1. Project Clover database Fri Dec 6 2024 13:47:14 GMT
  2. Package jalview.io.vcf

File VCFLoader.java

 

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Classes

Class
Line #
Actions
VCFLoader 79 405 151
0.770%
VCFLoader.VCFMap 109 3 2
0.660%
 

Contributing tests

This file is covered by 4 tests. .

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1    /*
2    * Jalview - A Sequence Alignment Editor and Viewer ($$Version-Rel$$)
3    * Copyright (C) $$Year-Rel$$ The Jalview Authors
4    *
5    * This file is part of Jalview.
6    *
7    * Jalview is free software: you can redistribute it and/or
8    * modify it under the terms of the GNU General Public License
9    * as published by the Free Software Foundation, either version 3
10    * of the License, or (at your option) any later version.
11    *
12    * Jalview is distributed in the hope that it will be useful, but
13    * WITHOUT ANY WARRANTY; without even the implied warranty
14    * of MERCHANTABILITY or FITNESS FOR A PARTICULAR
15    * PURPOSE. See the GNU General Public License for more details.
16    *
17    * You should have received a copy of the GNU General Public License
18    * along with Jalview. If not, see <http://www.gnu.org/licenses/>.
19    * The Jalview Authors are detailed in the 'AUTHORS' file.
20    */
21    package jalview.io.vcf;
22   
23    import java.util.Locale;
24   
25    import java.io.File;
26    import java.io.IOException;
27    import java.util.ArrayList;
28    import java.util.HashMap;
29    import java.util.HashSet;
30    import java.util.Iterator;
31    import java.util.List;
32    import java.util.Map;
33    import java.util.Map.Entry;
34    import java.util.Set;
35    import java.util.regex.Pattern;
36    import java.util.regex.PatternSyntaxException;
37   
38    import htsjdk.samtools.SAMException;
39    import htsjdk.samtools.SAMSequenceDictionary;
40    import htsjdk.samtools.SAMSequenceRecord;
41    import htsjdk.samtools.util.CloseableIterator;
42    import htsjdk.tribble.TribbleException;
43    import htsjdk.variant.variantcontext.Allele;
44    import htsjdk.variant.variantcontext.VariantContext;
45    import htsjdk.variant.vcf.VCFConstants;
46    import htsjdk.variant.vcf.VCFHeader;
47    import htsjdk.variant.vcf.VCFHeaderLine;
48    import htsjdk.variant.vcf.VCFHeaderLineCount;
49    import htsjdk.variant.vcf.VCFHeaderLineType;
50    import htsjdk.variant.vcf.VCFInfoHeaderLine;
51    import jalview.analysis.Dna;
52    import jalview.api.AlignViewControllerGuiI;
53    import jalview.bin.Cache;
54    import jalview.bin.Console;
55    import jalview.datamodel.DBRefEntry;
56    import jalview.datamodel.GeneLociI;
57    import jalview.datamodel.Mapping;
58    import jalview.datamodel.SequenceFeature;
59    import jalview.datamodel.SequenceI;
60    import jalview.datamodel.features.FeatureAttributeType;
61    import jalview.datamodel.features.FeatureSource;
62    import jalview.datamodel.features.FeatureSources;
63    import jalview.ext.ensembl.EnsemblMap;
64    import jalview.ext.htsjdk.HtsContigDb;
65    import jalview.ext.htsjdk.VCFReader;
66    import jalview.io.gff.Gff3Helper;
67    import jalview.io.gff.SequenceOntologyI;
68    import jalview.util.MapList;
69    import jalview.util.MappingUtils;
70    import jalview.util.MessageManager;
71    import jalview.util.StringUtils;
72   
73    /**
74    * A class to read VCF data (using the htsjdk) and add variants as sequence
75    * features on dna and any related protein product sequences
76    *
77    * @author gmcarstairs
78    */
 
79    public class VCFLoader
80    {
81    private static final String VCF_ENCODABLE = ":;=%,";
82   
83    /*
84    * Jalview feature attributes for VCF fixed column data
85    */
86    private static final String VCF_POS = "POS";
87   
88    private static final String VCF_ID = "ID";
89   
90    private static final String VCF_QUAL = "QUAL";
91   
92    private static final String VCF_FILTER = "FILTER";
93   
94    private static final String NO_VALUE = VCFConstants.MISSING_VALUE_v4; // '.'
95   
96    private static final String DEFAULT_SPECIES = "homo_sapiens";
97   
98    /**
99    * A class to model the mapping from sequence to VCF coordinates. Cases
100    * include
101    * <ul>
102    * <li>a direct 1:1 mapping where the sequence is one of the VCF contigs</li>
103    * <li>a mapping of sequence to chromosomal coordinates, where sequence and
104    * VCF use the same reference assembly</li>
105    * <li>a modified mapping of sequence to chromosomal coordinates, where
106    * sequence and VCF use different reference assembles</li>
107    * </ul>
108    */
 
109    class VCFMap
110    {
111    final String chromosome;
112   
113    final MapList map;
114   
 
115  24 toggle VCFMap(String chr, MapList m)
116    {
117  24 chromosome = chr;
118  24 map = m;
119    }
120   
 
121  0 toggle @Override
122    public String toString()
123    {
124  0 return chromosome + ":" + map.toString();
125    }
126    }
127   
128    /*
129    * Lookup keys, and default values, for Preference entries that describe
130    * patterns for VCF and VEP fields to capture
131    */
132    private static final String VEP_FIELDS_PREF = "VEP_FIELDS";
133   
134    private static final String VCF_FIELDS_PREF = "VCF_FIELDS";
135   
136    private static final String DEFAULT_VCF_FIELDS = ".*";
137   
138    private static final String DEFAULT_VEP_FIELDS = ".*";// "Allele,Consequence,IMPACT,SWISSPROT,SIFT,PolyPhen,CLIN_SIG";
139   
140    /*
141    * Lookup keys, and default values, for Preference entries that give
142    * mappings from tokens in the 'reference' header to species or assembly
143    */
144    private static final String VCF_ASSEMBLY = "VCF_ASSEMBLY";
145   
146    private static final String DEFAULT_VCF_ASSEMBLY = "assembly19=GRCh37,hs37=GRCh37,grch37=GRCh37,grch38=GRCh38";
147   
148    private static final String VCF_SPECIES = "VCF_SPECIES"; // default is human
149   
150    private static final String DEFAULT_REFERENCE = "grch37"; // fallback default
151    // is human GRCh37
152   
153    /*
154    * keys to fields of VEP CSQ consequence data
155    * see https://www.ensembl.org/info/docs/tools/vep/vep_formats.html
156    */
157    private static final String CSQ_CONSEQUENCE_KEY = "Consequence";
158   
159    private static final String CSQ_ALLELE_KEY = "Allele";
160   
161    private static final String CSQ_ALLELE_NUM_KEY = "ALLELE_NUM"; // 0 (ref),
162    // 1...
163   
164    private static final String CSQ_FEATURE_KEY = "Feature"; // Ensembl stable id
165   
166    /*
167    * default VCF INFO key for VEP consequence data
168    * NB this can be overridden running VEP with --vcf_info_field
169    * - we don't handle this case (require identifier to be CSQ)
170    */
171    private static final String CSQ_FIELD = "CSQ";
172   
173    /*
174    * separator for fields in consequence data is '|'
175    */
176    private static final String PIPE_REGEX = "\\|";
177   
178    /*
179    * delimiter that separates multiple consequence data blocks
180    */
181    private static final String COMMA = ",";
182   
183    /*
184    * the feature group assigned to a VCF variant in Jalview
185    */
186    private static final String FEATURE_GROUP_VCF = "VCF";
187   
188    /*
189    * internal delimiter used to build keys for assemblyMappings
190    *
191    */
192    private static final String EXCL = "!";
193   
194    /*
195    * the VCF file we are processing
196    */
197    protected String vcfFilePath;
198   
199    /*
200    * mappings between VCF and sequence reference assembly regions, as
201    * key = "species!chromosome!fromAssembly!toAssembly
202    * value = Map{fromRange, toRange}
203    */
204    private Map<String, Map<int[], int[]>> assemblyMappings;
205   
206    private VCFReader reader;
207   
208    /*
209    * holds details of the VCF header lines (metadata)
210    */
211    private VCFHeader header;
212   
213    /*
214    * species (as a valid Ensembl term) the VCF is for
215    */
216    private String vcfSpecies;
217   
218    /*
219    * genome assembly version (as a valid Ensembl identifier) the VCF is for
220    */
221    private String vcfAssembly;
222   
223    /*
224    * a Dictionary of contigs (if present) referenced in the VCF file
225    */
226    private SAMSequenceDictionary dictionary;
227   
228    /*
229    * the position (0...) of field in each block of
230    * CSQ (consequence) data (if declared in the VCF INFO header for CSQ)
231    * see http://www.ensembl.org/info/docs/tools/vep/vep_formats.html
232    */
233    private int csqConsequenceFieldIndex = -1;
234   
235    private int csqAlleleFieldIndex = -1;
236   
237    private int csqAlleleNumberFieldIndex = -1;
238   
239    private int csqFeatureFieldIndex = -1;
240   
241    // todo the same fields for SnpEff ANN data if wanted
242    // see http://snpeff.sourceforge.net/SnpEff_manual.html#input
243   
244    /*
245    * a unique identifier under which to save metadata about feature
246    * attributes (selected INFO field data)
247    */
248    private String sourceId;
249   
250    /*
251    * The INFO IDs of data that is both present in the VCF file, and
252    * also matched by any filters for data of interest
253    */
254    List<String> vcfFieldsOfInterest;
255   
256    /*
257    * The field offsets and identifiers for VEP (CSQ) data that is both present
258    * in the VCF file, and also matched by any filters for data of interest
259    * for example 0 -> Allele, 1 -> Consequence, ..., 36 -> SIFT, ...
260    */
261    Map<Integer, String> vepFieldsOfInterest;
262   
263    /*
264    * key:value for which rejected data has been seen
265    * (the error is logged only once for each combination)
266    */
267    private Set<String> badData;
268   
269    /**
270    * Constructor given a VCF file
271    *
272    * @param alignment
273    */
 
274  4 toggle public VCFLoader(String vcfFile)
275    {
276  4 try
277    {
278  4 initialise(vcfFile);
279    } catch (IOException e)
280    {
281  0 jalview.bin.Console
282    .errPrintln("Error opening VCF file: " + e.getMessage());
283    }
284   
285    // map of species!chromosome!fromAssembly!toAssembly to {fromRange, toRange}
286  4 assemblyMappings = new HashMap<>();
287    }
288   
289    /**
290    * Starts a new thread to query and load VCF variant data on to the given
291    * sequences
292    * <p>
293    * This method is not thread safe - concurrent threads should use separate
294    * instances of this class.
295    *
296    * @param seqs
297    * @param gui
298    */
 
299  0 toggle public void loadVCF(SequenceI[] seqs, final AlignViewControllerGuiI gui)
300    {
301  0 if (gui != null)
302    {
303  0 gui.setStatus(MessageManager.getString("label.searching_vcf"));
304    }
305   
306  0 new Thread()
307    {
 
308  0 toggle @Override
309    public void run()
310    {
311  0 VCFLoader.this.doLoad(seqs, gui);
312    }
313    }.start();
314    }
315   
316    /**
317    * Reads the specified contig sequence and adds its VCF variants to it
318    *
319    * @param contig
320    * the id of a single sequence (contig) to load
321    * @return
322    */
 
323  3 toggle public SequenceI loadVCFContig(String contig)
324    {
325  3 VCFHeaderLine headerLine = header
326    .getOtherHeaderLine(VCFHeader.REFERENCE_KEY);
327  3 if (headerLine == null)
328    {
329  0 Console.error("VCF reference header not found");
330  0 return null;
331    }
332  3 String ref = headerLine.getValue();
333  3 if (ref.startsWith("file://"))
334    {
335  0 ref = ref.substring(7);
336    }
337  3 setSpeciesAndAssembly(ref);
338   
339  3 SequenceI seq = null;
340  3 File dbFile = new File(ref);
341   
342  3 if (dbFile.exists())
343    {
344  3 HtsContigDb db = new HtsContigDb("", dbFile);
345  3 seq = db.getSequenceProxy(contig);
346  3 loadSequenceVCF(seq);
347  3 db.close();
348    }
349    else
350    {
351  0 Console.error("VCF reference not found: " + ref);
352    }
353   
354  3 return seq;
355    }
356   
357    /**
358    * Loads VCF on to one or more sequences
359    *
360    * @param seqs
361    * @param gui
362    * optional callback handler for messages
363    */
 
364  3 toggle protected void doLoad(SequenceI[] seqs, AlignViewControllerGuiI gui)
365    {
366  3 try
367    {
368  3 VCFHeaderLine ref = header
369    .getOtherHeaderLine(VCFHeader.REFERENCE_KEY);
370  3 String reference = ref == null ? null : ref.getValue();
371   
372  3 setSpeciesAndAssembly(reference);
373   
374  3 int varCount = 0;
375  3 int seqCount = 0;
376   
377    /*
378    * query for VCF overlapping each sequence in turn
379    */
380  3 for (SequenceI seq : seqs)
381    {
382  21 int added = loadSequenceVCF(seq);
383  21 if (added > 0)
384    {
385  11 seqCount++;
386  11 varCount += added;
387  11 transferAddedFeatures(seq);
388    }
389    }
390  3 if (gui != null)
391    {
392  0 String msg = MessageManager.formatMessage("label.added_vcf",
393    varCount, seqCount);
394  0 gui.setStatus(msg);
395  0 if (gui.getFeatureSettingsUI() != null)
396    {
397  0 gui.getFeatureSettingsUI().discoverAllFeatureData();
398    }
399    }
400    } catch (Throwable e)
401    {
402  0 jalview.bin.Console
403    .errPrintln("Error processing VCF: " + e.getMessage());
404  0 e.printStackTrace();
405  0 if (gui != null)
406    {
407  0 gui.setStatus("Error occurred - see console for details");
408    }
409    } finally
410    {
411  3 if (reader != null)
412    {
413  3 try
414    {
415  3 reader.close();
416    } catch (IOException e)
417    {
418    // ignore
419    }
420    }
421  3 header = null;
422  3 dictionary = null;
423    }
424    }
425   
426    /**
427    * Attempts to determine and save the species and genome assembly version to
428    * which the VCF data applies. This may be done by parsing the
429    * {@code reference} header line, configured in a property file, or
430    * (potentially) confirmed interactively by the user.
431    * <p>
432    * The saved values should be identifiers valid for Ensembl's REST service
433    * {@code map} endpoint, so they can be used (if necessary) to retrieve the
434    * mapping between VCF coordinates and sequence coordinates.
435    *
436    * @param reference
437    * @see https://rest.ensembl.org/documentation/info/assembly_map
438    * @see https://rest.ensembl.org/info/assembly/human?content-type=text/xml
439    * @see https://rest.ensembl.org/info/species?content-type=text/xml
440    */
 
441  6 toggle protected void setSpeciesAndAssembly(String reference)
442    {
443  6 if (reference == null)
444    {
445  0 Console.error("No VCF ##reference found, defaulting to "
446    + DEFAULT_REFERENCE + ":" + DEFAULT_SPECIES);
447  0 reference = DEFAULT_REFERENCE; // default to GRCh37 if not specified
448    }
449  6 reference = reference.toLowerCase(Locale.ROOT);
450   
451    /*
452    * for a non-human species, or other assembly identifier,
453    * specify as a Jalview property file entry e.g.
454    * VCF_ASSEMBLY = hs37=GRCh37,assembly19=GRCh37
455    * VCF_SPECIES = c_elegans=celegans
456    * to map a token in the reference header to a value
457    */
458  6 String prop = Cache.getDefault(VCF_ASSEMBLY, DEFAULT_VCF_ASSEMBLY);
459  6 for (String token : prop.split(","))
460    {
461  6 String[] tokens = token.split("=");
462  6 if (tokens.length == 2)
463    {
464  6 if (reference.contains(tokens[0].trim().toLowerCase(Locale.ROOT)))
465    {
466  3 vcfAssembly = tokens[1].trim();
467  3 break;
468    }
469    }
470    }
471   
472  6 vcfSpecies = DEFAULT_SPECIES;
473  6 prop = Cache.getProperty(VCF_SPECIES);
474  6 if (prop != null)
475    {
476  0 for (String token : prop.split(","))
477    {
478  0 String[] tokens = token.split("=");
479  0 if (tokens.length == 2)
480    {
481  0 if (reference.contains(tokens[0].trim().toLowerCase(Locale.ROOT)))
482    {
483  0 vcfSpecies = tokens[1].trim();
484  0 break;
485    }
486    }
487    }
488    }
489    }
490   
491    /**
492    * Opens the VCF file and parses header data
493    *
494    * @param filePath
495    * @throws IOException
496    */
 
497  4 toggle private void initialise(String filePath) throws IOException
498    {
499  4 vcfFilePath = filePath;
500   
501  4 reader = new VCFReader(filePath);
502   
503  4 header = reader.getFileHeader();
504   
505  4 try
506    {
507  4 dictionary = header.getSequenceDictionary();
508    } catch (SAMException e)
509    {
510    // ignore - thrown if any contig line lacks length info
511    }
512   
513  4 sourceId = filePath;
514   
515  4 saveMetadata(sourceId);
516   
517    /*
518    * get offset of CSQ ALLELE_NUM and Feature if declared
519    */
520  4 parseCsqHeader();
521    }
522   
523    /**
524    * Reads metadata (such as INFO field descriptions and datatypes) and saves
525    * them for future reference
526    *
527    * @param theSourceId
528    */
 
529  4 toggle void saveMetadata(String theSourceId)
530    {
531  4 List<Pattern> vcfFieldPatterns = getFieldMatchers(VCF_FIELDS_PREF,
532    DEFAULT_VCF_FIELDS);
533  4 vcfFieldsOfInterest = new ArrayList<>();
534   
535  4 FeatureSource metadata = new FeatureSource(theSourceId);
536   
537  4 for (VCFInfoHeaderLine info : header.getInfoHeaderLines())
538    {
539  13 String attributeId = info.getID();
540  13 String desc = info.getDescription();
541  13 VCFHeaderLineType type = info.getType();
542  13 FeatureAttributeType attType = null;
543  13 switch (type)
544    {
545  0 case Character:
546  0 attType = FeatureAttributeType.Character;
547  0 break;
548  0 case Flag:
549  0 attType = FeatureAttributeType.Flag;
550  0 break;
551  7 case Float:
552  7 attType = FeatureAttributeType.Float;
553  7 break;
554  5 case Integer:
555  5 attType = FeatureAttributeType.Integer;
556  5 break;
557  1 case String:
558  1 attType = FeatureAttributeType.String;
559  1 break;
560    }
561  13 metadata.setAttributeName(attributeId, desc);
562  13 metadata.setAttributeType(attributeId, attType);
563   
564  13 if (isFieldWanted(attributeId, vcfFieldPatterns))
565    {
566  13 vcfFieldsOfInterest.add(attributeId);
567    }
568    }
569   
570  4 FeatureSources.getInstance().addSource(theSourceId, metadata);
571    }
572   
573    /**
574    * Answers true if the field id is matched by any of the filter patterns, else
575    * false. Matching is against regular expression patterns, and is not
576    * case-sensitive.
577    *
578    * @param id
579    * @param filters
580    * @return
581    */
 
582  22 toggle private boolean isFieldWanted(String id, List<Pattern> filters)
583    {
584  22 for (Pattern p : filters)
585    {
586  22 if (p.matcher(id.toUpperCase(Locale.ROOT)).matches())
587    {
588  22 return true;
589    }
590    }
591  0 return false;
592    }
593   
594    /**
595    * Records 'wanted' fields defined in the CSQ INFO header (if there is one).
596    * Also records the position of selected fields (Allele, ALLELE_NUM, Feature)
597    * required for processing.
598    * <p>
599    * CSQ fields are declared in the CSQ INFO Description e.g.
600    * <p>
601    * Description="Consequence ...from ... VEP. Format: Allele|Consequence|...
602    */
 
603  4 toggle protected void parseCsqHeader()
604    {
605  4 List<Pattern> vepFieldFilters = getFieldMatchers(VEP_FIELDS_PREF,
606    DEFAULT_VEP_FIELDS);
607  4 vepFieldsOfInterest = new HashMap<>();
608   
609  4 VCFInfoHeaderLine csqInfo = header.getInfoHeaderLine(CSQ_FIELD);
610  4 if (csqInfo == null)
611    {
612  3 return;
613    }
614   
615    /*
616    * parse out the pipe-separated list of CSQ fields; we assume here that
617    * these form the last part of the description, and contain no spaces
618    */
619  1 String desc = csqInfo.getDescription();
620  1 int spacePos = desc.lastIndexOf(" ");
621  1 desc = desc.substring(spacePos + 1);
622   
623  1 if (desc != null)
624    {
625  1 String[] format = desc.split(PIPE_REGEX);
626  1 int index = 0;
627  1 for (String field : format)
628    {
629  9 if (CSQ_CONSEQUENCE_KEY.equals(field))
630    {
631  1 csqConsequenceFieldIndex = index;
632    }
633  9 if (CSQ_ALLELE_NUM_KEY.equals(field))
634    {
635  0 csqAlleleNumberFieldIndex = index;
636    }
637  9 if (CSQ_ALLELE_KEY.equals(field))
638    {
639  1 csqAlleleFieldIndex = index;
640    }
641  9 if (CSQ_FEATURE_KEY.equals(field))
642    {
643  1 csqFeatureFieldIndex = index;
644    }
645   
646  9 if (isFieldWanted(field, vepFieldFilters))
647    {
648  9 vepFieldsOfInterest.put(index, field);
649    }
650   
651  9 index++;
652    }
653    }
654    }
655   
656    /**
657    * Reads the Preference value for the given key, with default specified if no
658    * preference set. The value is interpreted as a comma-separated list of
659    * regular expressions, and converted into a list of compiled patterns ready
660    * for matching. Patterns are forced to upper-case for non-case-sensitive
661    * matching.
662    * <p>
663    * This supports user-defined filters for fields of interest to capture while
664    * processing data. For example, VCF_FIELDS = AF,AC* would mean that VCF INFO
665    * fields with an ID of AF, or starting with AC, would be matched.
666    *
667    * @param key
668    * @param def
669    * @return
670    */
 
671  8 toggle private List<Pattern> getFieldMatchers(String key, String def)
672    {
673  8 String pref = Cache.getDefault(key, def);
674  8 List<Pattern> patterns = new ArrayList<>();
675  8 String[] tokens = pref.split(",");
676  8 for (String token : tokens)
677    {
678  8 try
679    {
680  8 patterns.add(Pattern.compile(token.toUpperCase(Locale.ROOT)));
681    } catch (PatternSyntaxException e)
682    {
683  0 jalview.bin.Console.errPrintln("Invalid pattern ignored: " + token);
684    }
685    }
686  8 return patterns;
687    }
688   
689    /**
690    * Transfers VCF features to sequences to which this sequence has a mapping.
691    *
692    * @param seq
693    */
 
694  11 toggle protected void transferAddedFeatures(SequenceI seq)
695    {
696  11 List<DBRefEntry> dbrefs = seq.getDBRefs();
697  11 if (dbrefs == null)
698    {
699  0 return;
700    }
701  11 for (DBRefEntry dbref : dbrefs)
702    {
703  16 Mapping mapping = dbref.getMap();
704  16 if (mapping == null || mapping.getTo() == null)
705    {
706  11 continue;
707    }
708   
709  5 SequenceI mapTo = mapping.getTo();
710  5 MapList map = mapping.getMap();
711  5 if (map.getFromRatio() == 3)
712    {
713    /*
714    * dna-to-peptide product mapping
715    */
716    // JAL-3187 render on the fly instead
717    // AlignmentUtils.computeProteinFeatures(seq, mapTo, map);
718    }
719    else
720    {
721    /*
722    * nucleotide-to-nucleotide mapping e.g. transcript to CDS
723    */
724  0 List<SequenceFeature> features = seq.getFeatures()
725    .getPositionalFeatures(SequenceOntologyI.SEQUENCE_VARIANT);
726  0 for (SequenceFeature sf : features)
727    {
728  0 if (FEATURE_GROUP_VCF.equals(sf.getFeatureGroup()))
729    {
730  0 transferFeature(sf, mapTo, map);
731    }
732    }
733    }
734    }
735    }
736   
737    /**
738    * Tries to add overlapping variants read from a VCF file to the given
739    * sequence, and returns the number of variant features added
740    *
741    * @param seq
742    * @return
743    */
 
744  24 toggle protected int loadSequenceVCF(SequenceI seq)
745    {
746  24 VCFMap vcfMap = getVcfMap(seq);
747  24 if (vcfMap == null)
748    {
749  0 return 0;
750    }
751   
752    /*
753    * work with the dataset sequence here
754    */
755  24 SequenceI dss = seq.getDatasetSequence();
756  24 if (dss == null)
757    {
758  3 dss = seq;
759    }
760  24 return addVcfVariants(dss, vcfMap);
761    }
762   
763    /**
764    * Answers a map from sequence coordinates to VCF chromosome ranges
765    *
766    * @param seq
767    * @return
768    */
 
769  24 toggle private VCFMap getVcfMap(SequenceI seq)
770    {
771    /*
772    * simplest case: sequence has id and length matching a VCF contig
773    */
774  24 VCFMap vcfMap = null;
775  24 if (dictionary != null)
776    {
777  3 vcfMap = getContigMap(seq);
778    }
779  24 if (vcfMap != null)
780    {
781  3 return vcfMap;
782    }
783   
784    /*
785    * otherwise, map to VCF from chromosomal coordinates
786    * of the sequence (if known)
787    */
788  21 GeneLociI seqCoords = seq.getGeneLoci();
789  21 if (seqCoords == null)
790    {
791  0 Console.warn(String.format(
792    "Can't query VCF for %s as chromosome coordinates not known",
793    seq.getName()));
794  0 return null;
795    }
796   
797  21 String species = seqCoords.getSpeciesId();
798  21 String chromosome = seqCoords.getChromosomeId();
799  21 String seqRef = seqCoords.getAssemblyId();
800  21 MapList map = seqCoords.getMapping();
801   
802    // note this requires the configured species to match that
803    // returned with the Ensembl sequence; todo: support aliases?
804  21 if (!vcfSpecies.equalsIgnoreCase(species))
805    {
806  0 Console.warn("No VCF loaded to " + seq.getName()
807    + " as species not matched");
808  0 return null;
809    }
810   
811  21 if (seqRef.equalsIgnoreCase(vcfAssembly))
812    {
813  21 return new VCFMap(chromosome, map);
814    }
815   
816    /*
817    * VCF data has a different reference assembly to the sequence:
818    * query Ensembl to map chromosomal coordinates from sequence to VCF
819    */
820  0 List<int[]> toVcfRanges = new ArrayList<>();
821  0 List<int[]> fromSequenceRanges = new ArrayList<>();
822   
823  0 for (int[] range : map.getToRanges())
824    {
825  0 int[] fromRange = map.locateInFrom(range[0], range[1]);
826  0 if (fromRange == null)
827    {
828    // corrupted map?!?
829  0 continue;
830    }
831   
832  0 int[] newRange = mapReferenceRange(range, chromosome, "human", seqRef,
833    vcfAssembly);
834  0 if (newRange == null)
835    {
836  0 Console.error(String.format("Failed to map %s:%s:%s:%d:%d to %s",
837    species, chromosome, seqRef, range[0], range[1],
838    vcfAssembly));
839  0 continue;
840    }
841    else
842    {
843  0 toVcfRanges.add(newRange);
844  0 fromSequenceRanges.add(fromRange);
845    }
846    }
847   
848  0 return new VCFMap(chromosome,
849    new MapList(fromSequenceRanges, toVcfRanges, 1, 1));
850    }
851   
852    /**
853    * If the sequence id matches a contig declared in the VCF file, and the
854    * sequence length matches the contig length, then returns a 1:1 map of the
855    * sequence to the contig, else returns null
856    *
857    * @param seq
858    * @return
859    */
 
860  3 toggle private VCFMap getContigMap(SequenceI seq)
861    {
862  3 String id = seq.getName();
863  3 SAMSequenceRecord contig = dictionary.getSequence(id);
864  3 if (contig != null)
865    {
866  3 int len = seq.getLength();
867  3 if (len == contig.getSequenceLength())
868    {
869  3 MapList map = new MapList(new int[] { 1, len },
870    new int[]
871    { 1, len }, 1, 1);
872  3 return new VCFMap(id, map);
873    }
874    }
875  0 return null;
876    }
877   
878    /**
879    * Queries the VCF reader for any variants that overlap the mapped chromosome
880    * ranges of the sequence, and adds as variant features. Returns the number of
881    * overlapping variants found.
882    *
883    * @param seq
884    * @param map
885    * mapping from sequence to VCF coordinates
886    * @return
887    */
 
888  24 toggle protected int addVcfVariants(SequenceI seq, VCFMap map)
889    {
890  24 boolean forwardStrand = map.map.isToForwardStrand();
891   
892    /*
893    * query the VCF for overlaps of each contiguous chromosomal region
894    */
895  24 int count = 0;
896   
897  24 for (int[] range : map.map.getToRanges())
898    {
899  39 int vcfStart = Math.min(range[0], range[1]);
900  39 int vcfEnd = Math.max(range[0], range[1]);
901  39 try
902    {
903  39 CloseableIterator<VariantContext> variants = reader
904    .query(map.chromosome, vcfStart, vcfEnd);
905  75 while (variants.hasNext())
906    {
907  36 VariantContext variant = variants.next();
908   
909  36 int[] featureRange = map.map.locateInFrom(variant.getStart(),
910    variant.getEnd());
911   
912    /*
913    * only take features whose range is fully mappable to sequence positions
914    */
915  36 if (featureRange != null)
916    {
917  36 int featureStart = Math.min(featureRange[0], featureRange[1]);
918  36 int featureEnd = Math.max(featureRange[0], featureRange[1]);
919  36 if (featureEnd - featureStart == variant.getEnd()
920    - variant.getStart())
921    {
922  34 count += addAlleleFeatures(seq, variant, featureStart,
923    featureEnd, forwardStrand);
924    }
925    }
926    }
927  39 variants.close();
928    } catch (TribbleException e)
929    {
930    /*
931    * RuntimeException throwable by htsjdk
932    */
933  0 String msg = String.format("Error reading VCF for %s:%d-%d: %s ",
934    map.chromosome, vcfStart, vcfEnd, e.getLocalizedMessage());
935  0 Console.error(msg);
936    }
937    }
938   
939  24 return count;
940    }
941   
942    /**
943    * A convenience method to get an attribute value for an alternate allele
944    *
945    * @param variant
946    * @param attributeName
947    * @param alleleIndex
948    * @return
949    */
 
950  100 toggle protected String getAttributeValue(VariantContext variant,
951    String attributeName, int alleleIndex)
952    {
953  100 Object att = variant.getAttribute(attributeName);
954   
955  100 if (att instanceof String)
956    {
957  39 return (String) att;
958    }
959  61 else if (att instanceof ArrayList)
960    {
961  61 return ((List<String>) att).get(alleleIndex);
962    }
963   
964  0 return null;
965    }
966   
967    /**
968    * Adds one variant feature for each allele in the VCF variant record, and
969    * returns the number of features added.
970    *
971    * @param seq
972    * @param variant
973    * @param featureStart
974    * @param featureEnd
975    * @param forwardStrand
976    * @return
977    */
 
978  34 toggle protected int addAlleleFeatures(SequenceI seq, VariantContext variant,
979    int featureStart, int featureEnd, boolean forwardStrand)
980    {
981  34 int added = 0;
982   
983    /*
984    * Javadoc says getAlternateAlleles() imposes no order on the list returned
985    * so we proceed defensively to get them in strict order
986    */
987  34 int altAlleleCount = variant.getAlternateAlleles().size();
988  85 for (int i = 0; i < altAlleleCount; i++)
989    {
990  51 added += addAlleleFeature(seq, variant, i, featureStart, featureEnd,
991    forwardStrand);
992    }
993  34 return added;
994    }
995   
996    /**
997    * Inspects one allele and attempts to add a variant feature for it to the
998    * sequence. The additional data associated with this allele is extracted to
999    * store in the feature's key-value map. Answers the number of features added
1000    * (0 or 1).
1001    *
1002    * @param seq
1003    * @param variant
1004    * @param altAlleleIndex
1005    * (0, 1..)
1006    * @param featureStart
1007    * @param featureEnd
1008    * @param forwardStrand
1009    * @return
1010    */
 
1011  51 toggle protected int addAlleleFeature(SequenceI seq, VariantContext variant,
1012    int altAlleleIndex, int featureStart, int featureEnd,
1013    boolean forwardStrand)
1014    {
1015  51 String reference = variant.getReference().getBaseString();
1016  51 Allele alt = variant.getAlternateAllele(altAlleleIndex);
1017  51 String allele = alt.getBaseString();
1018   
1019    /*
1020    * insertion after a genomic base, if on reverse strand, has to be
1021    * converted to insertion of complement after the preceding position
1022    */
1023  51 int referenceLength = reference.length();
1024  51 if (!forwardStrand && allele.length() > referenceLength
1025    && allele.startsWith(reference))
1026    {
1027  4 featureStart -= referenceLength;
1028  4 featureEnd = featureStart;
1029  4 char insertAfter = seq.getCharAt(featureStart - seq.getStart());
1030  4 reference = Dna.reverseComplement(String.valueOf(insertAfter));
1031  4 allele = allele.substring(referenceLength) + reference;
1032    }
1033   
1034    /*
1035    * build the ref,alt allele description e.g. "G,A", using the base
1036    * complement if the sequence is on the reverse strand
1037    */
1038  51 StringBuilder sb = new StringBuilder();
1039  51 sb.append(forwardStrand ? reference : Dna.reverseComplement(reference));
1040  51 sb.append(COMMA);
1041  51 sb.append(forwardStrand ? allele : Dna.reverseComplement(allele));
1042  51 String alleles = sb.toString(); // e.g. G,A
1043   
1044    /*
1045    * pick out the consequence data (if any) that is for the current allele
1046    * and feature (transcript) that matches the current sequence
1047    */
1048  51 String consequence = getConsequenceForAlleleAndFeature(variant,
1049    CSQ_FIELD, altAlleleIndex, csqAlleleFieldIndex,
1050    csqAlleleNumberFieldIndex,
1051    seq.getName().toLowerCase(Locale.ROOT), csqFeatureFieldIndex);
1052   
1053    /*
1054    * pick out the ontology term for the consequence type
1055    */
1056  51 String type = SequenceOntologyI.SEQUENCE_VARIANT;
1057  51 if (consequence != null)
1058    {
1059  7 type = getOntologyTerm(consequence);
1060    }
1061   
1062  51 SequenceFeature sf = new SequenceFeature(type, alleles, featureStart,
1063    featureEnd, FEATURE_GROUP_VCF);
1064  51 sf.setSource(sourceId);
1065   
1066    /*
1067    * save the derived alleles as a named attribute; this will be
1068    * needed when Jalview computes derived peptide variants
1069    */
1070  51 addFeatureAttribute(sf, Gff3Helper.ALLELES, alleles);
1071   
1072    /*
1073    * add selected VCF fixed column data as feature attributes
1074    */
1075  51 addFeatureAttribute(sf, VCF_POS, String.valueOf(variant.getStart()));
1076  51 addFeatureAttribute(sf, VCF_ID, variant.getID());
1077  51 addFeatureAttribute(sf, VCF_QUAL,
1078    String.valueOf(variant.getPhredScaledQual()));
1079  51 addFeatureAttribute(sf, VCF_FILTER, getFilter(variant));
1080   
1081  51 addAlleleProperties(variant, sf, altAlleleIndex, consequence);
1082   
1083  51 seq.addSequenceFeature(sf);
1084   
1085  51 return 1;
1086    }
1087   
1088    /**
1089    * Answers the VCF FILTER value for the variant - or an approximation to it.
1090    * This field is either PASS, or a semi-colon separated list of filters not
1091    * passed. htsjdk saves filters as a HashSet, so the order when reassembled
1092    * into a list may be different.
1093    *
1094    * @param variant
1095    * @return
1096    */
 
1097  51 toggle String getFilter(VariantContext variant)
1098    {
1099  51 Set<String> filters = variant.getFilters();
1100  51 if (filters.isEmpty())
1101    {
1102  21 return NO_VALUE;
1103    }
1104  30 Iterator<String> iterator = filters.iterator();
1105  30 String first = iterator.next();
1106  30 if (filters.size() == 1)
1107    {
1108  11 return first;
1109    }
1110   
1111  19 StringBuilder sb = new StringBuilder(first);
1112  38 while (iterator.hasNext())
1113    {
1114  19 sb.append(";").append(iterator.next());
1115    }
1116   
1117  19 return sb.toString();
1118    }
1119   
1120    /**
1121    * Adds one feature attribute unless the value is null, empty or '.'
1122    *
1123    * @param sf
1124    * @param key
1125    * @param value
1126    */
 
1127  347 toggle void addFeatureAttribute(SequenceFeature sf, String key, String value)
1128    {
1129  347 if (value != null && !value.isEmpty() && !NO_VALUE.equals(value))
1130    {
1131  275 sf.setValue(key, value);
1132    }
1133    }
1134   
1135    /**
1136    * Determines the Sequence Ontology term to use for the variant feature type
1137    * in Jalview. The default is 'sequence_variant', but a more specific term is
1138    * used if:
1139    * <ul>
1140    * <li>VEP (or SnpEff) Consequence annotation is included in the VCF</li>
1141    * <li>sequence id can be matched to VEP Feature (or SnpEff Feature_ID)</li>
1142    * </ul>
1143    *
1144    * @param consequence
1145    * @return
1146    * @see http://www.sequenceontology.org/browser/current_svn/term/SO:0001060
1147    */
 
1148  7 toggle String getOntologyTerm(String consequence)
1149    {
1150  7 String type = SequenceOntologyI.SEQUENCE_VARIANT;
1151   
1152    /*
1153    * could we associate Consequence data with this allele and feature (transcript)?
1154    * if so, prefer the consequence term from that data
1155    */
1156  7 if (csqAlleleFieldIndex == -1) // && snpEffAlleleFieldIndex == -1
1157    {
1158    /*
1159    * no Consequence data so we can't refine the ontology term
1160    */
1161  0 return type;
1162    }
1163   
1164  7 if (consequence != null)
1165    {
1166  7 String[] csqFields = consequence.split(PIPE_REGEX);
1167  7 if (csqFields.length > csqConsequenceFieldIndex)
1168    {
1169  7 type = csqFields[csqConsequenceFieldIndex];
1170    }
1171    }
1172    else
1173    {
1174    // todo the same for SnpEff consequence data matching if wanted
1175    }
1176   
1177    /*
1178    * if of the form (e.g.) missense_variant&splice_region_variant,
1179    * just take the first ('most severe') consequence
1180    */
1181  7 if (type != null)
1182    {
1183  7 int pos = type.indexOf('&');
1184  7 if (pos > 0)
1185    {
1186  0 type = type.substring(0, pos);
1187    }
1188    }
1189  7 return type;
1190    }
1191   
1192    /**
1193    * Returns matched consequence data if it can be found, else null.
1194    * <ul>
1195    * <li>inspects the VCF data for key 'vcfInfoId'</li>
1196    * <li>splits this on comma (to distinct consequences)</li>
1197    * <li>returns the first consequence (if any) where</li>
1198    * <ul>
1199    * <li>the allele matches the altAlleleIndex'th allele of variant</li>
1200    * <li>the feature matches the sequence name (e.g. transcript id)</li>
1201    * </ul>
1202    * </ul>
1203    * If matched, the consequence is returned (as pipe-delimited fields).
1204    *
1205    * @param variant
1206    * @param vcfInfoId
1207    * @param altAlleleIndex
1208    * @param alleleFieldIndex
1209    * @param alleleNumberFieldIndex
1210    * @param seqName
1211    * @param featureFieldIndex
1212    * @return
1213    */
 
1214  51 toggle private String getConsequenceForAlleleAndFeature(VariantContext variant,
1215    String vcfInfoId, int altAlleleIndex, int alleleFieldIndex,
1216    int alleleNumberFieldIndex, String seqName, int featureFieldIndex)
1217    {
1218  51 if (alleleFieldIndex == -1 || featureFieldIndex == -1)
1219    {
1220  37 return null;
1221    }
1222  14 Object value = variant.getAttribute(vcfInfoId);
1223   
1224  14 if (value == null || !(value instanceof List<?>))
1225    {
1226  0 return null;
1227    }
1228   
1229    /*
1230    * inspect each consequence in turn (comma-separated blocks
1231    * extracted by htsjdk)
1232    */
1233  14 List<String> consequences = (List<String>) value;
1234   
1235  14 for (String consequence : consequences)
1236    {
1237  41 String[] csqFields = consequence.split(PIPE_REGEX);
1238  41 if (csqFields.length > featureFieldIndex)
1239    {
1240  41 String featureIdentifier = csqFields[featureFieldIndex];
1241  41 if (featureIdentifier.length() > 4 && seqName
1242    .indexOf(featureIdentifier.toLowerCase(Locale.ROOT)) > -1)
1243    {
1244    /*
1245    * feature (transcript) matched - now check for allele match
1246    */
1247  10 if (matchAllele(variant, altAlleleIndex, csqFields,
1248    alleleFieldIndex, alleleNumberFieldIndex))
1249    {
1250  7 return consequence;
1251    }
1252    }
1253    }
1254    }
1255  7 return null;
1256    }
1257   
 
1258  10 toggle private boolean matchAllele(VariantContext variant, int altAlleleIndex,
1259    String[] csqFields, int alleleFieldIndex,
1260    int alleleNumberFieldIndex)
1261    {
1262    /*
1263    * if ALLELE_NUM is present, it must match altAlleleIndex
1264    * NB first alternate allele is 1 for ALLELE_NUM, 0 for altAlleleIndex
1265    */
1266  10 if (alleleNumberFieldIndex > -1)
1267    {
1268  0 if (csqFields.length <= alleleNumberFieldIndex)
1269    {
1270  0 return false;
1271    }
1272  0 String alleleNum = csqFields[alleleNumberFieldIndex];
1273  0 return String.valueOf(altAlleleIndex + 1).equals(alleleNum);
1274    }
1275   
1276    /*
1277    * else consequence allele must match variant allele
1278    */
1279  10 if (alleleFieldIndex > -1 && csqFields.length > alleleFieldIndex)
1280    {
1281  10 String csqAllele = csqFields[alleleFieldIndex];
1282  10 String vcfAllele = variant.getAlternateAllele(altAlleleIndex)
1283    .getBaseString();
1284  10 return csqAllele.equals(vcfAllele);
1285    }
1286  0 return false;
1287    }
1288   
1289    /**
1290    * Add any allele-specific VCF key-value data to the sequence feature
1291    *
1292    * @param variant
1293    * @param sf
1294    * @param altAlelleIndex
1295    * (0, 1..)
1296    * @param consequence
1297    * if not null, the consequence specific to this sequence (transcript
1298    * feature) and allele
1299    */
 
1300  51 toggle protected void addAlleleProperties(VariantContext variant,
1301    SequenceFeature sf, final int altAlelleIndex, String consequence)
1302    {
1303  51 Map<String, Object> atts = variant.getAttributes();
1304   
1305  51 for (Entry<String, Object> att : atts.entrySet())
1306    {
1307  174 String key = att.getKey();
1308   
1309    /*
1310    * extract Consequence data (if present) that we are able to
1311    * associated with the allele for this variant feature
1312    */
1313  174 if (CSQ_FIELD.equals(key))
1314    {
1315  14 addConsequences(variant, sf, consequence);
1316  14 continue;
1317    }
1318   
1319    /*
1320    * filter out fields we don't want to capture
1321    */
1322  160 if (!vcfFieldsOfInterest.contains(key))
1323    {
1324  46 continue;
1325    }
1326   
1327    /*
1328    * we extract values for other data which are allele-specific;
1329    * these may be per alternate allele (INFO[key].Number = 'A')
1330    * or per allele including reference (INFO[key].Number = 'R')
1331    */
1332  114 VCFInfoHeaderLine infoHeader = header.getInfoHeaderLine(key);
1333  114 if (infoHeader == null)
1334    {
1335    /*
1336    * can't be sure what data belongs to this allele, so
1337    * play safe and don't take any
1338    */
1339  0 continue;
1340    }
1341   
1342  114 VCFHeaderLineCount number = infoHeader.getCountType();
1343  114 int index = altAlelleIndex;
1344  114 if (number == VCFHeaderLineCount.R)
1345    {
1346    /*
1347    * one value per allele including reference, so bump index
1348    * e.g. the 3rd value is for the 2nd alternate allele
1349    */
1350  14 index++;
1351    }
1352  100 else if (number != VCFHeaderLineCount.A)
1353    {
1354    /*
1355    * don't save other values as not allele-related
1356    */
1357  14 continue;
1358    }
1359   
1360    /*
1361    * take the index'th value
1362    */
1363  100 String value = getAttributeValue(variant, key, index);
1364  100 if (value != null && isValid(variant, key, value))
1365    {
1366    /*
1367    * decode colon, semicolon, equals sign, percent sign, comma (only)
1368    * as required by the VCF specification (para 1.2)
1369    */
1370  92 value = StringUtils.urlDecode(value, VCF_ENCODABLE);
1371  92 addFeatureAttribute(sf, key, value);
1372    }
1373    }
1374    }
1375   
1376    /**
1377    * Answers true for '.', null, or an empty value, or if the INFO type is
1378    * String. If the INFO type is Integer or Float, answers false if the value is
1379    * not in valid format.
1380    *
1381    * @param variant
1382    * @param infoId
1383    * @param value
1384    * @return
1385    */
 
1386  100 toggle protected boolean isValid(VariantContext variant, String infoId,
1387    String value)
1388    {
1389  100 if (value == null || value.isEmpty() || NO_VALUE.equals(value))
1390    {
1391  8 return true;
1392    }
1393  92 VCFInfoHeaderLine infoHeader = header.getInfoHeaderLine(infoId);
1394  92 if (infoHeader == null)
1395    {
1396  0 Console.error("Field " + infoId + " has no INFO header");
1397  0 return false;
1398    }
1399  92 VCFHeaderLineType infoType = infoHeader.getType();
1400  92 try
1401    {
1402  92 if (infoType == VCFHeaderLineType.Integer)
1403    {
1404  27 Integer.parseInt(value);
1405    }
1406  65 else if (infoType == VCFHeaderLineType.Float)
1407    {
1408  65 Float.parseFloat(value);
1409    }
1410    } catch (NumberFormatException e)
1411    {
1412  8 logInvalidValue(variant, infoId, value);
1413  8 return false;
1414    }
1415  84 return true;
1416    }
1417   
1418    /**
1419    * Logs an error message for malformed data; duplicate messages (same id and
1420    * value) are not logged
1421    *
1422    * @param variant
1423    * @param infoId
1424    * @param value
1425    */
 
1426  8 toggle private void logInvalidValue(VariantContext variant, String infoId,
1427    String value)
1428    {
1429  8 if (badData == null)
1430    {
1431  2 badData = new HashSet<>();
1432    }
1433  8 String token = infoId + ":" + value;
1434  8 if (!badData.contains(token))
1435    {
1436  4 badData.add(token);
1437  4 Console.error(String.format("Invalid VCF data at %s:%d %s=%s",
1438    variant.getContig(), variant.getStart(), infoId, value));
1439    }
1440    }
1441   
1442    /**
1443    * Inspects CSQ data blocks (consequences) and adds attributes on the sequence
1444    * feature.
1445    * <p>
1446    * If <code>myConsequence</code> is not null, then this is the specific
1447    * consequence data (pipe-delimited fields) that is for the current allele and
1448    * transcript (sequence) being processed)
1449    *
1450    * @param variant
1451    * @param sf
1452    * @param myConsequence
1453    */
 
1454  14 toggle protected void addConsequences(VariantContext variant, SequenceFeature sf,
1455    String myConsequence)
1456    {
1457  14 Object value = variant.getAttribute(CSQ_FIELD);
1458   
1459  14 if (value == null || !(value instanceof List<?>))
1460    {
1461  0 return;
1462    }
1463   
1464  14 List<String> consequences = (List<String>) value;
1465   
1466    /*
1467    * inspect CSQ consequences; restrict to the consequence
1468    * associated with the current transcript (Feature)
1469    */
1470  14 Map<String, String> csqValues = new HashMap<>();
1471   
1472  14 for (String consequence : consequences)
1473    {
1474  50 if (myConsequence == null || myConsequence.equals(consequence))
1475    {
1476  31 String[] csqFields = consequence.split(PIPE_REGEX);
1477   
1478    /*
1479    * inspect individual fields of this consequence, copying non-null
1480    * values which are 'fields of interest'
1481    */
1482  31 int i = 0;
1483  31 for (String field : csqFields)
1484    {
1485  279 if (field != null && field.length() > 0)
1486    {
1487  279 String id = vepFieldsOfInterest.get(i);
1488  279 if (id != null)
1489    {
1490    /*
1491    * VCF spec requires encoding of special characters e.g. '='
1492    * so decode them here before storing
1493    */
1494  279 field = StringUtils.urlDecode(field, VCF_ENCODABLE);
1495  279 csqValues.put(id, field);
1496    }
1497    }
1498  279 i++;
1499    }
1500    }
1501    }
1502   
1503  14 if (!csqValues.isEmpty())
1504    {
1505  14 sf.setValue(CSQ_FIELD, csqValues);
1506    }
1507    }
1508   
1509    /**
1510    * A convenience method to complement a dna base and return the string value
1511    * of its complement
1512    *
1513    * @param reference
1514    * @return
1515    */
 
1516  0 toggle protected String complement(byte[] reference)
1517    {
1518  0 return String.valueOf(Dna.getComplement((char) reference[0]));
1519    }
1520   
1521    /**
1522    * Determines the location of the query range (chromosome positions) in a
1523    * different reference assembly.
1524    * <p>
1525    * If the range is just a subregion of one for which we already have a mapping
1526    * (for example, an exon sub-region of a gene), then the mapping is just
1527    * computed arithmetically.
1528    * <p>
1529    * Otherwise, calls the Ensembl REST service that maps from one assembly
1530    * reference's coordinates to another's
1531    *
1532    * @param queryRange
1533    * start-end chromosomal range in 'fromRef' coordinates
1534    * @param chromosome
1535    * @param species
1536    * @param fromRef
1537    * assembly reference for the query coordinates
1538    * @param toRef
1539    * assembly reference we wish to translate to
1540    * @return the start-end range in 'toRef' coordinates
1541    */
 
1542  0 toggle protected int[] mapReferenceRange(int[] queryRange, String chromosome,
1543    String species, String fromRef, String toRef)
1544    {
1545    /*
1546    * first try shorcut of computing the mapping as a subregion of one
1547    * we already have (e.g. for an exon, if we have the gene mapping)
1548    */
1549  0 int[] mappedRange = findSubsumedRangeMapping(queryRange, chromosome,
1550    species, fromRef, toRef);
1551  0 if (mappedRange != null)
1552    {
1553  0 return mappedRange;
1554    }
1555   
1556    /*
1557    * call (e.g.) http://rest.ensembl.org/map/human/GRCh38/17:45051610..45109016:1/GRCh37
1558    */
1559  0 EnsemblMap mapper = new EnsemblMap();
1560  0 int[] mapping = mapper.getAssemblyMapping(species, chromosome, fromRef,
1561    toRef, queryRange);
1562   
1563  0 if (mapping == null)
1564    {
1565    // mapping service failure
1566  0 return null;
1567    }
1568   
1569    /*
1570    * save mapping for possible future re-use
1571    */
1572  0 String key = makeRangesKey(chromosome, species, fromRef, toRef);
1573  0 if (!assemblyMappings.containsKey(key))
1574    {
1575  0 assemblyMappings.put(key, new HashMap<int[], int[]>());
1576    }
1577   
1578  0 assemblyMappings.get(key).put(queryRange, mapping);
1579   
1580  0 return mapping;
1581    }
1582   
1583    /**
1584    * If we already have a 1:1 contiguous mapping which subsumes the given query
1585    * range, this method just calculates and returns the subset of that mapping,
1586    * else it returns null. In practical terms, if a gene has a contiguous
1587    * mapping between (for example) GRCh37 and GRCh38, then we assume that its
1588    * subsidiary exons occupy unchanged relative positions, and just compute
1589    * these as offsets, rather than do another lookup of the mapping.
1590    * <p>
1591    * If in future these assumptions prove invalid (e.g. for bacterial dna?!),
1592    * simply remove this method or let it always return null.
1593    * <p>
1594    * Warning: many rapid calls to the /map service map result in a 429 overload
1595    * error response
1596    *
1597    * @param queryRange
1598    * @param chromosome
1599    * @param species
1600    * @param fromRef
1601    * @param toRef
1602    * @return
1603    */
 
1604  0 toggle protected int[] findSubsumedRangeMapping(int[] queryRange,
1605    String chromosome, String species, String fromRef, String toRef)
1606    {
1607  0 String key = makeRangesKey(chromosome, species, fromRef, toRef);
1608  0 if (assemblyMappings.containsKey(key))
1609    {
1610  0 Map<int[], int[]> mappedRanges = assemblyMappings.get(key);
1611  0 for (Entry<int[], int[]> mappedRange : mappedRanges.entrySet())
1612    {
1613  0 int[] fromRange = mappedRange.getKey();
1614  0 int[] toRange = mappedRange.getValue();
1615  0 if (fromRange[1] - fromRange[0] == toRange[1] - toRange[0])
1616    {
1617    /*
1618    * mapping is 1:1 in length, so we trust it to have no discontinuities
1619    */
1620  0 if (MappingUtils.rangeContains(fromRange, queryRange))
1621    {
1622    /*
1623    * fromRange subsumes our query range
1624    */
1625  0 int offset = queryRange[0] - fromRange[0];
1626  0 int mappedRangeFrom = toRange[0] + offset;
1627  0 int mappedRangeTo = mappedRangeFrom
1628    + (queryRange[1] - queryRange[0]);
1629  0 return new int[] { mappedRangeFrom, mappedRangeTo };
1630    }
1631    }
1632    }
1633    }
1634  0 return null;
1635    }
1636   
1637    /**
1638    * Transfers the sequence feature to the target sequence, locating its start
1639    * and end range based on the mapping. Features which do not overlap the
1640    * target sequence are ignored.
1641    *
1642    * @param sf
1643    * @param targetSequence
1644    * @param mapping
1645    * mapping from the feature's coordinates to the target sequence
1646    */
 
1647  0 toggle protected void transferFeature(SequenceFeature sf,
1648    SequenceI targetSequence, MapList mapping)
1649    {
1650  0 int[] mappedRange = mapping.locateInTo(sf.getBegin(), sf.getEnd());
1651   
1652  0 if (mappedRange != null)
1653    {
1654  0 String group = sf.getFeatureGroup();
1655  0 int newBegin = Math.min(mappedRange[0], mappedRange[1]);
1656  0 int newEnd = Math.max(mappedRange[0], mappedRange[1]);
1657  0 SequenceFeature copy = new SequenceFeature(sf, newBegin, newEnd,
1658    group, sf.getScore());
1659  0 targetSequence.addSequenceFeature(copy);
1660    }
1661    }
1662   
1663    /**
1664    * Formats a ranges map lookup key
1665    *
1666    * @param chromosome
1667    * @param species
1668    * @param fromRef
1669    * @param toRef
1670    * @return
1671    */
 
1672  0 toggle protected static String makeRangesKey(String chromosome, String species,
1673    String fromRef, String toRef)
1674    {
1675  0 return species + EXCL + chromosome + EXCL + fromRef + EXCL + toRef;
1676    }
1677    }