package jalview.ext.ensembl;
import jalview.datamodel.AlignmentI;
import jalview.datamodel.Sequence;
import jalview.datamodel.SequenceFeature;
import jalview.datamodel.SequenceI;
import jalview.io.gff.SequenceOntologyFactory;
import jalview.io.gff.SequenceOntologyI;
import jalview.util.MapList;
import jalview.util.StringUtils;
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
{
private static final String GENE_PREFIX = "gene:";
/*
* 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 };
@Override
public String getDbName()
{
return "ENSEMBL (GENE)";
}
@Override
protected EnsemblFeatureType[] getFeaturesToFetch()
{
return FEATURES_TO_FETCH;
}
@Override
protected EnsemblSeqType getSourceEnsemblType()
{
return EnsemblSeqType.GENOMIC;
}
/**
* 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:
*
* - resolves a transcript identifier by looking up its parent gene id
* - resolves an external identifier by looking up xref-ed gene ids
* - fetches the gene sequence
* - fetches features on the sequence
* - identifies "transcript" features whose Parent is the requested gene
* - fetches the transcript sequence for each transcript
* - makes a mapping from the gene to each transcript
* - copies features from gene to transcript sequences
* - fetches the protein sequence for each transcript, maps and saves it as
* a cross-reference
* - aligns each transcript against the gene sequence based on the position
* mappings
*
*
* @param query
* one or more identifiers separated by a space
* @return an alignment containing one or more genes, and possibly
* transcripts, or null
*/
@Override
public AlignmentI getSequenceRecords(String query) throws Exception
{
// todo: tidy up handling of one or multiple accession ids
String[] queries = query.split(getAccessionSeparator());
/*
* if given a transcript id, look up its gene parent
*/
if (isTranscriptIdentifier(query))
{
// we are assuming all transcripts have the same gene parent here
query = new EnsemblLookup().getParent(queries[0]);
if (query == null)
{
return null;
}
}
/*
* if given a gene or other external name, lookup and fetch
* the corresponding gene for all model organisms
*/
if (!isGeneIdentifier(query))
{
List geneIds = new EnsemblSymbol().getIds(query);
if (geneIds.isEmpty())
{
return null;
}
String theIds = StringUtils.listToDelimitedString(geneIds,
getAccessionSeparator());
return getSequenceRecords(theIds);
}
AlignmentI al = super.getSequenceRecords(query);
/*
* if we retrieved a single gene, get its transcripts as well
*/
if (al.getHeight() == 1)
{
getTranscripts(al, query);
}
return al;
}
/**
* Attempts to get Ensembl stable identifiers for model organisms for a gene
* name by calling the xrefs symbol REST service to resolve the gene name.
*
* @param query
* @return
*/
protected String getGeneIdentifiersForName(String query)
{
List ids = new EnsemblSymbol().getIds(query);
if (ids != null)
{
for (String id : ids)
{
if (isGeneIdentifier(id))
{
return id;
}
}
}
return null;
}
/**
* 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);
}
}
/**
* 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 = "transcript:" + accId;
List splices = findFeatures(gene,
SequenceOntologyI.EXON, parentId);
if (splices.isEmpty())
{
splices = findFeatures(gene, SequenceOntologyI.CDS, parentId);
}
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);
String geneName = (String) transcriptFeature.getValue(NAME);
if (geneName != null)
{
transcript.setDescription(geneName);
}
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);
new EnsemblCdna().transferFeatures(gene.getSequenceFeatures(),
transcript.getDatasetSequence(), mapping, parentId);
/*
* fetch and save cross-references
*/
super.getCrossReferences(transcript);
/*
* and finally fetch the protein product and save as a cross-reference
*/
new EnsemblCdna().addProteinProduct(transcript);
return transcript;
}
/**
* Returns the 'transcript_id' property of the sequence feature (or null)
*
* @param feature
* @return
*/
protected String getTranscriptId(SequenceFeature feature)
{
return (String) feature.getValue("transcript_id");
}
/**
* Returns a list of the transcript features on the sequence whose Parent is
* the gene for the accession id.
*
* @param accId
* @param geneSequence
* @return
*/
protected List getTranscriptFeatures(String accId,
SequenceI geneSequence)
{
List transcriptFeatures = new ArrayList();
String parentIdentifier = GENE_PREFIX + accId;
SequenceFeature[] sfs = geneSequence.getSequenceFeatures();
if (sfs != null)
{
for (SequenceFeature sf : sfs)
{
if (isTranscript(sf.getType()))
{
String parent = (String) sf.getValue(PARENT);
if (parentIdentifier.equals(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 "ENSG00000157764"; // BRAF, 5 transcripts, reverse strand
// ENSG00000090266 // NDUFB2, 15 transcripts, forward strand
// ENSG00000101812 // H2BFM histone, 3 transcripts, forward strand
// ENSG00000123569 // H2BFWT histone, 2 transcripts, reverse strand
}
/**
* Answers true for a feature of type 'gene' (or a sub-type of gene in the
* Sequence Ontology), whose ID is the accession we are retrieving
*/
@Override
protected boolean identifiesSequence(SequenceFeature sf, String accId)
{
if (SequenceOntologyFactory.getInstance().isA(sf.getType(),
SequenceOntologyI.GENE))
{
String id = (String) sf.getValue(ID);
if ((GENE_PREFIX + accId).equals(id))
{
return true;
}
}
return false;
}
/**
* 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)
{
if (SequenceOntologyFactory.getInstance().isA(sf.getType(),
SequenceOntologyI.GENE))
{
return false;
}
if (isTranscript(sf.getType()))
{
String parent = (String) sf.getValue(PARENT);
if (!(GENE_PREFIX + accessionId).equals(parent))
{
return false;
}
}
return true;
}
/**
* Answers false. This allows an optimisation - a single 'gene' feature is all
* that is needed to identify the positions of the gene on the genomic
* sequence.
*/
@Override
protected boolean isSpliceable()
{
return false;
}
@Override
protected List getCrossReferenceDatabases()
{
// found these for ENSG00000157764 on 30/01/2016:
// return new String[] {"Vega_gene", "OTTG", "ENS_LRG_gene", "ArrayExpress",
// "EntrezGene", "HGNC", "MIM_GENE", "MIM_MORBID", "WikiGene"};
return super.getCrossReferenceDatabases();
}
/**
* 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;
}
}