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 28.1 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
}

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

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

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

82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100

// E-values

void Segmenter::checkLeftRightEvaluesThreshold(double threshold, int strand)
{
  if (threshold == NO_LIMIT_VALUE)
    return ;

  if (evalue_left >= threshold && evalue_right >= threshold)
    because = UNSEG_TOO_FEW_ZERO ;
  else if ((strand == 1 ? evalue_left : evalue_right) >= threshold)
    because = UNSEG_TOO_FEW_V ;
  else if ((strand == 1 ? evalue_right : evalue_left) >= threshold)
    because = UNSEG_TOO_FEW_J ;
  else if (evalue >= threshold) // left and right are <= threshold, but their sum is > threshold
    because = UNSEG_TOO_FEW_ZERO ;
}


Mikaël Salson's avatar
Mikaël Salson committed
101 102 103 104 105 106 107 108
// Chevauchement

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

Mathieu Giraud's avatar
Mathieu Giraud committed
109
  if (Vend >= Jstart)
Mikaël Salson's avatar
Mikaël Salson committed
110
    {
Mathieu Giraud's avatar
Mathieu Giraud committed
111
      int middle = (Vend + Jstart) / 2 ;
112
      chevauchement = " !ov " + string_of_int (Vend - Jstart + 1);
Mathieu Giraud's avatar
Mathieu Giraud committed
113 114
      Vend = middle ;
      Jstart = middle+1 ;
Mikaël Salson's avatar
Mikaël Salson committed
115 116 117 118 119 120 121 122 123 124 125 126 127 128
    }

  return chevauchement ;
}

// Prettyprint


bool Segmenter::finishSegmentation() 
{
  assert(isSegmented());
  
  string seq = getSequence().sequence;
    
Mathieu Giraud's avatar
Mathieu Giraud committed
129 130 131 132 133
  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
134 135 136 137 138 139 140 141 142 143 144 145 146

  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
147 148
  seg_V = seq.substr(0, Vend+1) ; // From pos. 0 to Vend
  seg_J = seq.substr(Jstart) ;
149
  seg_N = seq.substr(Vend+1, Jstart-Vend-1) ;  // Twice computed for FineSegmenter, but only once in KmerSegmenter !
Mathieu Giraud's avatar
Mathieu Giraud committed
150
  seg_D  = seq.substr(Dstart, Dend-Dstart+1) ; // From Dstart to Dend
Mikaël Salson's avatar
Mikaël Salson committed
151
  
Mathieu Giraud's avatar
Mathieu Giraud committed
152 153 154 155
  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
156 157 158 159 160 161 162 163 164
		" " + string_of_int(seq.size()-1+FIRST_POS) ;
		
  info += "\t" + code ;
  
  info = (reversed ? "- " : "+ ") + info ;

  return true ;
}

165 166
string Segmenter::getInfoLine() const
{
167
  string s = "" ;
168 169 170 171 172

  s += (segmented ? "" : "! ") + info ;
  s += " " + info_extra ;
  s += " " + segmented_germline->code ;
  s += " " + string(segmented_mesg[because]) ;
173 174 175 176

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

177 178 179 180 181
  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);

182 183 184
  return s ;
}

185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200
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
201 202
ostream &operator<<(ostream &out, const Segmenter &s)
{
203
  out << ">" << s.label << " " ;
204
  out << s.getInfoLine() << endl;
Mikaël Salson's avatar
Mikaël Salson committed
205 206 207 208 209 210 211 212 213

  if (s.segmented)
    {
      out << s.seg_V << endl ;
      out << s.seg_N << endl ;
      out << s.seg_J << endl ;
    }
  else
    {
214
      out << s.getSequence().sequence << endl ;
Mikaël Salson's avatar
Mikaël Salson committed
215 216 217 218 219 220 221 222
    }

  return out ;
}


// KmerSegmenter (Cheap)

223 224
KmerSegmenter::KmerSegmenter() { kaa = 0 ; }

225
KmerSegmenter::KmerSegmenter(Sequence seq, Germline *germline, double threshold, int multiplier)
Mikaël Salson's avatar
Mikaël Salson committed
226 227 228 229
{
  label = seq.label ;
  sequence = seq.sequence ;
  info = "" ;
230
  info_extra = "seed";
Mikaël Salson's avatar
Mikaël Salson committed
231
  segmented = false;
232
  segmented_germline = germline ;
233
  system = germline->code; // useful ?
234
  reversed = false;
Mathieu Giraud's avatar
Mathieu Giraud committed
235
  Dend=0;
236
  because = NOT_PROCESSED ; // Cause of unsegmentation
237
  score = 0 ;
238
  evalue = NO_LIMIT_VALUE;
239 240
  evalue_left = NO_LIMIT_VALUE;
  evalue_right = NO_LIMIT_VALUE;
241

242
  int s = (size_t)germline->index->getS() ;
Mikaël Salson's avatar
Mikaël Salson committed
243
  int length = sequence.length() ;
Mikaël Salson's avatar
Mikaël Salson committed
244

245
  if (length < s) 
Mikaël Salson's avatar
Mikaël Salson committed
246
    {
Mathieu Giraud's avatar
Mathieu Giraud committed
247 248
      because = UNSEG_TOO_SHORT;
      kaa = NULL;
249
      return ;
Mikaël Salson's avatar
Mikaël Salson committed
250 251
    }
 
252
  kaa = new KmerAffectAnalyser(*(germline->index), sequence);
Mikaël Salson's avatar
Mikaël Salson committed
253 254
  
  // Check strand consistency among the affectations.
Mikaël Salson's avatar
Mikaël Salson committed
255 256 257 258 259 260 261 262 263
  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
264 265 266
    }
  }

267 268
  score = nb_strand[0] + nb_strand[1] ; // Used only for non-segmented germlines

269 270
  if ((germline->seg_method == SEG_METHOD_MAX12)
      || (germline->seg_method == SEG_METHOD_MAX1U))
271 272 273 274
    { // Pseudo-germline, MAX12 and MAX1U
      pair <KmerAffect, KmerAffect> max12 ;
      CountKmerAffectAnalyser ckaa(*(germline->index), sequence);

275 276 277 278 279

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

280
      if (germline->seg_method == SEG_METHOD_MAX12)
281 282 283
        // MAX12: two maximum k-mers (no unknown)
        {
          max12 = ckaa.max12(forbidden);
284

285 286 287 288 289 290
          if (max12.first.isUnknown() || max12.second.isUnknown())
            {
              because = UNSEG_TOO_FEW_ZERO ;
              return ;
            }
        }
291

292 293
      else
        // MAX1U: the maximum k-mers (no unknown) + unknown
294
        {
295 296 297 298 299 300 301 302 303
          CountKmerAffectAnalyser ckaa(*(germline->index), sequence);
          KmerAffect max = ckaa.max(forbidden);

          if (max.isUnknown())
            {
              because = UNSEG_TOO_FEW_ZERO ;
              return ;
            }
          max12 = make_pair(max, KmerAffect::getUnknown());
304 305
        }

306 307 308 309 310
      pair <KmerAffect, KmerAffect> before_after =  ckaa.sortLeftRight(max12);

      before = before_after.first ;
      after = before_after.second ;

311 312 313
      // This strand computation is only a heuristic, especially for chimera +/- reads
      // Anyway, it allows to gather such reads and their reverse complement into a unique window...
      // ... except when the read is quite different outside the window
314 315 316 317 318 319
      strand = nb_strand[0] > nb_strand[1] ? -1 : 1 ;
    }

  else
    { // Regular germline

320
  // Test on which strand we are, select the before and after KmerAffects
Mikaël Salson's avatar
Mikaël Salson committed
321
  if (nb_strand[0] == 0 && nb_strand[1] == 0) {
322
    because = UNSEG_TOO_FEW_ZERO ;
323
    return ;
Mikaël Salson's avatar
Mikaël Salson committed
324 325
  } else if (nb_strand[0] > RATIO_STRAND * nb_strand[1]) {
    strand = -1;
326 327
    before = KmerAffect(germline->affect_3, -1); 
    after = KmerAffect(germline->affect_5, -1);
Mikaël Salson's avatar
Mikaël Salson committed
328 329
  } else if (nb_strand[1] > RATIO_STRAND * nb_strand[0]) {
    strand = 1;
330 331
    before = KmerAffect(germline->affect_5, 1); 
    after = KmerAffect(germline->affect_3, 1);    
Mikaël Salson's avatar
Mikaël Salson committed
332 333
  } else {
    // Ambiguous information: we have positive and negative strands
334 335 336 337 338
    // and there is not enough difference to put them apart.
    if (nb_strand[0] + nb_strand[1] >= DETECT_THRESHOLD_STRAND)
      because = UNSEG_STRAND_NOT_CONSISTENT ;
    else
      because = UNSEG_TOO_FEW_ZERO ;
339
    return ;
Mikaël Salson's avatar
Mikaël Salson committed
340 341
  }

342
    } // endif Pseudo-germline
343
 
344
  computeSegmentation(strand, before, after, threshold, multiplier);
Mathieu Giraud's avatar
Mathieu Giraud committed
345
}
Mikaël Salson's avatar
Mikaël Salson committed
346

Mathieu Giraud's avatar
Mathieu Giraud committed
347
KmerSegmenter::~KmerSegmenter() {
348 349
  if (kaa)
    delete kaa;
350 351
}

352 353
KmerMultiSegmenter::KmerMultiSegmenter(Sequence seq, MultiGermline *multigermline, ostream *out_unsegmented,
                                       double threshold, int nb_reads_for_evalue)
354
{
355 356
  bool found_seg = false ; // Found a segmentation
  double best_evalue_seg = NO_LIMIT_VALUE ; // Best evalue, segmented sequences
357
  int best_score_unseg = 0 ; // Best score, unsegmented sequences
358
  the_kseg = NULL;
359
  multi_germline = multigermline;
360
  threshold_nb_expected = threshold;
361 362 363

  // E-value multiplier
  int multiplier = multi_germline->germlines.size() * nb_reads_for_evalue;
364
  
365 366 367 368 369
  // Iterate over the germlines
  for (list<Germline*>::const_iterator it = multigermline->germlines.begin(); it != multigermline->germlines.end(); ++it)
    {
      Germline *germline = *it ;

370
      KmerSegmenter *kseg = new KmerSegmenter(seq, germline, threshold, multiplier);
371
      bool keep_seg = false;
372

373 374 375
      if (out_unsegmented)
        {
          // Debug, display k-mer affectation and segmentation result for this germline
376
          *out_unsegmented << kseg->getInfoLineWithAffects() << endl ;
377 378
        }

379 380
      // Always remember the first kseg
      if (the_kseg == NULL)
381
        keep_seg = true;
382
      
383
      if (kseg->isSegmented())
384 385
        {
          // Yes, it is segmented
386
          // Should we keep the kseg ?
387
          if (!found_seg || (kseg->evalue < best_evalue_seg))
388
            {
389
              keep_seg = true;
390 391 392
              best_evalue_seg = kseg->evalue ;

              found_seg = true;
393
            }
394
        }
395 396 397 398 399 400 401
      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 ;
402
              if (!found_seg)
403 404 405 406
                keep_seg = true;
            }
        }
      
407
      if (keep_seg) {
408 409
        if (the_kseg)
          delete the_kseg;
410 411 412 413
        the_kseg = kseg;
      } else {
        delete kseg;
      }
414 415 416
    } // end for (Germlines)
}

417
KmerMultiSegmenter::~KmerMultiSegmenter() {
418 419
  if (the_kseg)
    delete the_kseg;
Mathieu Giraud's avatar
Mathieu Giraud committed
420 421
}

422 423
void KmerSegmenter::computeSegmentation(int strand, KmerAffect before, KmerAffect after,
                                        double threshold, int multiplier) {
424
  // Try to segment, computing 'Vend' and 'Jstart'
425 426
  // If not segmented, put the cause of unsegmentation in 'because'

427
  affect_infos max;
428
  max = kaa->getMaximum(before, after);
Mikaël Salson's avatar
Mikaël Salson committed
429

430 431 432 433 434 435
  // We did not find a good segmentation point
  if (!max.max_found) {
    // We labeled it detected if there were both enough affect_5 and enough affect_3
    bool detected = (max.nb_before_left + max.nb_before_right >= DETECT_THRESHOLD)
      && (max.nb_after_left + max.nb_after_right >= DETECT_THRESHOLD);

436 437 438
    if (max.nb_before_left + max.nb_before_right + max.nb_after_left + max.nb_after_right == 0)
      because = UNSEG_TOO_FEW_ZERO ;
    else if ((strand == 1 && max.nb_before_left == 0) || (strand == -1 && max.nb_after_right == 0))
439 440 441 442 443 444 445 446 447 448
      because = detected ? UNSEG_AMBIGUOUS : UNSEG_TOO_FEW_V ;
    else if ((strand == 1 && max.nb_after_right == 0)|| (strand == -1 && max.nb_before_left == 0))
      because = detected ? UNSEG_AMBIGUOUS : UNSEG_TOO_FEW_J ;
    else
      because = UNSEG_AMBIGUOUS;

    return ;
  }


449
  // E-values
450 451 452
  pair <double, double> pvalues = kaa->getLeftRightProbabilityAtLeastOrAbove();
  evalue_left = pvalues.first * multiplier ;
  evalue_right = pvalues.second * multiplier ;
453
  evalue = evalue_left + evalue_right ;
454

455
  checkLeftRightEvaluesThreshold(threshold, strand);
456

457
  if (because != NOT_PROCESSED)
458 459
    return ;

460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481
   // 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;
   }

  // 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
482
}
Mikaël Salson's avatar
Mikaël Salson committed
483

484
KmerAffectAnalyser *KmerSegmenter::getKmerAffectAnalyser() const {
Mathieu Giraud's avatar
Mathieu Giraud committed
485 486
  return kaa;
}
Mikaël Salson's avatar
Mikaël Salson committed
487

488
int Segmenter::getSegmentationStatus() const {
Mathieu Giraud's avatar
Mathieu Giraud committed
489
  return because;
Mikaël Salson's avatar
Mikaël Salson committed
490 491
}

492 493 494 495 496
void Segmenter::setSegmentationStatus(int status) {
  because = status;
  segmented = (status == SEG_PLUS || status == SEG_MINUS);
}

Mikaël Salson's avatar
Mikaël Salson committed
497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521
// 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)
522
	score_r[i] = dp.B[dp.best_i-i][dp.best_j].score;
Mikaël Salson's avatar
Mikaël Salson committed
523 524 525
	else
	score_r[i] =0;
	if(dp1.best_i-i >0)
526
	score_l[i] = dp1.B[dp1.best_i-i][dp1.best_j].score;	
Mikaël Salson's avatar
Mikaël Salson committed
527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551
	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
552 553 554 555 556
bool comp_pair (pair<int,int> i,pair<int,int> j)
{
  return ( i.first > j.first);
}

Mathieu Giraud's avatar
Mathieu Giraud committed
557
int align_against_collection(string &read, Fasta &rep, bool reverse_both, bool local, int *tag, 
Mikaël Salson's avatar
Mikaël Salson committed
558
			     int *del, int *del2, int *begin, int *length, vector<pair<int, int> > *score
Mikaël Salson's avatar
Mikaël Salson committed
559 560 561 562 563 564 565 566 567 568
			    , 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
569
  vector<pair<int, int> > score_r;
Mikaël Salson's avatar
Mikaël Salson committed
570 571 572 573 574 575 576 577 578 579 580

  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
581
      
Mikaël Salson's avatar
Mikaël Salson committed
582 583 584 585 586 587 588 589 590 591 592 593 594 595
      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
596 597
	
	score_r.push_back(make_pair(score, r));
Mathieu Giraud's avatar
Mathieu Giraud committed
598 599 600 601 602 603

	// #define DEBUG_SEGMENT      

#ifdef DEBUG_SEGMENT	
	cout << rep.label(r) << " " << score << " " << dp.best_i << endl ;
#endif
Mikaël Salson's avatar
Mikaël Salson committed
604 605

    }
Mikaël Salson's avatar
Mikaël Salson committed
606
    sort(score_r.begin(),score_r.end(),comp_pair);
Mikaël Salson's avatar
Mikaël Salson committed
607 608 609 610

  *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
611
  *tag = best_r ; 
Mikaël Salson's avatar
Mikaël Salson committed
612 613
  
  *length -= *del ;
Mikaël Salson's avatar
Mikaël Salson committed
614 615
  
  *score=score_r;
Mathieu Giraud's avatar
Mathieu Giraud committed
616 617 618 619 620 621

#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
622 623 624 625 626 627 628 629 630
  
  return best_best_i ;
}

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

631
FineSegmenter::FineSegmenter(Sequence seq, Germline *germline, Cost segment_c)
Mikaël Salson's avatar
Mikaël Salson committed
632
{
633 634
  segmented = false;
  dSegmented = false;
635
  because = NOT_PROCESSED ;
636
  segmented_germline = germline ;
637
  info_extra = "" ;
638
  code_short = "" ;
Mikaël Salson's avatar
Mikaël Salson committed
639 640
  label = seq.label ;
  sequence = seq.sequence ;
Mathieu Giraud's avatar
Mathieu Giraud committed
641
  Dend=0;
Mikaël Salson's avatar
Mikaël Salson committed
642
  segment_cost=segment_c;
643
  evalue = NO_LIMIT_VALUE;
644 645
  evalue_left = NO_LIMIT_VALUE;
  evalue_right = NO_LIMIT_VALUE;
Mikaël Salson's avatar
Mikaël Salson committed
646

647 648 649
  CDR3start = -1;
  CDR3end = -1;
  
650
  if (!germline->rep_5.size() || !germline->rep_3.size())
651
    {
652
      // We check whether this sequence is segmented with MAX12 or MAX1U (with default e-value parameters)
653
      KmerSegmenter *kseg = new KmerSegmenter(seq, germline, THRESHOLD_NB_EXPECTED, 1);
654 655
      if (kseg->isSegmented() && ((germline->seg_method == SEG_METHOD_MAX12)
                                  || (germline->seg_method == SEG_METHOD_MAX1U)))
656
        {
657 658 659 660 661
          reversed = kseg->isReverse();

          KmerAffect left = reversed ? KmerAffect(kseg->after, true) : kseg->before ;
          KmerAffect right = reversed ? KmerAffect(kseg->before, true) : kseg->after ;

662
          code_short = "Unexpected ";
663 664

          code_short += left.toStringSigns() + germline->index->getLabel(left);
665
          code_short += "/";
666 667
          code_short += right.toStringSigns() + germline->index->getLabel(right);
          info_extra += " " + left.toString() + "/" + right.toString() + " (" + code_short + ")";
668 669 670
        }
      return ;
    }
671

Mikaël Salson's avatar
Mikaël Salson committed
672 673 674 675 676
  // 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
677
  int tag_plus_V, tag_plus_J;
Mikaël Salson's avatar
Mikaël Salson committed
678 679 680 681
  int plus_length = 0 ;
  int del_plus_V, del_plus_J ;
  int del2=0;
  int beg=0;
Mikaël Salson's avatar
Mikaël Salson committed
682 683 684 685
  
  vector<pair<int, int> > score_plus_V;
  vector<pair<int, int> > score_plus_J;
  
686
  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
687 688
					   &plus_length, &score_plus_V
					   , segment_cost);
689
  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
690 691
					    &plus_length, &score_plus_J
					    , segment_cost);
Mikaël Salson's avatar
Mikaël Salson committed
692 693
  plus_length += plus_right - plus_left ;

Mikaël Salson's avatar
Mikaël Salson committed
694 695
  plus_score=score_plus_V[0].first + score_plus_J[0].first ;
  
Mikaël Salson's avatar
Mikaël Salson committed
696 697 698
  // Strand -
  string rc = revcomp(sequence) ;
  int minus_score = 0 ;
Mathieu Giraud's avatar
Mathieu Giraud committed
699
  int tag_minus_V, tag_minus_J;
Mikaël Salson's avatar
Mikaël Salson committed
700 701
  int minus_length = 0 ;
  int del_minus_V, del_minus_J ;
Mikaël Salson's avatar
Mikaël Salson committed
702 703 704 705
  
  vector<pair<int, int> > score_minus_V;
  vector<pair<int, int> > score_minus_J;
  
706
  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
707 708
					    &minus_length, &score_minus_V
					    ,  segment_cost);
709
  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
710 711
					     &minus_length, &score_minus_J
					     , segment_cost);
Mikaël Salson's avatar
Mikaël Salson committed
712 713
  minus_length += minus_right - minus_left ;

Mikaël Salson's avatar
Mikaël Salson committed
714 715
  minus_score=score_minus_V[0].first + score_minus_J[0].first ;
  
Mikaël Salson's avatar
Mikaël Salson committed
716 717 718 719
  reversed = (minus_score > plus_score) ;

  if (!reversed)
    {
Mathieu Giraud's avatar
Mathieu Giraud committed
720 721 722 723
      Vend = plus_left ;
      Jstart = plus_right ;
      best_V = tag_plus_V ;
      best_J = tag_plus_J ;
Mikaël Salson's avatar
Mikaël Salson committed
724 725
      del_V = del_plus_V ;
      del_J = del_plus_J ;
Mikaël Salson's avatar
Mikaël Salson committed
726 727
      score_V=score_plus_V;
      score_J=score_plus_J;
Mikaël Salson's avatar
Mikaël Salson committed
728 729 730
    }
  else
    {
Mathieu Giraud's avatar
Mathieu Giraud committed
731 732 733 734
      Vend = minus_left ;
      Jstart = minus_right ;
      best_V = tag_minus_V ;
      best_J = tag_minus_J ;
Mikaël Salson's avatar
Mikaël Salson committed
735 736
      del_V = del_minus_V ;
      del_J = del_minus_J ;
Mikaël Salson's avatar
Mikaël Salson committed
737 738
      score_V=score_minus_V;
      score_J=score_minus_J;
Mikaël Salson's avatar
Mikaël Salson committed
739 740
    }

741 742 743

  /* Unsegmentation causes */
  if (Jstart - Vend < germline->delta_min)
Mikaël Salson's avatar
Mikaël Salson committed
744
    {
745 746
      because = UNSEG_BAD_DELTA_MIN  ;
    }
747

748 749 750 751
  if (Vend == (int) string::npos)
    {
      because = UNSEG_TOO_FEW_V ;
    }
752
      
753 754 755 756 757 758 759 760 761
  if (Jstart == (int) string::npos)
    {
      because = UNSEG_TOO_FEW_J ;
    }

  if (because != NOT_PROCESSED)
    {
      segmented = false;
      info = " @" + string_of_int (Vend + FIRST_POS) + "  @" + string_of_int(Jstart + FIRST_POS) ;
Mikaël Salson's avatar
Mikaël Salson committed
762 763
      return ;
    }
764 765 766 767

  /* The sequence is segmented */
  segmented = true ;
  because = reversed ? SEG_MINUS : SEG_PLUS ;
768
    
Mikaël Salson's avatar
Mikaël Salson committed
769
    //overlap VJ
Mathieu Giraud's avatar
Mathieu Giraud committed
770
    if(Jstart-Vend <=0){
Mikaël Salson's avatar
Mikaël Salson committed
771
      int b_r, b_l;
Mathieu Giraud's avatar
Mathieu Giraud committed
772
      int overlap=Vend-Jstart+1;
Mikaël Salson's avatar
Mikaël Salson committed
773
      
Mathieu Giraud's avatar
Mathieu Giraud committed
774 775
      string seq_left = sequence.substr(0, Vend+1);
      string seq_right = sequence.substr(Jstart);
Mikaël Salson's avatar
Mikaël Salson committed
776 777

      best_align(overlap, seq_left, seq_right, 
778
		 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
779
      // Trim V
Mathieu Giraud's avatar
Mathieu Giraud committed
780
      Vend -= b_l;
Mikaël Salson's avatar
Mikaël Salson committed
781 782 783
      del_V += b_l;

      // Trim J
Mathieu Giraud's avatar
Mathieu Giraud committed
784
      Jstart += b_r;
Mikaël Salson's avatar
Mikaël Salson committed
785
      del_J += b_r;
786
      if (Jstart>=(int) sequence.length())
Mathieu Giraud's avatar
Mathieu Giraud committed
787
	  Jstart=sequence.length()-1;
Mikaël Salson's avatar
Mikaël Salson committed
788 789 790
    }

    // string chevauchement = removeChevauchement();
Mikaël Salson's avatar
Mikaël Salson committed
791 792

    /// used only below, then recomputed in finishSegmentation() ;
Mathieu Giraud's avatar
Mathieu Giraud committed
793
    seg_N = revcomp(sequence, reversed).substr(Vend+1, Jstart-Vend-1); 
Mikaël Salson's avatar
Mikaël Salson committed
794

795
  code = germline->rep_5.label(best_V) +
Mikaël Salson's avatar
Mikaël Salson committed
796 797 798 799
    " "+ string_of_int(del_V) + 
    "/" + seg_N + 
    // chevauchement +
    "/" + string_of_int(del_J) +
800
    " " + germline->rep_3.label(best_J); 
Mikaël Salson's avatar
Mikaël Salson committed
801

Mikaël Salson's avatar
Mikaël Salson committed
802
    stringstream code_s;
803
   code_s<< germline->rep_5.label(best_V) <<
Mikaël Salson's avatar
Mikaël Salson committed
804 805 806 807
    " -" << string_of_int(del_V) << "/" 
    << seg_N.size()
    // chevauchement +
    << "/-" << string_of_int(del_J)
808
    <<" " << germline->rep_3.label(best_J);
Mikaël Salson's avatar
Mikaël Salson committed
809 810
    code_short=code_s.str();
    
811 812
  code_light = germline->rep_5.label(best_V) +
    "/ " + germline->rep_3.label(best_J); 
Mikaël Salson's avatar
Mikaël Salson committed
813 814

 
Mathieu Giraud's avatar
Mathieu Giraud committed
815
  info = string_of_int(Vend + FIRST_POS) + " " + string_of_int(Jstart + FIRST_POS) ;
Mikaël Salson's avatar
Mikaël Salson committed
816 817 818 819
  finishSegmentation();
}


820
void FineSegmenter::FineSegmentD(Germline *germline){
Mikaël Salson's avatar
Mikaël Salson committed
821 822 823 824
  
  if (segmented){
    
    int end = (int) string::npos ;
Mathieu Giraud's avatar
Mathieu Giraud committed
825
    int tag_D;
Mikaël Salson's avatar
Mikaël Salson committed
826 827 828 829
    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
830
    int l = Vend - EXTEND_D_ZONE;
Mikaël Salson's avatar
Mikaël Salson committed
831 832 833
    if (l<0) 
      l=0 ;

Mathieu Giraud's avatar
Mathieu Giraud committed
834
    int r = Jstart + EXTEND_D_ZONE;
Mikaël Salson's avatar
Mikaël Salson committed
835 836 837 838 839 840 841

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

    // Align
842
    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
843 844
				&length, &score_D, segment_cost);
    
Mathieu Giraud's avatar
Mathieu Giraud committed
845
    best_D = tag_D;
Mikaël Salson's avatar
Mikaël Salson committed
846
    
Mathieu Giraud's avatar
Mathieu Giraud committed
847 848
    Dstart = l + begin;
    Dend = l + end;
Mikaël Salson's avatar
Mikaël Salson committed
849 850
	
    string seq = getSequence().sequence;
851 852 853 854 855 856 857 858 859 860


    // 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
861 862
    
    //overlap VD
Mathieu Giraud's avatar
Mathieu Giraud committed
863
    if(Dstart-Vend <=0){
Mikaël Salson's avatar
Mikaël Salson committed
864
      int b_r, b_l;
Mathieu Giraud's avatar
Mathieu Giraud committed
865 866 867
      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
868 869

      best_align(overlap, seq_left, seq_right, 
870
		 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
871 872

      // Trim V
Mathieu Giraud's avatar
Mathieu Giraud committed
873
      Vend -= b_l;
Mikaël Salson's avatar
Mikaël Salson committed
874 875 876
      del_V += b_l;

      // Trim D
Mathieu Giraud's avatar
Mathieu Giraud committed
877
      Dstart += b_r;
Mikaël Salson's avatar
Mikaël Salson committed
878
    }
Mathieu Giraud's avatar
Mathieu Giraud committed
879
    seg_N1 = seq.substr(Vend+1, Dstart-Vend-1) ; // From Vend+1 to Dstart-1
Mikaël Salson's avatar
Mikaël Salson committed
880 881
    
    //overlap DJ
Mathieu Giraud's avatar
Mathieu Giraud committed
882
    if(Jstart-Dend <=0){
Mikaël Salson's avatar
Mikaël Salson committed
883
      int b_r, b_l;
Mathieu Giraud's avatar
Mathieu Giraud committed
884 885 886
      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
887 888

      best_align(overlap, seq_left, seq_right, 
889
		 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
890 891

      // Trim D
Mathieu Giraud's avatar
Mathieu Giraud committed
892
      Dend -= b_l;
Mikaël Salson's avatar
Mikaël Salson committed
893 894

      // Trim J
Mathieu Giraud's avatar
Mathieu Giraud committed
895
      Jstart += b_r;
Mikaël Salson's avatar
Mikaël Salson committed
896 897 898
      del_J += b_r;

    }
Mathieu Giraud's avatar
Mathieu Giraud committed
899
    seg_N2 = seq.substr(Dend+1, Jstart-Dend-1) ; // From Dend+1 to right-1
900
    code = germline->rep_5.label(best_V) +
Mikaël Salson's avatar
Mikaël Salson committed
901 902 903 904
    " "+ string_of_int(del_V) + 
    "/" + seg_N1 + 
    
    "/" + string_of_int(del_D_left) +
905
    " " + germline->rep_4.label(best_D) +
Mikaël Salson's avatar
Mikaël Salson committed
906 907 908 909
    " " + string_of_int(del_D_right) +
    
    "/" + seg_N2 +
    "/" + string_of_int(del_J) +
910
    " " + germline->rep_3.label(best_J); 
Mikaël Salson's avatar
Mikaël Salson committed
911

Mikaël Salson's avatar
Mikaël Salson committed
912
    stringstream code_s;
913
    code_s << germline->rep_5.label(best_V) 
Mikaël Salson's avatar
Mikaël Salson committed
914 915 916 917
    << " -" << string_of_int(del_V) << "/" 
    << seg_N1.size()
    
    << "/-" << string_of_int(del_D_left) 
918
    << " " << germline->rep_4.label(best_D) 
Mikaël Salson's avatar
Mikaël Salson committed
919 920 921 922
    << " -" << string_of_int(del_D_right) << "/"
    
    << seg_N2.size()
    << "/-" << string_of_int(del_J) 
923
    << " " << germline->rep_3.label(best_J);
Mikaël Salson's avatar
Mikaël Salson committed
924 925 926
    code_short=code_s.str();
    
    
927 928 929
    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
930 931 932 933
    
    finishSegmentationD();
  }
}
Mikaël Salson's avatar
Mikaël Salson committed
934

Marc Duez's avatar
Marc Duez committed
935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953
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;
954
        while ( loc != string::npos && loc < (size_t)Vend){
Marc Duez's avatar
Marc Duez committed
955
            loc = str.find(*it, loc+3);
956
            if (loc != string::npos && loc < (size_t)Vend) {
Marc Duez's avatar
Marc Duez committed
957 958 959 960 961 962 963 964 965 966 967 968 969 970 971
                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);
            }
        }
    }

972 973
    CDR3start = -1;
    CDR3end = -1;
Marc Duez's avatar
Marc Duez committed
974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992
    
    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;
                }
            }
        }
    }
    
}

Marc Duez's avatar
Marc Duez committed
993 994 995
json FineSegmenter::toJson(){
  json seg;
    
Mathieu Giraud's avatar
Mathieu Giraud committed
996
  if (isSegmented()) {
Marc Duez's avatar
Marc Duez committed
997 998 999
    seg["5"] = segmented_germline->rep_5.label(best_V);
    seg["5start"] = 0;
    seg["5end"] = Vend;
Mathieu Giraud's avatar
Mathieu Giraud committed
1000 1001
    
    if (score_D.size()>0){
Marc Duez's avatar
Marc Duez committed
1002 1003 1004
      seg["4"] = segmented_germline->rep_4.label(best_D);
      seg["4start"] = Dstart;
      seg["4end"] = Dend;
Mikaël Salson's avatar
Mikaël Salson committed
1005
    }