820ebcf85a344a03cf2279b6ceee42a25514f4a3 angie Mon May 23 09:41:50 2011 -0700 Feature #3711 (VCF haplotype clustering): User can select which variantis used as the center (for center-weighted clustering) by clicking on a link in its details page. diff --git src/hg/hgTracks/vcfTrack.c src/hg/hgTracks/vcfTrack.c index 036741b..420ade8 100644 --- src/hg/hgTracks/vcfTrack.c +++ src/hg/hgTracks/vcfTrack.c @@ -1,560 +1,590 @@ /* vcfTrack -- handlers for Variant Call Format data. */ #include "common.h" #include "bigWarn.h" #include "dystring.h" #include "errCatch.h" #include "hacTree.h" #include "hdb.h" #include "hgTracks.h" #include "pgSnp.h" #include "trashDir.h" #include "vcf.h" #if (defined USE_TABIX && defined KNETFILE_HOOKS) #include "knetUdc.h" #include "udc.h" #endif//def USE_TABIX && KNETFILE_HOOKS #ifdef USE_TABIX //#*** TODO: use trackDb/cart setting or something static boolean doHapClusterDisplay = TRUE; static boolean colorHapByRefAlt = TRUE; static struct pgSnp *vcfFileToPgSnp(struct vcfFile *vcff) /* Convert vcff's records to pgSnp; don't free vcff until you're done with pgSnp * because it contains pointers into vcff's records' chrom. */ { struct pgSnp *pgsList = NULL; struct vcfRecord *rec; for (rec = vcff->records; rec != NULL; rec = rec->next) { struct pgSnp *pgs = pgSnpFromVcfRecord(rec); slAddHead(&pgsList, pgs); } slReverse(&pgsList); return pgsList; } // Center-weighted alpha clustering of haplotypes -- see Redmine #3711, #2823 note 7 // It might be nice to use an allele-frequency representation here instead of [ACGTN] strings // with "N" for missing info or differences, but keep it simple. struct cwaExtraData /* Helper data for hacTree clustering of haplotypes by center-weighted alpha distance */ { int center; // index from which each point's contribution to distance is to be weighted int len; // total length of haplotype strings double alpha; // weighting factor for distance from center struct lm *localMem; }; // This is the representation of a cluster of up to 65,535 haplotypes of equal length, // where each variant's alleles are specified as 0 (reference) or 1 (alternate) // [or possibly 2 for second alternate, but those are rare so I'll ignore them]. // When an individual is heterozygous and unphased for some variant, we need to // account for missing data. struct hapCluster { struct hapCluster *next; // hacTree wants slList of items unsigned short *refCounts; // per-variant count of reference alleles observed unsigned short *unkCounts; // per-variant count of unknown (or unphased het) alleles unsigned short leafCount; // number of leaves under this node (or 1 if leaf) unsigned short gtHapIx; // if leaf, (genotype index << 1) + hapIx (0 or 1 for diploid) }; INLINE boolean isRef(const struct hapCluster *c, int varIx) // Return TRUE if the leaves of cluster have at least as many reference alleles // as alternate alleles for variant varIx. { unsigned short altCount = c->leafCount - c->refCounts[varIx] - c->unkCounts[varIx]; return (c->refCounts[varIx] >= altCount); } INLINE boolean hasUnk(const struct hapCluster *c, int varIx) // Return TRUE if at least one haplotype in this cluster has an unknown/unphased value at varIx. { return (c->unkCounts[varIx] > 0); } static double cwaDistance(const struct slList *item1, const struct slList *item2, void *extraData) /* Center-weighted alpha sequence distance function for hacTree clustering of haplotype seqs */ // This is inner-loop so I am not doing defensive checks. Caller must ensure: // 1. kids's sequences' lengths are both equal to helper->len // 2. 0 <= helper->center <= len // 3. 0.0 < helper->alpha <= 1.0 { const struct hapCluster *kid1 = (const struct hapCluster *)item1; const struct hapCluster *kid2 = (const struct hapCluster *)item2; struct cwaExtraData *helper = extraData; double distance = 0; double weight = 1; // start at center: alpha to the 0th power int i; for (i=helper->center; i >= 0; i--) { if (isRef(kid1, i) != isRef(kid2, i)) distance += weight; else if (hasUnk(kid1, i) != hasUnk(kid2, i)) distance += weight/2; weight *= helper->alpha; } weight = helper->alpha; // start at center+1: alpha to the 1st power for (i=helper->center+1; i < helper->len; i++) { if (isRef(kid1, i) != isRef(kid2, i)) distance += weight; weight *= helper->alpha; } return distance; } static struct hapCluster *lmHapCluster(struct cwaExtraData *helper) /* Use localMem to allocate a new cluster of the given len. */ { struct hapCluster *c = lmAlloc(helper->localMem, sizeof(struct hapCluster)); c->refCounts = lmAlloc(helper->localMem, helper->len * sizeof(unsigned short)); c->unkCounts = lmAlloc(helper->localMem, helper->len * sizeof(unsigned short)); return c; } static struct slList *cwaMerge(const struct slList *item1, const struct slList *item2, void *extraData) /* Make a consensus haplotype from two input haplotypes, for hacTree clustering by * center-weighted alpha distance. */ // This is inner-loop so I am not doing defensive checks. Caller must ensure that // kids's sequences' lengths are both equal to helper->len. { const struct hapCluster *kid1 = (const struct hapCluster *)item1; const struct hapCluster *kid2 = (const struct hapCluster *)item2; struct cwaExtraData *helper = extraData; struct hapCluster *consensus = lmHapCluster(helper); consensus->leafCount = kid1->leafCount + kid2->leafCount; consensus->gtHapIx = kid1->gtHapIx; int i; for (i=0; i < helper->len; i++) { consensus->refCounts[i] = kid1->refCounts[i] + kid2->refCounts[i]; consensus->unkCounts[i] = kid1->unkCounts[i] + kid2->unkCounts[i]; } return (struct slList *)consensus; } INLINE void hapClusterToString(const struct hapCluster *c, struct dyString *dy, int len) /* Write a text representation of hapCluster's alleles into dy. */ { dyStringClear(dy); int i; for (i=0; i < len; i++) dyStringAppendC(dy, (isRef(c, i) ? '0': '1')); } static int cwaCmp(const struct slList *item1, const struct slList *item2, void *extraData) /* Convert hapCluster to allele strings for easy comparison by strcmp. */ { const struct hapCluster *c1 = (const struct hapCluster *)item1; const struct hapCluster *c2 = (const struct hapCluster *)item2; struct cwaExtraData *helper = extraData; static struct dyString *dy1 = NULL, *dy2 = NULL; if (dy1 == NULL) { dy1 = dyStringNew(0); dy2 = dyStringNew(0); } hapClusterToString(c1, dy1, helper->len); hapClusterToString(c2, dy2, helper->len); return strcmp(dy1->string, dy2->string); } void rSetGtHapOrder(struct hacTree *ht, unsigned short *gtHapOrder, unsigned short *retGtHapEnd) /* Traverse hacTree and build an ordered array of genotype + haplotype indices. */ { if (ht->left == NULL && ht->right == NULL) { struct hapCluster *c = (struct hapCluster *)ht->itemOrCluster; gtHapOrder[(*retGtHapEnd)++] = c->gtHapIx; } else if (ht->left == NULL) rSetGtHapOrder(ht->right, gtHapOrder, retGtHapEnd); else if (ht->right == NULL) rSetGtHapOrder(ht->left, gtHapOrder, retGtHapEnd); else { struct hapCluster *cL = (struct hapCluster *)ht->left->itemOrCluster; struct hapCluster *cR = (struct hapCluster *)ht->right->itemOrCluster; if (cL->leafCount >= cR->leafCount) { rSetGtHapOrder(ht->left, gtHapOrder, retGtHapEnd); rSetGtHapOrder(ht->right, gtHapOrder, retGtHapEnd); } else { rSetGtHapOrder(ht->right, gtHapOrder, retGtHapEnd); rSetGtHapOrder(ht->left, gtHapOrder, retGtHapEnd); } } } static unsigned short *clusterChroms(const struct vcfFile *vcff, int centerIx, unsigned short *retGtHapEnd) /* Given a bunch of VCF records with phased genotypes, build up one haplotype string * per chromosome that is the sequence of alleles in all variants (simplified to one base * per variant). Each individual/sample will have two haplotype strings (unless haploid * like Y or male X). Independently cluster the haplotype strings using hacTree with the * center-weighted alpha functions above. Return an array of genotype+haplotype indices * in the order determined by the hacTree, and set retGtHapEnd to its length/end. */ { int len = slCount(vcff->records); // Should alpha depend on len? Should the penalty drop off with distance? Seems like // straight-up exponential will cause the signal to drop to nothing pretty quickly... double alpha = 0.5; struct lm *lm = lmInit(0); struct cwaExtraData helper = { centerIx, len, alpha, lm }; int ploidy = 2; // Assuming diploid genomes here, no XXY, tetraploid etc. int gtCount = vcff->genotypeCount; // Make an slList of hapClusters, but allocate in a big block so I can use // array indexing. struct hapCluster **hapArray = lmAlloc(lm, sizeof(struct hapCluster *) * gtCount * ploidy); int i; for (i=0; i < ploidy * gtCount; i++) { hapArray[i] = lmHapCluster(&helper); if (i > 0) hapArray[i-1]->next = hapArray[i]; } boolean haveHaploid = FALSE; int varIx; struct vcfRecord *rec; for (varIx = 0, rec = vcff->records; rec != NULL; varIx++, rec = rec->next) { vcfParseGenotypes(rec); int gtIx; for (gtIx=0; gtIx < gtCount; gtIx++) { struct vcfGenotype *gt = &(rec->genotypes[gtIx]); struct hapCluster *c1 = hapArray[gtIx]; struct hapCluster *c2 = hapArray[gtCount + gtIx]; // hardwired ploidy=2 if (gt->isPhased || gt->isHaploid || (gt->hapIxA == gt->hapIxB)) { // first chromosome: c1->leafCount = 1; c1->gtHapIx = gtIx << 1; if (gt->hapIxA == 0) c1->refCounts[varIx] = 1; if (gt->isHaploid) haveHaploid = TRUE; else { c2->leafCount = 1; c2->gtHapIx = (gtIx << 1) | 1; if (gt->hapIxB == 0) c2->refCounts[varIx] = 1; } } else { // Unphased heterozygote, don't use haplotype info for clustering c1->leafCount = c2->leafCount = 1; c1->gtHapIx = gtIx << 1; c2->gtHapIx = (gtIx << 1) | 1; c1->unkCounts[varIx] = c2->unkCounts[varIx] = 1; } } if (haveHaploid) { // Some array items will have an empty cluster for missing hap2 -- // trim those from the linked list. struct hapCluster *c = hapArray[0]; while (c != NULL && c->next != NULL) { if (c->next->leafCount == 0) c->next = c->next->next; c = c->next; } } } struct hacTree *ht = hacTreeFromItems((struct slList *)(hapArray[0]), lm, cwaDistance, cwaMerge, cwaCmp, &helper); unsigned short *gtHapOrder = needMem(vcff->genotypeCount * 2 * sizeof(unsigned short)); rSetGtHapOrder(ht, gtHapOrder, retGtHapEnd); return gtHapOrder; } INLINE char *hapIxToAllele(int hapIx, char *refAllele, char *altAlleles[]) /* Look up allele by index into reference allele and alternate allele(s). */ { return (hapIx == 0) ? refAllele : altAlleles[hapIx-1]; } INLINE Color colorFromGt(struct vcfGenotype *gt, int ploidIx, char *refAllele, char *altAlleles[], int altCount, boolean grayUnphasedHet) /* Color allele by base. */ { int hapIx = ploidIx ? gt->hapIxB : gt->hapIxA; char *allele = hapIxToAllele(hapIx, refAllele, altAlleles); if (gt->isHaploid && hapIx > 0) return shadesOfGray[5]; if (grayUnphasedHet && !gt->isPhased && gt->hapIxA != gt->hapIxB) return shadesOfGray[5]; // Copying pgSnp color scheme here, using first base of allele which is not ideal for multibase // but allows us to simplify it to 5 colors: else if (allele[0] == 'A') return MG_RED; else if (allele[0] == 'C') return MG_BLUE; else if (allele[0] == 'G') return darkGreenColor; else if (allele[0] == 'T') return MG_MAGENTA; else return shadesOfGray[5]; } INLINE Color colorFromRefAlt(struct vcfGenotype *gt, int hapIx, boolean grayUnphasedHet) /* Color allele red for alternate allele, blue for reference allele -- * except for special center variant, make it yellow/green for contrast. */ { if (grayUnphasedHet && !gt->isPhased && gt->hapIxA != gt->hapIxB) return shadesOfGray[5]; int alIx = hapIx ? gt->hapIxB : gt->hapIxA; return alIx ? MG_RED : MG_BLUE; } INLINE int drawOneHap(struct vcfGenotype *gt, int hapIx, char *ref, char *altAlleles[], int altCount, struct hvGfx *hvg, int x1, int y, int w, int itemHeight, int lineHeight) /* Draw a base-colored box for genotype[hapIx]. Return the new y offset. */ { Color color = colorHapByRefAlt ? colorFromRefAlt(gt, hapIx, TRUE) : colorFromGt(gt, hapIx, ref, altAlleles, altCount, TRUE); -if (w == 1) - { - x1--; - w = 3; - } hvGfxBox(hvg, x1, y, w, itemHeight+1, color); y += itemHeight+1; return y; } INLINE char *gtSummaryString(struct vcfRecord *rec, char **altAlleles, int altCount) // Make pgSnp-like mouseover text, but with genotype counts instead of allele counts. // NOTE 1: Returned string is statically allocated, don't free it! // NOTE 2: if revCmplDisp is set, this reverse-complements rec->ref and altAlleles! { static struct dyString *dy = NULL; if (dy == NULL) dy = dyStringNew(0); dyStringClear(dy); const struct vcfFile *vcff = rec->file; int gtRefRefCount = 0, gtRefAltCount = 0, gtAltAltCount = 0, gtOtherCount = 0; int i; for (i=0; i < vcff->genotypeCount; i++) { struct vcfGenotype *gt = &(rec->genotypes[i]); if (gt->hapIxA == 0 && gt->hapIxB == 0) gtRefRefCount++; else if (gt->hapIxA == 1 && gt->hapIxB == 1) gtAltAltCount++; else if ((gt->hapIxA == 0 && gt->hapIxB == 1) || (gt->hapIxA == 1 && gt->hapIxB == 0)) gtRefAltCount++; else gtOtherCount++; } if (revCmplDisp) { reverseComplement(rec->ref, strlen(rec->ref)); for (i=0; i < altCount; i++) reverseComplement(altAlleles[i], strlen(altAlleles[i])); } dyStringPrintf(dy, "%s/%s:%d %s/%s:%d %s/%s:%d", rec->ref, rec->ref, gtRefRefCount, rec->ref, altAlleles[0], gtRefAltCount, altAlleles[0], altAlleles[0], gtAltAltCount); if (gtOtherCount > 0) dyStringPrintf(dy, " other:%d", gtOtherCount); return dy->string; } static void drawOneRec(struct vcfRecord *rec, unsigned short *gtHapOrder, int gtHapEnd, struct track *tg, struct hvGfx *hvg, int xOff, int yOff, int width) /* Draw a stack of genotype bars for this record */ { static struct dyString *tmp = NULL; if (tmp == NULL) tmp = dyStringNew(0); char *altAlleles[256]; int altCount; const int lineHeight = tg->lineHeight; const int itemHeight = tg->heightPer; const double scale = scaleForPixels(width); int x1 = round((double)(rec->chromStart-winStart)*scale) + xOff; int x2 = round((double)(rec->chromEnd-winStart)*scale) + xOff; int w = x2-x1; -if (w < 1) - w = 1; +if (w <= 1) + { + x1--; + w = 3; + } int y = yOff; dyStringClear(tmp); dyStringAppend(tmp, rec->alt); altCount = chopCommas(tmp->string, altAlleles); int gtHapOrderIx; for (gtHapOrderIx = 0; gtHapOrderIx < gtHapEnd; gtHapOrderIx++) { int gtHapIx = gtHapOrder[gtHapOrderIx]; int hapIx = gtHapIx & 1; int gtIx = gtHapIx >>1; struct vcfGenotype *gt = &(rec->genotypes[gtIx]); y = drawOneHap(gt, hapIx, rec->ref, altAlleles, altCount, hvg, x1, y, w, itemHeight, lineHeight); } mapBoxHgcOrHgGene(hvg, rec->chromStart, rec->chromEnd, x1, yOff, w, tg->height, tg->track, rec->name, gtSummaryString(rec, altAlleles, altCount), NULL, TRUE, NULL); } +static int getCenterVariantIx(struct track *tg, int seqStart, int seqEnd, + struct vcfRecord *records) +// If the user hasn't specified a local variant/position to use as center, +// just use the median variant in window. +{ +int defaultIx = (slCount(records)-1) / 2; +char cartVar[512]; +safef(cartVar, sizeof(cartVar), "%s.centerVariantPos", tg->tdb->track); +char *centerPos = cartOptionalString(cart, cartVar); +if (centerPos != NULL) + { + char *words[3]; + int wordCount = chopByChar(cloneString(centerPos), ':', words, sizeof(words)); + if (wordCount != 2) + errAbort("Cart variable %s format error: expected 'chrom:pos', got %s", + cartVar, centerPos); + if (sameString(chromName, words[0])) + { + int pos = sqlUnsigned(words[1]); + int winSize = seqEnd - seqStart; + if (pos > (seqStart - winSize) && pos < (seqEnd + winSize)) + { + int i; + struct vcfRecord *rec; + for (rec = records, i = 0; rec != NULL; rec = rec->next, i++) + if (rec->chromStart >= pos) + return i; + return i-1; + } + } + } +return defaultIx; +} + static void vcfHapClusterDraw(struct track *tg, int seqStart, int seqEnd, struct hvGfx *hvg, int xOff, int yOff, int width, MgFont *font, Color color, enum trackVisibility vis) /* Split samples' chromosomes (haplotypes), cluster them by center-weighted * alpha similarity, and draw in the order determined by clustering. */ { const struct vcfFile *vcff = tg->extraUiData; if (vcff->records == NULL) return; unsigned short gtHapEnd = 0; -// Use the median variant in the window as the center; would be even nicer to allow -// the user to choose a variant (or position) to use as center: -int ix, centerIx = (slCount(vcff->records)-1) / 2; +int ix, centerIx = getCenterVariantIx(tg, seqStart, seqEnd, vcff->records); unsigned short *gtHapOrder = clusterChroms(vcff, centerIx, >HapEnd); struct vcfRecord *rec, *centerRec = NULL; for (rec = vcff->records, ix=0; rec != NULL; rec = rec->next, ix++) { drawOneRec(rec, gtHapOrder, gtHapEnd, tg, hvg, xOff, yOff, width); if (ix == centerIx) centerRec = rec; } // Draw the center rec on top, outlined with black lines, to make sure it is very visible: drawOneRec(centerRec, gtHapOrder, gtHapEnd, tg, hvg, xOff, yOff, width); const double scale = scaleForPixels(width); int x1 = round((double)(centerRec->chromStart-winStart)*scale) + xOff; int x2 = round((double)(centerRec->chromEnd-winStart)*scale) + xOff; int yBot = yOff + tg->height - 2; hvGfxBox(hvg, x1-4, yOff, 3, tg->height, color); hvGfxBox(hvg, x2+2, yOff, 3, tg->height, color); hvGfxLine(hvg, x1-2, yOff, x2+2, yOff, MG_BLACK); hvGfxLine(hvg, x1-2, yBot, x2+2, yBot, MG_BLACK); } static int vcfHapClusterTotalHeight(struct track *tg, enum trackVisibility vis) /* Return height of haplotype graph (2 * #samples * lineHeight); * 2 because we're assuming diploid genomes here, no XXY, tetraploid etc. */ { // Should we make it single-height when on chrY? const struct vcfFile *vcff = tg->extraUiData; if (vcff->records == NULL) return 0; int ploidy = 2; tg->height = ploidy * vcff->genotypeCount * tg->lineHeight; return tg->height; } static char *vcfHapClusterTrackName(struct track *tg, void *item) /* If someone asks for itemName/mapItemName, just send name of track like wiggle. */ { return tg->track; } static void vcfHapClusterOverloadMethods(struct track *tg, struct vcfFile *vcff) /* If we confirm at load time that we can draw a haplotype graph, use * this to overwrite the methods for the rest of execution: */ { tg->heightPer = (tg->visibility == tvSquish) ? (tl.fontHeight/4) : (tl.fontHeight / 2); tg->lineHeight = tg->heightPer + 1; tg->drawItems = vcfHapClusterDraw; tg->totalHeight = vcfHapClusterTotalHeight; tg->itemHeight = tgFixedItemHeight; tg->itemName = vcfHapClusterTrackName; tg->mapItemName = vcfHapClusterTrackName; tg->itemStart = tgItemNoStart; tg->itemEnd = tgItemNoEnd; tg->mapsSelf = TRUE; tg->extraUiData = vcff; } static void vcfTabixLoadItems(struct track *tg) /* Load items in window from VCF file using its tabix index file. */ { struct sqlConnection *conn = hAllocConnTrack(database, tg->tdb); // TODO: may need to handle per-chrom files like bam, maybe fold bamFileNameFromTable into this:: char *fileOrUrl = bbiNameFromSettingOrTable(tg->tdb, conn, tg->table); hFreeConn(&conn); int vcfMaxErr = 100; struct vcfFile *vcff = NULL; /* protect against temporary network error */ struct errCatch *errCatch = errCatchNew(); if (errCatchStart(errCatch)) { vcff = vcfTabixFileMayOpen(fileOrUrl, chromName, winStart, winEnd, vcfMaxErr); } errCatchEnd(errCatch); if (errCatch->gotError) { if (isNotEmpty(errCatch->message->string)) tg->networkErrMsg = cloneString(errCatch->message->string); tg->drawItems = bigDrawWarning; tg->totalHeight = bigWarnTotalHeight; } errCatchFree(&errCatch); if (vcff != NULL) { if (doHapClusterDisplay && vcff->genotypeCount > 0 && vcff->genotypeCount < 3000 && (tg->visibility == tvPack || tg->visibility == tvSquish)) vcfHapClusterOverloadMethods(tg, vcff); else { tg->items = vcfFileToPgSnp(vcff); // pgSnp bases coloring/display decision on count of items: tg->customInt = slCount(tg->items); } // Don't vcfFileFree here -- we are using its string pointers! } } void vcfTabixMethods(struct track *track) /* Methods for VCF + tabix files. */ { pgSnpMethods(track); track->loadItems = vcfTabixLoadItems; track->canPack = TRUE; } #else // no USE_TABIX: // If code was not built with USE_TABIX=1, but there are vcfTabix tracks, display a message // in place of the tracks (instead of annoying "No track handler" warning messages). static void drawUseVcfTabixWarning(struct track *tg, int seqStart, int seqEnd, struct hvGfx *hvg, int xOff, int yOff, int width, MgFont *font, Color color, enum trackVisibility vis) /* Draw a message saying that the code needs to be built with USE_TABIX=1. */ { char message[512]; safef(message, sizeof(message), "Get tabix from samtools.sourceforge.net and recompile kent/src with USE_TABIX=1"); Color yellow = hvGfxFindRgb(hvg, &undefinedYellowColor); hvGfxBox(hvg, xOff, yOff, width, tg->heightPer, yellow); hvGfxTextCentered(hvg, xOff, yOff, width, tg->heightPer, MG_BLACK, font, message); } void vcfTabixMethods(struct track *track) /* Methods for VCF alignment files, in absence of tabix lib. */ { #if (defined USE_TABIX && defined KNETFILE_HOOKS) knetUdcInstall(); #endif//def USE_TABIX && KNETFILE_HOOKS messageLineMethods(track); track->drawItems = drawUseVcfTabixWarning; } #endif // no USE_TABIX