Fix for right-shifting deletions on AA sequences.

CHANGELOG.md

@@ -7,6 +7,12 @@
 * Switching to Github Workflows for continuous integration.
 * Bumping a couple of dependencies.
 
+### jannovar-core
+
+* Apply fix for (#498, PR #499 by @roland-ewald of @limbus-medtec).
+  This fixes a problem with right-shifting deletions on amino acid sequences.
+  See the tickes and merge request for details.
+
 ## v0.34
 
 ### jannovar-cli

jannovar-core/src/main/java/de/charite/compbio/jannovar/annotation/builders/BlockSubstitutionAnnotationBuilder.java

@@ -153,6 +153,9 @@ public CDSExonicAnnotationBuilder() {
 				wtAASeq.substring(refChangeBeginPos.getPos() / 3, Math.min((refChangeLastPos.getPos() + 1 + 2) / 3, wtAASeq.length())),
 				varAASeq.substring(varChangeBeginPos.getPos() / 3, Math.min((varChangeLastPos.getPos() + 1 + 2) / 3, varAASeq.length())));
 
+			// Shift change in case it is by chance synonymous
+			this.aaChange = AminoAcidChangeNormalizer.shiftSynonymousChange(this.aaChange, wtAASeq, varAASeq);
+
 			// Look for stop codon, starting at change position.
 			this.varAAStopPos = varAASeq.indexOf('*', refChangeBeginPos.getPos() / 3);
 		}

jannovar-core/src/main/java/de/charite/compbio/jannovar/annotation/builders/DeletionAnnotationBuilder.java

@@ -135,8 +135,7 @@ public CDSExonicAnnotationBuilder() {
 			final int varAAEndPos = Math.min(changeBeginPos.getPos() / 3 + delta, varAASeq.length());
 			final String insAA = varAASeq.substring(changeBeginPos.getPos() / 3, varAAEndPos);
 			this.aaChange = new AminoAcidChange(changeBeginPos.getPos() / 3, delAA, insAA);
-			this.aaChange = AminoAcidChangeNormalizer.truncateBothSides(this.aaChange);
-			this.aaChange = AminoAcidChangeNormalizer.normalizeDeletion(wtAASeq, this.aaChange);
+			this.aaChange = AminoAcidChangeNormalizer.shiftSynonymousChange(this.aaChange, wtAASeq, varAASeq);
 		}
 
 		public Annotation build() {

jannovar-core/src/main/java/de/charite/compbio/jannovar/annotation/builders/InsertionAnnotationBuilder.java

@@ -179,8 +179,7 @@ public CDSExonicAnnotationBuilder() {
 			final String insertAA = varAASeq.substring(insertAAPos, insertAAPos + insertAALength);
 			this.aaChange = new AminoAcidChange(insertAAPos, delAA, insertAA);
 			this.aaChange = AminoAcidChangeNormalizer.truncateAltAfterStopCodon(aaChange);
-			this.aaChange = AminoAcidChangeNormalizer.truncateBothSides(aaChange);
-			this.aaChange = AminoAcidChangeNormalizer.shiftInsertion(aaChange, wtAASeq);
+			this.aaChange = AminoAcidChangeNormalizer.shiftSynonymousChange(aaChange, wtAASeq, varAASeq);
 			// Obtain amino acid insertion position.
 			this.varAAInsertPos = this.aaChange.getPos();
 		}

jannovar-core/src/main/java/de/charite/compbio/jannovar/reference/AminoAcidChangeNormalizer.java

@@ -7,6 +7,9 @@
  */
 public final class AminoAcidChangeNormalizer {
 
+	/** Utility class, should not be instantiated.*/
+	private AminoAcidChangeNormalizer() {}
+
 	/**
 	 * Search for stop codon in <code>change.alt</code> and truncate afterwards.
 	 *
@@ -21,44 +24,44 @@ public static AminoAcidChange truncateAltAfterStopCodon(AminoAcidChange change)
 	}
 
 	/**
-	 * Normalize deletion {@link AminoAcidChange} for amino acid string
-	 * <p>
-	 * Return <code>change</code> if it is not a clean deletion.
+	 * This shifts the amino acid and its position to be reported in the <code>proteinChange</code> HGVS annotation to the
+	 * first position where the amino acids actually differ. This is necessary because
+	 * {@link AminoAcidChangeNormalizer#truncateBothSides(AminoAcidChange)} does not suffice in all situations.
 	 *
-	 * @param ref    reference amino acid string to change
-	 * @param change the {@link AminoAcidChange} to normalize
-	 * @return normalized AminoAcidChange
+	 * @param change the original amino acid change to be shifted
+	 * @param wtAASeq the wildtype amino acid sequence (i.e. the translated reference sequence)
+	 * @param varAASeq the predicted amino acid sequence induced by the variant
+	 * @return the amino acid change shifted to the first difference in the sequence, or the end of the ref/alt CDS
 	 */
-	public static AminoAcidChange normalizeDeletion(String ref, AminoAcidChange change) {
-		if (change.getRef().length() == 0 || change.getAlt().length() != 0)
-			return change;
-
-		// Compute shift of deletion.
-		int shift = 0;
-		final int LEN = change.getRef().length();
-		while (change.getPos() + LEN + shift < ref.length()
-			&& ref.charAt(change.getPos()) == ref.charAt(change.getPos() + LEN + shift))
-			shift += 1;
-		if (shift == 0)
-			return change;
-
-		// Build new AminoAcidChange.
-		StringBuilder changeRefBuilder = new StringBuilder();
-		changeRefBuilder.append(ref.substring(change.getPos() + shift, change.getPos() + shift + change.getRef().length()));
-		return new AminoAcidChange(change.getPos() + shift, changeRefBuilder.toString(), "");
+	public static AminoAcidChange shiftSynonymousChange(AminoAcidChange change, String wtAASeq, String varAASeq) {
+	  AminoAcidChange aminoAcidChange = truncateBothSides(change);
+		int position = aminoAcidChange.getPos();
+		int originalPosition = position;
+		int maxPosition = Math.min(
+				wtAASeq.length() - aminoAcidChange.getRef().length(),
+				varAASeq.length() - aminoAcidChange.getAlt().length());
+		while (position < maxPosition && wtAASeq.charAt(position) != '*'
+				&& wtAASeq.charAt(position) == varAASeq.charAt(position)) {
+			position++;
+		}
+		if (position == originalPosition) {
+			return aminoAcidChange;
+		}
+		return new AminoAcidChange(position,
+				wtAASeq.substring(position, position + aminoAcidChange.getRef().length()),
+				varAASeq.substring(position, position + aminoAcidChange.getAlt().length()));
 	}
 
 	/**
 	 * Truncate {@link AminoAcidChange} from both sides for matching ref/alt prefixes/suffixes.
 	 * <p>
 	 * Truncating of the prefixes is given higher priority to conform with the HGVS notation (you have to call
-	 * {@link #shiftInsertion}) afterwards.
+	 * {@link #shiftSynonymousChange}) afterwards.
 	 *
 	 * @param aaChange {@link AminoAcidChange} to truncate
 	 * @return updated {@link AminoAcidChange}
 	 */
-	public static AminoAcidChange truncateBothSides(AminoAcidChange aaChange) {
-		// TODO(holtgrem): Test me!
+	private static AminoAcidChange truncateBothSides(AminoAcidChange aaChange) {
 
 		// Truncate suffixes / from the right.
 		final int REFLEN = aaChange.getRef().length() - 1;
@@ -84,38 +87,4 @@ public static AminoAcidChange truncateBothSides(AminoAcidChange aaChange) {
 		return aaChange;
 	}
 
-	/**
-	 * Shift insertion {@link AminoAcidChange} to the right in WT AA sequence.
-	 * <p>
-	 * Returns <code>aaChange</code> if <code>aaChange.ref</code> is not the empty string.
-	 *
-	 * @param aaChange {@link AminoAcidChange} to normalize
-	 * @param wtAASeq  WT AA sequence to use for shifting
-	 * @return updated {@link AminoAcidChange}
-	 */
-	public static AminoAcidChange shiftInsertion(AminoAcidChange aaChange, String wtAASeq) {
-		// TODO(holtgrem): Test me!
-		if (aaChange.getRef().length() != 0)
-			return aaChange;
-
-		// Insert the alternative bases at the position indicated by txPos.
-		StringBuilder builder = new StringBuilder(wtAASeq);
-		builder.insert(aaChange.getPos(), aaChange.getAlt());
-
-		// Execute algorithm and compute the shift.
-		int pos = aaChange.getPos();
-		int shift = 0;
-		final int LEN = aaChange.getAlt().length();
-		final String seq = builder.toString();
-		while ((pos + LEN < seq.length()) && (seq.charAt(pos) == seq.charAt(pos + LEN))) {
-			++shift;
-			++pos;
-		}
-
-		if (shift == 0) // only rebuild if shift > 0
-			return aaChange;
-		else
-			return new AminoAcidChange(pos, "", seq.substring(pos, pos + LEN));
-	}
-
 }

jannovar-core/src/test/java/de/charite/compbio/jannovar/annotation/builders/DeletionAnnotationBuilderTest.java

@@ -326,6 +326,20 @@ public void testForwardFrameShiftDeletion() throws InvalidGenomeVariant {
 		Assert.assertEquals(ImmutableSortedSet.of(VariantEffect.FRAMESHIFT_TRUNCATION), annotation1.getEffects());
 	}
 
+	@Test
+	public void testForwardInternalFrameShiftNormalization() throws InvalidGenomeVariant {
+		// The following starts with a codon but still causes a shift in the nucleotide sequence.
+		GenomeVariant change1 = new GenomeVariant(new GenomePosition(refDict, Strand.FWD, 1, 6645991,
+				PositionType.ZERO_BASED), "GAGAAACCCT", "");
+		Annotation annotation1 = new DeletionAnnotationBuilder(infoForward, change1, new AnnotationBuilderOptions())
+				.build();
+		Assert.assertEquals(infoForward.getAccession(), annotation1.getTranscript().getAccession());
+		Assert.assertEquals(3, annotation1.getAnnoLoc().getRank());
+		Assert.assertEquals("946_955del", annotation1.getCDSNTChange().toHGVSString());
+		Assert.assertEquals("(Glu316Leufs*25)", annotation1.getProteinChange().toHGVSString(AminoAcidCode.THREE_LETTER));
+		Assert.assertEquals(ImmutableSortedSet.of(VariantEffect.FRAMESHIFT_TRUNCATION), annotation1.getEffects());
+	}
+
 	@Test
 	public void testForwardNonFrameShiftDeletion() throws InvalidGenomeVariant {
 		// clean (FS of begin position is 0) deletion of one codon, starting in intron (thus no "exon3" annotation is
@@ -1207,7 +1221,7 @@ public void testRealWorldCase_uc011mcs_() throws InvalidGenomeVariant {
 		Assert.assertEquals(infoForward.getAccession(), annotation1.getTranscript().getAccession());
 		Assert.assertEquals(12, annotation1.getAnnoLoc().getRank());
 		Assert.assertEquals("1068_1071del", annotation1.getCDSNTChange().toHGVSString());
-		Assert.assertEquals("(Glu358del)", annotation1.getProteinChange().toHGVSString(AminoAcidCode.THREE_LETTER));
+		Assert.assertEquals("(Glu357Lysfs*?)", annotation1.getProteinChange().toHGVSString(AminoAcidCode.THREE_LETTER));
 		Assert.assertEquals(ImmutableSortedSet.of(VariantEffect.FRAMESHIFT_TRUNCATION), annotation1.getEffects());
 	}
 

jannovar-core/src/test/java/de/charite/compbio/jannovar/reference/AminoAcidChangeTest.java

@@ -13,42 +13,84 @@ public class AminoAcidChangeTest {
 
 	@Before
 	public void setUp() throws Exception {
-		this.ref = "AAACCCAAACCC";
-		this.ref2 = "CATCATCTTCA";
+		this.ref = "LLLCCCLLLCCC";
+		this.ref2 = "CLTCLTCTTCL";
 	}
 
 	@Test
 	public void testShiftNoRefChange() {
 		AminoAcidChange origChange = new AminoAcidChange(3, "CC", "");
-		AminoAcidChange modChange = AminoAcidChangeNormalizer.normalizeDeletion(ref, origChange);
+		AminoAcidChange modChange = AminoAcidChangeNormalizer.shiftSynonymousChange(origChange, ref, "LLLCLLLCCC");
 		Assert.assertEquals(new AminoAcidChange(4, "CC", ""), modChange);
 	}
 
 	@Test
 	public void testShiftNoRefChangeEnd() {
 		AminoAcidChange origChange = new AminoAcidChange(9, "CC", "");
-		AminoAcidChange modChange = AminoAcidChangeNormalizer.normalizeDeletion(ref, origChange);
+		AminoAcidChange modChange = AminoAcidChangeNormalizer.shiftSynonymousChange(origChange, ref, "LLLCCCLLLC");
 		Assert.assertEquals(new AminoAcidChange(10, "CC", ""), modChange);
 	}
 
 	@Test
 	public void testShiftRefChange() {
-		AminoAcidChange origChange = new AminoAcidChange(3, "CAT", "");
-		AminoAcidChange modChange = AminoAcidChangeNormalizer.normalizeDeletion(ref2, origChange);
-		Assert.assertEquals(new AminoAcidChange(4, "ATC", ""), modChange);
+		AminoAcidChange origChange = new AminoAcidChange(3, "CLT", "");
+		AminoAcidChange modChange = AminoAcidChangeNormalizer.shiftSynonymousChange(origChange, ref2, "CLTCTTCL");
+		Assert.assertEquals(new AminoAcidChange(4, "LTC", ""), modChange);
+	}
+
+	@Test
+	public void testShiftDeletionFrameshiftNoInsAA() {
+		AminoAcidChange origChange = new AminoAcidChange(3, "CQY", "");
+		AminoAcidChange modChange = AminoAcidChangeNormalizer.shiftSynonymousChange(origChange, "LLLCQYCLLL", "LLLCQYVA");
+				Assert.assertEquals(new AminoAcidChange(6, "CLL", ""), modChange);
+	}
+
+	@Test
+	public void testShiftDeletionFrameshiftInsAA() {
+		AminoAcidChange origChange = new AminoAcidChange(3, "CQY", "C");
+		AminoAcidChange modChange = AminoAcidChangeNormalizer.shiftSynonymousChange(origChange, "LLLCQYCLLL", "LLLCQYVA");
+		Assert.assertEquals(new AminoAcidChange(6, "CL", ""), modChange);
+	}
+
+	@Test
+	public void testShiftInsertionNoFrameshift() {
+		AminoAcidChange origChange = new AminoAcidChange(3, "C", "CQY");
+		AminoAcidChange modChange = AminoAcidChangeNormalizer.shiftSynonymousChange(origChange, "LLLCQYCLLL", "LLLCQYQYCLLL");
+		Assert.assertEquals(new AminoAcidChange(6, "", "QY"), modChange);
+	}
+
+	@Test
+	public void testShiftInsertionFrameshift() {
+		AminoAcidChange origChange = new AminoAcidChange(3, "C", "CQY");
+		AminoAcidChange modChange = AminoAcidChangeNormalizer.shiftSynonymousChange(origChange, "LLLCQYCLLL", "LLLCQYQYVAAA");
+		Assert.assertEquals(new AminoAcidChange(6, "", "QY"), modChange);
+	}
+
+	@Test
+	public void testShiftSubstitutionNoFrameshift() {
+		AminoAcidChange origChange = new AminoAcidChange(3, "CQYC", "CQLC");
+		AminoAcidChange modChange = AminoAcidChangeNormalizer.shiftSynonymousChange(origChange, "LLLCQYCLLL", "LLLCQLCLLL");
+		Assert.assertEquals(new AminoAcidChange(5, "Y", "L"), modChange);
+	}
+
+	@Test
+	public void testShiftSubstitutionFrameshift() {
+		AminoAcidChange origChange = new AminoAcidChange(3, "CQYC", "CQYQ");
+		AminoAcidChange modChange = AminoAcidChangeNormalizer.shiftSynonymousChange(origChange, "LLLCQYCLLL", "LLLCQYQYVAAA");
+		Assert.assertEquals(new AminoAcidChange(6, "C", "Q"), modChange);
 	}
 
 	@Test
 	public void testNoShift() {
 		AminoAcidChange origChange = new AminoAcidChange(3, "CCC", "");
-		AminoAcidChange modChange = AminoAcidChangeNormalizer.normalizeDeletion(ref, origChange);
+		AminoAcidChange modChange = AminoAcidChangeNormalizer.shiftSynonymousChange(origChange, ref, "LLLLLLCCC");
 		Assert.assertEquals(new AminoAcidChange(3, "CCC", ""), modChange);
 	}
 
 	@Test
 	public void testNoShiftEnd() {
 		AminoAcidChange origChange = new AminoAcidChange(9, "CCC", "");
-		AminoAcidChange modChange = AminoAcidChangeNormalizer.normalizeDeletion(ref, origChange);
+		AminoAcidChange modChange = AminoAcidChangeNormalizer.shiftSynonymousChange(origChange, ref, "LLLCCCLLL");
 		Assert.assertEquals(new AminoAcidChange(9, "CCC", ""), modChange);
 	}