Mise à jour terminée. Pour connaître les apports de la version 13.8.4 par rapport à notre ancienne version vous pouvez lire les "Release Notes" suivantes :
https://about.gitlab.com/releases/2021/02/11/security-release-gitlab-13-8-4-released/
https://about.gitlab.com/releases/2021/02/05/gitlab-13-8-3-released/

segment.cpp 26.9 KB
Newer Older
Mikaël Salson's avatar
Mikaël Salson committed
1
/*
2 3 4 5 6 7 8
  This file is part of Vidjil <http://www.vidjil.org>
  Copyright (C) 2011, 2012, 2013, 2014, 2015 by Bonsai bioinformatics 
  at CRIStAL (UMR CNRS 9189, Université Lille) and Inria Lille
  Contributors: 
      Mathieu Giraud <mathieu.giraud@vidjil.org>
      Mikaël Salson <mikael.salson@vidjil.org>
      Marc Duez <marc.duez@vidjil.org>
Mikaël Salson's avatar
Mikaël Salson committed
9 10 11 12 13 14 15 16 17 18 19 20 21 22

  "Vidjil" is free software: you can redistribute it and/or modify
  it under the terms of the GNU General Public License as published by
  the Free Software Foundation, either version 3 of the License, or
  (at your option) any later version.

  "Vidjil" is distributed in the hope that it will be useful,
  but WITHOUT ANY WARRANTY; without even the implied warranty of
  MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE.  See the
  GNU General Public License for more details.

  You should have received a copy of the GNU General Public License
  along with "Vidjil". If not, see <http://www.gnu.org/licenses/>
*/
Mikaël Salson's avatar
Mikaël Salson committed
23
#include <algorithm>    // std::sort
Mikaël Salson's avatar
Mikaël Salson committed
24 25 26 27
#include <cassert>
#include "segment.h"
#include "tools.h"
#include "affectanalyser.h"
Mikaël Salson's avatar
Mikaël Salson committed
28
#include <sstream>
29
#include <cstring>
Marc Duez's avatar
Marc Duez committed
30
#include <string>
Mikaël Salson's avatar
Mikaël Salson committed
31

Mathieu Giraud's avatar
Mathieu Giraud committed
32
Segmenter::~Segmenter() {}
Mikaël Salson's avatar
Mikaël Salson committed
33

Mathieu Giraud's avatar
Mathieu Giraud committed
34
Sequence Segmenter::getSequence() const {
Mikaël Salson's avatar
Mikaël Salson committed
35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54
  Sequence s ;
  s.label_full = info ;
  s.label = label + " " + (reversed ? "-" : "+");
  s.sequence = revcomp(sequence, reversed);

  return s ;
}

string Segmenter::getJunction(int l) const {
  assert(isSegmented());

  int start = (getLeft() + getRight())/2 - l/2;
  
  if (start < 0 or start + l > (int)sequence.size())  // TODO: +l ou +l-1 ?
    return "" ;

  return getSequence().sequence.substr(start, l);
}

int Segmenter::getLeft() const {
Mathieu Giraud's avatar
Mathieu Giraud committed
55
  return Vend;
Mikaël Salson's avatar
Mikaël Salson committed
56 57 58
}
  
int Segmenter::getRight() const {
Mathieu Giraud's avatar
Mathieu Giraud committed
59
  return Jstart;
Mikaël Salson's avatar
Mikaël Salson committed
60 61 62
}

int Segmenter::getLeftD() const {
Mathieu Giraud's avatar
Mathieu Giraud committed
63
  return Dstart;
Mikaël Salson's avatar
Mikaël Salson committed
64 65 66
}
  
int Segmenter::getRightD() const {
Mathieu Giraud's avatar
Mathieu Giraud committed
67
  return Dend;
Mikaël Salson's avatar
Mikaël Salson committed
68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89
}

bool Segmenter::isReverse() const {
  return reversed;
}

bool Segmenter::isSegmented() const {
  return segmented;
}

bool Segmenter::isDSegmented() const {
  return dSegmented;
}

// Chevauchement

string Segmenter::removeChevauchement()
{
  assert(isSegmented());
  
  string chevauchement = "" ;

Mathieu Giraud's avatar
Mathieu Giraud committed
90
  if (Vend >= Jstart)
Mikaël Salson's avatar
Mikaël Salson committed
91
    {
Mathieu Giraud's avatar
Mathieu Giraud committed
92
      int middle = (Vend + Jstart) / 2 ;
93
      chevauchement = " !ov " + string_of_int (Vend - Jstart + 1);
Mathieu Giraud's avatar
Mathieu Giraud committed
94 95
      Vend = middle ;
      Jstart = middle+1 ;
Mikaël Salson's avatar
Mikaël Salson committed
96 97 98 99 100 101 102 103 104 105 106 107 108 109
    }

  return chevauchement ;
}

// Prettyprint


bool Segmenter::finishSegmentation() 
{
  assert(isSegmented());
  
  string seq = getSequence().sequence;
    
Mathieu Giraud's avatar
Mathieu Giraud committed
110 111 112 113 114
  seg_V = seq.substr(0, Vend+1) ;
  seg_N = seq.substr(Vend+1, Jstart-Vend-1) ;  // Twice computed for FineSegmenter, but only once in KmerSegmenter !
  seg_J = seq.substr(Jstart) ;
  Dstart=0;
  Dend=0;
Mikaël Salson's avatar
Mikaël Salson committed
115 116 117 118 119 120 121 122 123 124 125 126 127

  info = "VJ \t" + string_of_int(FIRST_POS) + " " + info + " " + string_of_int(seq.size() - 1 + FIRST_POS) ;
  info += "\t" + code ;

  info = (reversed ? "- " : "+ ") + info ;

  return true ;
}

bool Segmenter::finishSegmentationD() 
{
  string seq = getSequence().sequence;

Mathieu Giraud's avatar
Mathieu Giraud committed
128 129
  seg_V = seq.substr(0, Vend+1) ; // From pos. 0 to Vend
  seg_J = seq.substr(Jstart) ;
Mikaël Salson's avatar
Mikaël Salson committed
130
  
Mathieu Giraud's avatar
Mathieu Giraud committed
131
  seg_D  = seq.substr(Dstart, Dend-Dstart+1) ; // From Dstart to Dend
Mikaël Salson's avatar
Mikaël Salson committed
132
  
Mathieu Giraud's avatar
Mathieu Giraud committed
133 134 135 136
  info = "VDJ \t0 " + string_of_int(Vend) +
		" " + string_of_int(Dstart) + 
		" " + string_of_int(Dend) +
		" " + string_of_int(Jstart) +
Mikaël Salson's avatar
Mikaël Salson committed
137 138 139 140 141 142 143 144 145
		" " + string_of_int(seq.size()-1+FIRST_POS) ;
		
  info += "\t" + code ;
  
  info = (reversed ? "- " : "+ ") + info ;

  return true ;
}

146 147
string Segmenter::getInfoLine() const
{
148
  string s = "" ;
149 150 151 152 153

  s += (segmented ? "" : "! ") + info ;
  s += " " + info_extra ;
  s += " " + segmented_germline->code ;
  s += " " + string(segmented_mesg[because]) ;
154 155 156 157

  if (evalue > NO_LIMIT_VALUE)
    s += " " + scientific_string_of_double(evalue);

158 159 160 161 162
  if (evalue_left > NO_LIMIT_VALUE)
    s += " " + scientific_string_of_double(evalue_left);
  if (evalue_right > NO_LIMIT_VALUE)
    s += "/" + scientific_string_of_double(evalue_right);

163 164 165
  return s ;
}

166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181
string KmerSegmenter::getInfoLineWithAffects() const
{
   stringstream ss;

   ss << "# "
      << right << setw(3) << score << " "
      << left << setw(30)
      << getInfoLine() ;

   if (getSegmentationStatus() != UNSEG_TOO_SHORT)
     ss << getKmerAffectAnalyser()->toString();

   return ss.str();
}


Mikaël Salson's avatar
Mikaël Salson committed
182 183
ostream &operator<<(ostream &out, const Segmenter &s)
{
184
  out << ">" << s.label << " " ;
185
  out << s.getInfoLine() << endl;
Mikaël Salson's avatar
Mikaël Salson committed
186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203

  if (s.segmented)
    {
      out << s.seg_V << endl ;
      out << s.seg_N << endl ;
      out << s.seg_J << endl ;
    }
  else
    {
      out << s.sequence << endl ;
    }

  return out ;
}


// KmerSegmenter (Cheap)

204 205
KmerSegmenter::KmerSegmenter() { kaa = 0 ; }

206
KmerSegmenter::KmerSegmenter(Sequence seq, Germline *germline, double threshold, int multiplier)
Mikaël Salson's avatar
Mikaël Salson committed
207 208 209 210
{
  label = seq.label ;
  sequence = seq.sequence ;
  info = "" ;
211
  info_extra = "seed";
Mikaël Salson's avatar
Mikaël Salson committed
212
  segmented = false;
213
  segmented_germline = germline ;
214
  system = germline->code; // useful ?
215
  reversed = false;
Mathieu Giraud's avatar
Mathieu Giraud committed
216
  Dend=0;
217
  because = NOT_PROCESSED ; // Cause of unsegmentation
218
  score = 0 ;
219
  evalue = NO_LIMIT_VALUE;
220 221
  evalue_left = NO_LIMIT_VALUE;
  evalue_right = NO_LIMIT_VALUE;
222

223
  int s = (size_t)germline->index->getS() ;
Mikaël Salson's avatar
Mikaël Salson committed
224
  int length = sequence.length() ;
Mikaël Salson's avatar
Mikaël Salson committed
225

226
  if (length < s) 
Mikaël Salson's avatar
Mikaël Salson committed
227
    {
Mathieu Giraud's avatar
Mathieu Giraud committed
228 229
      because = UNSEG_TOO_SHORT;
      kaa = NULL;
230
      return ;
Mikaël Salson's avatar
Mikaël Salson committed
231 232
    }
 
233
  kaa = new KmerAffectAnalyser(*(germline->index), sequence);
Mikaël Salson's avatar
Mikaël Salson committed
234 235
  
  // Check strand consistency among the affectations.
Mikaël Salson's avatar
Mikaël Salson committed
236 237 238 239 240 241 242 243 244
  int strand;
  int nb_strand[2] = {0,0};     // In cell 0 we'll put the number of negative
                                // strand, while in cell 1 we'll put the
                                // positives
  for (int i = 0; i < kaa->count(); i++) { 
    KmerAffect it = kaa->getAffectation(i);
    if (! it.isAmbiguous() && ! it.isUnknown()) {
      strand = affect_strand(it.affect);
      nb_strand[(strand + 1) / 2] ++; // (strand+1) / 2 → 0 if strand == -1; 1 if strand == 1
Mikaël Salson's avatar
Mikaël Salson committed
245 246 247
    }
  }

248 249
  score = nb_strand[0] + nb_strand[1] ; // Used only for non-segmented germlines

250 251 252 253 254 255 256 257
  if (!strcmp(germline->code.c_str(), PSEUDO_GERMLINE_MAX12))
    { // Pseudo-germline, max12

      set<KmerAffect> forbidden;
      forbidden.insert(KmerAffect::getAmbiguous());
      forbidden.insert(KmerAffect::getUnknown());

      CountKmerAffectAnalyser ckaa(*(germline->index), sequence);
258
      pair <KmerAffect, KmerAffect> max12 = ckaa.sortLeftRight(ckaa.max12(forbidden));
259

260 261 262
      before = max12.first ;
      after = max12.second ;

263 264 265 266 267 268
      if (max12.first.isUnknown() || max12.second.isUnknown())
        {
          because = UNSEG_TOO_FEW_ZERO ;
          return ;
        }

269 270
      strand = nb_strand[0] > nb_strand[1] ? -1 : 1 ;

271
      // The pseudo-germline should never take precedence over regular germlines of similar e-value
272
      multiplier *= PSEUDO_GERMLINE_MAX12_EVALUE_PENALTY ;
273 274 275 276 277
    }

  else
    { // Regular germline

278
  // Test on which strand we are, select the before and after KmerAffects
Mikaël Salson's avatar
Mikaël Salson committed
279
  if (nb_strand[0] == 0 && nb_strand[1] == 0) {
280
    because = UNSEG_TOO_FEW_ZERO ;
281
    return ;
Mikaël Salson's avatar
Mikaël Salson committed
282 283
  } else if (nb_strand[0] > RATIO_STRAND * nb_strand[1]) {
    strand = -1;
284 285
    before = KmerAffect(germline->affect_3, -1); 
    after = KmerAffect(germline->affect_5, -1);
Mikaël Salson's avatar
Mikaël Salson committed
286 287
  } else if (nb_strand[1] > RATIO_STRAND * nb_strand[0]) {
    strand = 1;
288 289
    before = KmerAffect(germline->affect_5, 1); 
    after = KmerAffect(germline->affect_3, 1);    
Mikaël Salson's avatar
Mikaël Salson committed
290 291 292
  } else {
    // Ambiguous information: we have positive and negative strands
    // and there is not enough difference to put them aparat.
293 294
    because = UNSEG_STRAND_NOT_CONSISTENT ;
    return ;
Mikaël Salson's avatar
Mikaël Salson committed
295 296
  }

297
    } // endif Pseudo-germline
298
 
299
  computeSegmentation(strand, before, after, germline->delta_min, germline->delta_max, threshold, multiplier);
Mathieu Giraud's avatar
Mathieu Giraud committed
300
}
Mikaël Salson's avatar
Mikaël Salson committed
301

Mathieu Giraud's avatar
Mathieu Giraud committed
302
KmerSegmenter::~KmerSegmenter() {
303 304
  if (kaa)
    delete kaa;
305 306
}

307 308
KmerMultiSegmenter::KmerMultiSegmenter(Sequence seq, MultiGermline *multigermline, ostream *out_unsegmented,
                                       double threshold, int nb_reads_for_evalue)
309
{
310 311
  bool found_seg = false ; // Found a segmentation
  double best_evalue_seg = NO_LIMIT_VALUE ; // Best evalue, segmented sequences
312
  int best_score_unseg = 0 ; // Best score, unsegmented sequences
313
  the_kseg = NULL;
314
  multi_germline = multigermline;
315
  threshold_nb_expected = threshold;
316 317 318

  // E-value multiplier
  int multiplier = multi_germline->germlines.size() * nb_reads_for_evalue;
319
  
320 321 322 323 324
  // Iterate over the germlines
  for (list<Germline*>::const_iterator it = multigermline->germlines.begin(); it != multigermline->germlines.end(); ++it)
    {
      Germline *germline = *it ;

325
      KmerSegmenter *kseg = new KmerSegmenter(seq, germline, threshold, multiplier);
326
      bool keep_seg = false;
327

328 329 330
      if (out_unsegmented)
        {
          // Debug, display k-mer affectation and segmentation result for this germline
331
          *out_unsegmented << kseg->getInfoLineWithAffects() << endl ;
332 333
        }

334 335
      // Always remember the first kseg
      if (the_kseg == NULL)
336
        keep_seg = true;
337
      
338
      if (kseg->isSegmented())
339 340
        {
          // Yes, it is segmented
341
          // Should we keep the kseg ?
342
          if (!found_seg || (kseg->evalue < best_evalue_seg))
343
            {
344
              keep_seg = true;
345 346 347
              best_evalue_seg = kseg->evalue ;

              found_seg = true;
348
            }
349
        }
350 351 352 353 354 355 356
      else
        {
          // It is not segmented
          // Should we keep the kseg (with the unsegmentation cause) ?
            if (kseg->score > best_score_unseg)
            {              
              best_score_unseg = kseg->score ;
357
              if (!found_seg)
358 359 360 361
                keep_seg = true;
            }
        }
      
362
      if (keep_seg) {
363 364
        if (the_kseg)
          delete the_kseg;
365 366 367 368
        the_kseg = kseg;
      } else {
        delete kseg;
      }
369 370 371
    } // end for (Germlines)
}

372
KmerMultiSegmenter::~KmerMultiSegmenter() {
373 374
  if (the_kseg)
    delete the_kseg;
Mathieu Giraud's avatar
Mathieu Giraud committed
375 376
}

377 378 379
void KmerSegmenter::computeSegmentation(int strand, KmerAffect before, KmerAffect after,
                                        int delta_min, int delta_max,
                                        double threshold, int multiplier) {
380
  // Try to segment, computing 'Vend' and 'Jstart'
381 382
  // If not segmented, put the cause of unsegmentation in 'because'

383
  affect_infos max;
384
  max = kaa->getMaximum(before, after);
Mikaël Salson's avatar
Mikaël Salson committed
385

386 387 388
  pair <double, double> pvalues = kaa->getLeftRightProbabilityAtLeastOrAbove();
  evalue_left = pvalues.first * multiplier ;
  evalue_right = pvalues.second * multiplier ;
389
  evalue = evalue_left + evalue_right ;
390

391
  // E-value threshold
392
  if (threshold > NO_LIMIT_VALUE && evalue >= threshold) {
393 394

    // Detail the unsegmentation cause
395
    if (evalue_left >= threshold && evalue_right >= threshold)
396
      because = UNSEG_TOO_FEW_ZERO ;
397
    else if (evalue_left >= threshold)
398
      because = UNSEG_TOO_FEW_V ;
399
    else if (evalue_right >= threshold)
400 401 402 403 404 405 406 407 408
      because = UNSEG_TOO_FEW_J ;
    else // left and right are <= threshold, but their sum is > threshold
      because = UNSEG_TOO_FEW_ZERO ;

    return ;
  }

  //

409
      // We labeled it detected if there were both enough affect_5 and enough affect_3
410
      bool detected = (max.nb_before_left + max.nb_before_right >= DETECT_THRESHOLD)
411 412
        && (max.nb_after_left + max.nb_after_right >= DETECT_THRESHOLD);
      
413
      if (! max.max_found) {
414 415
        if ((strand == 1 && max.nb_before_left == 0)
            || (strand == -1 && max.nb_after_right == 0)) 
416
          because = detected ? UNSEG_AMBIGUOUS : UNSEG_TOO_FEW_V ;
417 418
        else if ((strand == 1 && max.nb_after_right == 0)
                 || (strand == -1 && max.nb_before_left == 0))
Mikaël Salson's avatar
Mikaël Salson committed
419
	{
420
	  because = detected ? UNSEG_AMBIGUOUS : UNSEG_TOO_FEW_J ;
421
	} else 
422
          because = UNSEG_AMBIGUOUS; 
423 424

        return ;
425
      }
426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465

   // There was a good segmentation point

   Vend = max.first_pos_max;
   Jstart = max.last_pos_max + 1;
   if (strand == -1) {
     int tmp = sequence.size() - Vend - 1;
     Vend = sequence.size() - Jstart - 1;
     Jstart = tmp;
   }


  // Now we check the delta between Vend and right

  if (Jstart - Vend < delta_min)
    {
      because = UNSEG_BAD_DELTA_MIN ;
      return ;
    }

  if (Jstart - Vend > delta_max)
    {
      because = UNSEG_BAD_DELTA_MAX ;
      return ;
    }

  assert(because == NOT_PROCESSED);

  // Yes, it is segmented
  segmented = true;
  reversed = (strand == -1);
  because = reversed ? SEG_MINUS : SEG_PLUS ;

  info = string_of_int(Vend + FIRST_POS) + " " + string_of_int(Jstart + FIRST_POS)  ;

  // removeChevauchement is called once info was already computed: it is only to output info_extra
  info_extra += removeChevauchement();
  finishSegmentation();

  return ;
Mathieu Giraud's avatar
Mathieu Giraud committed
466
}
Mikaël Salson's avatar
Mikaël Salson committed
467

468
KmerAffectAnalyser *KmerSegmenter::getKmerAffectAnalyser() const {
Mathieu Giraud's avatar
Mathieu Giraud committed
469 470
  return kaa;
}
Mikaël Salson's avatar
Mikaël Salson committed
471

472
int Segmenter::getSegmentationStatus() const {
Mathieu Giraud's avatar
Mathieu Giraud committed
473
  return because;
Mikaël Salson's avatar
Mikaël Salson committed
474 475
}

476 477 478 479 480
void Segmenter::setSegmentationStatus(int status) {
  because = status;
  segmented = (status == SEG_PLUS || status == SEG_MINUS);
}

Mikaël Salson's avatar
Mikaël Salson committed
481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505
// FineSegmenter

void best_align(int overlap, string seq_left, string seq_right,
		string ref_left ,string ref_right, int *b_r, int *b_l, Cost segment_cost)
{
      int score_r[overlap+1];
      int score_l[overlap+1];
      
      //LEFT
      ref_left=string(ref_left.rbegin(), ref_left.rend());
      seq_left=string(seq_left.rbegin(), seq_left.rend()); 
      
      DynProg dp1 = DynProg(seq_left, ref_left,
			   DynProg::Local, segment_cost);
      score_l[0] = dp1.compute();
      dp1.backtrack();
      
      //RIGHT
      DynProg dp = DynProg(seq_right, ref_right,
			   DynProg::Local, segment_cost);
      score_r[0] = dp.compute();
      dp.backtrack();    
      
      for(int i=1; i<=overlap; i++){
	if(dp.best_i-i >0)
506
	score_r[i] = dp.B[dp.best_i-i][dp.best_j].score;
Mikaël Salson's avatar
Mikaël Salson committed
507 508 509
	else
	score_r[i] =0;
	if(dp1.best_i-i >0)
510
	score_l[i] = dp1.B[dp1.best_i-i][dp1.best_j].score;	
Mikaël Salson's avatar
Mikaël Salson committed
511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535
	else
	score_l[i] =0;
      }
      int score=-1000000;
      int best_r=0;
      int best_l=0;

      for (int i=0; i<=overlap; i++){
	for (int j=overlap-i; j<=overlap; j++){
	  if ( ((score_r[i]+score_l[j]) == score) && (i+j < best_r+best_l )){
	    best_r=i;
	    best_l=j;
	    score=(score_r[i]+score_l[j]) ;
	  }
	  if ( (score_r[i]+score_l[j]) > score){
	    best_r=i;
	    best_l=j;
	    score=(score_r[i]+score_l[j]) ;
	  }
	}
      }
      *b_r=best_r;
      *b_l=best_l;
}

Mikaël Salson's avatar
Mikaël Salson committed
536 537 538 539 540
bool comp_pair (pair<int,int> i,pair<int,int> j)
{
  return ( i.first > j.first);
}

Mathieu Giraud's avatar
Mathieu Giraud committed
541
int align_against_collection(string &read, Fasta &rep, bool reverse_both, bool local, int *tag, 
Mikaël Salson's avatar
Mikaël Salson committed
542
			     int *del, int *del2, int *begin, int *length, vector<pair<int, int> > *score
Mikaël Salson's avatar
Mikaël Salson committed
543 544 545 546 547 548 549 550 551 552
			    , Cost segment_cost)
{
  
  int best_score = MINUS_INF ;
  int best_r = MINUS_INF ;
  int best_best_i = (int) string::npos ;
  int best_best_j = (int) string::npos ;
  int best_first_i = (int) string::npos ;
  int best_first_j = (int) string::npos ;
  string best_label = "" ;
Mikaël Salson's avatar
Mikaël Salson committed
553
  vector<pair<int, int> > score_r;
Mikaël Salson's avatar
Mikaël Salson committed
554 555 556 557 558 559 560 561 562 563 564

  DynProg::DynProgMode dpMode = DynProg::LocalEndWithSomeDeletions;
  if (local==true) dpMode = DynProg::Local;
  
  for (int r = 0 ; r < rep.size() ; r++)
    {
      DynProg dp = DynProg(read, rep.sequence(r),
			   dpMode, // DynProg::SemiGlobalTrans, 
			   segment_cost, // DNA
			   reverse_both, reverse_both);
      int score = dp.compute();
Mikaël Salson's avatar
Mikaël Salson committed
565
      
Mikaël Salson's avatar
Mikaël Salson committed
566 567 568 569 570 571 572 573 574 575 576 577 578 579
      if (local==true){ 
	dp.backtrack();
      }
      
      if (score > best_score)
	{
	  best_score = score ;
	  best_best_i = dp.best_i ;
	  best_best_j = dp.best_j ;
	  best_first_i = dp.first_i ;
	  best_first_j = dp.first_j ;
	  best_r = r ;
	  best_label = rep.label(r) ;
	}
Mikaël Salson's avatar
Mikaël Salson committed
580 581
	
	score_r.push_back(make_pair(score, r));
Mathieu Giraud's avatar
Mathieu Giraud committed
582 583 584 585 586 587

	// #define DEBUG_SEGMENT      

#ifdef DEBUG_SEGMENT	
	cout << rep.label(r) << " " << score << " " << dp.best_i << endl ;
#endif
Mikaël Salson's avatar
Mikaël Salson committed
588 589

    }
Mikaël Salson's avatar
Mikaël Salson committed
590
    sort(score_r.begin(),score_r.end(),comp_pair);
Mikaël Salson's avatar
Mikaël Salson committed
591 592 593 594

  *del = reverse_both ? best_best_j : rep.sequence(best_r).size() - best_best_j - 1;
  *del2 = best_first_j;
  *begin = best_first_i;
Mathieu Giraud's avatar
Mathieu Giraud committed
595
  *tag = best_r ; 
Mikaël Salson's avatar
Mikaël Salson committed
596 597
  
  *length -= *del ;
Mikaël Salson's avatar
Mikaël Salson committed
598 599
  
  *score=score_r;
Mathieu Giraud's avatar
Mathieu Giraud committed
600 601 602 603 604 605

#ifdef DEBUG_SEGMENT	
  cout << "best: " << best_labels << " " << best_score ;
  cout << "del/del2/begin:" << (*del) << "/" << (*del2) << "/" << (*begin) << endl;
  cout << endl;
#endif
Mikaël Salson's avatar
Mikaël Salson committed
606 607 608 609 610 611 612 613 614
  
  return best_best_i ;
}

string format_del(int deletions)
{
  return deletions ? *"(" + string_of_int(deletions) + " del)" : "" ;
}

615
FineSegmenter::FineSegmenter(Sequence seq, Germline *germline, Cost segment_c)
Mikaël Salson's avatar
Mikaël Salson committed
616
{
617 618
  segmented = false;
  dSegmented = false;
619
  because = NOT_PROCESSED ;
620
  segmented_germline = germline ;
621
  info_extra = "" ;
Mikaël Salson's avatar
Mikaël Salson committed
622 623
  label = seq.label ;
  sequence = seq.sequence ;
Mathieu Giraud's avatar
Mathieu Giraud committed
624
  Dend=0;
Mikaël Salson's avatar
Mikaël Salson committed
625
  segment_cost=segment_c;
626
  evalue = NO_LIMIT_VALUE;
627 628
  evalue_left = NO_LIMIT_VALUE;
  evalue_right = NO_LIMIT_VALUE;
Mikaël Salson's avatar
Mikaël Salson committed
629

630 631 632
  CDR3start = -1;
  CDR3end = -1;
  
633 634 635
  if (!germline->rep_5.size() || !germline->rep_3.size())
    return ;

Mikaël Salson's avatar
Mikaël Salson committed
636 637 638 639 640
  // TODO: factoriser tout cela, peut-etre en lancant deux segmenteurs, un +, un -, puis un qui chapote
  
  // Strand +
  
  int plus_score = 0 ;
Mathieu Giraud's avatar
Mathieu Giraud committed
641
  int tag_plus_V, tag_plus_J;
Mikaël Salson's avatar
Mikaël Salson committed
642 643 644 645
  int plus_length = 0 ;
  int del_plus_V, del_plus_J ;
  int del2=0;
  int beg=0;
Mikaël Salson's avatar
Mikaël Salson committed
646 647 648 649
  
  vector<pair<int, int> > score_plus_V;
  vector<pair<int, int> > score_plus_J;
  
650
  int plus_left = align_against_collection(sequence, germline->rep_5, false, false, &tag_plus_V, &del_plus_V, &del2, &beg, 
Mikaël Salson's avatar
Mikaël Salson committed
651 652
					   &plus_length, &score_plus_V
					   , segment_cost);
653
  int plus_right = align_against_collection(sequence, germline->rep_3, true, false, &tag_plus_J, &del_plus_J, &del2, &beg,
Mikaël Salson's avatar
Mikaël Salson committed
654 655
					    &plus_length, &score_plus_J
					    , segment_cost);
Mikaël Salson's avatar
Mikaël Salson committed
656 657
  plus_length += plus_right - plus_left ;

Mikaël Salson's avatar
Mikaël Salson committed
658 659
  plus_score=score_plus_V[0].first + score_plus_J[0].first ;
  
Mikaël Salson's avatar
Mikaël Salson committed
660 661 662
  // Strand -
  string rc = revcomp(sequence) ;
  int minus_score = 0 ;
Mathieu Giraud's avatar
Mathieu Giraud committed
663
  int tag_minus_V, tag_minus_J;
Mikaël Salson's avatar
Mikaël Salson committed
664 665
  int minus_length = 0 ;
  int del_minus_V, del_minus_J ;
Mikaël Salson's avatar
Mikaël Salson committed
666 667 668 669
  
  vector<pair<int, int> > score_minus_V;
  vector<pair<int, int> > score_minus_J;
  
670
  int minus_left = align_against_collection(rc, germline->rep_5, false, false, &tag_minus_V, &del_minus_V, &del2, &beg,
Mikaël Salson's avatar
Mikaël Salson committed
671 672
					    &minus_length, &score_minus_V
					    ,  segment_cost);
673
  int minus_right = align_against_collection(rc, germline->rep_3, true, false, &tag_minus_J, &del_minus_J, &del2, &beg,
Mikaël Salson's avatar
Mikaël Salson committed
674 675
					     &minus_length, &score_minus_J
					     , segment_cost);
Mikaël Salson's avatar
Mikaël Salson committed
676 677
  minus_length += minus_right - minus_left ;

Mikaël Salson's avatar
Mikaël Salson committed
678 679
  minus_score=score_minus_V[0].first + score_minus_J[0].first ;
  
Mikaël Salson's avatar
Mikaël Salson committed
680 681 682 683
  reversed = (minus_score > plus_score) ;

  if (!reversed)
    {
Mathieu Giraud's avatar
Mathieu Giraud committed
684 685 686 687
      Vend = plus_left ;
      Jstart = plus_right ;
      best_V = tag_plus_V ;
      best_J = tag_plus_J ;
Mikaël Salson's avatar
Mikaël Salson committed
688 689
      del_V = del_plus_V ;
      del_J = del_plus_J ;
Mikaël Salson's avatar
Mikaël Salson committed
690 691
      score_V=score_plus_V;
      score_J=score_plus_J;
Mikaël Salson's avatar
Mikaël Salson committed
692 693 694
    }
  else
    {
Mathieu Giraud's avatar
Mathieu Giraud committed
695 696 697 698
      Vend = minus_left ;
      Jstart = minus_right ;
      best_V = tag_minus_V ;
      best_J = tag_minus_J ;
Mikaël Salson's avatar
Mikaël Salson committed
699 700
      del_V = del_minus_V ;
      del_J = del_minus_J ;
Mikaël Salson's avatar
Mikaël Salson committed
701 702
      score_V=score_minus_V;
      score_J=score_minus_J;
Mikaël Salson's avatar
Mikaël Salson committed
703 704
    }

Mathieu Giraud's avatar
Mathieu Giraud committed
705
  segmented = (Vend != (int) string::npos) && (Jstart != (int) string::npos) && 
706
    (Jstart - Vend >= germline->delta_min) && (Jstart - Vend <= germline->delta_max);
Mikaël Salson's avatar
Mikaël Salson committed
707 708 709
    
  if (!segmented)
    {
710
      because = NOT_PROCESSED;
Mathieu Giraud's avatar
Mathieu Giraud committed
711
      info = " @" + string_of_int (Vend + FIRST_POS) + "  @" + string_of_int(Jstart + FIRST_POS) ;
712
      
713
      if (Jstart - Vend < germline->delta_min)
714 715 716 717
        {
          because = UNSEG_BAD_DELTA_MIN  ;
        }

718
      if (Jstart - Vend > germline->delta_max)
719 720 721 722 723 724 725 726 727 728 729 730 731 732
        {
          because = UNSEG_BAD_DELTA_MAX  ;
        }
        
      if (Vend == (int) string::npos) 
        {
          because = UNSEG_TOO_FEW_V ;
        }
      
      if (Jstart == (int) string::npos)
        {
          because = UNSEG_TOO_FEW_J ;
        }
      
Mikaël Salson's avatar
Mikaël Salson committed
733 734 735
      return ;
    }
    
736 737
    because = reversed ? SEG_MINUS : SEG_PLUS ;
    
Mikaël Salson's avatar
Mikaël Salson committed
738
    //overlap VJ
Mathieu Giraud's avatar
Mathieu Giraud committed
739
    if(Jstart-Vend <=0){
Mikaël Salson's avatar
Mikaël Salson committed
740
      int b_r, b_l;
Mathieu Giraud's avatar
Mathieu Giraud committed
741
      int overlap=Vend-Jstart+1;
Mikaël Salson's avatar
Mikaël Salson committed
742
      
Mathieu Giraud's avatar
Mathieu Giraud committed
743 744
      string seq_left = sequence.substr(0, Vend+1);
      string seq_right = sequence.substr(Jstart);
Mikaël Salson's avatar
Mikaël Salson committed
745 746

      best_align(overlap, seq_left, seq_right, 
747
		 germline->rep_5.sequence(best_V), germline->rep_3.sequence(best_J), &b_r,&b_l, segment_cost);
Mikaël Salson's avatar
Mikaël Salson committed
748
      // Trim V
Mathieu Giraud's avatar
Mathieu Giraud committed
749
      Vend -= b_l;
Mikaël Salson's avatar
Mikaël Salson committed
750 751 752
      del_V += b_l;

      // Trim J
Mathieu Giraud's avatar
Mathieu Giraud committed
753
      Jstart += b_r;
Mikaël Salson's avatar
Mikaël Salson committed
754
      del_J += b_r;
755
      if (Jstart>=(int) sequence.length())
Mathieu Giraud's avatar
Mathieu Giraud committed
756
	  Jstart=sequence.length()-1;
Mikaël Salson's avatar
Mikaël Salson committed
757 758 759
    }

    // string chevauchement = removeChevauchement();
Mikaël Salson's avatar
Mikaël Salson committed
760 761

    /// used only below, then recomputed in finishSegmentation() ;
Mathieu Giraud's avatar
Mathieu Giraud committed
762
    seg_N = revcomp(sequence, reversed).substr(Vend+1, Jstart-Vend-1); 
Mikaël Salson's avatar
Mikaël Salson committed
763

764
  code = germline->rep_5.label(best_V) +
Mikaël Salson's avatar
Mikaël Salson committed
765 766 767 768
    " "+ string_of_int(del_V) + 
    "/" + seg_N + 
    // chevauchement +
    "/" + string_of_int(del_J) +
769
    " " + germline->rep_3.label(best_J); 
Mikaël Salson's avatar
Mikaël Salson committed
770

Mikaël Salson's avatar
Mikaël Salson committed
771
    stringstream code_s;
772
   code_s<< germline->rep_5.label(best_V) <<
Mikaël Salson's avatar
Mikaël Salson committed
773 774 775 776
    " -" << string_of_int(del_V) << "/" 
    << seg_N.size()
    // chevauchement +
    << "/-" << string_of_int(del_J)
777
    <<" " << germline->rep_3.label(best_J);
Mikaël Salson's avatar
Mikaël Salson committed
778 779
    code_short=code_s.str();
    
780 781
  code_light = germline->rep_5.label(best_V) +
    "/ " + germline->rep_3.label(best_J); 
Mikaël Salson's avatar
Mikaël Salson committed
782 783

 
Mathieu Giraud's avatar
Mathieu Giraud committed
784
  info = string_of_int(Vend + FIRST_POS) + " " + string_of_int(Jstart + FIRST_POS) ;
Mikaël Salson's avatar
Mikaël Salson committed
785 786 787 788
  finishSegmentation();
}


789
void FineSegmenter::FineSegmentD(Germline *germline){
Mikaël Salson's avatar
Mikaël Salson committed
790 791 792 793
  
  if (segmented){
    
    int end = (int) string::npos ;
Mathieu Giraud's avatar
Mathieu Giraud committed
794
    int tag_D;
Mikaël Salson's avatar
Mikaël Salson committed
795 796 797 798
    int length = 0 ;
    int begin = 0;
    
    // Create a zone where to look for D, adding at most EXTEND_D_ZONE nucleotides at each side
Mathieu Giraud's avatar
Mathieu Giraud committed
799
    int l = Vend - EXTEND_D_ZONE;
Mikaël Salson's avatar
Mikaël Salson committed
800 801 802
    if (l<0) 
      l=0 ;

Mathieu Giraud's avatar
Mathieu Giraud committed
803
    int r = Jstart + EXTEND_D_ZONE;
Mikaël Salson's avatar
Mikaël Salson committed
804 805 806 807 808 809 810

    if (r > (int)getSequence().sequence.length()) 
      r = getSequence().sequence.length();
      
    string str = getSequence().sequence.substr(l, r-l);

    // Align
811
    end = align_against_collection(str, germline->rep_4, false, true, &tag_D, &del_D_right, &del_D_left, &begin,
Mikaël Salson's avatar
Mikaël Salson committed
812 813
				&length, &score_D, segment_cost);
    
Mathieu Giraud's avatar
Mathieu Giraud committed
814
    best_D = tag_D;
Mikaël Salson's avatar
Mikaël Salson committed
815
    
Mathieu Giraud's avatar
Mathieu Giraud committed
816 817
    Dstart = l + begin;
    Dend = l + end;
Mikaël Salson's avatar
Mikaël Salson committed
818 819
	
    string seq = getSequence().sequence;
820 821 822 823 824 825 826 827 828 829


    // recompute remaining length for D
    length = germline->rep_4.sequence(best_D).length() - del_D_right - del_D_left;

    if (length < MIN_D_LENGTH)
      return ;


    dSegmented=true;
Mikaël Salson's avatar
Mikaël Salson committed
830 831
    
    //overlap VD
Mathieu Giraud's avatar
Mathieu Giraud committed
832
    if(Dstart-Vend <=0){
Mikaël Salson's avatar
Mikaël Salson committed
833
      int b_r, b_l;
Mathieu Giraud's avatar
Mathieu Giraud committed
834 835 836
      int overlap=Vend-Dstart+1;
      string seq_left = seq.substr(0, Vend+1);
      string seq_right = seq.substr(Dstart, Dend-Dstart+1);
Mikaël Salson's avatar
Mikaël Salson committed
837 838

      best_align(overlap, seq_left, seq_right, 
839
		 germline->rep_5.sequence(best_V), germline->rep_4.sequence(best_D), &b_r,&b_l, segment_cost);
Mikaël Salson's avatar
Mikaël Salson committed
840 841

      // Trim V
Mathieu Giraud's avatar
Mathieu Giraud committed
842
      Vend -= b_l;
Mikaël Salson's avatar
Mikaël Salson committed
843 844 845
      del_V += b_l;

      // Trim D
Mathieu Giraud's avatar
Mathieu Giraud committed
846
      Dstart += b_r;
Mikaël Salson's avatar
Mikaël Salson committed
847
    }
Mathieu Giraud's avatar
Mathieu Giraud committed
848
    seg_N1 = seq.substr(Vend+1, Dstart-Vend-1) ; // From Vend+1 to Dstart-1
Mikaël Salson's avatar
Mikaël Salson committed
849 850
    
    //overlap DJ
Mathieu Giraud's avatar
Mathieu Giraud committed
851
    if(Jstart-Dend <=0){
Mikaël Salson's avatar
Mikaël Salson committed
852
      int b_r, b_l;
Mathieu Giraud's avatar
Mathieu Giraud committed
853 854 855
      int overlap=Dend-Jstart+1;
      string seq_right = seq.substr(Dstart, Dend-Dstart+1);
      string seq_left = seq.substr(Jstart, seq.length()-Jstart);
Mikaël Salson's avatar
Mikaël Salson committed
856 857

      best_align(overlap, seq_left, seq_right, 
858
		 germline->rep_4.sequence(best_D), germline->rep_3.sequence(best_J), &b_r,&b_l, segment_cost);
Mikaël Salson's avatar
Mikaël Salson committed
859 860

      // Trim D
Mathieu Giraud's avatar
Mathieu Giraud committed
861
      Dend -= b_l;
Mikaël Salson's avatar
Mikaël Salson committed
862 863

      // Trim J
Mathieu Giraud's avatar
Mathieu Giraud committed
864
      Jstart += b_r;
Mikaël Salson's avatar
Mikaël Salson committed
865 866 867
      del_J += b_r;

    }
Mathieu Giraud's avatar
Mathieu Giraud committed
868
    seg_N2 = seq.substr(Dend+1, Jstart-Dend-1) ; // From Dend+1 to right-1
869
    code = germline->rep_5.label(best_V) +
Mikaël Salson's avatar
Mikaël Salson committed
870 871 872 873
    " "+ string_of_int(del_V) + 
    "/" + seg_N1 + 
    
    "/" + string_of_int(del_D_left) +
874
    " " + germline->rep_4.label(best_D) +
Mikaël Salson's avatar
Mikaël Salson committed
875 876 877 878
    " " + string_of_int(del_D_right) +
    
    "/" + seg_N2 +
    "/" + string_of_int(del_J) +
879
    " " + germline->rep_3.label(best_J); 
Mikaël Salson's avatar
Mikaël Salson committed
880

Mikaël Salson's avatar
Mikaël Salson committed
881
    stringstream code_s;
882
    code_s << germline->rep_5.label(best_V) 
Mikaël Salson's avatar
Mikaël Salson committed
883 884 885 886
    << " -" << string_of_int(del_V) << "/" 
    << seg_N1.size()
    
    << "/-" << string_of_int(del_D_left) 
887
    << " " << germline->rep_4.label(best_D) 
Mikaël Salson's avatar
Mikaël Salson committed
888 889 890 891
    << " -" << string_of_int(del_D_right) << "/"
    
    << seg_N2.size()
    << "/-" << string_of_int(del_J) 
892
    << " " << germline->rep_3.label(best_J);
Mikaël Salson's avatar
Mikaël Salson committed
893 894 895
    code_short=code_s.str();
    
    
896 897 898
    code_light = germline->rep_5.label(best_V) +
    "/ " + germline->rep_4.label(best_D) +
    "/ " + germline->rep_3.label(best_J); 
Mikaël Salson's avatar
Mikaël Salson committed
899 900 901 902
    
    finishSegmentationD();
  }
}
Mikaël Salson's avatar
Mikaël Salson committed
903

Marc Duez's avatar
Marc Duez committed
904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922
void FineSegmenter::findCDR3(){
    string str = getSequence().sequence;
    
    list<string> codon_start;
    codon_start.push_back("TGT");
    codon_start.push_back("TGC");
    
    list<string> codon_end;
    codon_end.push_back("TTT");
    codon_end.push_back("TTC");
    codon_end.push_back("TGG");
    
    list<int> p_start;
    list<int> p_end;

    size_t loc;
    std::list<string>::const_iterator it;
    for (it = codon_start.begin(); it != codon_start.end(); ++it) {//filter 1 : start codon must be in V
        loc = 0;
923
        while ( loc != string::npos && loc < (size_t)Vend){
Marc Duez's avatar
Marc Duez committed
924
            loc = str.find(*it, loc+3);
925
            if (loc != string::npos && loc < (size_t)Vend) {
Marc Duez's avatar
Marc Duez committed
926 927 928 929 930 931 932 933 934 935 936 937 938 939 940
                p_start.push_front(loc);
            }
        }
    }

    for (it = codon_end.begin(); it != codon_end.end(); ++it) {//filter 2 : end codon must be in J
        loc = Jstart;
        while ( loc != string::npos){
            loc = str.find(*it, loc+3);
            if (loc != string::npos) {
                p_end.push_back(loc);
            }
        }
    }

941 942
    CDR3start = -1;
    CDR3end = -1;
Marc Duez's avatar
Marc Duez committed
943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961
    
    std::list<int>::const_iterator it1;
    for (it1 = p_start.begin(); it1 != p_start.end(); ++it1) {
        
        std::list<int>::const_iterator it2;
        for (it2 = p_end.begin(); it2 != p_end.end(); ++it2) {
            
            if ( (*it2-*it1)%3 == 0){       //filter 3 : start/stop codon must be seprated by a multiple of 3
                
                if ( fabs((*it2-*it1)-36 ) < fabs((CDR3end-CDR3start)-36) ){ //filter 4 : cdr3 length must be close to 12 AA
                    CDR3start = *it1;
                    CDR3end = *it2;
                }
            }
        }
    }
    
}

962
void FineSegmenter::toJsonList(JsonList *seg){
Tatiana Rocher's avatar
Tatiana Rocher committed
963

Mathieu Giraud's avatar
Mathieu Giraud committed
964
  if (isSegmented()) {
965 966 967
    seg->add("5", segmented_germline->rep_5.label(best_V));
    seg->add("5start", 0);
    seg->add("5end", Vend);
Mathieu Giraud's avatar
Mathieu Giraud committed
968 969
    
    if (score_D.size()>0){
970 971 972
      seg->add("4", segmented_germline->rep_4.label(best_D));
      seg->add("4start", Dstart);
      seg->add("4end", Dend);
Mikaël Salson's avatar
Mikaël Salson committed
973
    }
Mathieu Giraud's avatar
Mathieu Giraud committed
974
    
975 976
    seg->add("3", segmented_germline->rep_3.label(best_J));
    seg->add("3start", Jstart);
977 978 979

    if (CDR3start >= 0)
      {
Marc Duez's avatar
Marc Duez committed
980 981 982 983
    JsonList *json_cdr;
    json_cdr=new JsonList();
    json_cdr->add("start", CDR3start);
    json_cdr->add("stop", CDR3end);
984
    seg->add("cdr3", *json_cdr);
985
      }
Tatiana Rocher's avatar
Tatiana Rocher committed
986

987 988
  }
}
989

990 991
void KmerSegmenter::toJsonList(JsonList *seg)
{
992 993
    int sequenceSize = sequence.size();

994
    if (evalue > NO_LIMIT_VALUE)