = String.valueOf(cdnaSeqChars, cdnaLength - 3, 3)
.toUpperCase();
for (String stop : ResidueProperties.STOP)
{
if (lastCodon.equals(stop))
{
cdnaEnd -= 3;
cdnaLength -= 3;
break;
}
}
}
/*
* If lengths still don't match, try ignoring start codon.
*/
int startOffset = 0;
if (cdnaLength != mappedLength
&& cdnaLength > 2
&& String.valueOf(cdnaSeqChars, 0, 3).toUpperCase()
.equals(ResidueProperties.START))
{
startOffset += 3;
cdnaStart += 3;
cdnaLength -= 3;
}
if (translatesAs(cdnaSeqChars, startOffset, aaSeqChars))
{
/*
* protein is translation of dna (+/- start/stop codons)
*/
MapList map = new MapList(new int[] { cdnaStart, cdnaEnd }, new int[]
{ proteinStart, proteinEnd }, 3, 1);
return map;
}
/*
* translation failed - try mapping CDS annotated regions of dna
*/
return mapCdsToProtein(cdnaSeq, proteinSeq);
}
/**
* Test whether the given cdna sequence, starting at the given offset,
* translates to the given amino acid sequence, using the standard translation
* table. Designed to fail fast i.e. as soon as a mismatch position is found.
*
* @param cdnaSeqChars
* @param cdnaStart
* @param aaSeqChars
* @return
*/
protected static boolean translatesAs(char[] cdnaSeqChars, int cdnaStart,
char[] aaSeqChars)
{
if (cdnaSeqChars == null || aaSeqChars == null)
{
return false;
}
int aaPos = 0;
int dnaPos = cdnaStart;
for (; dnaPos < cdnaSeqChars.length - 2
&& aaPos < aaSeqChars.length; dnaPos += 3, aaPos++)
{
String codon = String.valueOf(cdnaSeqChars, dnaPos, 3);
final String translated = ResidueProperties.codonTranslate(codon);
/*
* allow * in protein to match untranslatable in dna
*/
final char aaRes = aaSeqChars[aaPos];
if ((translated == null || "STOP".equals(translated)) && aaRes == '*')
{
continue;
}
if (translated == null || !(aaRes == translated.charAt(0)))
{
// debug
// System.out.println(("Mismatch at " + i + "/" + aaResidue + ": "
// + codon + "(" + translated + ") != " + aaRes));
return false;
}
}
/*
* check we matched all of the protein sequence
*/
if (aaPos != aaSeqChars.length)
{
return false;
}
/*
* check we matched all of the dna except
* for optional trailing STOP codon
*/
if (dnaPos == cdnaSeqChars.length)
{
return true;
}
if (dnaPos == cdnaSeqChars.length - 3)
{
String codon = String.valueOf(cdnaSeqChars, dnaPos, 3);
if ("STOP".equals(ResidueProperties.codonTranslate(codon)))
{
return true;
}
}
return false;
}
/**
* Align sequence 'seq' to match the alignment of a mapped sequence. Note this
* currently assumes that we are aligning cDNA to match protein.
*
* @param seq
* the sequence to be realigned
* @param al
* the alignment whose sequence alignment is to be 'copied'
* @param gap
* character string represent a gap in the realigned sequence
* @param preserveUnmappedGaps
* @param preserveMappedGaps
* @return true if the sequence was realigned, false if it could not be
*/
public static boolean alignSequenceAs(SequenceI seq, AlignmentI al,
String gap, boolean preserveMappedGaps,
boolean preserveUnmappedGaps)
{
/*
* Get any mappings from the source alignment to the target (dataset)
* sequence.
*/
// TODO there may be one AlignedCodonFrame per dataset sequence, or one with
// all mappings. Would it help to constrain this?
List mappings = al.getCodonFrame(seq);
if (mappings == null || mappings.isEmpty())
{
return false;
}
/*
* Locate the aligned source sequence whose dataset sequence is mapped. We
* just take the first match here (as we can't align like more than one
* sequence).
*/
SequenceI alignFrom = null;
AlignedCodonFrame mapping = null;
for (AlignedCodonFrame mp : mappings)
{
alignFrom = mp.findAlignedSequence(seq, al);
if (alignFrom != null)
{
mapping = mp;
break;
}
}
if (alignFrom == null)
{
return false;
}
alignSequenceAs(seq, alignFrom, mapping, gap, al.getGapCharacter(),
preserveMappedGaps, preserveUnmappedGaps);
return true;
}
/**
* Align sequence 'alignTo' the same way as 'alignFrom', using the mapping to
* match residues and codons. Flags control whether existing gaps in unmapped
* (intron) and mapped (exon) regions are preserved or not. Gaps between
* intron and exon are only retained if both flags are set.
*
* @param alignTo
* @param alignFrom
* @param mapping
* @param myGap
* @param sourceGap
* @param preserveUnmappedGaps
* @param preserveMappedGaps
*/
public static void alignSequenceAs(SequenceI alignTo,
SequenceI alignFrom, AlignedCodonFrame mapping, String myGap,
char sourceGap, boolean preserveMappedGaps,
boolean preserveUnmappedGaps)
{
// TODO generalise to work for Protein-Protein, dna-dna, dna-protein
// aligned and dataset sequence positions, all base zero
int thisSeqPos = 0;
int sourceDsPos = 0;
int basesWritten = 0;
char myGapChar = myGap.charAt(0);
int ratio = myGap.length();
int fromOffset = alignFrom.getStart() - 1;
int toOffset = alignTo.getStart() - 1;
int sourceGapMappedLength = 0;
boolean inExon = false;
final char[] thisSeq = alignTo.getSequence();
final char[] thatAligned = alignFrom.getSequence();
StringBuilder thisAligned = new StringBuilder(2 * thisSeq.length);
/*
* Traverse the 'model' aligned sequence
*/
for (char sourceChar : thatAligned)
{
if (sourceChar == sourceGap)
{
sourceGapMappedLength += ratio;
continue;
}
/*
* Found a non-gap character. Locate its mapped region if any.
*/
sourceDsPos++;
// Note mapping positions are base 1, our sequence positions base 0
int[] mappedPos = mapping.getMappedRegion(alignTo, alignFrom,
sourceDsPos + fromOffset);
if (mappedPos == null)
{
/*
* unmapped position; treat like a gap
*/
sourceGapMappedLength += ratio;
// System.err.println("Can't align: no codon mapping to residue "
// + sourceDsPos + "(" + sourceChar + ")");
// return;
continue;
}
int mappedCodonStart = mappedPos[0]; // position (1...) of codon start
int mappedCodonEnd = mappedPos[mappedPos.length - 1]; // codon end pos
StringBuilder trailingCopiedGap = new StringBuilder();
/*
* Copy dna sequence up to and including this codon. Optionally, include
* gaps before the codon starts (in introns) and/or after the codon starts
* (in exons).
*
* Note this only works for 'linear' splicing, not reverse or interleaved.
* But then 'align dna as protein' doesn't make much sense otherwise.
*/
int intronLength = 0;
while (basesWritten + toOffset < mappedCodonEnd
&& thisSeqPos < thisSeq.length)
{
final char c = thisSeq[thisSeqPos++];
if (c != myGapChar)
{
basesWritten++;
int sourcePosition = basesWritten + toOffset;
if (sourcePosition < mappedCodonStart)
{
/*
* Found an unmapped (intron) base. First add in any preceding gaps
* (if wanted).
*/
if (preserveUnmappedGaps && trailingCopiedGap.length() > 0)
{
thisAligned.append(trailingCopiedGap.toString());
intronLength += trailingCopiedGap.length();
trailingCopiedGap = new StringBuilder();
}
intronLength++;
inExon = false;
}
else
{
final boolean startOfCodon = sourcePosition == mappedCodonStart;
int gapsToAdd = calculateGapsToInsert(preserveMappedGaps,
preserveUnmappedGaps, sourceGapMappedLength, inExon,
trailingCopiedGap.length(), intronLength, startOfCodon);
for (int i = 0; i < gapsToAdd; i++)
{
thisAligned.append(myGapChar);
}
sourceGapMappedLength = 0;
inExon = true;
}
thisAligned.append(c);
trailingCopiedGap = new StringBuilder();
}
else
{
if (inExon && preserveMappedGaps)
{
trailingCopiedGap.append(myGapChar);
}
else if (!inExon && preserveUnmappedGaps)
{
trailingCopiedGap.append(myGapChar);
}
}
}
}
/*
* At end of model aligned sequence. Copy any remaining target sequence, optionally
* including (intron) gaps.
*/
while (thisSeqPos < thisSeq.length)
{
final char c = thisSeq[thisSeqPos++];
if (c != myGapChar || preserveUnmappedGaps)
{
thisAligned.append(c);
}
sourceGapMappedLength--;
}
/*
* finally add gaps to pad for any trailing source gaps or
* unmapped characters
*/
if (preserveUnmappedGaps)
{
while (sourceGapMappedLength > 0)
{
thisAligned.append(myGapChar);
sourceGapMappedLength--;
}
}
/*
* All done aligning, set the aligned sequence.
*/
alignTo.setSequence(new String(thisAligned));
}
/**
* Helper method to work out how many gaps to insert when realigning.
*
* @param preserveMappedGaps
* @param preserveUnmappedGaps
* @param sourceGapMappedLength
* @param inExon
* @param trailingCopiedGap
* @param intronLength
* @param startOfCodon
* @return
*/
protected static int calculateGapsToInsert(boolean preserveMappedGaps,
boolean preserveUnmappedGaps, int sourceGapMappedLength,
boolean inExon, int trailingGapLength, int intronLength,
final boolean startOfCodon)
{
int gapsToAdd = 0;
if (startOfCodon)
{
/*
* Reached start of codon. Ignore trailing gaps in intron unless we are
* preserving gaps in both exon and intron. Ignore them anyway if the
* protein alignment introduces a gap at least as large as the intronic
* region.
*/
if (inExon && !preserveMappedGaps)
{
trailingGapLength = 0;
}
if (!inExon && !(preserveMappedGaps && preserveUnmappedGaps))
{
trailingGapLength = 0;
}
if (inExon)
{
gapsToAdd = Math.max(sourceGapMappedLength, trailingGapLength);
}
else
{
if (intronLength + trailingGapLength <= sourceGapMappedLength)
{
gapsToAdd = sourceGapMappedLength - intronLength;
}
else
{
gapsToAdd = Math.min(intronLength + trailingGapLength
- sourceGapMappedLength, trailingGapLength);
}
}
}
else
{
/*
* second or third base of codon; check for any gaps in dna
*/
if (!preserveMappedGaps)
{
trailingGapLength = 0;
}
gapsToAdd = Math.max(sourceGapMappedLength, trailingGapLength);
}
return gapsToAdd;
}
/**
* Realigns the given protein to match the alignment of the dna, using codon
* mappings to translate aligned codon positions to protein residues.
*
* @param protein
* the alignment whose sequences are realigned by this method
* @param dna
* the dna alignment whose alignment we are 'copying'
* @return the number of sequences that were realigned
*/
public static int alignProteinAsDna(AlignmentI protein, AlignmentI dna)
{
List unmappedProtein = new ArrayList();
Map> alignedCodons = buildCodonColumnsMap(
protein, dna, unmappedProtein);
return alignProteinAs(protein, alignedCodons, unmappedProtein);
}
/**
* Builds a map whose key is an aligned codon position (3 alignment column
* numbers base 0), and whose value is a map from protein sequence to each
* protein's peptide residue for that codon. The map generates an ordering of
* the codons, and allows us to read off the peptides at each position in
* order to assemble 'aligned' protein sequences.
*
* @param protein
* the protein alignment
* @param dna
* the coding dna alignment
* @param unmappedProtein
* any unmapped proteins are added to this list
* @return
*/
protected static Map> buildCodonColumnsMap(
AlignmentI protein, AlignmentI dna,
List unmappedProtein)
{
/*
* maintain a list of any proteins with no mappings - these will be
* rendered 'as is' in the protein alignment as we can't align them
*/
unmappedProtein.addAll(protein.getSequences());
List mappings = protein.getCodonFrames();
/*
* Map will hold, for each aligned codon position e.g. [3, 5, 6], a map of
* {dnaSequence, {proteinSequence, codonProduct}} at that position. The
* comparator keeps the codon positions ordered.
*/
Map> alignedCodons = new TreeMap>(
new CodonComparator());
for (SequenceI dnaSeq : dna.getSequences())
{
for (AlignedCodonFrame mapping : mappings)
{
SequenceI prot = mapping.findAlignedSequence(dnaSeq, protein);
if (prot != null)
{
Mapping seqMap = mapping.getMappingForSequence(dnaSeq);
addCodonPositions(dnaSeq, prot, protein.getGapCharacter(),
seqMap, alignedCodons);
unmappedProtein.remove(prot);
}
}
}
/*
* Finally add any unmapped peptide start residues (e.g. for incomplete
* codons) as if at the codon position before the second residue
*/
// TODO resolve JAL-2022 so this fudge can be removed
int mappedSequenceCount = protein.getHeight() - unmappedProtein.size();
addUnmappedPeptideStarts(alignedCodons, mappedSequenceCount);
return alignedCodons;
}
/**
* Scans for any protein mapped from position 2 (meaning unmapped start
* position e.g. an incomplete codon), and synthesizes a 'codon' for it at the
* preceding position in the alignment
*
* @param alignedCodons
* the codon-to-peptide map
* @param mappedSequenceCount
* the number of distinct sequences in the map
*/
protected static void addUnmappedPeptideStarts(
Map> alignedCodons,
int mappedSequenceCount)
{
// TODO delete this ugly hack once JAL-2022 is resolved
// i.e. we can model startPhase > 0 (incomplete start codon)
List sequencesChecked = new ArrayList();
AlignedCodon lastCodon = null;
Map toAdd = new HashMap();
for (Entry> entry : alignedCodons
.entrySet())
{
for (Entry sequenceCodon : entry.getValue()
.entrySet())
{
SequenceI seq = sequenceCodon.getKey();
if (sequencesChecked.contains(seq))
{
continue;
}
sequencesChecked.add(seq);
AlignedCodon codon = sequenceCodon.getValue();
if (codon.peptideCol > 1)
{
System.err
.println("Problem mapping protein with >1 unmapped start positions: "
+ seq.getName());
}
else if (codon.peptideCol == 1)
{
/*
* first position (peptideCol == 0) was unmapped - add it
*/
if (lastCodon != null)
{
AlignedCodon firstPeptide = new AlignedCodon(lastCodon.pos1,
lastCodon.pos2, lastCodon.pos3, String.valueOf(seq
.getCharAt(0)), 0);
toAdd.put(seq, firstPeptide);
}
else
{
/*
* unmapped residue at start of alignment (no prior column) -
* 'insert' at nominal codon [0, 0, 0]
*/
AlignedCodon firstPeptide = new AlignedCodon(0, 0, 0,
String.valueOf(seq.getCharAt(0)), 0);
toAdd.put(seq, firstPeptide);
}
}
if (sequencesChecked.size() == mappedSequenceCount)
{
// no need to check past first mapped position in all sequences
break;
}
}
lastCodon = entry.getKey();
}
/*
* add any new codons safely after iterating over the map
*/
for (Entry startCodon : toAdd.entrySet())
{
addCodonToMap(alignedCodons, startCodon.getValue(),
startCodon.getKey());
}
}
/**
* Update the aligned protein sequences to match the codon alignments given in
* the map.
*
* @param protein
* @param alignedCodons
* an ordered map of codon positions (columns), with sequence/peptide
* values present in each column
* @param unmappedProtein
* @return
*/
protected static int alignProteinAs(AlignmentI protein,
Map> alignedCodons,
List unmappedProtein)
{
/*
* Prefill aligned sequences with gaps before inserting aligned protein
* residues.
*/
int alignedWidth = alignedCodons.size();
char[] gaps = new char[alignedWidth];
Arrays.fill(gaps, protein.getGapCharacter());
String allGaps = String.valueOf(gaps);
for (SequenceI seq : protein.getSequences())
{
if (!unmappedProtein.contains(seq))
{
seq.setSequence(allGaps);
}
}
int column = 0;
for (AlignedCodon codon : alignedCodons.keySet())
{
final Map columnResidues = alignedCodons
.get(codon);
for (Entry entry : columnResidues.entrySet())
{
// place translated codon at its column position in sequence
entry.getKey().getSequence()[column] = entry.getValue().product
.charAt(0);
}
column++;
}
return 0;
}
/**
* Populate the map of aligned codons by traversing the given sequence
* mapping, locating the aligned positions of mapped codons, and adding those
* positions and their translation products to the map.
*
* @param dna
* the aligned sequence we are mapping from
* @param protein
* the sequence to be aligned to the codons
* @param gapChar
* the gap character in the dna sequence
* @param seqMap
* a mapping to a sequence translation
* @param alignedCodons
* the map we are building up
*/
static void addCodonPositions(SequenceI dna, SequenceI protein,
char gapChar, Mapping seqMap,
Map> alignedCodons)
{
Iterator codons = seqMap.getCodonIterator(dna, gapChar);
/*
* add codon positions, and their peptide translations, to the alignment
* map, while remembering the first codon mapped
*/
while (codons.hasNext())
{
try
{
AlignedCodon codon = codons.next();
addCodonToMap(alignedCodons, codon, protein);
} catch (IncompleteCodonException e)
{
// possible incomplete trailing codon - ignore
} catch (NoSuchElementException e)
{
// possibly peptide lacking STOP
}
}
}
/**
* Helper method to add a codon-to-peptide entry to the aligned codons map
*
* @param alignedCodons
* @param codon
* @param protein
*/
protected static void addCodonToMap(
Map> alignedCodons,
AlignedCodon codon, SequenceI protein)
{
Map seqProduct = alignedCodons.get(codon);
if (seqProduct == null)
{
seqProduct = new HashMap();
alignedCodons.put(codon, seqProduct);
}
seqProduct.put(protein, codon);
}
/**
* Returns true if a cDNA/Protein mapping either exists, or could be made,
* between at least one pair of sequences in the two alignments. Currently,
* the logic is:
*
* - One alignment must be nucleotide, and the other protein
* - At least one pair of sequences must be already mapped, or mappable
* - Mappable means the nucleotide translation matches the protein sequence
* - The translation may ignore start and stop codons if present in the
* nucleotide
*
*
* @param al1
* @param al2
* @return
*/
public static boolean isMappable(AlignmentI al1, AlignmentI al2)
{
if (al1 == null || al2 == null)
{
return false;
}
/*
* Require one nucleotide and one protein
*/
if (al1.isNucleotide() == al2.isNucleotide())
{
return false;
}
AlignmentI dna = al1.isNucleotide() ? al1 : al2;
AlignmentI protein = dna == al1 ? al2 : al1;
List mappings = protein.getCodonFrames();
for (SequenceI dnaSeq : dna.getSequences())
{
for (SequenceI proteinSeq : protein.getSequences())
{
if (isMappable(dnaSeq, proteinSeq, mappings))
{
return true;
}
}
}
return false;
}
/**
* Returns true if the dna sequence is mapped, or could be mapped, to the
* protein sequence.
*
* @param dnaSeq
* @param proteinSeq
* @param mappings
* @return
*/
protected static boolean isMappable(SequenceI dnaSeq,
SequenceI proteinSeq, List mappings)
{
if (dnaSeq == null || proteinSeq == null)
{
return false;
}
SequenceI dnaDs = dnaSeq.getDatasetSequence() == null ? dnaSeq : dnaSeq
.getDatasetSequence();
SequenceI proteinDs = proteinSeq.getDatasetSequence() == null ? proteinSeq
: proteinSeq.getDatasetSequence();
for (AlignedCodonFrame mapping : mappings)
{
if (proteinDs == mapping.getAaForDnaSeq(dnaDs))
{
/*
* already mapped
*/
return true;
}
}
/*
* Just try to make a mapping (it is not yet stored), test whether
* successful.
*/
return mapCdnaToProtein(proteinDs, dnaDs) != null;
}
/**
* Finds any reference annotations associated with the sequences in
* sequenceScope, that are not already added to the alignment, and adds them
* to the 'candidates' map. Also populates a lookup table of annotation
* labels, keyed by calcId, for use in constructing tooltips or the like.
*
* @param sequenceScope
* the sequences to scan for reference annotations
* @param labelForCalcId
* (optional) map to populate with label for calcId
* @param candidates
* map to populate with annotations for sequence
* @param al
* the alignment to check for presence of annotations
*/
public static void findAddableReferenceAnnotations(
List sequenceScope,
Map labelForCalcId,
final Map> candidates,
AlignmentI al)
{
if (sequenceScope == null)
{
return;
}
/*
* For each sequence in scope, make a list of any annotations on the
* underlying dataset sequence which are not already on the alignment.
*
* Add to a map of { alignmentSequence, }
*/
for (SequenceI seq : sequenceScope)
{
SequenceI dataset = seq.getDatasetSequence();
if (dataset == null)
{
continue;
}
AlignmentAnnotation[] datasetAnnotations = dataset.getAnnotation();
if (datasetAnnotations == null)
{
continue;
}
final List result = new ArrayList();
for (AlignmentAnnotation dsann : datasetAnnotations)
{
/*
* Find matching annotations on the alignment. If none is found, then
* add this annotation to the list of 'addable' annotations for this
* sequence.
*/
final Iterable matchedAlignmentAnnotations = al
.findAnnotations(seq, dsann.getCalcId(), dsann.label);
if (!matchedAlignmentAnnotations.iterator().hasNext())
{
result.add(dsann);
if (labelForCalcId != null)
{
labelForCalcId.put(dsann.getCalcId(), dsann.label);
}
}
}
/*
* Save any addable annotations for this sequence
*/
if (!result.isEmpty())
{
candidates.put(seq, result);
}
}
}
/**
* Adds annotations to the top of the alignment annotations, in the same order
* as their related sequences.
*
* @param annotations
* the annotations to add
* @param alignment
* the alignment to add them to
* @param selectionGroup
* current selection group (or null if none)
*/
public static void addReferenceAnnotations(
Map> annotations,
final AlignmentI alignment, final SequenceGroup selectionGroup)
{
for (SequenceI seq : annotations.keySet())
{
for (AlignmentAnnotation ann : annotations.get(seq))
{
AlignmentAnnotation copyAnn = new AlignmentAnnotation(ann);
int startRes = 0;
int endRes = ann.annotations.length;
if (selectionGroup != null)
{
startRes = selectionGroup.getStartRes();
endRes = selectionGroup.getEndRes();
}
copyAnn.restrict(startRes, endRes);
/*
* Add to the sequence (sets copyAnn.datasetSequence), unless the
* original annotation is already on the sequence.
*/
if (!seq.hasAnnotation(ann))
{
seq.addAlignmentAnnotation(copyAnn);
}
// adjust for gaps
copyAnn.adjustForAlignment();
// add to the alignment and set visible
alignment.addAnnotation(copyAnn);
copyAnn.visible = true;
}
}
}
/**
* Set visibility of alignment annotations of specified types (labels), for
* specified sequences. This supports controls like
* "Show all secondary structure", "Hide all Temp factor", etc.
*
* @al the alignment to scan for annotations
* @param types
* the types (labels) of annotations to be updated
* @param forSequences
* if not null, only annotations linked to one of these sequences are
* in scope for update; if null, acts on all sequence annotations
* @param anyType
* if this flag is true, 'types' is ignored (label not checked)
* @param doShow
* if true, set visibility on, else set off
*/
public static void showOrHideSequenceAnnotations(AlignmentI al,
Collection types, List forSequences,
boolean anyType, boolean doShow)
{
for (AlignmentAnnotation aa : al.getAlignmentAnnotation())
{
if (anyType || types.contains(aa.label))
{
if ((aa.sequenceRef != null)
&& (forSequences == null || forSequences
.contains(aa.sequenceRef)))
{
aa.visible = doShow;
}
}
}
}
/**
* Returns true if either sequence has a cross-reference to the other
*
* @param seq1
* @param seq2
* @return
*/
public static boolean haveCrossRef(SequenceI seq1, SequenceI seq2)
{
// Note: moved here from class CrossRef as the latter class has dependencies
// not availability to the applet's classpath
return hasCrossRef(seq1, seq2) || hasCrossRef(seq2, seq1);
}
/**
* Returns true if seq1 has a cross-reference to seq2. Currently this assumes
* that sequence name is structured as Source|AccessionId.
*
* @param seq1
* @param seq2
* @return
*/
public static boolean hasCrossRef(SequenceI seq1, SequenceI seq2)
{
if (seq1 == null || seq2 == null)
{
return false;
}
String name = seq2.getName();
final DBRefEntry[] xrefs = seq1.getDBRefs();
if (xrefs != null)
{
for (DBRefEntry xref : xrefs)
{
String xrefName = xref.getSource() + "|" + xref.getAccessionId();
// case-insensitive test, consistent with DBRefEntry.equalRef()
if (xrefName.equalsIgnoreCase(name))
{
return true;
}
}
}
return false;
}
/**
* Constructs an alignment consisting of the mapped (CDS) regions in the given
* nucleotide sequences, and updates mappings to match. The CDS sequences are
* added to the original alignment's dataset, which is shared by the new
* alignment. Mappings from nucleotide to CDS, and from CDS to protein, are
* added to the alignment dataset.
*
* @param dna
* aligned dna sequences
* @param mappings
* from dna to protein
* @param al
* @return an alignment whose sequences are the cds-only parts of the dna
* sequences (or null if no mappings are found)
*/
public static AlignmentI makeCdsAlignment(SequenceI[] dna,
List mappings, AlignmentI al)
{
List cdsSeqs = new ArrayList();
for (SequenceI seq : dna)
{
AlignedCodonFrame cdsMappings = new AlignedCodonFrame();
List seqMappings = MappingUtils
.findMappingsForSequence(seq, mappings);
List alignmentMappings = al.getCodonFrames();
for (AlignedCodonFrame mapping : seqMappings)
{
for (Mapping aMapping : mapping.getMappingsFromSequence(seq))
{
SequenceI cdsSeq = makeCdsSequence(seq.getDatasetSequence(),
aMapping);
cdsSeqs.add(cdsSeq);
/*
* add a mapping from CDS to the (unchanged) mapped to range
*/
List cdsRange = Collections.singletonList(new int[] { 1,
cdsSeq.getLength() });
MapList map = new MapList(cdsRange, aMapping.getMap()
.getToRanges(), aMapping.getMap().getFromRatio(),
aMapping.getMap().getToRatio());
cdsMappings.addMap(cdsSeq, aMapping.getTo(), map);
/*
* add another mapping from original 'from' range to CDS
*/
map = new MapList(aMapping.getMap().getFromRanges(), cdsRange, 1,
1);
cdsMappings.addMap(seq.getDatasetSequence(), cdsSeq, map);
alignmentMappings.add(cdsMappings);
/*
* transfer any features on dna that overlap the CDS
*/
transferFeatures(seq, cdsSeq, map, null, SequenceOntologyI.CDS);
}
}
}
/*
* add CDS seqs to shared dataset
*/
Alignment dataset = al.getDataset();
for (SequenceI seq : cdsSeqs)
{
if (!dataset.getSequences().contains(seq.getDatasetSequence()))
{
dataset.addSequence(seq.getDatasetSequence());
}
}
AlignmentI cds = new Alignment(cdsSeqs.toArray(new SequenceI[cdsSeqs
.size()]));
cds.setDataset(dataset);
return cds;
}
/**
* Helper method that makes a CDS sequence as defined by the mappings from the
* given sequence i.e. extracts the 'mapped from' ranges (which may be on
* forward or reverse strand).
*
* @param seq
* @param mapping
* @return
*/
static SequenceI makeCdsSequence(SequenceI seq, Mapping mapping)
{
char[] seqChars = seq.getSequence();
List fromRanges = mapping.getMap().getFromRanges();
int cdsWidth = MappingUtils.getLength(fromRanges);
char[] newSeqChars = new char[cdsWidth];
int newPos = 0;
for (int[] range : fromRanges)
{
if (range[0] <= range[1])
{
// forward strand mapping - just copy the range
int length = range[1] - range[0] + 1;
System.arraycopy(seqChars, range[0] - 1, newSeqChars, newPos,
length);
newPos += length;
}
else
{
// reverse strand mapping - copy and complement one by one
for (int i = range[0]; i >= range[1]; i--)
{
newSeqChars[newPos++] = Dna.getComplement(seqChars[i - 1]);
}
}
}
SequenceI newSeq = new Sequence(seq.getName() + "|"
+ mapping.getTo().getName(), newSeqChars, 1, newPos);
newSeq.createDatasetSequence();
return newSeq;
}
/**
* Transfers co-located features on 'fromSeq' to 'toSeq', adjusting the
* feature start/end ranges, optionally omitting specified feature types.
* Returns the number of features copied.
*
* @param fromSeq
* @param toSeq
* @param select
* if not null, only features of this type are copied (including
* subtypes in the Sequence Ontology)
* @param mapping
* the mapping from 'fromSeq' to 'toSeq'
* @param omitting
*/
public static int transferFeatures(SequenceI fromSeq, SequenceI toSeq,
MapList mapping, String select, String... omitting)
{
SequenceI copyTo = toSeq;
while (copyTo.getDatasetSequence() != null)
{
copyTo = copyTo.getDatasetSequence();
}
SequenceOntologyI so = SequenceOntologyFactory.getInstance();
int count = 0;
SequenceFeature[] sfs = fromSeq.getSequenceFeatures();
if (sfs != null)
{
for (SequenceFeature sf : sfs)
{
String type = sf.getType();
if (select != null && !so.isA(type, select))
{
continue;
}
boolean omit = false;
for (String toOmit : omitting)
{
if (type.equals(toOmit))
{
omit = true;
}
}
if (omit)
{
continue;
}
/*
* locate the mapped range - null if either start or end is
* not mapped (no partial overlaps are calculated)
*/
int start = sf.getBegin();
int end = sf.getEnd();
int[] mappedTo = mapping.locateInTo(start, end);
/*
* if whole exon range doesn't map, try interpreting it
* as 5' or 3' exon overlapping the CDS range
*/
if (mappedTo == null)
{
mappedTo = mapping.locateInTo(end, end);
if (mappedTo != null)
{
/*
* end of exon is in CDS range - 5' overlap
* to a range from the start of the peptide
*/
mappedTo[0] = 1;
}
}
if (mappedTo == null)
{
mappedTo = mapping.locateInTo(start, start);
if (mappedTo != null)
{
/*
* start of exon is in CDS range - 3' overlap
* to a range up to the end of the peptide
*/
mappedTo[1] = toSeq.getLength();
}
}
if (mappedTo != null)
{
SequenceFeature copy = new SequenceFeature(sf);
copy.setBegin(Math.min(mappedTo[0], mappedTo[1]));
copy.setEnd(Math.max(mappedTo[0], mappedTo[1]));
copyTo.addSequenceFeature(copy);
count++;
}
}
}
return count;
}
/**
* Returns a mapping from dna to protein by inspecting sequence features of
* type "CDS" on the dna.
*
* @param dnaSeq
* @param proteinSeq
* @return
*/
public static MapList mapCdsToProtein(SequenceI dnaSeq,
SequenceI proteinSeq)
{
List ranges = findCdsPositions(dnaSeq);
int mappedDnaLength = MappingUtils.getLength(ranges);
int proteinLength = proteinSeq.getLength();
int proteinStart = proteinSeq.getStart();
int proteinEnd = proteinSeq.getEnd();
/*
* incomplete start codon may mean X at start of peptide
* we ignore both for mapping purposes
*/
if (proteinSeq.getCharAt(0) == 'X')
{
// todo JAL-2022 support startPhase > 0
proteinStart++;
proteinLength--;
}
List proteinRange = new ArrayList();
/*
* dna length should map to protein (or protein plus stop codon)
*/
int codesForResidues = mappedDnaLength / 3;
if (codesForResidues == (proteinLength + 1))
{
// assuming extra codon is for STOP and not in peptide
codesForResidues--;
}
if (codesForResidues == proteinLength)
{
proteinRange.add(new int[] { proteinStart, proteinEnd });
return new MapList(ranges, proteinRange, 3, 1);
}
return null;
}
/**
* Returns a list of CDS ranges found (as sequence positions base 1), i.e. of
* start/end positions of sequence features of type "CDS" (or a sub-type of
* CDS in the Sequence Ontology). The ranges are sorted into ascending start
* position order, so this method is only valid for linear CDS in the same
* sense as the protein product.
*
* @param dnaSeq
* @return
*/
public static List findCdsPositions(SequenceI dnaSeq)
{
List result = new ArrayList();
SequenceFeature[] sfs = dnaSeq.getSequenceFeatures();
if (sfs == null)
{
return result;
}
SequenceOntologyI so = SequenceOntologyFactory.getInstance();
int startPhase = 0;
for (SequenceFeature sf : sfs)
{
/*
* process a CDS feature (or a sub-type of CDS)
*/
if (so.isA(sf.getType(), SequenceOntologyI.CDS))
{
int phase = 0;
try
{
phase = Integer.parseInt(sf.getPhase());
} catch (NumberFormatException e)
{
// ignore
}
/*
* phase > 0 on first codon means 5' incomplete - skip to the start
* of the next codon; example ENST00000496384
*/
int begin = sf.getBegin();
int end = sf.getEnd();
if (result.isEmpty())
{
begin += phase;
if (begin > end)
{
// shouldn't happen!
System.err
.println("Error: start phase extends beyond start CDS in "
+ dnaSeq.getName());
}
}
result.add(new int[] { begin, end });
}
}
/*
* remove 'startPhase' positions (usually 0) from the first range
* so we begin at the start of a complete codon
*/
if (!result.isEmpty())
{
// TODO JAL-2022 correctly model start phase > 0
result.get(0)[0] += startPhase;
}
/*
* Finally sort ranges by start position. This avoids a dependency on
* keeping features in order on the sequence (if they are in order anyway,
* the sort will have almost no work to do). The implicit assumption is CDS
* ranges are assembled in order. Other cases should not use this method,
* but instead construct an explicit mapping for CDS (e.g. EMBL parsing).
*/
Collections.sort(result, new Comparator()
{
@Override
public int compare(int[] o1, int[] o2)
{
return Integer.compare(o1[0], o2[0]);
}
});
return result;
}
/**
* Maps exon features from dna to protein, and computes variants in peptide
* product generated by variants in dna, and adds them as sequence_variant
* features on the protein sequence. Returns the number of variant features
* added.
*
* @param dnaSeq
* @param peptide
* @param dnaToProtein
*/
public static int computeProteinFeatures(SequenceI dnaSeq,
SequenceI peptide, MapList dnaToProtein)
{
while (dnaSeq.getDatasetSequence() != null)
{
dnaSeq = dnaSeq.getDatasetSequence();
}
while (peptide.getDatasetSequence() != null)
{
peptide = peptide.getDatasetSequence();
}
transferFeatures(dnaSeq, peptide, dnaToProtein, SequenceOntologyI.EXON);
/*
* compute protein variants from dna variants and codon mappings;
* NB - alternatively we could retrieve this using the REST service e.g.
* http://rest.ensembl.org/overlap/translation
* /ENSP00000288602?feature=transcript_variation;content-type=text/xml
* which would be a bit slower but possibly more reliable
*/
/*
* build a map with codon variations for each potentially varying peptide
*/
LinkedHashMap[]> variants = buildDnaVariantsMap(
dnaSeq, dnaToProtein);
/*
* scan codon variations, compute peptide variants and add to peptide sequence
*/
int count = 0;
for (Entry[]> variant : variants.entrySet())
{
int peptidePos = variant.getKey();
List[] codonVariants = variant.getValue();
count += computePeptideVariants(peptide, peptidePos, codonVariants);
}
/*
* sort to get sequence features in start position order
* - would be better to store in Sequence as a TreeSet or NCList?
*/
Arrays.sort(peptide.getSequenceFeatures(),
new Comparator()
{
@Override
public int compare(SequenceFeature o1, SequenceFeature o2)
{
int c = Integer.compare(o1.getBegin(), o2.getBegin());
return c == 0 ? Integer.compare(o1.getEnd(), o2.getEnd())
: c;
}
});
return count;
}
/**
* Computes non-synonymous peptide variants from codon variants and adds them
* as sequence_variant features on the protein sequence (one feature per
* allele variant). Selected attributes (variant id, clinical significance)
* are copied over to the new features.
*
* @param peptide
* the protein sequence
* @param peptidePos
* the position to compute peptide variants for
* @param codonVariants
* a list of dna variants per codon position
* @return the number of features added
*/
static int computePeptideVariants(SequenceI peptide, int peptidePos,
List[] codonVariants)
{
String residue = String.valueOf(peptide.getCharAt(peptidePos - 1));
int count = 0;
String base1 = codonVariants[0].get(0).base;
String base2 = codonVariants[1].get(0).base;
String base3 = codonVariants[2].get(0).base;
/*
* variants in first codon base
*/
for (DnaVariant var : codonVariants[0])
{
if (var.variant != null)
{
String alleles = (String) var.variant.getValue("alleles");
if (alleles != null)
{
for (String base : alleles.split(","))
{
String codon = base + base2 + base3;
if (addPeptideVariant(peptide, peptidePos, residue, var, codon))
{
count++;
}
}
}
}
}
/*
* variants in second codon base
*/
for (DnaVariant var : codonVariants[1])
{
if (var.variant != null)
{
String alleles = (String) var.variant.getValue("alleles");
if (alleles != null)
{
for (String base : alleles.split(","))
{
String codon = base1 + base + base3;
if (addPeptideVariant(peptide, peptidePos, residue, var, codon))
{
count++;
}
}
}
}
}
/*
* variants in third codon base
*/
for (DnaVariant var : codonVariants[2])
{
if (var.variant != null)
{
String alleles = (String) var.variant.getValue("alleles");
if (alleles != null)
{
for (String base : alleles.split(","))
{
String codon = base1 + base2 + base;
if (addPeptideVariant(peptide, peptidePos, residue, var, codon))
{
count++;
}
}
}
}
}
return count;
}
/**
* Helper method that adds a peptide variant feature, provided the given codon
* translates to a value different to the current residue (is a non-synonymous
* variant). ID and clinical_significance attributes of the dna variant (if
* present) are copied to the new feature.
*
* @param peptide
* @param peptidePos
* @param residue
* @param var
* @param codon
* @return true if a feature was added, else false
*/
static boolean addPeptideVariant(SequenceI peptide, int peptidePos,
String residue, DnaVariant var, String codon)
{
/*
* get peptide translation of codon e.g. GAT -> D
* note that variants which are not single alleles,
* e.g. multibase variants or HGMD_MUTATION etc
* are currently ignored here
*/
String trans = codon.contains("-") ? "-"
: (codon.length() > 3 ? null : ResidueProperties
.codonTranslate(codon));
if (trans != null && !trans.equals(residue))
{
String desc = residue + "->" + trans;
// set score to 0f so 'graduated colour' option is offered!
SequenceFeature sf = new SequenceFeature(
SequenceOntologyI.SEQUENCE_VARIANT, desc, peptidePos,
peptidePos, 0f, null);
String id = (String) var.variant.getValue(ID);
if (id != null)
{
if (id.startsWith(SEQUENCE_VARIANT))
{
id = id.substring(SEQUENCE_VARIANT.length());
}
sf.setValue(ID, id);
// TODO handle other species variants
StringBuilder link = new StringBuilder(32);
try
{
link.append(desc).append(" ").append(id)
.append("|http://www.ensembl.org/Homo_sapiens/Variation/Summary?v=")
.append(URLEncoder.encode(id, "UTF-8"));
sf.addLink(link.toString());
} catch (UnsupportedEncodingException e)
{
// as if
}
}
String clinSig = (String) var.variant
.getValue(CLINICAL_SIGNIFICANCE);
if (clinSig != null)
{
sf.setValue(CLINICAL_SIGNIFICANCE, clinSig);
}
peptide.addSequenceFeature(sf);
return true;
}
return false;
}
/**
* Builds a map whose key is position in the protein sequence, and value is a
* list of the base and all variants for each corresponding codon position
*
* @param dnaSeq
* @param dnaToProtein
* @return
*/
static LinkedHashMap[]> buildDnaVariantsMap(
SequenceI dnaSeq, MapList dnaToProtein)
{
/*
* map from peptide position to all variants of the codon which codes for it
* LinkedHashMap ensures we keep the peptide features in sequence order
*/
LinkedHashMap[]> variants = new LinkedHashMap[]>();
SequenceOntologyI so = SequenceOntologyFactory.getInstance();
SequenceFeature[] dnaFeatures = dnaSeq.getSequenceFeatures();
if (dnaFeatures == null)
{
return variants;
}
int dnaStart = dnaSeq.getStart();
int[] lastCodon = null;
int lastPeptidePostion = 0;
/*
* build a map of codon variations for peptides
*/
for (SequenceFeature sf : dnaFeatures)
{
int dnaCol = sf.getBegin();
if (dnaCol != sf.getEnd())
{
// not handling multi-locus variant features
continue;
}
if (so.isA(sf.getType(), SequenceOntologyI.SEQUENCE_VARIANT))
{
int[] mapsTo = dnaToProtein.locateInTo(dnaCol, dnaCol);
if (mapsTo == null)
{
// feature doesn't lie within coding region
continue;
}
int peptidePosition = mapsTo[0];
List[] codonVariants = variants.get(peptidePosition);
if (codonVariants == null)
{
codonVariants = new ArrayList[3];
codonVariants[0] = new ArrayList();
codonVariants[1] = new ArrayList();
codonVariants[2] = new ArrayList();
variants.put(peptidePosition, codonVariants);
}
/*
* extract dna variants to a string array
*/
String alls = (String) sf.getValue("alleles");
if (alls == null)
{
continue;
}
String[] alleles = alls.toUpperCase().split(",");
int i = 0;
for (String allele : alleles)
{
alleles[i++] = allele.trim(); // lose any space characters "A, G"
}
/*
* get this peptide's codon positions e.g. [3, 4, 5] or [4, 7, 10]
*/
int[] codon = peptidePosition == lastPeptidePostion ? lastCodon
: MappingUtils.flattenRanges(dnaToProtein.locateInFrom(
peptidePosition, peptidePosition));
lastPeptidePostion = peptidePosition;
lastCodon = codon;
/*
* save nucleotide (and any variant) for each codon position
*/
for (int codonPos = 0; codonPos < 3; codonPos++)
{
String nucleotide = String.valueOf(
dnaSeq.getCharAt(codon[codonPos] - dnaStart))
.toUpperCase();
List codonVariant = codonVariants[codonPos];
if (codon[codonPos] == dnaCol)
{
if (!codonVariant.isEmpty()
&& codonVariant.get(0).variant == null)
{
/*
* already recorded base value, add this variant
*/
codonVariant.get(0).variant = sf;
}
else
{
/*
* add variant with base value
*/
codonVariant.add(new DnaVariant(nucleotide, sf));
}
}
else if (codonVariant.isEmpty())
{
/*
* record (possibly non-varying) base value
*/
codonVariant.add(new DnaVariant(nucleotide));
}
}
}
}
return variants;
}
/**
* Makes an alignment with a copy of the given sequences, adding in any
* non-redundant sequences which are mapped to by the cross-referenced
* sequences.
*
* @param seqs
* @param xrefs
* @return
*/
public static AlignmentI makeCopyAlignment(SequenceI[] seqs,
SequenceI[] xrefs)
{
AlignmentI copy = new Alignment(new Alignment(seqs));
SequenceIdMatcher matcher = new SequenceIdMatcher(seqs);
if (xrefs != null)
{
for (SequenceI xref : xrefs)
{
DBRefEntry[] dbrefs = xref.getDBRefs();
if (dbrefs != null)
{
for (DBRefEntry dbref : dbrefs)
{
if (dbref.getMap() == null || dbref.getMap().getTo() == null)
{
continue;
}
SequenceI mappedTo = dbref.getMap().getTo();
SequenceI match = matcher.findIdMatch(mappedTo);
if (match == null)
{
matcher.add(mappedTo);
copy.addSequence(mappedTo);
}
}
}
}
}
return copy;
}
/**
* Try to align sequences in 'unaligned' to match the alignment of their
* mapped regions in 'aligned'. For example, could use this to align CDS
* sequences which are mapped to their parent cDNA sequences.
*
* This method handles 1:1 mappings (dna-to-dna or protein-to-protein). For
* dna-to-protein or protein-to-dna use alternative methods.
*
* @param unaligned
* sequences to be aligned
* @param aligned
* holds aligned sequences and their mappings
* @return
*/
public static int alignAs(AlignmentI unaligned, AlignmentI aligned)
{
List unmapped = new ArrayList();
Map> columnMap = buildMappedColumnsMap(
unaligned, aligned, unmapped);
int width = columnMap.size();
char gap = unaligned.getGapCharacter();
int realignedCount = 0;
for (SequenceI seq : unaligned.getSequences())
{
if (!unmapped.contains(seq))
{
char[] newSeq = new char[width];
Arrays.fill(newSeq, gap);
int newCol = 0;
int lastCol = 0;
/*
* traverse the map to find columns populated
* by our sequence
*/
for (Integer column : columnMap.keySet())
{
Character c = columnMap.get(column).get(seq);
if (c != null)
{
/*
* sequence has a character at this position
*
*/
newSeq[newCol] = c;
lastCol = newCol;
}
newCol++;
}
/*
* trim trailing gaps
*/
if (lastCol < width)
{
char[] tmp = new char[lastCol + 1];
System.arraycopy(newSeq, 0, tmp, 0, lastCol + 1);
newSeq = tmp;
}
seq.setSequence(String.valueOf(newSeq));
realignedCount++;
}
}
return realignedCount;
}
/**
* Returns a map whose key is alignment column number (base 1), and whose
* values are a map of sequence characters in that column.
*
* @param unaligned
* @param aligned
* @param unmapped
* @return
*/
static Map> buildMappedColumnsMap(
AlignmentI unaligned, AlignmentI aligned, List unmapped)
{
/*
* Map will hold, for each aligned column position, a map of
* {unalignedSequence, sequenceCharacter} at that position.
* TreeMap keeps the entries in ascending column order.
*/
Map> map = new TreeMap>();
/*
* r any sequences that have no mapping so can't be realigned
*/
unmapped.addAll(unaligned.getSequences());
List mappings = aligned.getCodonFrames();
for (SequenceI seq : unaligned.getSequences())
{
for (AlignedCodonFrame mapping : mappings)
{
SequenceI fromSeq = mapping.findAlignedSequence(seq, aligned);
if (fromSeq != null)
{
Mapping seqMap = mapping.getMappingBetween(fromSeq, seq);
if (addMappedPositions(seq, fromSeq, seqMap, map))
{
unmapped.remove(seq);
}
}
}
}
return map;
}
/**
* Helper method that adds to a map the mapped column positions of a sequence.
* For example if aaTT-Tg-gAAA is mapped to TTTAAA then the map should record
* that columns 3,4,6,10,11,12 map to characters T,T,T,A,A,A of the mapped to
* sequence.
*
* @param seq
* the sequence whose column positions we are recording
* @param fromSeq
* a sequence that is mapped to the first sequence
* @param seqMap
* the mapping from 'fromSeq' to 'seq'
* @param map
* a map to add the column positions (in fromSeq) of the mapped
* positions of seq
* @return
*/
static boolean addMappedPositions(SequenceI seq, SequenceI fromSeq,
Mapping seqMap, Map> map)
{
if (seqMap == null)
{
return false;
}
char[] fromChars = fromSeq.getSequence();
int toStart = seq.getStart();
char[] toChars = seq.getSequence();
/*
* traverse [start, end, start, end...] ranges in fromSeq
*/
for (int[] fromRange : seqMap.getMap().getFromRanges())
{
for (int i = 0; i < fromRange.length - 1; i += 2)
{
boolean forward = fromRange[i + 1] >= fromRange[i];
/*
* find the range mapped to (sequence positions base 1)
*/
int[] range = seqMap.locateMappedRange(fromRange[i],
fromRange[i + 1]);
if (range == null)
{
System.err.println("Error in mapping " + seqMap + " from "
+ fromSeq.getName());
return false;
}
int fromCol = fromSeq.findIndex(fromRange[i]);
int mappedCharPos = range[0];
/*
* walk over the 'from' aligned sequence in forward or reverse
* direction; when a non-gap is found, record the column position
* of the next character of the mapped-to sequence; stop when all
* the characters of the range have been counted
*/
while (mappedCharPos <= range[1])
{
if (!Comparison.isGap(fromChars[fromCol - 1]))
{
/*
* mapped from sequence has a character in this column
* record the column position for the mapped to character
*/
Map seqsMap = map.get(fromCol);
if (seqsMap == null)
{
seqsMap = new HashMap();
map.put(fromCol, seqsMap);
}
seqsMap.put(seq, toChars[mappedCharPos - toStart]);
mappedCharPos++;
}
fromCol += (forward ? 1 : -1);
}
}
}
return true;
}
// strictly temporary hack until proper criteria for aligning protein to cds
// are in place; this is so Ensembl -> fetch xrefs Uniprot aligns the Uniprot
public static boolean looksLikeEnsembl(AlignmentI alignment)
{
for (SequenceI seq : alignment.getSequences())
{
String name = seq.getName();
if (!name.startsWith("ENSG") && !name.startsWith("ENST"))
{
return false;
}
}
return true;
}
}