2f19b4081ef0f0d93daf8f7ff1c26cf8879a4d14
braney
  Thu Apr 26 17:26:10 2012 -0700
more work on #6152.   Now with in-frame deletions!
diff --git src/hg/lib/gpFx.c src/hg/lib/gpFx.c
index 5af7432..1689539 100644
--- src/hg/lib/gpFx.c
+++ src/hg/lib/gpFx.c
@@ -1,447 +1,521 @@
 
 /* gpFx --- routines to calculate the effect of variation on a genePred */
 
 #include "common.h"
 #include "genePred.h"
 #include "gpFx.h"
 
 
+unsigned countDashes(char *string)
+{
+int count = 0;
+
+while(*string)
+    {
+    if (*string == '-')
+	count++;
+    string++;
+    }
+
+return count;
+}
+
+static void mergeAllele(char *transcript, int variantWidth,
+    char *newAlleleSeq, int alleleLength)
+{
+if (variantWidth == alleleLength)
+    {
+    // for the moment, we're sticking the dashes into the transcripts
+    if (1) //noDashes(newAlleleSeq))
+	memcpy(transcript, newAlleleSeq, alleleLength);
+    else
+	{
+	char *transcriptSource = transcript;
+	int ii;
+	for(ii=0; ii < variantWidth; ii++)
+	    {
+	    if (*newAlleleSeq == '-')
+		{
+		transcriptSource++;
+		}
+	    else
+		{
+		*transcript++ = *newAlleleSeq++;
+		transcriptSource++;
+		}
+	    }
+	while(*transcriptSource)
+	    *transcript++ = *transcriptSource++;
+	*transcript = 0;
+	}
+    }
+}
+
 char *gpFxModifySequence(struct allele *allele, struct genePred *pred, 
     int exonNum, struct psl *transcriptPsl, struct dnaSeq *transcriptSequence)
 /* modify a transcript to what it'd be if the alternate allele were present */
 {
 // clip allele to exon
 struct allele *clipAllele = alleleClip(allele, transcriptPsl->tStarts[exonNum], 
 	transcriptPsl->tStarts[exonNum] + transcriptPsl->blockSizes[exonNum]);
 
 // change transcript at variant point
 int exonOffset = clipAllele->variant->chromStart - transcriptPsl->tStarts[exonNum];
 int transcriptOffset = transcriptPsl->qStarts[exonNum] + exonOffset;
 
-if (clipAllele->length != clipAllele->variant->chromEnd - clipAllele->variant->chromStart)
+int variantWidth = clipAllele->variant->chromEnd - clipAllele->variant->chromStart;
+if (clipAllele->length !=  variantWidth)
     errAbort("only support alleles the same length as the reference");
 
 char *retSequence = cloneString(transcriptSequence->dna);
 char *newAlleleSeq = cloneString(clipAllele->sequence);
 if (*pred->strand == '-')
     {
-    transcriptOffset = transcriptSequence->size - (transcriptOffset + 1);
+    transcriptOffset = transcriptSequence->size - (transcriptOffset + strlen(newAlleleSeq));
     reverseComplement(newAlleleSeq, strlen(newAlleleSeq));
     }
 
 // make the change in the sequence
-memcpy(&retSequence[transcriptOffset], newAlleleSeq, allele->length);
+mergeAllele( &retSequence[transcriptOffset], variantWidth, newAlleleSeq, allele->length);
 
 // clean up
 freeMem(newAlleleSeq);
 
 return retSequence;
 }
 
 static char *getCodingSequence(struct genePred *pred, char *transcriptSequence)
 /* extract the CDS from a transcript */
 {
 int ii;
 
 if (*pred->strand == '-')
     reverseComplement(transcriptSequence, strlen(transcriptSequence));
 
 // trim off the 5' UTR ( or 3' if on the minus strand)
 char *ptr = transcriptSequence;
 for(ii=0; ii < pred->exonCount; ii++)
     {
     int exonSize = pred->exonEnds[ii] - pred->exonStarts[ii];
     if ((pred->cdsStart > pred->exonStarts[ii]) &&
 	(pred->cdsStart < pred->exonEnds[ii]))
 	break;
 
     ptr += exonSize;
     }
 
 // clip off part of UTR in exon that has CDS in it too
 int exonOffset = pred->cdsStart - pred->exonStarts[ii];
 ptr += exonOffset;
 
 char *newString = cloneString(ptr);
 
 // trim off 3' (or 5' if on minus strand)
 newString[genePredCdsSize(pred)] = 0;
 
 // correct for strand
 if (*pred->strand == '-')
     {
     reverseComplement(transcriptSequence, strlen(transcriptSequence));
     reverseComplement(newString, strlen(newString));
     }
 
 return newString;
 }
 
 static int firstChange(char *string1, char *string2, int *numDifferent)
 /* return the position of the first difference between the two sequences */
+/* if numDifferent is non-NULL, return number of characters between first 
+ * difference, and the last difference */
 {
 int count = 0;
 
-while (*string1++ == *string2++)
-    count++;
+for(; *string1 == *string2; count++, string1++, string2++)
+    ;
+
+int firstChange = count;
+int lastChange = firstChange;
 
 if (numDifferent != NULL)
     {
-    *numDifferent = 1;
-    while ((*string1) && (*string2) && (*string1++ != *string2++))
-	(*numDifferent)++;
+    for (; (*string1) && (*string2); string1++, string2++, count++)
+	{
+	if (*string1 != *string2)
+	    lastChange = count;
+	}
+    *numDifferent = lastChange - firstChange + 1;
     }
 
-return count;
+return firstChange;
 }
 
 static void getSequences(struct genePred *pred, char *transcriptSequence,
     char **codingSequence,  aaSeq **aaSeq)
 /* get coding sequences for a transcript and a variant transcript */
 {
 *codingSequence = getCodingSequence(pred, transcriptSequence);
 struct dnaSeq *codingDna = newDnaSeq(*codingSequence, strlen(*codingSequence), NULL);
 *aaSeq = translateSeq(codingDna, 0, FALSE);
 freez(codingDna);
 }
 
 static char *
 codonChangeString(int codonPos, int numCodons, char *oldCodingSequence, char *newCodingSequence)
 /* generate string that describes a codon change */
 {
 struct dyString *dy = newDyString(100);
 int ii;
 
 for(ii=0; ii < numCodons; ii++)
     {
     dyStringPrintf(dy, "%c%c%c > %c%c%c",
 	toupper(oldCodingSequence[codonPos + 0]),
 	toupper(oldCodingSequence[codonPos + 1]),
 	toupper(oldCodingSequence[codonPos + 2]),
 	toupper(newCodingSequence[codonPos + 0]),
 	toupper(newCodingSequence[codonPos + 1]),
 	toupper(newCodingSequence[codonPos + 2]));
     if (ii < numCodons - 1)
 	dyStringPrintf(dy, ",");
     codonPos += 3;
     }
 
 return dy->string;
 }
 
 static char *
 aaChangeString(int pepPosition, int numaa, char *oldaa, char *newaa)
 /* generate string that describes an amino acid change */
 {
 struct dyString *dy = newDyString(100);
 int ii;
 
 for(ii=0; ii < numaa; ii++)
     {
     dyStringPrintf(dy, "%c > %c", 
 	toupper(oldaa[pepPosition+ii]), toupper(newaa[pepPosition+ii]));
     if (ii < numaa - 1)
 	dyStringPrintf(dy, ",");
     }
 
 return dy->string;
 }
 
+struct gpFx *gpFxInCdsDeletion( struct allele *allele, struct genePred *pred, 
+    int exonNum, struct psl *transcriptPsl, struct dnaSeq *transcriptSequence,
+    char *newSequence)
+{
+struct gpFx *effects;
+AllocVar(effects);
+return effects;
+}
+
 struct gpFx *gpFxCheckUtr( struct allele *allele, struct genePred *pred, 
     int exonNum, struct psl *transcriptPsl, struct dnaSeq *transcriptSequence,
     char *newSequence)
 /* check for effects in UTR of coding gene */
 {
 if (positiveRangeIntersection(pred->txStart, pred->cdsStart,
 	allele->variant->chromStart, allele->variant->chromEnd))
     {
     // we're in 5' UTR ( or UTR intron )
     errAbort("don't support variants in 5' UTR");
     }
 
 if (positiveRangeIntersection(pred->txStart, pred->cdsStart,
 	allele->variant->chromStart, allele->variant->chromEnd))
     {
     // we're in 3' UTR
     errAbort("don't support variants in 3' UTR");
     }
 
 return NULL;
 }
 
 struct gpFx *gpFxChangedNoncodingTranscript( struct allele *allele, struct genePred *pred, 
     int exonNum, struct psl *transcriptPsl, struct dnaSeq *transcriptSequence,
     char *newSequence)
 /* generate an effect for a variant in a non-coding transcript */
 {
 return NULL;
 //    errAbort("found a change in non-coding gene. we don't support non-coding genes at the moment");
 }
 
 struct gpFx *gpFxChangedCodingTranscript( struct allele *allele, struct genePred *pred, 
     int exonNum, struct psl *transcriptPsl, struct dnaSeq *transcriptSequence,
     char *newSequence)
 /* calculate effect of allele change on coding transcript */
 {
 struct gpFx *effectsList = NULL;
 
 // first find effects of allele in UTR
 effectsList = gpFxCheckUtr(allele, pred, exonNum, transcriptPsl, 
     transcriptSequence, newSequence);
 
 // check to see if coding sequence is changed
 // calculate original and variant coding AA's
 char *oldCodingSequence, *newCodingSequence;
 aaSeq *oldaa, *newaa;
 
 getSequences(pred, transcriptSequence->dna, &oldCodingSequence, &oldaa);
 getSequences(pred, newSequence, &newCodingSequence, &newaa);
 
 // if coding region hasn't changed, we're done
 if (sameString(oldCodingSequence, newCodingSequence))
     return effectsList;
 
+
 // start allocating the effect structure
 struct gpFx *effects;
 AllocVar(effects);
 slAddHead(&effectsList, effects);
 
 struct codingChange *cc = &effects->so.sub.codingChange;
 cc->transcript = cloneString(pred->name);
 int dnaChangeLength;
 cc->cDnaPosition = firstChange( newSequence, transcriptSequence->dna, &dnaChangeLength);
 int cdsChangeLength;
 cc->cdsPosition = firstChange( newCodingSequence, oldCodingSequence, &cdsChangeLength);
 if (*pred->strand == '-')
     cc->exonNumber = pred->exonCount - exonNum;
 else
     cc->exonNumber = exonNum;
 
 // calc codon change
-int codonPosStart = (cc->cdsPosition / 3) * 3;
-int codonPosEnd = ((cdsChangeLength + cc->cdsPosition) / 3) * 3;
-int numCodons = (codonPosEnd - codonPosStart) / 3 + 1;
-cc->codonChanges = codonChangeString( codonPosStart, numCodons, oldCodingSequence, newCodingSequence);
+int codonPosStart = (cc->cdsPosition / 3) ;
+int codonPosEnd = ((cdsChangeLength - 1 + cc->cdsPosition) / 3) ;
+int numCodons = (codonPosEnd - codonPosStart + 1);
+cc->codonChanges = codonChangeString( codonPosStart*3, numCodons, oldCodingSequence, newCodingSequence);
+// by convention we zero out these fields if they aren't used
+cc->pepPosition = 0;
+cc->aaChanges = "";
 
+int numDashes;
 if (sameString(newaa->dna, oldaa->dna))
     {
     // synonymous change
     effects->so.soNumber = synonymous_variant;
-    
-    // by convention we zero out these fields since they aren't used
-    cc->pepPosition = 0;
-    cc->aaChanges = "";
     }
 else
     {
-    // non-synonymous change
-    effects->so.soNumber = non_synonymous_variant;
-
     int numDifferent;
     cc->pepPosition = firstChange( newaa->dna, oldaa->dna, &numDifferent);
     cc->aaChanges = aaChangeString( cc->pepPosition, numDifferent, 
 	oldaa->dna, newaa->dna);
+
+    if ((numDashes = countDashes(newCodingSequence)) != 0)
+	{
+	if ((numDashes % 3) == 0)
+	    effects->so.soNumber = inframe_deletion;
+	else
+	    effects->so.soNumber = frameshift_variant;
+	}
+    else
+	{
+	// non-synonymous change
+	effects->so.soNumber = non_synonymous_variant;
+	}
     }
 
 return effectsList;
 }
 
 
 struct gpFx *gpFxInExon(struct allele *allele, struct genePred *pred, 
     int exonNum, struct psl *transcriptPsl, struct dnaSeq *transcriptSequence)
 /* generate an effect from a different allele in an exon */
 {
 char *newSequence = gpFxModifySequence(allele, pred, exonNum,
 	transcriptPsl, transcriptSequence);
 
 if (sameString(newSequence, transcriptSequence->dna))
     return NULL;  // no change in transcript
 
 struct gpFx *effectsList;
 if (pred->cdsStart != pred->cdsEnd)
     effectsList = gpFxChangedCodingTranscript( allele, pred, exonNum, transcriptPsl, 
 	transcriptSequence, newSequence);
 else
     effectsList = gpFxChangedNoncodingTranscript( allele, pred, exonNum, transcriptPsl, 
 	transcriptSequence, newSequence);
 
 return effectsList;
 }
 
 static struct psl *genePredToPsl(struct genePred *pred)
 /* generate a PSL alignment to a transcript from a genePred */
 {
 int qSize = genePredBases(pred);
 #define BOGUS_CHROM_SIZE  0
 struct psl *psl = pslNew(pred->name, qSize, 0, qSize,
                          pred->chrom, BOGUS_CHROM_SIZE, 
 			 pred->txStart, pred->txEnd,
 			 pred->strand, pred->exonCount, 0);
 psl->match = psl->qSize;
 
 int i, qNext = 0;
 for (i = 0; i < pred->exonCount; i++)
     {
     int exonSize =  pred->exonEnds[i] - pred->exonStarts[i];
 
     psl->qStarts[i] = qNext;
     //psl->tStarts[i] = pred->exonStarts[i] + pred->txStart;
     psl->tStarts[i] = pred->exonStarts[i];
     psl->blockSizes[i] = exonSize;
 
 /* notnow
     if (i > 0)
         {
         psl->tNumInsert += 1;
         psl->tBaseInsert += psl->tStarts[i] - pslTEnd(psl, i-1);
         }
 */
 
     psl->blockCount++;
     qNext += psl->blockSizes[i];
     }
 
 return psl;
 }
 
 static struct gpFx *gpFxCheckExons(struct variant *variant, 
     struct genePred *pred, struct dnaSeq *transcriptSequence)
 // check to see if the variant is in an exon
 {
 int ii;
 struct gpFx *effectsList = NULL;
 struct psl *transcriptPsl = genePredToPsl(pred);
 
 // should copy transcriptSequence if we have more than one variant!!
 for(; variant ; variant = variant->next)
     {
     struct allele *allele = variant->alleles;
     for(; allele ; allele = allele->next)
 	{
 	for(ii=0; ii < pred->exonCount; ii++)
 	    {
 	    // check if in an exon
 	    int size;
 	    if ((size = positiveRangeIntersection(pred->exonStarts[ii], 
 		pred->exonEnds[ii], 
 		variant->chromStart, variant->chromEnd)) > 0)
 		{
 
 		if (size != variant->chromEnd - variant->chromStart)
 		    errAbort("variant crosses exon boundary");
 
 		effectsList = slCat(effectsList, gpFxInExon(allele, pred, ii,
 		    transcriptPsl, transcriptSequence));
 		}
 	    }
 	}
     }
 
 return effectsList;
 }
 
 static struct gpFx *gpFxCheckIntrons(struct variant *variant, 
     struct genePred *pred)
 // check to see if a single variant is in an exon or an intron
 {
 int ii;
 struct gpFx *effectsList = NULL;
 
 for(ii=0; ii < pred->exonCount - 1; ii++)
     {
     // check if in intron
     if (positiveRangeIntersection(pred->exonEnds[ii], 
 	    pred->exonStarts[ii+1],
 	    variant->chromStart, variant->chromEnd))
 	{
 	struct gpFx *effects;
 	AllocVar(effects);
 	effects->so.soNumber = intron_variant;
 	effects->so.sub.intron.transcript = cloneString(pred->name);
 	effects->so.sub.intron.intronNumber = ii;
 	slAddHead(&effectsList, effects);
 	}
     }
 
 return effectsList;
 }
 
 
 static struct gpFx *gpFxCheckBackground(struct variant *variant, 
     struct genePred *pred)
 // check to see if the variant is up or downstream or in intron of the gene 
 {
 struct gpFx *effectsList = NULL, *effects;
 
 for(; variant ; variant = variant->next)
     {
     // is this variant in an intron
     effectsList = slCat(effectsList, gpFxCheckIntrons(variant, pred));
 
     if (positiveRangeIntersection(pred->txStart - GPRANGE, pred->txStart,
 	    variant->chromStart, variant->chromEnd))
 	{
 	AllocVar(effects);
 	if (*pred->strand == '+')
 	    ;//effects->gpFxType = gpFxUpstream;
 	else
 	    ;//ffects->gpFxType = gpFxDownstream;
 	effectsList = slCat(effectsList, effects);
 	}
 
     if (positiveRangeIntersection(pred->txEnd, pred->txEnd + GPRANGE,
 	    variant->chromStart, variant->chromEnd))
 	{
 	AllocVar(effects);
 	if (*pred->strand == '+')
 	    ;//ffects->gpFxType = gpFxDownstream;
 	else
 	    ;//ffects->gpFxType = gpFxUpstream;
 	effectsList = slCat(effectsList, effects);
 	}
     }
 
 return effectsList;
 }
 
 static void checkVariantList(struct variant *variant)
 // check to see that we either have one variant (possibly with multiple
 // alleles) or that if we have a list of variants, they only have
 // one allele a piece.
 {
 if (variant->next == NULL)	 // just one variant
     return;
 
 for(; variant; variant = variant->next)
     if (variant->numAlleles != 1)
 	errAbort("gpFxPredEffect needs either 1 variant, or only 1 allele in all variants");
 }
 
 struct gpFx *gpFxPredEffect(struct variant *variant, struct genePred *pred,
     struct dnaSeq *transcriptSequence)
 // return the predicted effect(s) of a variation list on a genePred
 {
 struct gpFx *effectsList = NULL;
 
 // make sure we can deal with the variants that are coming in
 checkVariantList(variant);
 
 // check to see if SNP is up or downstream in intron 
 effectsList = slCat(effectsList, gpFxCheckBackground(variant, pred));
 
 // check to see if SNP is in the transcript
 effectsList = slCat(effectsList, gpFxCheckExons(variant, pred, 
     transcriptSequence));
 
 if (effectsList != NULL)
     return effectsList;
 
 // default is no effect
 struct gpFx *noEffect;
 
 AllocVar(noEffect);
 noEffect->next = NULL;
 ;//oEffect->gpFxType = gpFxNone;
 
 return noEffect;
 }