- * Maps exon features from dna to protein, and computes variants in peptide
- * product generated by variants in dna, and adds them as sequence_variant
- * features on the protein sequence. Returns the number of variant features
- * added.
- *
- * @param dnaSeq
- * @param peptide
- * @param dnaToProtein
- */
- public static int computeProteinFeatures(SequenceI dnaSeq,
- SequenceI peptide, MapList dnaToProtein)
- {
- while (dnaSeq.getDatasetSequence() != null)
- {
- dnaSeq = dnaSeq.getDatasetSequence();
- }
- while (peptide.getDatasetSequence() != null)
- {
- peptide = peptide.getDatasetSequence();
- }
-
- transferFeatures(dnaSeq, peptide, dnaToProtein, SequenceOntologyI.EXON);
-
- /*
- * compute protein variants from dna variants and codon mappings;
- * NB - alternatively we could retrieve this using the REST service e.g.
- * http://rest.ensembl.org/overlap/translation
- * /ENSP00000288602?feature=transcript_variation;content-type=text/xml
- * which would be a bit slower but possibly more reliable
- */
-
- /*
- * build a map with codon variations for each potentially varying peptide
- */
- LinkedHashMap<Integer, List<DnaVariant>[]> variants = buildDnaVariantsMap(
- dnaSeq, dnaToProtein);
-
- /*
- * scan codon variations, compute peptide variants and add to peptide sequence
- */
- int count = 0;
- for (Entry<Integer, List<DnaVariant>[]> variant : variants.entrySet())
- {
- int peptidePos = variant.getKey();
- List<DnaVariant>[] codonVariants = variant.getValue();
- count += computePeptideVariants(peptide, peptidePos, codonVariants);
- }
-
- return count;
- }
-
- /**
- * Computes non-synonymous peptide variants from codon variants and adds them
- * as sequence_variant features on the protein sequence (one feature per
- * allele variant). Selected attributes (variant id, clinical significance)
- * are copied over to the new features.
- *
- * @param peptide
- * the protein sequence
- * @param peptidePos
- * the position to compute peptide variants for
- * @param codonVariants
- * a list of dna variants per codon position
- * @return the number of features added
- */
- static int computePeptideVariants(SequenceI peptide, int peptidePos,
- List<DnaVariant>[] codonVariants)
- {
- String residue = String
- .valueOf(peptide.getCharAt(peptidePos - peptide.getStart()));
- int count = 0;
- String base1 = codonVariants[0].get(0).base;
- String base2 = codonVariants[1].get(0).base;
- String base3 = codonVariants[2].get(0).base;
-
- /*
- * variants in first codon base
- */
- for (DnaVariant var : codonVariants[0])
- {
- if (var.variant != null)
- {
- String alleles = (String) var.variant.getValue(Gff3Helper.ALLELES);
- if (alleles != null)
- {
- for (String base : alleles.split(","))
- {
- if (!base1.equalsIgnoreCase(base))
- {
- String codon = base.toUpperCase() + base2.toLowerCase()
- + base3.toLowerCase();
- String canonical = base1.toUpperCase() + base2.toLowerCase()
- + base3.toLowerCase();
- if (addPeptideVariant(peptide, peptidePos, residue, var,
- codon, canonical))
- {
- count++;
- }
- }
- }
- }
- }
- }
-
- /*
- * variants in second codon base
- */
- for (DnaVariant var : codonVariants[1])
- {
- if (var.variant != null)
- {
- String alleles = (String) var.variant.getValue(Gff3Helper.ALLELES);
- if (alleles != null)
- {
- for (String base : alleles.split(","))
- {
- if (!base2.equalsIgnoreCase(base))
- {
- String codon = base1.toLowerCase() + base.toUpperCase()
- + base3.toLowerCase();
- String canonical = base1.toLowerCase() + base2.toUpperCase()
- + base3.toLowerCase();
- if (addPeptideVariant(peptide, peptidePos, residue, var,
- codon, canonical))
- {
- count++;
- }
- }
- }
- }
- }
- }
-
- /*
- * variants in third codon base
- */
- for (DnaVariant var : codonVariants[2])
- {
- if (var.variant != null)
- {
- String alleles = (String) var.variant.getValue(Gff3Helper.ALLELES);
- if (alleles != null)
- {
- for (String base : alleles.split(","))
- {
- if (!base3.equalsIgnoreCase(base))
- {
- String codon = base1.toLowerCase() + base2.toLowerCase()
- + base.toUpperCase();
- String canonical = base1.toLowerCase() + base2.toLowerCase()
- + base3.toUpperCase();
- if (addPeptideVariant(peptide, peptidePos, residue, var,
- codon, canonical))
- {
- count++;
- }
- }
- }
- }
- }
- }
-
- return count;
- }
-
- /**
- * Helper method that adds a peptide variant feature. ID and
- * clinical_significance attributes of the dna variant (if present) are copied
- * to the new feature.
- *
- * @param peptide
- * @param peptidePos
- * @param residue
- * @param var
- * @param codon
- * the variant codon e.g. aCg
- * @param canonical
- * the 'normal' codon e.g. aTg
- * @return true if a feature was added, else false
- */
- static boolean addPeptideVariant(SequenceI peptide, int peptidePos,
- String residue, DnaVariant var, String codon, String canonical)
- {
- /*
- * get peptide translation of codon e.g. GAT -> D
- * note that variants which are not single alleles,
- * e.g. multibase variants or HGMD_MUTATION etc
- * are currently ignored here
- */
- String trans = codon.contains("-") ? null
- : (codon.length() > CODON_LENGTH ? null
- : ResidueProperties.codonTranslate(codon));
- if (trans == null)
- {
- return false;
- }
- String desc = canonical + "/" + codon;
- String featureType = "";
- if (trans.equals(residue))
- {
- featureType = SequenceOntologyI.SYNONYMOUS_VARIANT;
- }
- else if (ResidueProperties.STOP.equals(trans))
- {
- featureType = SequenceOntologyI.STOP_GAINED;
- }
- else
- {
- String residue3Char = StringUtils
- .toSentenceCase(ResidueProperties.aa2Triplet.get(residue));
- String trans3Char = StringUtils
- .toSentenceCase(ResidueProperties.aa2Triplet.get(trans));
- desc = "p." + residue3Char + peptidePos + trans3Char;
- featureType = SequenceOntologyI.NONSYNONYMOUS_VARIANT;
- }
- SequenceFeature sf = new SequenceFeature(featureType, desc, peptidePos,
- peptidePos, var.getSource());
-
- StringBuilder attributes = new StringBuilder(32);
- String id = (String) var.variant.getValue(VARIANT_ID);
- if (id != null)
- {
- if (id.startsWith(SEQUENCE_VARIANT))
- {
- id = id.substring(SEQUENCE_VARIANT.length());
- }
- sf.setValue(VARIANT_ID, id);
- attributes.append(VARIANT_ID).append("=").append(id);
- // TODO handle other species variants JAL-2064
- StringBuilder link = new StringBuilder(32);
- try
- {
- link.append(desc).append(" ").append(id).append(
- "|http://www.ensembl.org/Homo_sapiens/Variation/Summary?v=")
- .append(URLEncoder.encode(id, "UTF-8"));
- sf.addLink(link.toString());
- } catch (UnsupportedEncodingException e)
- {
- // as if
- }
- }
- String clinSig = (String) var.variant.getValue(CLINICAL_SIGNIFICANCE);
- if (clinSig != null)
- {
- sf.setValue(CLINICAL_SIGNIFICANCE, clinSig);
- attributes.append(";").append(CLINICAL_SIGNIFICANCE).append("=")
- .append(clinSig);
- }
- peptide.addSequenceFeature(sf);
- if (attributes.length() > 0)
- {
- sf.setAttributes(attributes.toString());
- }
- return true;
- }
-
- /**
- * Builds a map whose key is position in the protein sequence, and value is a
- * list of the base and all variants for each corresponding codon position.
- * <p>
- * This depends on dna variants being held as a comma-separated list as
- * property "alleles" on variant features.
- *
- * @param dnaSeq
- * @param dnaToProtein
- * @return
- */
- @SuppressWarnings("unchecked")
- static LinkedHashMap<Integer, List<DnaVariant>[]> buildDnaVariantsMap(
- SequenceI dnaSeq, MapList dnaToProtein)
- {
- /*
- * map from peptide position to all variants of the codon which codes for it
- * LinkedHashMap ensures we keep the peptide features in sequence order
- */
- LinkedHashMap<Integer, List<DnaVariant>[]> variants = new LinkedHashMap<>();
-
- List<SequenceFeature> dnaFeatures = dnaSeq.getFeatures()
- .getFeaturesByOntology(SequenceOntologyI.SEQUENCE_VARIANT);
- if (dnaFeatures.isEmpty())
- {
- return variants;
- }
-
- int dnaStart = dnaSeq.getStart();
- int[] lastCodon = null;
- int lastPeptidePostion = 0;
-
- /*
- * build a map of codon variations for peptides
- */
- for (SequenceFeature sf : dnaFeatures)
- {
- int dnaCol = sf.getBegin();
- if (dnaCol != sf.getEnd())
- {
- // not handling multi-locus variant features
- continue;
- }
-
- /*
- * ignore variant if not a SNP
- */
- String alls = (String) sf.getValue(Gff3Helper.ALLELES);
- if (alls == null)
- {
- continue; // non-SNP VCF variant perhaps - can't process this
- }
-
- String[] alleles = alls.toUpperCase().split(",");
- boolean isSnp = true;
- for (String allele : alleles)
- {
- if (allele.trim().length() > 1)
- {
- isSnp = false;
- }
- }
- if (!isSnp)
- {
- continue;
- }
-
- int[] mapsTo = dnaToProtein.locateInTo(dnaCol, dnaCol);
- if (mapsTo == null)
- {
- // feature doesn't lie within coding region
- continue;
- }
- int peptidePosition = mapsTo[0];
- List<DnaVariant>[] codonVariants = variants.get(peptidePosition);
- if (codonVariants == null)
- {
- codonVariants = new ArrayList[CODON_LENGTH];
- codonVariants[0] = new ArrayList<>();
- codonVariants[1] = new ArrayList<>();
- codonVariants[2] = new ArrayList<>();
- variants.put(peptidePosition, codonVariants);
- }
-
- /*
- * get this peptide's codon positions e.g. [3, 4, 5] or [4, 7, 10]
- */
- int[] codon = peptidePosition == lastPeptidePostion ? lastCodon
- : MappingUtils.flattenRanges(dnaToProtein.locateInFrom(
- peptidePosition, peptidePosition));
- lastPeptidePostion = peptidePosition;
- lastCodon = codon;
-
- /*
- * save nucleotide (and any variant) for each codon position
- */
- for (int codonPos = 0; codonPos < CODON_LENGTH; codonPos++)
- {
- String nucleotide = String.valueOf(
- dnaSeq.getCharAt(codon[codonPos] - dnaStart)).toUpperCase();
- List<DnaVariant> codonVariant = codonVariants[codonPos];
- if (codon[codonPos] == dnaCol)
- {
- if (!codonVariant.isEmpty()
- && codonVariant.get(0).variant == null)
- {
- /*
- * already recorded base value, add this variant
- */
- codonVariant.get(0).variant = sf;
- }
- else
- {
- /*
- * add variant with base value
- */
- codonVariant.add(new DnaVariant(nucleotide, sf));
- }
- }
- else if (codonVariant.isEmpty())
- {
- /*
- * record (possibly non-varying) base value
- */
- codonVariant.add(new DnaVariant(nucleotide));
- }
- }
- }
- return variants;
- }
-
- /**