1 package jalview.io.vcf;
3 import jalview.analysis.AlignmentUtils;
4 import jalview.analysis.Dna;
5 import jalview.api.AlignViewControllerGuiI;
6 import jalview.bin.Cache;
7 import jalview.datamodel.DBRefEntry;
8 import jalview.datamodel.GeneLociI;
9 import jalview.datamodel.Mapping;
10 import jalview.datamodel.SequenceFeature;
11 import jalview.datamodel.SequenceI;
12 import jalview.datamodel.features.FeatureAttributeType;
13 import jalview.datamodel.features.FeatureSource;
14 import jalview.datamodel.features.FeatureSources;
15 import jalview.ext.ensembl.EnsemblMap;
16 import jalview.ext.htsjdk.HtsContigDb;
17 import jalview.ext.htsjdk.VCFReader;
18 import jalview.io.gff.Gff3Helper;
19 import jalview.io.gff.SequenceOntologyI;
20 import jalview.util.MapList;
21 import jalview.util.MappingUtils;
22 import jalview.util.MessageManager;
25 import java.io.IOException;
26 import java.util.ArrayList;
27 import java.util.HashMap;
28 import java.util.List;
30 import java.util.Map.Entry;
31 import java.util.regex.Pattern;
32 import java.util.regex.PatternSyntaxException;
34 import htsjdk.samtools.SAMException;
35 import htsjdk.samtools.SAMSequenceDictionary;
36 import htsjdk.samtools.SAMSequenceRecord;
37 import htsjdk.samtools.util.CloseableIterator;
38 import htsjdk.variant.variantcontext.Allele;
39 import htsjdk.variant.variantcontext.VariantContext;
40 import htsjdk.variant.vcf.VCFHeader;
41 import htsjdk.variant.vcf.VCFHeaderLine;
42 import htsjdk.variant.vcf.VCFHeaderLineCount;
43 import htsjdk.variant.vcf.VCFHeaderLineType;
44 import htsjdk.variant.vcf.VCFInfoHeaderLine;
47 * A class to read VCF data (using the htsjdk) and add variants as sequence
48 * features on dna and any related protein product sequences
52 public class VCFLoader
54 private static final String DEFAULT_SPECIES = "homo_sapiens";
57 * A class to model the mapping from sequence to VCF coordinates. Cases include
59 * <li>a direct 1:1 mapping where the sequence is one of the VCF contigs</li>
60 * <li>a mapping of sequence to chromosomal coordinates, where sequence and VCF
61 * use the same reference assembly</li>
62 * <li>a modified mapping of sequence to chromosomal coordinates, where sequence
63 * and VCF use different reference assembles</li>
68 final String chromosome;
72 VCFMap(String chr, MapList m)
79 public String toString()
81 return chromosome + ":" + map.toString();
86 * Lookup keys, and default values, for Preference entries that describe
87 * patterns for VCF and VEP fields to capture
89 private static final String VEP_FIELDS_PREF = "VEP_FIELDS";
91 private static final String VCF_FIELDS_PREF = "VCF_FIELDS";
93 private static final String DEFAULT_VCF_FIELDS = ".*";
95 private static final String DEFAULT_VEP_FIELDS = ".*";// "Allele,Consequence,IMPACT,SWISSPROT,SIFT,PolyPhen,CLIN_SIG";
98 * Lookup keys, and default values, for Preference entries that give
99 * mappings from tokens in the 'reference' header to species or assembly
101 private static final String VCF_ASSEMBLY = "VCF_ASSEMBLY";
103 private static final String DEFAULT_VCF_ASSEMBLY = "assembly19=GRCh37,hs37=GRCh37,grch37=GRCh37,grch38=GRCh38";
105 private static final String VCF_SPECIES = "VCF_SPECIES"; // default is human
107 private static final String DEFAULT_REFERENCE = "grch37"; // fallback default is human GRCh37
110 * keys to fields of VEP CSQ consequence data
111 * see https://www.ensembl.org/info/docs/tools/vep/vep_formats.html
113 private static final String CSQ_CONSEQUENCE_KEY = "Consequence";
114 private static final String CSQ_ALLELE_KEY = "Allele";
115 private static final String CSQ_ALLELE_NUM_KEY = "ALLELE_NUM"; // 0 (ref), 1...
116 private static final String CSQ_FEATURE_KEY = "Feature"; // Ensembl stable id
119 * default VCF INFO key for VEP consequence data
120 * NB this can be overridden running VEP with --vcf_info_field
121 * - we don't handle this case (require identifier to be CSQ)
123 private static final String CSQ_FIELD = "CSQ";
126 * separator for fields in consequence data is '|'
128 private static final String PIPE_REGEX = "\\|";
131 * delimiter that separates multiple consequence data blocks
133 private static final String COMMA = ",";
136 * the feature group assigned to a VCF variant in Jalview
138 private static final String FEATURE_GROUP_VCF = "VCF";
141 * internal delimiter used to build keys for assemblyMappings
144 private static final String EXCL = "!";
147 * the VCF file we are processing
149 protected String vcfFilePath;
152 * mappings between VCF and sequence reference assembly regions, as
153 * key = "species!chromosome!fromAssembly!toAssembly
154 * value = Map{fromRange, toRange}
156 private Map<String, Map<int[], int[]>> assemblyMappings;
158 private VCFReader reader;
161 * holds details of the VCF header lines (metadata)
163 private VCFHeader header;
166 * species (as a valid Ensembl term) the VCF is for
168 private String vcfSpecies;
171 * genome assembly version (as a valid Ensembl identifier) the VCF is for
173 private String vcfAssembly;
176 * a Dictionary of contigs (if present) referenced in the VCF file
178 private SAMSequenceDictionary dictionary;
181 * the position (0...) of field in each block of
182 * CSQ (consequence) data (if declared in the VCF INFO header for CSQ)
183 * see http://www.ensembl.org/info/docs/tools/vep/vep_formats.html
185 private int csqConsequenceFieldIndex = -1;
186 private int csqAlleleFieldIndex = -1;
187 private int csqAlleleNumberFieldIndex = -1;
188 private int csqFeatureFieldIndex = -1;
190 // todo the same fields for SnpEff ANN data if wanted
191 // see http://snpeff.sourceforge.net/SnpEff_manual.html#input
194 * a unique identifier under which to save metadata about feature
195 * attributes (selected INFO field data)
197 private String sourceId;
200 * The INFO IDs of data that is both present in the VCF file, and
201 * also matched by any filters for data of interest
203 List<String> vcfFieldsOfInterest;
206 * The field offsets and identifiers for VEP (CSQ) data that is both present
207 * in the VCF file, and also matched by any filters for data of interest
208 * for example 0 -> Allele, 1 -> Consequence, ..., 36 -> SIFT, ...
210 Map<Integer, String> vepFieldsOfInterest;
213 * Constructor given a VCF file
217 public VCFLoader(String vcfFile)
222 } catch (IOException e)
224 System.err.println("Error opening VCF file: " + e.getMessage());
227 // map of species!chromosome!fromAssembly!toAssembly to {fromRange, toRange}
228 assemblyMappings = new HashMap<>();
232 * Starts a new thread to query and load VCF variant data on to the given
235 * This method is not thread safe - concurrent threads should use separate
236 * instances of this class.
241 public void loadVCF(SequenceI[] seqs, final AlignViewControllerGuiI gui)
245 gui.setStatus(MessageManager.getString("label.searching_vcf"));
253 VCFLoader.this.doLoad(seqs, gui);
259 * Reads the specified contig sequence and adds its VCF variants to it
262 * the id of a single sequence (contig) to load
265 public SequenceI loadVCFContig(String contig)
267 VCFHeaderLine headerLine = header.getOtherHeaderLine(VCFHeader.REFERENCE_KEY);
268 if (headerLine == null)
270 Cache.log.error("VCF reference header not found");
273 String ref = headerLine.getValue();
274 if (ref.startsWith("file://"))
276 ref = ref.substring(7);
278 setSpeciesAndAssembly(ref);
280 SequenceI seq = null;
281 File dbFile = new File(ref);
285 HtsContigDb db = new HtsContigDb("", dbFile);
286 seq = db.getSequenceProxy(contig);
287 loadSequenceVCF(seq);
292 Cache.log.error("VCF reference not found: " + ref);
299 * Loads VCF on to one or more sequences
303 * optional callback handler for messages
305 protected void doLoad(SequenceI[] seqs, AlignViewControllerGuiI gui)
309 VCFHeaderLine ref = header
310 .getOtherHeaderLine(VCFHeader.REFERENCE_KEY);
311 String reference = ref == null ? null : ref.getValue();
313 setSpeciesAndAssembly(reference);
319 * query for VCF overlapping each sequence in turn
321 for (SequenceI seq : seqs)
323 int added = loadSequenceVCF(seq);
328 transferAddedFeatures(seq);
333 String msg = MessageManager.formatMessage("label.added_vcf",
336 if (gui.getFeatureSettingsUI() != null)
338 gui.getFeatureSettingsUI().discoverAllFeatureData();
341 } catch (Throwable e)
343 System.err.println("Error processing VCF: " + e.getMessage());
347 gui.setStatus("Error occurred - see console for details");
356 } catch (IOException e)
367 * Attempts to determine and save the species and genome assembly version to
368 * which the VCF data applies. This may be done by parsing the {@code reference}
369 * header line, configured in a property file, or (potentially) confirmed
370 * interactively by the user.
372 * The saved values should be identifiers valid for Ensembl's REST service
373 * {@code map} endpoint, so they can be used (if necessary) to retrieve the
374 * mapping between VCF coordinates and sequence coordinates.
377 * @see https://rest.ensembl.org/documentation/info/assembly_map
378 * @see https://rest.ensembl.org/info/assembly/human?content-type=text/xml
379 * @see https://rest.ensembl.org/info/species?content-type=text/xml
381 protected void setSpeciesAndAssembly(String reference)
383 if (reference == null)
385 Cache.log.error("No VCF ##reference found, defaulting to "
386 + DEFAULT_REFERENCE + ":" + DEFAULT_SPECIES);
387 reference = DEFAULT_REFERENCE; // default to GRCh37 if not specified
389 reference = reference.toLowerCase();
392 * for a non-human species, or other assembly identifier,
393 * specify as a Jalview property file entry e.g.
394 * VCF_ASSEMBLY = hs37=GRCh37,assembly19=GRCh37
395 * VCF_SPECIES = c_elegans=celegans
396 * to map a token in the reference header to a value
398 String prop = Cache.getDefault(VCF_ASSEMBLY, DEFAULT_VCF_ASSEMBLY);
399 for (String token : prop.split(","))
401 String[] tokens = token.split("=");
402 if (tokens.length == 2)
404 if (reference.contains(tokens[0].trim().toLowerCase()))
406 vcfAssembly = tokens[1].trim();
412 vcfSpecies = DEFAULT_SPECIES;
413 prop = Cache.getProperty(VCF_SPECIES);
416 for (String token : prop.split(","))
418 String[] tokens = token.split("=");
419 if (tokens.length == 2)
421 if (reference.contains(tokens[0].trim().toLowerCase()))
423 vcfSpecies = tokens[1].trim();
432 * Opens the VCF file and parses header data
435 * @throws IOException
437 private void initialise(String filePath) throws IOException
439 vcfFilePath = filePath;
441 reader = new VCFReader(filePath);
443 header = reader.getFileHeader();
447 dictionary = header.getSequenceDictionary();
448 } catch (SAMException e)
450 // ignore - thrown if any contig line lacks length info
455 saveMetadata(sourceId);
458 * get offset of CSQ ALLELE_NUM and Feature if declared
464 * Reads metadata (such as INFO field descriptions and datatypes) and saves
465 * them for future reference
469 void saveMetadata(String theSourceId)
471 List<Pattern> vcfFieldPatterns = getFieldMatchers(VCF_FIELDS_PREF,
473 vcfFieldsOfInterest = new ArrayList<>();
475 FeatureSource metadata = new FeatureSource(theSourceId);
477 for (VCFInfoHeaderLine info : header.getInfoHeaderLines())
479 String attributeId = info.getID();
480 String desc = info.getDescription();
481 VCFHeaderLineType type = info.getType();
482 FeatureAttributeType attType = null;
486 attType = FeatureAttributeType.Character;
489 attType = FeatureAttributeType.Flag;
492 attType = FeatureAttributeType.Float;
495 attType = FeatureAttributeType.Integer;
498 attType = FeatureAttributeType.String;
501 metadata.setAttributeName(attributeId, desc);
502 metadata.setAttributeType(attributeId, attType);
504 if (isFieldWanted(attributeId, vcfFieldPatterns))
506 vcfFieldsOfInterest.add(attributeId);
510 FeatureSources.getInstance().addSource(theSourceId, metadata);
514 * Answers true if the field id is matched by any of the filter patterns, else
515 * false. Matching is against regular expression patterns, and is not
522 private boolean isFieldWanted(String id, List<Pattern> filters)
524 for (Pattern p : filters)
526 if (p.matcher(id.toUpperCase()).matches())
535 * Records 'wanted' fields defined in the CSQ INFO header (if there is one).
536 * Also records the position of selected fields (Allele, ALLELE_NUM, Feature)
537 * required for processing.
539 * CSQ fields are declared in the CSQ INFO Description e.g.
541 * Description="Consequence ...from ... VEP. Format: Allele|Consequence|...
543 protected void parseCsqHeader()
545 List<Pattern> vepFieldFilters = getFieldMatchers(VEP_FIELDS_PREF,
547 vepFieldsOfInterest = new HashMap<>();
549 VCFInfoHeaderLine csqInfo = header.getInfoHeaderLine(CSQ_FIELD);
556 * parse out the pipe-separated list of CSQ fields; we assume here that
557 * these form the last part of the description, and contain no spaces
559 String desc = csqInfo.getDescription();
560 int spacePos = desc.lastIndexOf(" ");
561 desc = desc.substring(spacePos + 1);
565 String[] format = desc.split(PIPE_REGEX);
567 for (String field : format)
569 if (CSQ_CONSEQUENCE_KEY.equals(field))
571 csqConsequenceFieldIndex = index;
573 if (CSQ_ALLELE_NUM_KEY.equals(field))
575 csqAlleleNumberFieldIndex = index;
577 if (CSQ_ALLELE_KEY.equals(field))
579 csqAlleleFieldIndex = index;
581 if (CSQ_FEATURE_KEY.equals(field))
583 csqFeatureFieldIndex = index;
586 if (isFieldWanted(field, vepFieldFilters))
588 vepFieldsOfInterest.put(index, field);
597 * Reads the Preference value for the given key, with default specified if no
598 * preference set. The value is interpreted as a comma-separated list of
599 * regular expressions, and converted into a list of compiled patterns ready
600 * for matching. Patterns are forced to upper-case for non-case-sensitive
603 * This supports user-defined filters for fields of interest to capture while
604 * processing data. For example, VCF_FIELDS = AF,AC* would mean that VCF INFO
605 * fields with an ID of AF, or starting with AC, would be matched.
611 private List<Pattern> getFieldMatchers(String key, String def)
613 String pref = Cache.getDefault(key, def);
614 List<Pattern> patterns = new ArrayList<>();
615 String[] tokens = pref.split(",");
616 for (String token : tokens)
620 patterns.add(Pattern.compile(token.toUpperCase()));
621 } catch (PatternSyntaxException e)
623 System.err.println("Invalid pattern ignored: " + token);
630 * Transfers VCF features to sequences to which this sequence has a mapping.
631 * If the mapping is 3:1, computes peptide variants from nucleotide variants.
635 protected void transferAddedFeatures(SequenceI seq)
637 DBRefEntry[] dbrefs = seq.getDBRefs();
642 for (DBRefEntry dbref : dbrefs)
644 Mapping mapping = dbref.getMap();
645 if (mapping == null || mapping.getTo() == null)
650 SequenceI mapTo = mapping.getTo();
651 MapList map = mapping.getMap();
652 if (map.getFromRatio() == 3)
655 * dna-to-peptide product mapping
657 AlignmentUtils.computeProteinFeatures(seq, mapTo, map);
662 * nucleotide-to-nucleotide mapping e.g. transcript to CDS
664 List<SequenceFeature> features = seq.getFeatures()
665 .getPositionalFeatures(SequenceOntologyI.SEQUENCE_VARIANT);
666 for (SequenceFeature sf : features)
668 if (FEATURE_GROUP_VCF.equals(sf.getFeatureGroup()))
670 transferFeature(sf, mapTo, map);
678 * Tries to add overlapping variants read from a VCF file to the given sequence,
679 * and returns the number of variant features added
684 protected int loadSequenceVCF(SequenceI seq)
686 VCFMap vcfMap = getVcfMap(seq);
693 * work with the dataset sequence here
695 SequenceI dss = seq.getDatasetSequence();
700 return addVcfVariants(dss, vcfMap);
704 * Answers a map from sequence coordinates to VCF chromosome ranges
709 private VCFMap getVcfMap(SequenceI seq)
712 * simplest case: sequence has id and length matching a VCF contig
714 VCFMap vcfMap = null;
715 if (dictionary != null)
717 vcfMap = getContigMap(seq);
725 * otherwise, map to VCF from chromosomal coordinates
726 * of the sequence (if known)
728 GeneLociI seqCoords = seq.getGeneLoci();
729 if (seqCoords == null)
731 Cache.log.warn(String.format(
732 "Can't query VCF for %s as chromosome coordinates not known",
737 String species = seqCoords.getSpeciesId();
738 String chromosome = seqCoords.getChromosomeId();
739 String seqRef = seqCoords.getAssemblyId();
740 MapList map = seqCoords.getMapping();
742 // note this requires the configured species to match that
743 // returned with the Ensembl sequence; todo: support aliases?
744 if (!vcfSpecies.equalsIgnoreCase(species))
746 Cache.log.warn("No VCF loaded to " + seq.getName()
747 + " as species not matched");
751 if (seqRef.equalsIgnoreCase(vcfAssembly))
753 return new VCFMap(chromosome, map);
757 * VCF data has a different reference assembly to the sequence:
758 * query Ensembl to map chromosomal coordinates from sequence to VCF
760 List<int[]> toVcfRanges = new ArrayList<>();
761 List<int[]> fromSequenceRanges = new ArrayList<>();
763 for (int[] range : map.getToRanges())
765 int[] fromRange = map.locateInFrom(range[0], range[1]);
766 if (fromRange == null)
772 int[] newRange = mapReferenceRange(range, chromosome, "human", seqRef,
774 if (newRange == null)
777 String.format("Failed to map %s:%s:%s:%d:%d to %s", species,
778 chromosome, seqRef, range[0], range[1],
784 toVcfRanges.add(newRange);
785 fromSequenceRanges.add(fromRange);
789 return new VCFMap(chromosome,
790 new MapList(fromSequenceRanges, toVcfRanges, 1, 1));
794 * If the sequence id matches a contig declared in the VCF file, and the
795 * sequence length matches the contig length, then returns a 1:1 map of the
796 * sequence to the contig, else returns null
801 private VCFMap getContigMap(SequenceI seq)
803 String id = seq.getName();
804 SAMSequenceRecord contig = dictionary.getSequence(id);
807 int len = seq.getLength();
808 if (len == contig.getSequenceLength())
810 MapList map = new MapList(new int[] { 1, len },
813 return new VCFMap(id, map);
820 * Queries the VCF reader for any variants that overlap the mapped chromosome
821 * ranges of the sequence, and adds as variant features. Returns the number of
822 * overlapping variants found.
826 * mapping from sequence to VCF coordinates
829 protected int addVcfVariants(SequenceI seq, VCFMap map)
831 boolean forwardStrand = map.map.isToForwardStrand();
834 * query the VCF for overlaps of each contiguous chromosomal region
838 for (int[] range : map.map.getToRanges())
840 int vcfStart = Math.min(range[0], range[1]);
841 int vcfEnd = Math.max(range[0], range[1]);
842 CloseableIterator<VariantContext> variants = reader
843 .query(map.chromosome, vcfStart, vcfEnd);
844 while (variants.hasNext())
846 VariantContext variant = variants.next();
848 int[] featureRange = map.map.locateInFrom(variant.getStart(),
851 if (featureRange != null)
853 int featureStart = Math.min(featureRange[0], featureRange[1]);
854 int featureEnd = Math.max(featureRange[0], featureRange[1]);
855 count += addAlleleFeatures(seq, variant, featureStart, featureEnd,
866 * A convenience method to get an attribute value for an alternate allele
869 * @param attributeName
873 protected String getAttributeValue(VariantContext variant,
874 String attributeName, int alleleIndex)
876 Object att = variant.getAttribute(attributeName);
878 if (att instanceof String)
882 else if (att instanceof ArrayList)
884 return ((List<String>) att).get(alleleIndex);
891 * Adds one variant feature for each allele in the VCF variant record, and
892 * returns the number of features added.
896 * @param featureStart
898 * @param forwardStrand
901 protected int addAlleleFeatures(SequenceI seq, VariantContext variant,
902 int featureStart, int featureEnd, boolean forwardStrand)
907 * Javadoc says getAlternateAlleles() imposes no order on the list returned
908 * so we proceed defensively to get them in strict order
910 int altAlleleCount = variant.getAlternateAlleles().size();
911 for (int i = 0; i < altAlleleCount; i++)
913 added += addAlleleFeature(seq, variant, i, featureStart, featureEnd,
920 * Inspects one allele and attempts to add a variant feature for it to the
921 * sequence. The additional data associated with this allele is extracted to
922 * store in the feature's key-value map. Answers the number of features added (0
927 * @param altAlleleIndex
929 * @param featureStart
931 * @param forwardStrand
934 protected int addAlleleFeature(SequenceI seq, VariantContext variant,
935 int altAlleleIndex, int featureStart, int featureEnd,
936 boolean forwardStrand)
938 String reference = variant.getReference().getBaseString();
939 Allele alt = variant.getAlternateAllele(altAlleleIndex);
940 String allele = alt.getBaseString();
943 * insertion after a genomic base, if on reverse strand, has to be
944 * converted to insertion of complement after the preceding position
946 int referenceLength = reference.length();
947 if (!forwardStrand && allele.length() > referenceLength
948 && allele.startsWith(reference))
950 featureStart -= referenceLength;
951 featureEnd = featureStart;
952 char insertAfter = seq.getCharAt(featureStart - seq.getStart());
953 reference = Dna.reverseComplement(String.valueOf(insertAfter));
954 allele = allele.substring(referenceLength) + reference;
958 * build the ref,alt allele description e.g. "G,A", using the base
959 * complement if the sequence is on the reverse strand
961 StringBuilder sb = new StringBuilder();
962 sb.append(forwardStrand ? reference : Dna.reverseComplement(reference));
964 sb.append(forwardStrand ? allele : Dna.reverseComplement(allele));
965 String alleles = sb.toString(); // e.g. G,A
968 * pick out the consequence data (if any) that is for the current allele
969 * and feature (transcript) that matches the current sequence
971 String consequence = getConsequenceForAlleleAndFeature(variant, CSQ_FIELD,
972 altAlleleIndex, csqAlleleFieldIndex,
973 csqAlleleNumberFieldIndex, seq.getName().toLowerCase(),
974 csqFeatureFieldIndex);
977 * pick out the ontology term for the consequence type
979 String type = SequenceOntologyI.SEQUENCE_VARIANT;
980 if (consequence != null)
982 type = getOntologyTerm(consequence);
985 SequenceFeature sf = new SequenceFeature(type, alleles, featureStart,
986 featureEnd, FEATURE_GROUP_VCF);
987 sf.setSource(sourceId);
989 sf.setValue(Gff3Helper.ALLELES, alleles);
991 addAlleleProperties(variant, sf, altAlleleIndex, consequence);
993 seq.addSequenceFeature(sf);
999 * Determines the Sequence Ontology term to use for the variant feature type in
1000 * Jalview. The default is 'sequence_variant', but a more specific term is used
1003 * <li>VEP (or SnpEff) Consequence annotation is included in the VCF</li>
1004 * <li>sequence id can be matched to VEP Feature (or SnpEff Feature_ID)</li>
1007 * @param consequence
1009 * @see http://www.sequenceontology.org/browser/current_svn/term/SO:0001060
1011 String getOntologyTerm(String consequence)
1013 String type = SequenceOntologyI.SEQUENCE_VARIANT;
1016 * could we associate Consequence data with this allele and feature (transcript)?
1017 * if so, prefer the consequence term from that data
1019 if (csqAlleleFieldIndex == -1) // && snpEffAlleleFieldIndex == -1
1022 * no Consequence data so we can't refine the ontology term
1027 if (consequence != null)
1029 String[] csqFields = consequence.split(PIPE_REGEX);
1030 if (csqFields.length > csqConsequenceFieldIndex)
1032 type = csqFields[csqConsequenceFieldIndex];
1037 // todo the same for SnpEff consequence data matching if wanted
1041 * if of the form (e.g.) missense_variant&splice_region_variant,
1042 * just take the first ('most severe') consequence
1046 int pos = type.indexOf('&');
1049 type = type.substring(0, pos);
1056 * Returns matched consequence data if it can be found, else null.
1058 * <li>inspects the VCF data for key 'vcfInfoId'</li>
1059 * <li>splits this on comma (to distinct consequences)</li>
1060 * <li>returns the first consequence (if any) where</li>
1062 * <li>the allele matches the altAlleleIndex'th allele of variant</li>
1063 * <li>the feature matches the sequence name (e.g. transcript id)</li>
1066 * If matched, the consequence is returned (as pipe-delimited fields).
1070 * @param altAlleleIndex
1071 * @param alleleFieldIndex
1072 * @param alleleNumberFieldIndex
1074 * @param featureFieldIndex
1077 private String getConsequenceForAlleleAndFeature(VariantContext variant,
1078 String vcfInfoId, int altAlleleIndex, int alleleFieldIndex,
1079 int alleleNumberFieldIndex,
1080 String seqName, int featureFieldIndex)
1082 if (alleleFieldIndex == -1 || featureFieldIndex == -1)
1086 Object value = variant.getAttribute(vcfInfoId);
1088 if (value == null || !(value instanceof List<?>))
1094 * inspect each consequence in turn (comma-separated blocks
1095 * extracted by htsjdk)
1097 List<String> consequences = (List<String>) value;
1099 for (String consequence : consequences)
1101 String[] csqFields = consequence.split(PIPE_REGEX);
1102 if (csqFields.length > featureFieldIndex)
1104 String featureIdentifier = csqFields[featureFieldIndex];
1105 if (featureIdentifier.length() > 4
1106 && seqName.indexOf(featureIdentifier.toLowerCase()) > -1)
1109 * feature (transcript) matched - now check for allele match
1111 if (matchAllele(variant, altAlleleIndex, csqFields,
1112 alleleFieldIndex, alleleNumberFieldIndex))
1122 private boolean matchAllele(VariantContext variant, int altAlleleIndex,
1123 String[] csqFields, int alleleFieldIndex,
1124 int alleleNumberFieldIndex)
1127 * if ALLELE_NUM is present, it must match altAlleleIndex
1128 * NB first alternate allele is 1 for ALLELE_NUM, 0 for altAlleleIndex
1130 if (alleleNumberFieldIndex > -1)
1132 if (csqFields.length <= alleleNumberFieldIndex)
1136 String alleleNum = csqFields[alleleNumberFieldIndex];
1137 return String.valueOf(altAlleleIndex + 1).equals(alleleNum);
1141 * else consequence allele must match variant allele
1143 if (alleleFieldIndex > -1 && csqFields.length > alleleFieldIndex)
1145 String csqAllele = csqFields[alleleFieldIndex];
1146 String vcfAllele = variant.getAlternateAllele(altAlleleIndex)
1148 return csqAllele.equals(vcfAllele);
1154 * Add any allele-specific VCF key-value data to the sequence feature
1158 * @param altAlelleIndex
1160 * @param consequence
1161 * if not null, the consequence specific to this sequence (transcript
1162 * feature) and allele
1164 protected void addAlleleProperties(VariantContext variant,
1165 SequenceFeature sf, final int altAlelleIndex, String consequence)
1167 Map<String, Object> atts = variant.getAttributes();
1169 for (Entry<String, Object> att : atts.entrySet())
1171 String key = att.getKey();
1174 * extract Consequence data (if present) that we are able to
1175 * associated with the allele for this variant feature
1177 if (CSQ_FIELD.equals(key))
1179 addConsequences(variant, sf, consequence);
1184 * filter out fields we don't want to capture
1186 if (!vcfFieldsOfInterest.contains(key))
1192 * filter out fields we don't want to capture
1194 if (!vcfFieldsOfInterest.contains(key))
1200 * we extract values for other data which are allele-specific;
1201 * these may be per alternate allele (INFO[key].Number = 'A')
1202 * or per allele including reference (INFO[key].Number = 'R')
1204 VCFInfoHeaderLine infoHeader = header.getInfoHeaderLine(key);
1205 if (infoHeader == null)
1208 * can't be sure what data belongs to this allele, so
1209 * play safe and don't take any
1214 VCFHeaderLineCount number = infoHeader.getCountType();
1215 int index = altAlelleIndex;
1216 if (number == VCFHeaderLineCount.R)
1219 * one value per allele including reference, so bump index
1220 * e.g. the 3rd value is for the 2nd alternate allele
1224 else if (number != VCFHeaderLineCount.A)
1227 * don't save other values as not allele-related
1233 * take the index'th value
1235 String value = getAttributeValue(variant, key, index);
1238 sf.setValue(key, value);
1244 * Inspects CSQ data blocks (consequences) and adds attributes on the sequence
1247 * If <code>myConsequence</code> is not null, then this is the specific
1248 * consequence data (pipe-delimited fields) that is for the current allele and
1249 * transcript (sequence) being processed)
1253 * @param myConsequence
1255 protected void addConsequences(VariantContext variant, SequenceFeature sf,
1256 String myConsequence)
1258 Object value = variant.getAttribute(CSQ_FIELD);
1260 if (value == null || !(value instanceof List<?>))
1265 List<String> consequences = (List<String>) value;
1268 * inspect CSQ consequences; restrict to the consequence
1269 * associated with the current transcript (Feature)
1271 Map<String, String> csqValues = new HashMap<>();
1273 for (String consequence : consequences)
1275 if (myConsequence == null || myConsequence.equals(consequence))
1277 String[] csqFields = consequence.split(PIPE_REGEX);
1280 * inspect individual fields of this consequence, copying non-null
1281 * values which are 'fields of interest'
1284 for (String field : csqFields)
1286 if (field != null && field.length() > 0)
1288 String id = vepFieldsOfInterest.get(i);
1291 csqValues.put(id, field);
1299 if (!csqValues.isEmpty())
1301 sf.setValue(CSQ_FIELD, csqValues);
1306 * A convenience method to complement a dna base and return the string value
1312 protected String complement(byte[] reference)
1314 return String.valueOf(Dna.getComplement((char) reference[0]));
1318 * Determines the location of the query range (chromosome positions) in a
1319 * different reference assembly.
1321 * If the range is just a subregion of one for which we already have a mapping
1322 * (for example, an exon sub-region of a gene), then the mapping is just
1323 * computed arithmetically.
1325 * Otherwise, calls the Ensembl REST service that maps from one assembly
1326 * reference's coordinates to another's
1329 * start-end chromosomal range in 'fromRef' coordinates
1333 * assembly reference for the query coordinates
1335 * assembly reference we wish to translate to
1336 * @return the start-end range in 'toRef' coordinates
1338 protected int[] mapReferenceRange(int[] queryRange, String chromosome,
1339 String species, String fromRef, String toRef)
1342 * first try shorcut of computing the mapping as a subregion of one
1343 * we already have (e.g. for an exon, if we have the gene mapping)
1345 int[] mappedRange = findSubsumedRangeMapping(queryRange, chromosome,
1346 species, fromRef, toRef);
1347 if (mappedRange != null)
1353 * call (e.g.) http://rest.ensembl.org/map/human/GRCh38/17:45051610..45109016:1/GRCh37
1355 EnsemblMap mapper = new EnsemblMap();
1356 int[] mapping = mapper.getAssemblyMapping(species, chromosome, fromRef,
1359 if (mapping == null)
1361 // mapping service failure
1366 * save mapping for possible future re-use
1368 String key = makeRangesKey(chromosome, species, fromRef, toRef);
1369 if (!assemblyMappings.containsKey(key))
1371 assemblyMappings.put(key, new HashMap<int[], int[]>());
1374 assemblyMappings.get(key).put(queryRange, mapping);
1380 * If we already have a 1:1 contiguous mapping which subsumes the given query
1381 * range, this method just calculates and returns the subset of that mapping,
1382 * else it returns null. In practical terms, if a gene has a contiguous
1383 * mapping between (for example) GRCh37 and GRCh38, then we assume that its
1384 * subsidiary exons occupy unchanged relative positions, and just compute
1385 * these as offsets, rather than do another lookup of the mapping.
1387 * If in future these assumptions prove invalid (e.g. for bacterial dna?!),
1388 * simply remove this method or let it always return null.
1390 * Warning: many rapid calls to the /map service map result in a 429 overload
1400 protected int[] findSubsumedRangeMapping(int[] queryRange, String chromosome,
1401 String species, String fromRef, String toRef)
1403 String key = makeRangesKey(chromosome, species, fromRef, toRef);
1404 if (assemblyMappings.containsKey(key))
1406 Map<int[], int[]> mappedRanges = assemblyMappings.get(key);
1407 for (Entry<int[], int[]> mappedRange : mappedRanges.entrySet())
1409 int[] fromRange = mappedRange.getKey();
1410 int[] toRange = mappedRange.getValue();
1411 if (fromRange[1] - fromRange[0] == toRange[1] - toRange[0])
1414 * mapping is 1:1 in length, so we trust it to have no discontinuities
1416 if (MappingUtils.rangeContains(fromRange, queryRange))
1419 * fromRange subsumes our query range
1421 int offset = queryRange[0] - fromRange[0];
1422 int mappedRangeFrom = toRange[0] + offset;
1423 int mappedRangeTo = mappedRangeFrom + (queryRange[1] - queryRange[0]);
1424 return new int[] { mappedRangeFrom, mappedRangeTo };
1433 * Transfers the sequence feature to the target sequence, locating its start
1434 * and end range based on the mapping. Features which do not overlap the
1435 * target sequence are ignored.
1438 * @param targetSequence
1440 * mapping from the feature's coordinates to the target sequence
1442 protected void transferFeature(SequenceFeature sf,
1443 SequenceI targetSequence, MapList mapping)
1445 int[] mappedRange = mapping.locateInTo(sf.getBegin(), sf.getEnd());
1447 if (mappedRange != null)
1449 String group = sf.getFeatureGroup();
1450 int newBegin = Math.min(mappedRange[0], mappedRange[1]);
1451 int newEnd = Math.max(mappedRange[0], mappedRange[1]);
1452 SequenceFeature copy = new SequenceFeature(sf, newBegin, newEnd,
1453 group, sf.getScore());
1454 targetSequence.addSequenceFeature(copy);
1459 * Formats a ranges map lookup key
1467 protected static String makeRangesKey(String chromosome, String species,
1468 String fromRef, String toRef)
1470 return species + EXCL + chromosome + EXCL + fromRef + EXCL