badData;
/**
* Constructor given a VCF file
*
* @param alignment
*/
public VCFLoader(String vcfFile)
{
try
{
initialise(vcfFile);
} catch (IOException e)
{
jalview.bin.Console.errPrintln("Error opening VCF file: " + e.getMessage());
}
// map of species!chromosome!fromAssembly!toAssembly to {fromRange, toRange}
assemblyMappings = new HashMap<>();
}
/**
* Starts a new thread to query and load VCF variant data on to the given
* sequences
*
* This method is not thread safe - concurrent threads should use separate
* instances of this class.
*
* @param seqs
* @param gui
*/
public void loadVCF(SequenceI[] seqs, final AlignViewControllerGuiI gui)
{
if (gui != null)
{
gui.setStatus(MessageManager.getString("label.searching_vcf"));
}
new Thread()
{
@Override
public void run()
{
VCFLoader.this.doLoad(seqs, gui);
}
}.start();
}
/**
* Reads the specified contig sequence and adds its VCF variants to it
*
* @param contig
* the id of a single sequence (contig) to load
* @return
*/
public SequenceI loadVCFContig(String contig)
{
VCFHeaderLine headerLine = header
.getOtherHeaderLine(VCFHeader.REFERENCE_KEY);
if (headerLine == null)
{
Console.error("VCF reference header not found");
return null;
}
String ref = headerLine.getValue();
if (ref.startsWith("file://"))
{
ref = ref.substring(7);
}
setSpeciesAndAssembly(ref);
SequenceI seq = null;
File dbFile = new File(ref);
if (dbFile.exists())
{
HtsContigDb db = new HtsContigDb("", dbFile);
seq = db.getSequenceProxy(contig);
loadSequenceVCF(seq);
db.close();
}
else
{
Console.error("VCF reference not found: " + ref);
}
return seq;
}
/**
* Loads VCF on to one or more sequences
*
* @param seqs
* @param gui
* optional callback handler for messages
*/
protected void doLoad(SequenceI[] seqs, AlignViewControllerGuiI gui)
{
try
{
VCFHeaderLine ref = header
.getOtherHeaderLine(VCFHeader.REFERENCE_KEY);
String reference = ref == null ? null : ref.getValue();
setSpeciesAndAssembly(reference);
int varCount = 0;
int seqCount = 0;
/*
* query for VCF overlapping each sequence in turn
*/
for (SequenceI seq : seqs)
{
int added = loadSequenceVCF(seq);
if (added > 0)
{
seqCount++;
varCount += added;
transferAddedFeatures(seq);
}
}
if (gui != null)
{
String msg = MessageManager.formatMessage("label.added_vcf",
varCount, seqCount);
gui.setStatus(msg);
if (gui.getFeatureSettingsUI() != null)
{
gui.getFeatureSettingsUI().discoverAllFeatureData();
}
}
} catch (Throwable e)
{
jalview.bin.Console.errPrintln("Error processing VCF: " + e.getMessage());
e.printStackTrace();
if (gui != null)
{
gui.setStatus("Error occurred - see console for details");
}
} finally
{
if (reader != null)
{
try
{
reader.close();
} catch (IOException e)
{
// ignore
}
}
header = null;
dictionary = null;
}
}
/**
* Attempts to determine and save the species and genome assembly version to
* which the VCF data applies. This may be done by parsing the
* {@code reference} header line, configured in a property file, or
* (potentially) confirmed interactively by the user.
*
* The saved values should be identifiers valid for Ensembl's REST service
* {@code map} endpoint, so they can be used (if necessary) to retrieve the
* mapping between VCF coordinates and sequence coordinates.
*
* @param reference
* @see https://rest.ensembl.org/documentation/info/assembly_map
* @see https://rest.ensembl.org/info/assembly/human?content-type=text/xml
* @see https://rest.ensembl.org/info/species?content-type=text/xml
*/
protected void setSpeciesAndAssembly(String reference)
{
if (reference == null)
{
Console.error("No VCF ##reference found, defaulting to "
+ DEFAULT_REFERENCE + ":" + DEFAULT_SPECIES);
reference = DEFAULT_REFERENCE; // default to GRCh37 if not specified
}
reference = reference.toLowerCase(Locale.ROOT);
/*
* for a non-human species, or other assembly identifier,
* specify as a Jalview property file entry e.g.
* VCF_ASSEMBLY = hs37=GRCh37,assembly19=GRCh37
* VCF_SPECIES = c_elegans=celegans
* to map a token in the reference header to a value
*/
String prop = Cache.getDefault(VCF_ASSEMBLY, DEFAULT_VCF_ASSEMBLY);
for (String token : prop.split(","))
{
String[] tokens = token.split("=");
if (tokens.length == 2)
{
if (reference.contains(tokens[0].trim().toLowerCase(Locale.ROOT)))
{
vcfAssembly = tokens[1].trim();
break;
}
}
}
vcfSpecies = DEFAULT_SPECIES;
prop = Cache.getProperty(VCF_SPECIES);
if (prop != null)
{
for (String token : prop.split(","))
{
String[] tokens = token.split("=");
if (tokens.length == 2)
{
if (reference.contains(tokens[0].trim().toLowerCase(Locale.ROOT)))
{
vcfSpecies = tokens[1].trim();
break;
}
}
}
}
}
/**
* Opens the VCF file and parses header data
*
* @param filePath
* @throws IOException
*/
private void initialise(String filePath) throws IOException
{
vcfFilePath = filePath;
reader = new VCFReader(filePath);
header = reader.getFileHeader();
try
{
dictionary = header.getSequenceDictionary();
} catch (SAMException e)
{
// ignore - thrown if any contig line lacks length info
}
sourceId = filePath;
saveMetadata(sourceId);
/*
* get offset of CSQ ALLELE_NUM and Feature if declared
*/
parseCsqHeader();
}
/**
* Reads metadata (such as INFO field descriptions and datatypes) and saves
* them for future reference
*
* @param theSourceId
*/
void saveMetadata(String theSourceId)
{
List vcfFieldPatterns = getFieldMatchers(VCF_FIELDS_PREF,
DEFAULT_VCF_FIELDS);
vcfFieldsOfInterest = new ArrayList<>();
FeatureSource metadata = new FeatureSource(theSourceId);
for (VCFInfoHeaderLine info : header.getInfoHeaderLines())
{
String attributeId = info.getID();
String desc = info.getDescription();
VCFHeaderLineType type = info.getType();
FeatureAttributeType attType = null;
switch (type)
{
case Character:
attType = FeatureAttributeType.Character;
break;
case Flag:
attType = FeatureAttributeType.Flag;
break;
case Float:
attType = FeatureAttributeType.Float;
break;
case Integer:
attType = FeatureAttributeType.Integer;
break;
case String:
attType = FeatureAttributeType.String;
break;
}
metadata.setAttributeName(attributeId, desc);
metadata.setAttributeType(attributeId, attType);
if (isFieldWanted(attributeId, vcfFieldPatterns))
{
vcfFieldsOfInterest.add(attributeId);
}
}
FeatureSources.getInstance().addSource(theSourceId, metadata);
}
/**
* Answers true if the field id is matched by any of the filter patterns, else
* false. Matching is against regular expression patterns, and is not
* case-sensitive.
*
* @param id
* @param filters
* @return
*/
private boolean isFieldWanted(String id, List filters)
{
for (Pattern p : filters)
{
if (p.matcher(id.toUpperCase(Locale.ROOT)).matches())
{
return true;
}
}
return false;
}
/**
* Records 'wanted' fields defined in the CSQ INFO header (if there is one).
* Also records the position of selected fields (Allele, ALLELE_NUM, Feature)
* required for processing.
*
* CSQ fields are declared in the CSQ INFO Description e.g.
*
* Description="Consequence ...from ... VEP. Format: Allele|Consequence|...
*/
protected void parseCsqHeader()
{
List vepFieldFilters = getFieldMatchers(VEP_FIELDS_PREF,
DEFAULT_VEP_FIELDS);
vepFieldsOfInterest = new HashMap<>();
VCFInfoHeaderLine csqInfo = header.getInfoHeaderLine(CSQ_FIELD);
if (csqInfo == null)
{
return;
}
/*
* parse out the pipe-separated list of CSQ fields; we assume here that
* these form the last part of the description, and contain no spaces
*/
String desc = csqInfo.getDescription();
int spacePos = desc.lastIndexOf(" ");
desc = desc.substring(spacePos + 1);
if (desc != null)
{
String[] format = desc.split(PIPE_REGEX);
int index = 0;
for (String field : format)
{
if (CSQ_CONSEQUENCE_KEY.equals(field))
{
csqConsequenceFieldIndex = index;
}
if (CSQ_ALLELE_NUM_KEY.equals(field))
{
csqAlleleNumberFieldIndex = index;
}
if (CSQ_ALLELE_KEY.equals(field))
{
csqAlleleFieldIndex = index;
}
if (CSQ_FEATURE_KEY.equals(field))
{
csqFeatureFieldIndex = index;
}
if (isFieldWanted(field, vepFieldFilters))
{
vepFieldsOfInterest.put(index, field);
}
index++;
}
}
}
/**
* Reads the Preference value for the given key, with default specified if no
* preference set. The value is interpreted as a comma-separated list of
* regular expressions, and converted into a list of compiled patterns ready
* for matching. Patterns are forced to upper-case for non-case-sensitive
* matching.
*
* This supports user-defined filters for fields of interest to capture while
* processing data. For example, VCF_FIELDS = AF,AC* would mean that VCF INFO
* fields with an ID of AF, or starting with AC, would be matched.
*
* @param key
* @param def
* @return
*/
private List getFieldMatchers(String key, String def)
{
String pref = Cache.getDefault(key, def);
List patterns = new ArrayList<>();
String[] tokens = pref.split(",");
for (String token : tokens)
{
try
{
patterns.add(Pattern.compile(token.toUpperCase(Locale.ROOT)));
} catch (PatternSyntaxException e)
{
jalview.bin.Console.errPrintln("Invalid pattern ignored: " + token);
}
}
return patterns;
}
/**
* Transfers VCF features to sequences to which this sequence has a mapping.
*
* @param seq
*/
protected void transferAddedFeatures(SequenceI seq)
{
List dbrefs = seq.getDBRefs();
if (dbrefs == null)
{
return;
}
for (DBRefEntry dbref : dbrefs)
{
Mapping mapping = dbref.getMap();
if (mapping == null || mapping.getTo() == null)
{
continue;
}
SequenceI mapTo = mapping.getTo();
MapList map = mapping.getMap();
if (map.getFromRatio() == 3)
{
/*
* dna-to-peptide product mapping
*/
// JAL-3187 render on the fly instead
// AlignmentUtils.computeProteinFeatures(seq, mapTo, map);
}
else
{
/*
* nucleotide-to-nucleotide mapping e.g. transcript to CDS
*/
List features = seq.getFeatures()
.getPositionalFeatures(SequenceOntologyI.SEQUENCE_VARIANT);
for (SequenceFeature sf : features)
{
if (FEATURE_GROUP_VCF.equals(sf.getFeatureGroup()))
{
transferFeature(sf, mapTo, map);
}
}
}
}
}
/**
* Tries to add overlapping variants read from a VCF file to the given
* sequence, and returns the number of variant features added
*
* @param seq
* @return
*/
protected int loadSequenceVCF(SequenceI seq)
{
VCFMap vcfMap = getVcfMap(seq);
if (vcfMap == null)
{
return 0;
}
/*
* work with the dataset sequence here
*/
SequenceI dss = seq.getDatasetSequence();
if (dss == null)
{
dss = seq;
}
return addVcfVariants(dss, vcfMap);
}
/**
* Answers a map from sequence coordinates to VCF chromosome ranges
*
* @param seq
* @return
*/
private VCFMap getVcfMap(SequenceI seq)
{
/*
* simplest case: sequence has id and length matching a VCF contig
*/
VCFMap vcfMap = null;
if (dictionary != null)
{
vcfMap = getContigMap(seq);
}
if (vcfMap != null)
{
return vcfMap;
}
/*
* otherwise, map to VCF from chromosomal coordinates
* of the sequence (if known)
*/
GeneLociI seqCoords = seq.getGeneLoci();
if (seqCoords == null)
{
Console.warn(String.format(
"Can't query VCF for %s as chromosome coordinates not known",
seq.getName()));
return null;
}
String species = seqCoords.getSpeciesId();
String chromosome = seqCoords.getChromosomeId();
String seqRef = seqCoords.getAssemblyId();
MapList map = seqCoords.getMapping();
// note this requires the configured species to match that
// returned with the Ensembl sequence; todo: support aliases?
if (!vcfSpecies.equalsIgnoreCase(species))
{
Console.warn("No VCF loaded to " + seq.getName()
+ " as species not matched");
return null;
}
if (seqRef.equalsIgnoreCase(vcfAssembly))
{
return new VCFMap(chromosome, map);
}
/*
* VCF data has a different reference assembly to the sequence:
* query Ensembl to map chromosomal coordinates from sequence to VCF
*/
List toVcfRanges = new ArrayList<>();
List fromSequenceRanges = new ArrayList<>();
for (int[] range : map.getToRanges())
{
int[] fromRange = map.locateInFrom(range[0], range[1]);
if (fromRange == null)
{
// corrupted map?!?
continue;
}
int[] newRange = mapReferenceRange(range, chromosome, "human", seqRef,
vcfAssembly);
if (newRange == null)
{
Console.error(String.format("Failed to map %s:%s:%s:%d:%d to %s",
species, chromosome, seqRef, range[0], range[1],
vcfAssembly));
continue;
}
else
{
toVcfRanges.add(newRange);
fromSequenceRanges.add(fromRange);
}
}
return new VCFMap(chromosome,
new MapList(fromSequenceRanges, toVcfRanges, 1, 1));
}
/**
* If the sequence id matches a contig declared in the VCF file, and the
* sequence length matches the contig length, then returns a 1:1 map of the
* sequence to the contig, else returns null
*
* @param seq
* @return
*/
private VCFMap getContigMap(SequenceI seq)
{
String id = seq.getName();
SAMSequenceRecord contig = dictionary.getSequence(id);
if (contig != null)
{
int len = seq.getLength();
if (len == contig.getSequenceLength())
{
MapList map = new MapList(new int[] { 1, len },
new int[]
{ 1, len }, 1, 1);
return new VCFMap(id, map);
}
}
return null;
}
/**
* Queries the VCF reader for any variants that overlap the mapped chromosome
* ranges of the sequence, and adds as variant features. Returns the number of
* overlapping variants found.
*
* @param seq
* @param map
* mapping from sequence to VCF coordinates
* @return
*/
protected int addVcfVariants(SequenceI seq, VCFMap map)
{
boolean forwardStrand = map.map.isToForwardStrand();
/*
* query the VCF for overlaps of each contiguous chromosomal region
*/
int count = 0;
for (int[] range : map.map.getToRanges())
{
int vcfStart = Math.min(range[0], range[1]);
int vcfEnd = Math.max(range[0], range[1]);
try
{
CloseableIterator variants = reader
.query(map.chromosome, vcfStart, vcfEnd);
while (variants.hasNext())
{
VariantContext variant = variants.next();
int[] featureRange = map.map.locateInFrom(variant.getStart(),
variant.getEnd());
/*
* only take features whose range is fully mappable to sequence positions
*/
if (featureRange != null)
{
int featureStart = Math.min(featureRange[0], featureRange[1]);
int featureEnd = Math.max(featureRange[0], featureRange[1]);
if (featureEnd - featureStart == variant.getEnd()
- variant.getStart())
{
count += addAlleleFeatures(seq, variant, featureStart,
featureEnd, forwardStrand);
}
}
}
variants.close();
} catch (TribbleException e)
{
/*
* RuntimeException throwable by htsjdk
*/
String msg = String.format("Error reading VCF for %s:%d-%d: %s ",
map.chromosome, vcfStart, vcfEnd, e.getLocalizedMessage());
Console.error(msg);
}
}
return count;
}
/**
* A convenience method to get an attribute value for an alternate allele
*
* @param variant
* @param attributeName
* @param alleleIndex
* @return
*/
protected String getAttributeValue(VariantContext variant,
String attributeName, int alleleIndex)
{
Object att = variant.getAttribute(attributeName);
if (att instanceof String)
{
return (String) att;
}
else if (att instanceof ArrayList)
{
return ((List) att).get(alleleIndex);
}
return null;
}
/**
* Adds one variant feature for each allele in the VCF variant record, and
* returns the number of features added.
*
* @param seq
* @param variant
* @param featureStart
* @param featureEnd
* @param forwardStrand
* @return
*/
protected int addAlleleFeatures(SequenceI seq, VariantContext variant,
int featureStart, int featureEnd, boolean forwardStrand)
{
int added = 0;
/*
* Javadoc says getAlternateAlleles() imposes no order on the list returned
* so we proceed defensively to get them in strict order
*/
int altAlleleCount = variant.getAlternateAlleles().size();
for (int i = 0; i < altAlleleCount; i++)
{
added += addAlleleFeature(seq, variant, i, featureStart, featureEnd,
forwardStrand);
}
return added;
}
/**
* Inspects one allele and attempts to add a variant feature for it to the
* sequence. The additional data associated with this allele is extracted to
* store in the feature's key-value map. Answers the number of features added
* (0 or 1).
*
* @param seq
* @param variant
* @param altAlleleIndex
* (0, 1..)
* @param featureStart
* @param featureEnd
* @param forwardStrand
* @return
*/
protected int addAlleleFeature(SequenceI seq, VariantContext variant,
int altAlleleIndex, int featureStart, int featureEnd,
boolean forwardStrand)
{
String reference = variant.getReference().getBaseString();
Allele alt = variant.getAlternateAllele(altAlleleIndex);
String allele = alt.getBaseString();
/*
* insertion after a genomic base, if on reverse strand, has to be
* converted to insertion of complement after the preceding position
*/
int referenceLength = reference.length();
if (!forwardStrand && allele.length() > referenceLength
&& allele.startsWith(reference))
{
featureStart -= referenceLength;
featureEnd = featureStart;
char insertAfter = seq.getCharAt(featureStart - seq.getStart());
reference = Dna.reverseComplement(String.valueOf(insertAfter));
allele = allele.substring(referenceLength) + reference;
}
/*
* build the ref,alt allele description e.g. "G,A", using the base
* complement if the sequence is on the reverse strand
*/
StringBuilder sb = new StringBuilder();
sb.append(forwardStrand ? reference : Dna.reverseComplement(reference));
sb.append(COMMA);
sb.append(forwardStrand ? allele : Dna.reverseComplement(allele));
String alleles = sb.toString(); // e.g. G,A
/*
* pick out the consequence data (if any) that is for the current allele
* and feature (transcript) that matches the current sequence
*/
String consequence = getConsequenceForAlleleAndFeature(variant,
CSQ_FIELD, altAlleleIndex, csqAlleleFieldIndex,
csqAlleleNumberFieldIndex,
seq.getName().toLowerCase(Locale.ROOT), csqFeatureFieldIndex);
/*
* pick out the ontology term for the consequence type
*/
String type = SequenceOntologyI.SEQUENCE_VARIANT;
if (consequence != null)
{
type = getOntologyTerm(consequence);
}
SequenceFeature sf = new SequenceFeature(type, alleles, featureStart,
featureEnd, FEATURE_GROUP_VCF);
sf.setSource(sourceId);
/*
* save the derived alleles as a named attribute; this will be
* needed when Jalview computes derived peptide variants
*/
addFeatureAttribute(sf, Gff3Helper.ALLELES, alleles);
/*
* add selected VCF fixed column data as feature attributes
*/
addFeatureAttribute(sf, VCF_POS, String.valueOf(variant.getStart()));
addFeatureAttribute(sf, VCF_ID, variant.getID());
addFeatureAttribute(sf, VCF_QUAL,
String.valueOf(variant.getPhredScaledQual()));
addFeatureAttribute(sf, VCF_FILTER, getFilter(variant));
addAlleleProperties(variant, sf, altAlleleIndex, consequence);
seq.addSequenceFeature(sf);
return 1;
}
/**
* Answers the VCF FILTER value for the variant - or an approximation to it.
* This field is either PASS, or a semi-colon separated list of filters not
* passed. htsjdk saves filters as a HashSet, so the order when reassembled
* into a list may be different.
*
* @param variant
* @return
*/
String getFilter(VariantContext variant)
{
Set filters = variant.getFilters();
if (filters.isEmpty())
{
return NO_VALUE;
}
Iterator iterator = filters.iterator();
String first = iterator.next();
if (filters.size() == 1)
{
return first;
}
StringBuilder sb = new StringBuilder(first);
while (iterator.hasNext())
{
sb.append(";").append(iterator.next());
}
return sb.toString();
}
/**
* Adds one feature attribute unless the value is null, empty or '.'
*
* @param sf
* @param key
* @param value
*/
void addFeatureAttribute(SequenceFeature sf, String key, String value)
{
if (value != null && !value.isEmpty() && !NO_VALUE.equals(value))
{
sf.setValue(key, value);
}
}
/**
* Determines the Sequence Ontology term to use for the variant feature type
* in Jalview. The default is 'sequence_variant', but a more specific term is
* used if:
*
* - VEP (or SnpEff) Consequence annotation is included in the VCF
* - sequence id can be matched to VEP Feature (or SnpEff Feature_ID)
*
*
* @param consequence
* @return
* @see http://www.sequenceontology.org/browser/current_svn/term/SO:0001060
*/
String getOntologyTerm(String consequence)
{
String type = SequenceOntologyI.SEQUENCE_VARIANT;
/*
* could we associate Consequence data with this allele and feature (transcript)?
* if so, prefer the consequence term from that data
*/
if (csqAlleleFieldIndex == -1) // && snpEffAlleleFieldIndex == -1
{
/*
* no Consequence data so we can't refine the ontology term
*/
return type;
}
if (consequence != null)
{
String[] csqFields = consequence.split(PIPE_REGEX);
if (csqFields.length > csqConsequenceFieldIndex)
{
type = csqFields[csqConsequenceFieldIndex];
}
}
else
{
// todo the same for SnpEff consequence data matching if wanted
}
/*
* if of the form (e.g.) missense_variant&splice_region_variant,
* just take the first ('most severe') consequence
*/
if (type != null)
{
int pos = type.indexOf('&');
if (pos > 0)
{
type = type.substring(0, pos);
}
}
return type;
}
/**
* Returns matched consequence data if it can be found, else null.
*
* - inspects the VCF data for key 'vcfInfoId'
* - splits this on comma (to distinct consequences)
* - returns the first consequence (if any) where
*
* - the allele matches the altAlleleIndex'th allele of variant
* - the feature matches the sequence name (e.g. transcript id)
*
*
* If matched, the consequence is returned (as pipe-delimited fields).
*
* @param variant
* @param vcfInfoId
* @param altAlleleIndex
* @param alleleFieldIndex
* @param alleleNumberFieldIndex
* @param seqName
* @param featureFieldIndex
* @return
*/
private String getConsequenceForAlleleAndFeature(VariantContext variant,
String vcfInfoId, int altAlleleIndex, int alleleFieldIndex,
int alleleNumberFieldIndex, String seqName, int featureFieldIndex)
{
if (alleleFieldIndex == -1 || featureFieldIndex == -1)
{
return null;
}
Object value = variant.getAttribute(vcfInfoId);
if (value == null || !(value instanceof List))
{
return null;
}
/*
* inspect each consequence in turn (comma-separated blocks
* extracted by htsjdk)
*/
List consequences = (List) value;
for (String consequence : consequences)
{
String[] csqFields = consequence.split(PIPE_REGEX);
if (csqFields.length > featureFieldIndex)
{
String featureIdentifier = csqFields[featureFieldIndex];
if (featureIdentifier.length() > 4 && seqName
.indexOf(featureIdentifier.toLowerCase(Locale.ROOT)) > -1)
{
/*
* feature (transcript) matched - now check for allele match
*/
if (matchAllele(variant, altAlleleIndex, csqFields,
alleleFieldIndex, alleleNumberFieldIndex))
{
return consequence;
}
}
}
}
return null;
}
private boolean matchAllele(VariantContext variant, int altAlleleIndex,
String[] csqFields, int alleleFieldIndex,
int alleleNumberFieldIndex)
{
/*
* if ALLELE_NUM is present, it must match altAlleleIndex
* NB first alternate allele is 1 for ALLELE_NUM, 0 for altAlleleIndex
*/
if (alleleNumberFieldIndex > -1)
{
if (csqFields.length <= alleleNumberFieldIndex)
{
return false;
}
String alleleNum = csqFields[alleleNumberFieldIndex];
return String.valueOf(altAlleleIndex + 1).equals(alleleNum);
}
/*
* else consequence allele must match variant allele
*/
if (alleleFieldIndex > -1 && csqFields.length > alleleFieldIndex)
{
String csqAllele = csqFields[alleleFieldIndex];
String vcfAllele = variant.getAlternateAllele(altAlleleIndex)
.getBaseString();
return csqAllele.equals(vcfAllele);
}
return false;
}
/**
* Add any allele-specific VCF key-value data to the sequence feature
*
* @param variant
* @param sf
* @param altAlelleIndex
* (0, 1..)
* @param consequence
* if not null, the consequence specific to this sequence (transcript
* feature) and allele
*/
protected void addAlleleProperties(VariantContext variant,
SequenceFeature sf, final int altAlelleIndex, String consequence)
{
Map atts = variant.getAttributes();
for (Entry att : atts.entrySet())
{
String key = att.getKey();
/*
* extract Consequence data (if present) that we are able to
* associated with the allele for this variant feature
*/
if (CSQ_FIELD.equals(key))
{
addConsequences(variant, sf, consequence);
continue;
}
/*
* filter out fields we don't want to capture
*/
if (!vcfFieldsOfInterest.contains(key))
{
continue;
}
/*
* we extract values for other data which are allele-specific;
* these may be per alternate allele (INFO[key].Number = 'A')
* or per allele including reference (INFO[key].Number = 'R')
*/
VCFInfoHeaderLine infoHeader = header.getInfoHeaderLine(key);
if (infoHeader == null)
{
/*
* can't be sure what data belongs to this allele, so
* play safe and don't take any
*/
continue;
}
VCFHeaderLineCount number = infoHeader.getCountType();
int index = altAlelleIndex;
if (number == VCFHeaderLineCount.R)
{
/*
* one value per allele including reference, so bump index
* e.g. the 3rd value is for the 2nd alternate allele
*/
index++;
}
else if (number != VCFHeaderLineCount.A)
{
/*
* don't save other values as not allele-related
*/
continue;
}
/*
* take the index'th value
*/
String value = getAttributeValue(variant, key, index);
if (value != null && isValid(variant, key, value))
{
/*
* decode colon, semicolon, equals sign, percent sign, comma (only)
* as required by the VCF specification (para 1.2)
*/
value = StringUtils.urlDecode(value, VCF_ENCODABLE);
addFeatureAttribute(sf, key, value);
}
}
}
/**
* Answers true for '.', null, or an empty value, or if the INFO type is
* String. If the INFO type is Integer or Float, answers false if the value is
* not in valid format.
*
* @param variant
* @param infoId
* @param value
* @return
*/
protected boolean isValid(VariantContext variant, String infoId,
String value)
{
if (value == null || value.isEmpty() || NO_VALUE.equals(value))
{
return true;
}
VCFInfoHeaderLine infoHeader = header.getInfoHeaderLine(infoId);
if (infoHeader == null)
{
Console.error("Field " + infoId + " has no INFO header");
return false;
}
VCFHeaderLineType infoType = infoHeader.getType();
try
{
if (infoType == VCFHeaderLineType.Integer)
{
Integer.parseInt(value);
}
else if (infoType == VCFHeaderLineType.Float)
{
Float.parseFloat(value);
}
} catch (NumberFormatException e)
{
logInvalidValue(variant, infoId, value);
return false;
}
return true;
}
/**
* Logs an error message for malformed data; duplicate messages (same id and
* value) are not logged
*
* @param variant
* @param infoId
* @param value
*/
private void logInvalidValue(VariantContext variant, String infoId,
String value)
{
if (badData == null)
{
badData = new HashSet<>();
}
String token = infoId + ":" + value;
if (!badData.contains(token))
{
badData.add(token);
Console.error(String.format("Invalid VCF data at %s:%d %s=%s",
variant.getContig(), variant.getStart(), infoId, value));
}
}
/**
* Inspects CSQ data blocks (consequences) and adds attributes on the sequence
* feature.
*
* If myConsequence is not null, then this is the specific
* consequence data (pipe-delimited fields) that is for the current allele and
* transcript (sequence) being processed)
*
* @param variant
* @param sf
* @param myConsequence
*/
protected void addConsequences(VariantContext variant, SequenceFeature sf,
String myConsequence)
{
Object value = variant.getAttribute(CSQ_FIELD);
if (value == null || !(value instanceof List))
{
return;
}
List consequences = (List) value;
/*
* inspect CSQ consequences; restrict to the consequence
* associated with the current transcript (Feature)
*/
Map csqValues = new HashMap<>();
for (String consequence : consequences)
{
if (myConsequence == null || myConsequence.equals(consequence))
{
String[] csqFields = consequence.split(PIPE_REGEX);
/*
* inspect individual fields of this consequence, copying non-null
* values which are 'fields of interest'
*/
int i = 0;
for (String field : csqFields)
{
if (field != null && field.length() > 0)
{
String id = vepFieldsOfInterest.get(i);
if (id != null)
{
/*
* VCF spec requires encoding of special characters e.g. '='
* so decode them here before storing
*/
field = StringUtils.urlDecode(field, VCF_ENCODABLE);
csqValues.put(id, field);
}
}
i++;
}
}
}
if (!csqValues.isEmpty())
{
sf.setValue(CSQ_FIELD, csqValues);
}
}
/**
* A convenience method to complement a dna base and return the string value
* of its complement
*
* @param reference
* @return
*/
protected String complement(byte[] reference)
{
return String.valueOf(Dna.getComplement((char) reference[0]));
}
/**
* Determines the location of the query range (chromosome positions) in a
* different reference assembly.
*
* If the range is just a subregion of one for which we already have a mapping
* (for example, an exon sub-region of a gene), then the mapping is just
* computed arithmetically.
*
* Otherwise, calls the Ensembl REST service that maps from one assembly
* reference's coordinates to another's
*
* @param queryRange
* start-end chromosomal range in 'fromRef' coordinates
* @param chromosome
* @param species
* @param fromRef
* assembly reference for the query coordinates
* @param toRef
* assembly reference we wish to translate to
* @return the start-end range in 'toRef' coordinates
*/
protected int[] mapReferenceRange(int[] queryRange, String chromosome,
String species, String fromRef, String toRef)
{
/*
* first try shorcut of computing the mapping as a subregion of one
* we already have (e.g. for an exon, if we have the gene mapping)
*/
int[] mappedRange = findSubsumedRangeMapping(queryRange, chromosome,
species, fromRef, toRef);
if (mappedRange != null)
{
return mappedRange;
}
/*
* call (e.g.) http://rest.ensembl.org/map/human/GRCh38/17:45051610..45109016:1/GRCh37
*/
EnsemblMap mapper = new EnsemblMap();
int[] mapping = mapper.getAssemblyMapping(species, chromosome, fromRef,
toRef, queryRange);
if (mapping == null)
{
// mapping service failure
return null;
}
/*
* save mapping for possible future re-use
*/
String key = makeRangesKey(chromosome, species, fromRef, toRef);
if (!assemblyMappings.containsKey(key))
{
assemblyMappings.put(key, new HashMap());
}
assemblyMappings.get(key).put(queryRange, mapping);
return mapping;
}
/**
* If we already have a 1:1 contiguous mapping which subsumes the given query
* range, this method just calculates and returns the subset of that mapping,
* else it returns null. In practical terms, if a gene has a contiguous
* mapping between (for example) GRCh37 and GRCh38, then we assume that its
* subsidiary exons occupy unchanged relative positions, and just compute
* these as offsets, rather than do another lookup of the mapping.
*
* If in future these assumptions prove invalid (e.g. for bacterial dna?!),
* simply remove this method or let it always return null.
*
* Warning: many rapid calls to the /map service map result in a 429 overload
* error response
*
* @param queryRange
* @param chromosome
* @param species
* @param fromRef
* @param toRef
* @return
*/
protected int[] findSubsumedRangeMapping(int[] queryRange,
String chromosome, String species, String fromRef, String toRef)
{
String key = makeRangesKey(chromosome, species, fromRef, toRef);
if (assemblyMappings.containsKey(key))
{
Map mappedRanges = assemblyMappings.get(key);
for (Entry mappedRange : mappedRanges.entrySet())
{
int[] fromRange = mappedRange.getKey();
int[] toRange = mappedRange.getValue();
if (fromRange[1] - fromRange[0] == toRange[1] - toRange[0])
{
/*
* mapping is 1:1 in length, so we trust it to have no discontinuities
*/
if (MappingUtils.rangeContains(fromRange, queryRange))
{
/*
* fromRange subsumes our query range
*/
int offset = queryRange[0] - fromRange[0];
int mappedRangeFrom = toRange[0] + offset;
int mappedRangeTo = mappedRangeFrom
+ (queryRange[1] - queryRange[0]);
return new int[] { mappedRangeFrom, mappedRangeTo };
}
}
}
}
return null;
}
/**
* Transfers the sequence feature to the target sequence, locating its start
* and end range based on the mapping. Features which do not overlap the
* target sequence are ignored.
*
* @param sf
* @param targetSequence
* @param mapping
* mapping from the feature's coordinates to the target sequence
*/
protected void transferFeature(SequenceFeature sf,
SequenceI targetSequence, MapList mapping)
{
int[] mappedRange = mapping.locateInTo(sf.getBegin(), sf.getEnd());
if (mappedRange != null)
{
String group = sf.getFeatureGroup();
int newBegin = Math.min(mappedRange[0], mappedRange[1]);
int newEnd = Math.max(mappedRange[0], mappedRange[1]);
SequenceFeature copy = new SequenceFeature(sf, newBegin, newEnd,
group, sf.getScore());
targetSequence.addSequenceFeature(copy);
}
}
/**
* Formats a ranges map lookup key
*
* @param chromosome
* @param species
* @param fromRef
* @param toRef
* @return
*/
protected static String makeRangesKey(String chromosome, String species,
String fromRef, String toRef)
{
return species + EXCL + chromosome + EXCL + fromRef + EXCL + toRef;
}
}