Fix coordinates in hgvs annotations.
[lightning.git] / tilelib.go
1 // Copyright (C) The Lightning Authors. All rights reserved.
2 //
3 // SPDX-License-Identifier: AGPL-3.0
4
5 package lightning
6
7 import (
8         "bufio"
9         "bytes"
10         "context"
11         "encoding/gob"
12         "fmt"
13         "io"
14         "os"
15         "regexp"
16         "runtime"
17         "sort"
18         "strings"
19         "sync"
20         "sync/atomic"
21
22         "github.com/klauspost/pgzip"
23         log "github.com/sirupsen/logrus"
24         "golang.org/x/crypto/blake2b"
25 )
26
27 type tileVariantID uint16 // 1-based
28
29 type tileLibRef struct {
30         Tag     tagID
31         Variant tileVariantID
32 }
33
34 type tileSeq map[string][]tileLibRef
35
36 func (tseq tileSeq) Variants() ([]tileVariantID, int, int) {
37         maxtag := 0
38         for _, refs := range tseq {
39                 for _, ref := range refs {
40                         if maxtag < int(ref.Tag) {
41                                 maxtag = int(ref.Tag)
42                         }
43                 }
44         }
45         vars := make([]tileVariantID, maxtag+1)
46         var kept, dropped int
47         for _, refs := range tseq {
48                 for _, ref := range refs {
49                         if vars[int(ref.Tag)] != 0 {
50                                 dropped++
51                         } else {
52                                 kept++
53                         }
54                         vars[int(ref.Tag)] = ref.Variant
55                 }
56         }
57         return vars, kept, dropped
58 }
59
60 type tileLibrary struct {
61         retainNoCalls       bool
62         skipOOO             bool
63         retainTileSequences bool
64
65         taglib         *tagLibrary
66         variant        [][][blake2b.Size256]byte
67         refseqs        map[string]map[string][]tileLibRef
68         compactGenomes map[string][]tileVariantID
69         seq2           map[[2]byte]map[[blake2b.Size256]byte][]byte
70         seq2lock       map[[2]byte]sync.Locker
71         variants       int64
72         // if non-nil, write out any tile variants added while tiling
73         encoder *gob.Encoder
74         // set Ref flag when writing new variants to encoder
75         encodeRef bool
76
77         onAddTileVariant func(libref tileLibRef, hash [blake2b.Size256]byte, seq []byte) error
78         onAddGenome      func(CompactGenome) error
79         onAddRefseq      func(CompactSequence) error
80
81         mtx   sync.RWMutex
82         vlock []sync.Locker
83 }
84
85 func (tilelib *tileLibrary) loadTagSet(newtagset [][]byte) error {
86         // Loading a tagset means either passing it through to the
87         // output (if it's the first one we've seen), or just ensuring
88         // it doesn't disagree with what we already have.
89         if len(newtagset) == 0 {
90                 return nil
91         }
92         tilelib.mtx.Lock()
93         defer tilelib.mtx.Unlock()
94         if tilelib.taglib == nil || tilelib.taglib.Len() == 0 {
95                 tilelib.taglib = &tagLibrary{}
96                 err := tilelib.taglib.setTags(newtagset)
97                 if err != nil {
98                         return err
99                 }
100                 if tilelib.encoder != nil {
101                         err = tilelib.encoder.Encode(LibraryEntry{
102                                 TagSet: newtagset,
103                         })
104                         if err != nil {
105                                 return err
106                         }
107                 }
108         } else if tilelib.taglib.Len() != len(newtagset) {
109                 return fmt.Errorf("cannot merge libraries with differing tagsets")
110         } else {
111                 current := tilelib.taglib.Tags()
112                 for i := range newtagset {
113                         if !bytes.Equal(newtagset[i], current[i]) {
114                                 return fmt.Errorf("cannot merge libraries with differing tagsets")
115                         }
116                 }
117         }
118         return nil
119 }
120
121 func (tilelib *tileLibrary) loadTileVariants(tvs []TileVariant, variantmap map[tileLibRef]tileVariantID) error {
122         for _, tv := range tvs {
123                 // Assign a new variant ID (unique across all inputs)
124                 // for each input variant.
125                 variantmap[tileLibRef{Tag: tv.Tag, Variant: tv.Variant}] = tilelib.getRef(tv.Tag, tv.Sequence, tv.Ref).Variant
126         }
127         return nil
128 }
129
130 func (tilelib *tileLibrary) loadCompactGenomes(cgs []CompactGenome, variantmap map[tileLibRef]tileVariantID) error {
131         log.Debugf("loadCompactGenomes: %d", len(cgs))
132         var wg sync.WaitGroup
133         errs := make(chan error, 1)
134         for _, cg := range cgs {
135                 wg.Add(1)
136                 cg := cg
137                 go func() {
138                         defer wg.Done()
139                         for i, variant := range cg.Variants {
140                                 if len(errs) > 0 {
141                                         return
142                                 }
143                                 if variant == 0 {
144                                         continue
145                                 }
146                                 tag := tagID(i / 2)
147                                 newvariant, ok := variantmap[tileLibRef{Tag: tag, Variant: variant}]
148                                 if !ok {
149                                         err := fmt.Errorf("oops: genome %q has variant %d for tag %d, but that variant was not in its library", cg.Name, variant, tag)
150                                         select {
151                                         case errs <- err:
152                                         default:
153                                         }
154                                         return
155                                 }
156                                 // log.Tracef("loadCompactGenomes: cg %s tag %d variant %d => %d", cg.Name, tag, variant, newvariant)
157                                 cg.Variants[i] = newvariant
158                         }
159                         if tilelib.onAddGenome != nil {
160                                 err := tilelib.onAddGenome(cg)
161                                 if err != nil {
162                                         select {
163                                         case errs <- err:
164                                         default:
165                                         }
166                                         return
167                                 }
168                         }
169                         if tilelib.encoder != nil {
170                                 err := tilelib.encoder.Encode(LibraryEntry{
171                                         CompactGenomes: []CompactGenome{cg},
172                                 })
173                                 if err != nil {
174                                         select {
175                                         case errs <- err:
176                                         default:
177                                         }
178                                         return
179                                 }
180                         }
181                         if tilelib.compactGenomes != nil {
182                                 tilelib.mtx.Lock()
183                                 defer tilelib.mtx.Unlock()
184                                 tilelib.compactGenomes[cg.Name] = cg.Variants
185                         }
186                 }()
187         }
188         wg.Wait()
189         go close(errs)
190         return <-errs
191 }
192
193 func (tilelib *tileLibrary) loadCompactSequences(cseqs []CompactSequence, variantmap map[tileLibRef]tileVariantID) error {
194         log.Infof("loadCompactSequences: %d todo", len(cseqs))
195         for _, cseq := range cseqs {
196                 log.Infof("loadCompactSequences: checking %s", cseq.Name)
197                 for _, tseq := range cseq.TileSequences {
198                         for i, libref := range tseq {
199                                 if libref.Variant == 0 {
200                                         // No variant (e.g., import
201                                         // dropped tiles with
202                                         // no-calls) = no translation.
203                                         continue
204                                 }
205                                 v, ok := variantmap[libref]
206                                 if !ok {
207                                         return fmt.Errorf("oops: CompactSequence %q has variant %d for tag %d, but that variant was not in its library", cseq.Name, libref.Variant, libref.Tag)
208                                 }
209                                 tseq[i].Variant = v
210                         }
211                 }
212                 if tilelib.encoder != nil {
213                         if err := tilelib.encoder.Encode(LibraryEntry{
214                                 CompactSequences: []CompactSequence{cseq},
215                         }); err != nil {
216                                 return err
217                         }
218                 }
219                 if tilelib.onAddRefseq != nil {
220                         err := tilelib.onAddRefseq(cseq)
221                         if err != nil {
222                                 return err
223                         }
224                 }
225                 log.Infof("loadCompactSequences: checking %s done", cseq.Name)
226         }
227         tilelib.mtx.Lock()
228         defer tilelib.mtx.Unlock()
229         if tilelib.refseqs == nil {
230                 tilelib.refseqs = map[string]map[string][]tileLibRef{}
231         }
232         for _, cseq := range cseqs {
233                 tilelib.refseqs[cseq.Name] = cseq.TileSequences
234         }
235         log.Info("loadCompactSequences: done")
236         return nil
237 }
238
239 func allGobFiles(path string) ([]string, error) {
240         var files []string
241         f, err := open(path)
242         if err != nil {
243                 return nil, err
244         }
245         defer f.Close()
246         fis, err := f.Readdir(-1)
247         if err != nil {
248                 return []string{path}, nil
249         }
250         for _, fi := range fis {
251                 if fi.Name() == "." || fi.Name() == ".." {
252                         continue
253                 } else if child := path + "/" + fi.Name(); fi.IsDir() {
254                         add, err := allGobFiles(child)
255                         if err != nil {
256                                 return nil, err
257                         }
258                         files = append(files, add...)
259                 } else if strings.HasSuffix(child, ".gob") || strings.HasSuffix(child, ".gob.gz") {
260                         files = append(files, child)
261                 }
262         }
263         return files, nil
264 }
265
266 func (tilelib *tileLibrary) LoadDir(ctx context.Context, path string) error {
267         log.Infof("LoadDir: walk dir %s", path)
268         files, err := allGobFiles(path)
269         if err != nil {
270                 return err
271         }
272         ctx, cancel := context.WithCancel(ctx)
273         defer cancel()
274         var mtx sync.Mutex
275         allcgs := make([][]CompactGenome, len(files))
276         allcseqs := make([][]CompactSequence, len(files))
277         allvariantmap := map[tileLibRef]tileVariantID{}
278         errs := make(chan error, len(files))
279         log.Infof("LoadDir: read %d files", len(files))
280         for fileno, path := range files {
281                 fileno, path := fileno, path
282                 go func() {
283                         f, err := open(path)
284                         if err != nil {
285                                 errs <- err
286                                 return
287                         }
288                         defer f.Close()
289                         defer log.Infof("LoadDir: finished reading %s", path)
290
291                         var variantmap = map[tileLibRef]tileVariantID{}
292                         var cgs []CompactGenome
293                         var cseqs []CompactSequence
294                         err = DecodeLibrary(f, strings.HasSuffix(path, ".gz"), func(ent *LibraryEntry) error {
295                                 if ctx.Err() != nil {
296                                         return ctx.Err()
297                                 }
298                                 if len(ent.TagSet) > 0 {
299                                         mtx.Lock()
300                                         if tilelib.taglib == nil || tilelib.taglib.Len() != len(ent.TagSet) {
301                                                 // load first set of tags, or
302                                                 // report mismatch if 2 sets
303                                                 // have different #tags.
304                                                 if err := tilelib.loadTagSet(ent.TagSet); err != nil {
305                                                         mtx.Unlock()
306                                                         return err
307                                                 }
308                                         }
309                                         mtx.Unlock()
310                                 }
311                                 for _, tv := range ent.TileVariants {
312                                         variantmap[tileLibRef{Tag: tv.Tag, Variant: tv.Variant}] = tilelib.getRef(tv.Tag, tv.Sequence, tv.Ref).Variant
313                                 }
314                                 cgs = append(cgs, ent.CompactGenomes...)
315                                 cseqs = append(cseqs, ent.CompactSequences...)
316                                 return nil
317                         })
318                         allcgs[fileno] = cgs
319                         allcseqs[fileno] = cseqs
320                         mtx.Lock()
321                         defer mtx.Unlock()
322                         for k, v := range variantmap {
323                                 allvariantmap[k] = v
324                         }
325                         errs <- err
326                 }()
327         }
328         for range files {
329                 err := <-errs
330                 if err != nil {
331                         return err
332                 }
333         }
334
335         log.Info("LoadDir: loadCompactGenomes")
336         var flatcgs []CompactGenome
337         for _, cgs := range allcgs {
338                 flatcgs = append(flatcgs, cgs...)
339         }
340         err = tilelib.loadCompactGenomes(flatcgs, allvariantmap)
341         if err != nil {
342                 return err
343         }
344
345         log.Info("LoadDir: loadCompactSequences")
346         var flatcseqs []CompactSequence
347         for _, cseqs := range allcseqs {
348                 flatcseqs = append(flatcseqs, cseqs...)
349         }
350         err = tilelib.loadCompactSequences(flatcseqs, allvariantmap)
351         if err != nil {
352                 return err
353         }
354
355         log.Info("LoadDir done")
356         return nil
357 }
358
359 func (tilelib *tileLibrary) WriteDir(dir string) error {
360         ntilefiles := 128
361         nfiles := ntilefiles + len(tilelib.refseqs)
362         files := make([]*os.File, nfiles)
363         for i := range files {
364                 f, err := os.OpenFile(fmt.Sprintf("%s/library.%04d.gob.gz", dir, i), os.O_CREATE|os.O_WRONLY, 0666)
365                 if err != nil {
366                         return err
367                 }
368                 defer f.Close()
369                 files[i] = f
370         }
371         bufws := make([]*bufio.Writer, nfiles)
372         for i := range bufws {
373                 bufws[i] = bufio.NewWriterSize(files[i], 1<<26)
374         }
375         zws := make([]*pgzip.Writer, nfiles)
376         for i := range zws {
377                 zws[i] = pgzip.NewWriter(bufws[i])
378                 defer zws[i].Close()
379         }
380         encoders := make([]*gob.Encoder, nfiles)
381         for i := range encoders {
382                 encoders[i] = gob.NewEncoder(zws[i])
383         }
384
385         cgnames := make([]string, 0, len(tilelib.compactGenomes))
386         for name := range tilelib.compactGenomes {
387                 cgnames = append(cgnames, name)
388         }
389         sort.Strings(cgnames)
390
391         refnames := make([]string, 0, len(tilelib.refseqs))
392         for name := range tilelib.refseqs {
393                 refnames = append(refnames, name)
394         }
395         sort.Strings(refnames)
396
397         log.Infof("WriteDir: writing %d files", nfiles)
398         ctx, cancel := context.WithCancel(context.Background())
399         defer cancel()
400         errs := make(chan error, nfiles)
401         for start := range files {
402                 start := start
403                 go func() {
404                         err := encoders[start].Encode(LibraryEntry{TagSet: tilelib.taglib.Tags()})
405                         if err != nil {
406                                 errs <- err
407                                 return
408                         }
409                         if refidx := start - ntilefiles; refidx >= 0 {
410                                 // write each ref to its own file
411                                 // (they seem to load very slowly)
412                                 name := refnames[refidx]
413                                 errs <- encoders[start].Encode(LibraryEntry{CompactSequences: []CompactSequence{{
414                                         Name:          name,
415                                         TileSequences: tilelib.refseqs[name],
416                                 }}})
417                                 return
418                         }
419                         for i := start; i < len(cgnames); i += ntilefiles {
420                                 err := encoders[start].Encode(LibraryEntry{CompactGenomes: []CompactGenome{{
421                                         Name:     cgnames[i],
422                                         Variants: tilelib.compactGenomes[cgnames[i]],
423                                 }}})
424                                 if err != nil {
425                                         errs <- err
426                                         return
427                                 }
428                         }
429                         tvs := []TileVariant{}
430                         for tag := start; tag < len(tilelib.variant) && ctx.Err() == nil; tag += ntilefiles {
431                                 tvs = tvs[:0]
432                                 for idx, hash := range tilelib.variant[tag] {
433                                         tvs = append(tvs, TileVariant{
434                                                 Tag:      tagID(tag),
435                                                 Variant:  tileVariantID(idx + 1),
436                                                 Blake2b:  hash,
437                                                 Sequence: tilelib.hashSequence(hash),
438                                         })
439                                 }
440                                 err := encoders[start].Encode(LibraryEntry{TileVariants: tvs})
441                                 if err != nil {
442                                         errs <- err
443                                         return
444                                 }
445                         }
446                         errs <- nil
447                 }()
448         }
449         for range files {
450                 err := <-errs
451                 if err != nil {
452                         return err
453                 }
454         }
455         log.Info("WriteDir: flushing")
456         for i := range zws {
457                 err := zws[i].Close()
458                 if err != nil {
459                         return err
460                 }
461                 err = bufws[i].Flush()
462                 if err != nil {
463                         return err
464                 }
465                 err = files[i].Close()
466                 if err != nil {
467                         return err
468                 }
469         }
470         log.Info("WriteDir: done")
471         return nil
472 }
473
474 // Load library data from rdr. Tile variants might be renumbered in
475 // the process; in that case, genomes variants will be renumbered to
476 // match.
477 func (tilelib *tileLibrary) LoadGob(ctx context.Context, rdr io.Reader, gz bool) error {
478         cgs := []CompactGenome{}
479         cseqs := []CompactSequence{}
480         variantmap := map[tileLibRef]tileVariantID{}
481         err := DecodeLibrary(rdr, gz, func(ent *LibraryEntry) error {
482                 if ctx.Err() != nil {
483                         return ctx.Err()
484                 }
485                 if err := tilelib.loadTagSet(ent.TagSet); err != nil {
486                         return err
487                 }
488                 if err := tilelib.loadTileVariants(ent.TileVariants, variantmap); err != nil {
489                         return err
490                 }
491                 cgs = append(cgs, ent.CompactGenomes...)
492                 cseqs = append(cseqs, ent.CompactSequences...)
493                 return nil
494         })
495         if err != nil {
496                 return err
497         }
498         if ctx.Err() != nil {
499                 return ctx.Err()
500         }
501         err = tilelib.loadCompactGenomes(cgs, variantmap)
502         if err != nil {
503                 return err
504         }
505         err = tilelib.loadCompactSequences(cseqs, variantmap)
506         if err != nil {
507                 return err
508         }
509         return nil
510 }
511
512 func (tilelib *tileLibrary) dump(out io.Writer) {
513         printTV := func(tag int, variant tileVariantID) {
514                 if variant < 1 {
515                         fmt.Fprintf(out, " -")
516                 } else if tag >= len(tilelib.variant) {
517                         fmt.Fprintf(out, " (!tag=%d)", tag)
518                 } else if int(variant) > len(tilelib.variant[tag]) {
519                         fmt.Fprintf(out, " (tag=%d,!variant=%d)", tag, variant)
520                 } else {
521                         fmt.Fprintf(out, " %x", tilelib.variant[tag][variant-1][:8])
522                 }
523         }
524         for refname, refseqs := range tilelib.refseqs {
525                 for seqname, seq := range refseqs {
526                         fmt.Fprintf(out, "ref %s %s", refname, seqname)
527                         for _, libref := range seq {
528                                 printTV(int(libref.Tag), libref.Variant)
529                         }
530                         fmt.Fprintf(out, "\n")
531                 }
532         }
533         for name, cg := range tilelib.compactGenomes {
534                 fmt.Fprintf(out, "cg %s", name)
535                 for tag, variant := range cg {
536                         printTV(tag/2, variant)
537                 }
538                 fmt.Fprintf(out, "\n")
539         }
540 }
541
542 type importStats struct {
543         InputFile              string
544         InputLabel             string
545         InputLength            int
546         InputCoverage          int
547         PathLength             int
548         DroppedOutOfOrderTiles int
549 }
550
551 func (tilelib *tileLibrary) TileFasta(filelabel string, rdr io.Reader, matchChromosome *regexp.Regexp, isRef bool) (tileSeq, []importStats, error) {
552         ret := tileSeq{}
553         type jobT struct {
554                 label string
555                 fasta []byte
556         }
557         todo := make(chan jobT, 1)
558         scanner := bufio.NewScanner(rdr)
559         go func() {
560                 defer close(todo)
561                 var fasta []byte
562                 var seqlabel string
563                 for scanner.Scan() {
564                         buf := scanner.Bytes()
565                         if len(buf) > 0 && buf[0] == '>' {
566                                 todo <- jobT{seqlabel, append([]byte(nil), fasta...)}
567                                 seqlabel, fasta = strings.SplitN(string(buf[1:]), " ", 2)[0], fasta[:0]
568                                 log.Debugf("%s %s reading fasta", filelabel, seqlabel)
569                         } else {
570                                 fasta = append(fasta, bytes.ToLower(buf)...)
571                         }
572                 }
573                 todo <- jobT{seqlabel, fasta}
574         }()
575         type foundtag struct {
576                 pos   int
577                 tagid tagID
578         }
579         found := make([]foundtag, 2000000)
580         path := make([]tileLibRef, 2000000)
581         totalFoundTags := 0
582         totalPathLen := 0
583         skippedSequences := 0
584         taglen := tilelib.taglib.TagLen()
585         var stats []importStats
586         for job := range todo {
587                 if len(job.fasta) == 0 {
588                         continue
589                 } else if !matchChromosome.MatchString(job.label) {
590                         skippedSequences++
591                         continue
592                 }
593                 log.Debugf("%s %s tiling", filelabel, job.label)
594
595                 found = found[:0]
596                 tilelib.taglib.FindAll(job.fasta, func(tagid tagID, pos, taglen int) {
597                         found = append(found, foundtag{pos: pos, tagid: tagid})
598                 })
599                 totalFoundTags += len(found)
600                 if len(found) == 0 {
601                         log.Warnf("%s %s no tags found", filelabel, job.label)
602                 }
603
604                 skipped := 0
605                 if tilelib.skipOOO {
606                         log.Infof("%s %s keeping longest increasing subsequence", filelabel, job.label)
607                         keep := longestIncreasingSubsequence(len(found), func(i int) int { return int(found[i].tagid) })
608                         for i, x := range keep {
609                                 found[i] = found[x]
610                         }
611                         skipped = len(found) - len(keep)
612                         found = found[:len(keep)]
613                 }
614
615                 log.Infof("%s %s getting %d librefs", filelabel, job.label, len(found))
616                 throttle := &throttle{Max: runtime.NumCPU()}
617                 path = path[:len(found)]
618                 var lowquality int64
619                 for i, f := range found {
620                         i, f := i, f
621                         throttle.Acquire()
622                         go func() {
623                                 defer throttle.Release()
624                                 var startpos, endpos int
625                                 if i == 0 {
626                                         startpos = 0
627                                 } else {
628                                         startpos = f.pos
629                                 }
630                                 if i == len(found)-1 {
631                                         endpos = len(job.fasta)
632                                 } else {
633                                         endpos = found[i+1].pos + taglen
634                                 }
635                                 path[i] = tilelib.getRef(f.tagid, job.fasta[startpos:endpos], isRef)
636                                 if countBases(job.fasta[startpos:endpos]) != endpos-startpos {
637                                         atomic.AddInt64(&lowquality, 1)
638                                 }
639                         }()
640                 }
641                 throttle.Wait()
642
643                 log.Infof("%s %s copying path", filelabel, job.label)
644
645                 pathcopy := make([]tileLibRef, len(path))
646                 copy(pathcopy, path)
647                 ret[job.label] = pathcopy
648
649                 basesIn := countBases(job.fasta)
650                 log.Infof("%s %s fasta in %d coverage in %d path len %d low-quality %d skipped-out-of-order %d", filelabel, job.label, len(job.fasta), basesIn, len(path), lowquality, skipped)
651                 stats = append(stats, importStats{
652                         InputFile:              filelabel,
653                         InputLabel:             job.label,
654                         InputLength:            len(job.fasta),
655                         InputCoverage:          basesIn,
656                         PathLength:             len(path),
657                         DroppedOutOfOrderTiles: skipped,
658                 })
659
660                 totalPathLen += len(path)
661         }
662         log.Printf("%s tiled with total path len %d in %d sequences (skipped %d sequences that did not match chromosome regexp, skipped %d out-of-order tags)", filelabel, totalPathLen, len(ret), skippedSequences, totalFoundTags-totalPathLen)
663         return ret, stats, scanner.Err()
664 }
665
666 func (tilelib *tileLibrary) Len() int64 {
667         return atomic.LoadInt64(&tilelib.variants)
668 }
669
670 // Return a tileLibRef for a tile with the given tag and sequence,
671 // adding the sequence to the library if needed.
672 func (tilelib *tileLibrary) getRef(tag tagID, seq []byte, usedByRef bool) tileLibRef {
673         dropSeq := false
674         if !tilelib.retainNoCalls {
675                 for _, b := range seq {
676                         if b != 'a' && b != 'c' && b != 'g' && b != 't' {
677                                 dropSeq = true
678                                 break
679                         }
680                 }
681         }
682         seqhash := blake2b.Sum256(seq)
683         var vlock sync.Locker
684
685         tilelib.mtx.RLock()
686         if len(tilelib.vlock) > int(tag) {
687                 vlock = tilelib.vlock[tag]
688         }
689         tilelib.mtx.RUnlock()
690
691         if vlock != nil {
692                 vlock.Lock()
693                 for i, varhash := range tilelib.variant[tag] {
694                         if varhash == seqhash {
695                                 vlock.Unlock()
696                                 return tileLibRef{Tag: tag, Variant: tileVariantID(i + 1)}
697                         }
698                 }
699                 vlock.Unlock()
700         } else {
701                 tilelib.mtx.Lock()
702                 if tilelib.variant == nil && tilelib.taglib != nil {
703                         tilelib.variant = make([][][blake2b.Size256]byte, tilelib.taglib.Len())
704                         tilelib.vlock = make([]sync.Locker, tilelib.taglib.Len())
705                         for i := range tilelib.vlock {
706                                 tilelib.vlock[i] = new(sync.Mutex)
707                         }
708                 }
709                 if int(tag) >= len(tilelib.variant) {
710                         oldlen := len(tilelib.vlock)
711                         for i := 0; i < oldlen; i++ {
712                                 tilelib.vlock[i].Lock()
713                         }
714                         // If we haven't seen the tag library yet (as
715                         // in a merge), tilelib.taglib.Len() is
716                         // zero. We can still behave correctly, we
717                         // just need to expand the tilelib.variant and
718                         // tilelib.vlock slices as needed.
719                         if int(tag) >= cap(tilelib.variant) {
720                                 // Allocate 2x capacity.
721                                 newslice := make([][][blake2b.Size256]byte, int(tag)+1, (int(tag)+1)*2)
722                                 copy(newslice, tilelib.variant)
723                                 tilelib.variant = newslice[:int(tag)+1]
724                                 newvlock := make([]sync.Locker, int(tag)+1, (int(tag)+1)*2)
725                                 copy(newvlock, tilelib.vlock)
726                                 tilelib.vlock = newvlock[:int(tag)+1]
727                         } else {
728                                 // Use previously allocated capacity,
729                                 // avoiding copy.
730                                 tilelib.variant = tilelib.variant[:int(tag)+1]
731                                 tilelib.vlock = tilelib.vlock[:int(tag)+1]
732                         }
733                         for i := oldlen; i < len(tilelib.vlock); i++ {
734                                 tilelib.vlock[i] = new(sync.Mutex)
735                         }
736                         for i := 0; i < oldlen; i++ {
737                                 tilelib.vlock[i].Unlock()
738                         }
739                 }
740                 vlock = tilelib.vlock[tag]
741                 tilelib.mtx.Unlock()
742         }
743
744         vlock.Lock()
745         for i, varhash := range tilelib.variant[tag] {
746                 if varhash == seqhash {
747                         vlock.Unlock()
748                         return tileLibRef{Tag: tag, Variant: tileVariantID(i + 1)}
749                 }
750         }
751         atomic.AddInt64(&tilelib.variants, 1)
752         tilelib.variant[tag] = append(tilelib.variant[tag], seqhash)
753         variant := tileVariantID(len(tilelib.variant[tag]))
754         vlock.Unlock()
755
756         if tilelib.retainTileSequences && !dropSeq {
757                 seqCopy := append([]byte(nil), seq...)
758                 if tilelib.seq2 == nil {
759                         tilelib.mtx.Lock()
760                         if tilelib.seq2 == nil {
761                                 tilelib.seq2lock = map[[2]byte]sync.Locker{}
762                                 m := map[[2]byte]map[[blake2b.Size256]byte][]byte{}
763                                 var k [2]byte
764                                 for i := 0; i < 256; i++ {
765                                         k[0] = byte(i)
766                                         for j := 0; j < 256; j++ {
767                                                 k[1] = byte(j)
768                                                 m[k] = map[[blake2b.Size256]byte][]byte{}
769                                                 tilelib.seq2lock[k] = &sync.Mutex{}
770                                         }
771                                 }
772                                 tilelib.seq2 = m
773                         }
774                         tilelib.mtx.Unlock()
775                 }
776                 var k [2]byte
777                 copy(k[:], seqhash[:])
778                 locker := tilelib.seq2lock[k]
779                 locker.Lock()
780                 tilelib.seq2[k][seqhash] = seqCopy
781                 locker.Unlock()
782         }
783
784         saveSeq := seq
785         if dropSeq {
786                 // Save the hash, but not the sequence
787                 saveSeq = nil
788         }
789         if tilelib.encoder != nil {
790                 tilelib.encoder.Encode(LibraryEntry{
791                         TileVariants: []TileVariant{{
792                                 Tag:      tag,
793                                 Ref:      usedByRef,
794                                 Variant:  variant,
795                                 Blake2b:  seqhash,
796                                 Sequence: saveSeq,
797                         }},
798                 })
799         }
800         if tilelib.onAddTileVariant != nil {
801                 tilelib.onAddTileVariant(tileLibRef{tag, variant}, seqhash, saveSeq)
802         }
803         return tileLibRef{Tag: tag, Variant: variant}
804 }
805
806 func (tilelib *tileLibrary) hashSequence(hash [blake2b.Size256]byte) []byte {
807         var partition [2]byte
808         copy(partition[:], hash[:])
809         return tilelib.seq2[partition][hash]
810 }
811
812 func (tilelib *tileLibrary) TileVariantSequence(libref tileLibRef) []byte {
813         if libref.Variant == 0 || len(tilelib.variant) <= int(libref.Tag) || len(tilelib.variant[libref.Tag]) < int(libref.Variant) {
814                 return nil
815         }
816         return tilelib.hashSequence(tilelib.variant[libref.Tag][libref.Variant-1])
817 }
818
819 // Tidy deletes unreferenced tile variants and renumbers variants so
820 // more common variants have smaller IDs.
821 func (tilelib *tileLibrary) Tidy() {
822         log.Print("Tidy: compute inref")
823         inref := map[tileLibRef]bool{}
824         for _, refseq := range tilelib.refseqs {
825                 for _, librefs := range refseq {
826                         for _, libref := range librefs {
827                                 inref[libref] = true
828                         }
829                 }
830         }
831         log.Print("Tidy: compute remap")
832         remap := make([][]tileVariantID, len(tilelib.variant))
833         throttle := throttle{Max: runtime.NumCPU() + 1}
834         for tag, oldvariants := range tilelib.variant {
835                 tag, oldvariants := tagID(tag), oldvariants
836                 if tag%1000000 == 0 {
837                         log.Printf("Tidy: tag %d", tag)
838                 }
839                 throttle.Acquire()
840                 go func() {
841                         defer throttle.Release()
842                         uses := make([]int, len(oldvariants))
843                         for _, cg := range tilelib.compactGenomes {
844                                 for phase := 0; phase < 2; phase++ {
845                                         cgi := int(tag)*2 + phase
846                                         if cgi < len(cg) && cg[cgi] > 0 {
847                                                 uses[cg[cgi]-1]++
848                                         }
849                                 }
850                         }
851
852                         // Compute desired order of variants:
853                         // neworder[x] == index in oldvariants that
854                         // should move to position x.
855                         neworder := make([]int, len(oldvariants))
856                         for i := range neworder {
857                                 neworder[i] = i
858                         }
859                         sort.Slice(neworder, func(i, j int) bool {
860                                 if cmp := uses[neworder[i]] - uses[neworder[j]]; cmp != 0 {
861                                         return cmp > 0
862                                 } else {
863                                         return bytes.Compare(oldvariants[neworder[i]][:], oldvariants[neworder[j]][:]) < 0
864                                 }
865                         })
866
867                         // Replace tilelib.variant[tag] with a new
868                         // re-ordered slice of hashes, and make a
869                         // mapping from old to new variant IDs.
870                         remaptag := make([]tileVariantID, len(oldvariants)+1)
871                         newvariants := make([][blake2b.Size256]byte, 0, len(neworder))
872                         for _, oldi := range neworder {
873                                 if uses[oldi] > 0 || inref[tileLibRef{Tag: tag, Variant: tileVariantID(oldi + 1)}] {
874                                         newvariants = append(newvariants, oldvariants[oldi])
875                                         remaptag[oldi+1] = tileVariantID(len(newvariants))
876                                 }
877                         }
878                         tilelib.variant[tag] = newvariants
879                         remap[tag] = remaptag
880                 }()
881         }
882         throttle.Wait()
883
884         // Apply remap to genomes and reference sequences, so they
885         // refer to the same tile variants using the changed IDs.
886         log.Print("Tidy: apply remap")
887         var wg sync.WaitGroup
888         for _, cg := range tilelib.compactGenomes {
889                 cg := cg
890                 wg.Add(1)
891                 go func() {
892                         defer wg.Done()
893                         for idx, variant := range cg {
894                                 cg[idx] = remap[tagID(idx/2)][variant]
895                         }
896                 }()
897         }
898         for _, refcs := range tilelib.refseqs {
899                 for _, refseq := range refcs {
900                         refseq := refseq
901                         wg.Add(1)
902                         go func() {
903                                 defer wg.Done()
904                                 for i, tv := range refseq {
905                                         refseq[i].Variant = remap[tv.Tag][tv.Variant]
906                                 }
907                         }()
908                 }
909         }
910         wg.Wait()
911         log.Print("Tidy: done")
912 }
913
914 func countBases(seq []byte) int {
915         n := 0
916         for _, c := range seq {
917                 if isbase[c] {
918                         n++
919                 }
920         }
921         return n
922 }