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// ==========================================================================
// Mason - A Read Simulator
// ==========================================================================
// Copyright (c) 2006-2026, Knut Reinert, FU Berlin
// All rights reserved.
//
// Redistribution and use in source and binary forms, with or without
// modification, are permitted provided that the following conditions are met:
//
// * Redistributions of source code must retain the above copyright
// notice, this list of conditions and the following disclaimer.
// * Redistributions in binary form must reproduce the above copyright
// notice, this list of conditions and the following disclaimer in the
// documentation and/or other materials provided with the distribution.
// * Neither the name of Knut Reinert or the FU Berlin nor the names of
// its contributors may be used to endorse or promote products derived
// from this software without specific prior written permission.
//
// THIS SOFTWARE IS PROVIDED BY THE COPYRIGHT HOLDERS AND CONTRIBUTORS "AS IS"
// AND ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT LIMITED TO, THE
// IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE
// ARE DISCLAIMED. IN NO EVENT SHALL KNUT REINERT OR THE FU BERLIN BE LIABLE
// FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL, EXEMPLARY, OR CONSEQUENTIAL
// DAMAGES (INCLUDING, BUT NOT LIMITED TO, PROCUREMENT OF SUBSTITUTE GOODS OR
// SERVICES; LOSS OF USE, DATA, OR PROFITS; OR BUSINESS INTERRUPTION) HOWEVER
// CAUSED AND ON ANY THEORY OF LIABILITY, WHETHER IN CONTRACT, STRICT
// LIABILITY, OR TORT (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY
// OUT OF THE USE OF THIS SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH
// DAMAGE.
//
// ==========================================================================
// Author: Manuel Holtgrewe <manuel.holtgrewe@fu-berlin.de>
// ==========================================================================
#include "genomic_variants.h"
std::ostream & operator<<(std::ostream & out, SnpRecord const & record)
{
out << "SnpRecord(" << record.haplotype << ", " << record.rId << ", " << record.pos
<< ", " << record.to << ")";
return out;
}
std::ostream & operator<<(std::ostream & out, SmallIndelRecord const & record)
{
out << "SnpRecord(" << record.haplotype << ", " << record.rId << ", " << record.pos
<< ", " << record.size << ", " << record.seq << ")";
return out;
}
int StructuralVariantRecord::endPosition() const
{
if (pos == -1)
return std::numeric_limits<int>::max();
switch (kind)
{
case INDEL:
if (size > 0)
return pos;
else
return pos - size; // for deletions, size is negative!
case INVERSION:
return pos + size;
case TRANSLOCATION:
return targetPos;
case DUPLICATION:
return targetPos;
default:
return -1;
}
}
bool StructuralVariantRecord::nearBreakend(int query) const
{
if (pos == -1)
return false; // invalid/sentinel has no breakends
switch (kind)
{
case INDEL:
if (size > 0)
return (query == pos || query == pos + 1);
else
return (query == pos || query == pos + 1 ||
query == pos - size || query == pos - size + 1);
case INVERSION:
return (query == pos || query == pos + 1 ||
query == pos + size || query == pos + size + 1);
case TRANSLOCATION:
return (query == pos || query == pos + 1 ||
query == targetPos || query == targetPos + 1);
case DUPLICATION:
return (query == pos || query == pos + 1 ||
query == targetPos || query == targetPos + 1);
default:
return false;
}
}
std::ostream & operator<<(std::ostream & out, StructuralVariantRecord const & record)
{
char const * kind;
switch (record.kind)
{
case StructuralVariantRecord::TRANSLOCATION:
kind = "TRANSLOCATION";
break;
case StructuralVariantRecord::INDEL:
kind = "INDEL";
break;
case StructuralVariantRecord::INVERSION:
kind = "INVERSION";
break;
case StructuralVariantRecord::DUPLICATION:
kind = "DUPLICATION";
break;
default:
kind = "INVALID";
break;
}
out << "StructuralVariantRecord(kind=" << kind << ", haplotype=" << record.haplotype
<< ", rId=" << record.rId << ", pos=" << record.pos << ", size=" << record.size
<< ", targetRId=" << record.targetRId << ", targetPos=" << record.targetPos
<< ", seq=\"" << record.seq << "\")";
return out;
}
// ----------------------------------------------------------------------------
// Function VariantMaterializer::_runImpl()
// ----------------------------------------------------------------------------
int VariantMaterializer::_runImpl(
seqan2::Dna5String * resultSeq,
PositionMap * posMap,
MethylationLevels * resultLvls,
std::vector<SmallVarInfo> & varInfos,
std::vector<std::pair<int, int> > & breakpoints,
seqan2::Dna5String const * ref,
MethylationLevels const * refLvls,
int haplotypeId)
{
breakpoints.clear();
clear(*resultSeq);
if (resultLvls)
resultLvls->clear();
// Apply small variants. We get a sequence with the small variants and a journal of the difference to contig.
seqan2::Dna5String seqSmallVariants;
TJournalEntries journal;
MethylationLevels levelsSmallVariants; // only used if revLevels != 0
MethylationLevels * smallLvlsPtr = refLvls ? &levelsSmallVariants : 0;
std::vector<SmallVarInfo> smallVarInfos;
if (_materializeSmallVariants(seqSmallVariants, journal, smallLvlsPtr, smallVarInfos, *ref, *variants,
refLvls, haplotypeId) != 0)
return 1;
// Build position map for large variant -> small variant and small variant <-> reference position mapping.
posMap->reinit(journal); // build mapping from small variant to reference positions
// Apply structural variants and build the interval tree of posMap
if (_materializeLargeVariants(*resultSeq, resultLvls, varInfos, breakpoints, *posMap, journal, seqSmallVariants,
smallVarInfos, *variants, smallLvlsPtr, haplotypeId) != 0)
return 1;
// Sort resulting variant infos.
std::sort(varInfos.begin(), varInfos.end());
// std::sort(breakpoints.begin(), breakpoints.end());
// std::cout << "SV Breakpoints\n";
// for (unsigned i = 0; i < breakpoints.size(); ++i)
// std::cout << " " << breakpoints[i] << "\n";
// Copy out SV breakpoints.
posMap->svBreakpoints.insert(breakpoints.begin(), breakpoints.end());
return 0;
}
// ----------------------------------------------------------------------------
// Function VariantMaterializer::_materializeSmallVariants()
// ----------------------------------------------------------------------------
int VariantMaterializer::_materializeSmallVariants(
seqan2::Dna5String & seq, // resulting sequence, original sequence with small variants applied
TJournalEntries & journal,
MethylationLevels * levelsSmallVariants,
std::vector<SmallVarInfo> & smallVarInfos,
seqan2::Dna5String const & contig, // contig == original sequence
Variants const & variants,
MethylationLevels const * levels,
int hId)
{
if (methSimOptions)
{
SEQAN_ASSERT_EQ(methSimOptions->simulateMethylationLevels, (levelsSmallVariants != 0));
SEQAN_ASSERT_EQ(methSimOptions->simulateMethylationLevels, (levels != 0));
}
// Clear journal and output methylation levels.
reinit(journal, length(contig));
if (levelsSmallVariants)
levelsSmallVariants->clear();
// Store variation points with a flag whether it is a SNP (true) or a breakpoint (false).
seqan2::String<std::pair<int, bool> > varPoints;
// Fors this, we have to iterate in parallel over SNP and small indel records.
//
// Current index in snp/small indel array.
unsigned snpsIdx = 0;
unsigned smallIndelIdx = 0;
// Current SNP record, default to sentinel.
SnpRecord snpRecord;
snpRecord.rId = std::numeric_limits<int>::max();
if (snpsIdx < length(variants.snps))
snpRecord = variants.snps[snpsIdx++];
// Current small indel record, default to sentinel.
SmallIndelRecord smallIndelRecord;
smallIndelRecord.rId = std::numeric_limits<int>::max();
if (smallIndelIdx < length(variants.smallIndels))
smallIndelRecord = variants.smallIndels[smallIndelIdx++];
// Track last position from contig appended to seq so far.
int lastPos = 0;
if (verbosity >= 3)
std::cerr << __LINE__ << "\tlastPos == " << lastPos << "\n";
// TODO(holtgrew): Extract contig building into their own functions.
if (verbosity >= 2)
std::cerr << "building output\n";
while (snpRecord.rId != std::numeric_limits<int>::max() || smallIndelRecord.rId != std::numeric_limits<int>::max())
{
// TODO(holtgrew): Extract SNP and small indel handling into their own functions.
if (snpRecord.getPos() < smallIndelRecord.getPos()) // process SNP records
{
if (snpRecord.haplotype == hId) // Ignore all but the current contig.
{
if (verbosity >= 3)
std::cerr << __LINE__ << "\tappend(seq, infix(contig, " << lastPos << ", " << snpRecord.pos << ")\n";
// Append interim sequence and methylation levels->
append(seq, infix(contig, lastPos, snpRecord.pos));
if (methSimOptions && methSimOptions->simulateMethylationLevels)
{
append(levelsSmallVariants->forward, infix(levels->forward, lastPos, snpRecord.pos + 1));
append(levelsSmallVariants->reverse, infix(levels->reverse, lastPos, snpRecord.pos + 1));
appendValue(varPoints, std::make_pair((int)length(seq), true)); // variation points before/after SNP
appendValue(varPoints, std::make_pair((int)length(seq) + 1, true));
}
SEQAN_ASSERT_GEQ(snpRecord.pos, lastPos);
if (verbosity >= 3)
std::cerr << __LINE__ << "\tappendValue(seq, " << snpRecord.to << "')\n";
appendValue(seq, snpRecord.to);
lastPos = snpRecord.pos + 1;
if (verbosity >= 3)
std::cerr << __LINE__ << "\tlastPos == " << lastPos << "\n";
// Register SNP as small variant info.
smallVarInfos.push_back(SmallVarInfo(SmallVarInfo::SNP, length(seq) - 1, 1));
}
if (snpsIdx >= length(variants.snps))
snpRecord.rId = std::numeric_limits<int>::max();
else
snpRecord = variants.snps[snpsIdx++];
}
else
{
if (smallIndelRecord.haplotype == hId) // Ignore all but the current contig.
{
if (smallIndelRecord.size > 0)
{
if (verbosity >= 3)
std::cerr << __LINE__ << "\tappend(seq, infix(contig, " << lastPos << ", " << smallIndelRecord.pos << ")\n";
// Simulate methylation levels for insertion.
MethylationLevels lvls;
if (methSimOptions && methSimOptions->simulateMethylationLevels)
{
MethylationLevelSimulator methSim(*rng, *methSimOptions);
methSim.run(lvls, smallIndelRecord.seq);
}
// Append interim sequence and methylation levels->
append(seq, infix(contig, lastPos, smallIndelRecord.pos));
if (methSimOptions && methSimOptions->simulateMethylationLevels)
{
append(levelsSmallVariants->forward, infix(levels->forward, lastPos, smallIndelRecord.pos));
append(levelsSmallVariants->reverse, infix(levels->reverse, lastPos, smallIndelRecord.pos));
appendValue(varPoints, std::make_pair((int)length(seq), false)); // variation point before insertion
}
SEQAN_ASSERT_GEQ(smallIndelRecord.pos, lastPos);
if (verbosity >= 3)
std::cerr << __LINE__ << "\tappend(seq, \"" << smallIndelRecord.seq << "\")\n";
// Register insertion as small variant info.
for (unsigned i = 0; i < length(smallIndelRecord.seq); ++i)
smallVarInfos.push_back(SmallVarInfo(SmallVarInfo::INS, length(seq) + i, 1));
// Append novel sequence and methylation levels->
append(seq, smallIndelRecord.seq);
if (methSimOptions && methSimOptions->simulateMethylationLevels)
{
append(levelsSmallVariants->forward, lvls.forward);
append(levelsSmallVariants->reverse, lvls.reverse);
appendValue(varPoints, std::make_pair((int)length(seq), false)); // variation point after insertion
}
lastPos = smallIndelRecord.pos;
recordInsertion(journal, hostToVirtualPosition(journal, smallIndelRecord.pos),
0, smallIndelRecord.size);
if (verbosity >= 3)
std::cerr << __LINE__ << "\tlastPos == " << lastPos << "\n";
}
else // deletion
{
if (verbosity >= 3)
std::cerr << __LINE__ << "\tappend(seq, infix(contig, " << lastPos << ", " << smallIndelRecord.pos << ")\n";
// Append interim sequence and methylation levels->
append(seq, infix(contig, lastPos, smallIndelRecord.pos)); // interim chars
if (methSimOptions && methSimOptions->simulateMethylationLevels)
{
appendValue(varPoints, std::make_pair((int)length(seq), false)); // variation point at deletion
append(levelsSmallVariants->forward, infix(levels->forward, lastPos, smallIndelRecord.pos));
append(levelsSmallVariants->reverse, infix(levels->reverse, lastPos, smallIndelRecord.pos));
}
lastPos = smallIndelRecord.pos - smallIndelRecord.size;
SEQAN_ASSERT_LT(lastPos, (int)length(contig));
recordErase(journal,
hostToVirtualPosition(journal, smallIndelRecord.pos),
hostToVirtualPosition(journal, smallIndelRecord.pos - smallIndelRecord.size));
if (verbosity >= 3)
std::cerr << __LINE__ << "\tlastPos == " << lastPos << "\n";
// Register deletion as small variant info.
smallVarInfos.push_back(SmallVarInfo(SmallVarInfo::DEL, length(seq), -smallIndelRecord.size));
}
}
if (smallIndelIdx >= length(variants.smallIndels))
smallIndelRecord.rId = std::numeric_limits<int>::max();
else
smallIndelRecord = variants.smallIndels[smallIndelIdx++];
}
}
// Insert remaining characters.
if (verbosity >= 3)
std::cerr << __LINE__ << "\tappend(seq, infix(contig, " << lastPos << ", " << length(contig) << ")\n";
append(seq, infix(contig, lastPos, length(contig)));
if (methSimOptions && methSimOptions->simulateMethylationLevels)
{
append(levelsSmallVariants->forward, infix(levels->forward, lastPos, length(contig)));
append(levelsSmallVariants->reverse, infix(levels->reverse, lastPos, length(contig)));
SEQAN_ASSERT_EQ(length(seq), length(levelsSmallVariants->forward));
SEQAN_ASSERT_EQ(length(seq), length(levelsSmallVariants->reverse));
fixVariationLevels(*levelsSmallVariants, *rng, seq, varPoints, *methSimOptions);
}
return 0;
}
// ----------------------------------------------------------------------------
// Function VariantMaterializer::_materializeLargeVariants()
// ----------------------------------------------------------------------------
int VariantMaterializer::_materializeLargeVariants(
seqan2::Dna5String & seq, // final result sequence
MethylationLevels * levelsLargeVariants,
std::vector<SmallVarInfo> & varInfos,
std::vector<std::pair<int, int> > & breakpoints,
PositionMap & positionMap,
TJournalEntries const & journal, // built over contig
seqan2::Dna5String const & contig, // sequence after applying small variants
std::vector<SmallVarInfo> const & smallVarInfos,
Variants const & variants,
MethylationLevels const * levels,
int hId)
{
if (methSimOptions)
{
SEQAN_ASSERT_EQ(methSimOptions->simulateMethylationLevels, (levelsLargeVariants != 0));
SEQAN_ASSERT_EQ(methSimOptions->simulateMethylationLevels, (levels != 0));
}
// We will record all intervals for the positionMap.svIntervalTree in this String.
seqan2::String<GenomicInterval> intervals;
// Clear output methylation levels->
if (levelsLargeVariants)
levelsLargeVariants->clear();
// Store variation points. We reuse the fixVariationLevels() function from small indel/snp simulation and thus
// have to store a bool that is always set to false.
seqan2::String<std::pair<int, bool> > varPoints;
// Track last position from contig appended to seq so far.
int lastPos = 0;
if (verbosity >= 3)
std::cerr << __LINE__ << "\tlastPos == " << lastPos << "\n";
// Pointer to the current small variant to write out translated to varInfo.
std::vector<SmallVarInfo>::const_iterator itSmallVar = smallVarInfos.begin();
// Number of bytes written out so far/current position in variant.
unsigned currentPos = 0;
for (unsigned i = 0; i < length(variants.svRecords); ++i)
{
if (variants.svRecords[i].haplotype != hId) // Ignore all but the current contig.
continue;
// We obtain a copy of the current SV record since we translate its positions below.
StructuralVariantRecord svRecord = variants.svRecords[i];
// Translate positions and lengths of SV record.
if (verbosity >= 2)
std::cerr << " Translating SvRecord\n " << svRecord << '\n';
// Avoid computing this for both size and position adjustment.
int const virtualPos = hostToVirtualPosition(journal, svRecord.pos);
// We do not need to adjust the sizes for insertions.
if (svRecord.kind != StructuralVariantRecord::INDEL || svRecord.size < 0)
{
// Use absolute value for size. Deletions have a negative size, we want the position after the variant.
int const virtualEndPos = hostToVirtualPosition(journal, svRecord.pos + std::abs(svRecord.size));
// The size of the variant in the contig:
// * contig is the sequence that already has small variants applied, e.g. small deletions are removed.
// * journal is built over contig.
// * hostToVirtualPosition maps the reference position to the contig position.
// * Variants may overlap.
// Example for overlapping:
// * Large deletion at position 10, size 50.
// * Small deletion at position 20, size 10.
// * Small insertion at position 30, size 5.
// The small deletion and insertion were already applied to contig via _materializeSmallVariants.
// Because 10 bases were already deleted, the size would be 40 for the large deletion.
// Together with the small insertion, the size would then be 45.
int const virtualSize = virtualEndPos - virtualPos;
// Keep sign of size, i.e. negative for deletions.
svRecord.size = (svRecord.size < 0 ? -1 : 1) * virtualSize;
}
// Adjust position after size. The original position is needed for adjusting the size.
svRecord.pos = virtualPos;
SEQAN_ASSERT_LT(svRecord.pos, (int)length(contig));
if (svRecord.targetPos != -1)
svRecord.targetPos = hostToVirtualPosition(journal, svRecord.targetPos);
if (verbosity >= 2)
std::cerr << " => " << svRecord << '\n';
// Copy out small variant infos for interim chars.
for (; itSmallVar != smallVarInfos.end() && itSmallVar->pos < svRecord.pos; ++itSmallVar)
{
int offset = (int)currentPos - lastPos;
varInfos.push_back(*itSmallVar);
varInfos.back().pos += offset;
}
// Copy from contig to seq with SVs.
if (verbosity >= 3)
std::cerr << __LINE__ << "\tappend(seq, infix(contig, " << lastPos << ", " << svRecord.pos << ") (interim)\n";
append(seq, infix(contig, lastPos, svRecord.pos)); // interim chars
if (methSimOptions && methSimOptions->simulateMethylationLevels)
{
append(levelsLargeVariants->forward, infix(levels->forward, lastPos, svRecord.pos));
append(levelsLargeVariants->reverse, infix(levels->reverse, lastPos, svRecord.pos));
appendValue(varPoints, std::make_pair((int)length(seq), false));
}
if (currentPos != length(seq))
appendValue(intervals, GenomicInterval(currentPos, length(seq), lastPos, svRecord.pos,
'+', GenomicInterval::NORMAL));
currentPos = length(seq);
switch (svRecord.kind)
{
case StructuralVariantRecord::INDEL:
{
if (svRecord.size > 0) // insertion
{
SEQAN_ASSERT_EQ((int)length(svRecord.seq), svRecord.size);
// Simulate methylation levels for insertion.
MethylationLevels lvls;
if (methSimOptions && methSimOptions->simulateMethylationLevels)
{
MethylationLevelSimulator methSim(*rng, *methSimOptions);
methSim.run(lvls, svRecord.seq);
}
// Append novel sequence and methylation levels.
append(seq, svRecord.seq);
if (methSimOptions && methSimOptions->simulateMethylationLevels)
{
append(levelsLargeVariants->forward, lvls.forward);
append(levelsLargeVariants->reverse, lvls.reverse);
appendValue(varPoints, std::make_pair((int)length(seq), false)); // variation point after insertion
}
if (currentPos != length(seq))
appendValue(intervals, GenomicInterval(currentPos, length(seq), -1, -1,
'+', GenomicInterval::INSERTED));
if (verbosity >= 3)
std::cerr << "append(seq, svRecord.seq (length == " << length(svRecord.seq) << ") " << __LINE__ << " (insertion)\n";
lastPos = svRecord.pos;
SEQAN_ASSERT_LT(lastPos, (int)length(contig));
// Copy out breakpoints.
breakpoints.push_back(std::make_pair(currentPos, variants.posToIdx(Variants::SV, i)));
breakpoints.push_back(std::make_pair((int)length(seq), variants.posToIdx(Variants::SV, i)));
currentPos = length(seq);
}
else // deletion
{
// skip forward in contig (which does not contain deletion)
lastPos = svRecord.pos - svRecord.size; // svRecord.size is negative
SEQAN_ASSERT_LT(lastPos, (int)length(contig));
// Copy out breakpoint.
breakpoints.push_back(std::make_pair(currentPos, variants.posToIdx(Variants::SV, i)));
}
}
break;
case StructuralVariantRecord::INVERSION:
{
unsigned oldLen = length(seq);
append(seq, infix(contig, svRecord.pos, svRecord.pos + svRecord.size));
if (methSimOptions && methSimOptions->simulateMethylationLevels)
{
appendValue(varPoints, std::make_pair((int)length(seq), false)); // variation point at deletion
append(levelsLargeVariants->forward, infix(levels->reverse, svRecord.pos, svRecord.pos + svRecord.size));
reverse(infix(levelsLargeVariants->forward, oldLen, length(levelsLargeVariants->forward)));
append(levelsLargeVariants->reverse, infix(levels->forward, svRecord.pos, svRecord.pos + svRecord.size));
reverse(infix(levelsLargeVariants->reverse, oldLen, length(levelsLargeVariants->reverse)));
}
if (currentPos != length(seq))
appendValue(intervals, GenomicInterval(currentPos, length(seq), svRecord.pos, svRecord.pos + svRecord.size,
'-', GenomicInterval::INVERTED));
// Copy out small variant infos for inversion.
for (; itSmallVar != smallVarInfos.end() && itSmallVar->pos < svRecord.pos + svRecord.size; ++itSmallVar)
{
varInfos.push_back(*itSmallVar);
varInfos.back().pos = currentPos + svRecord.size - (varInfos.back().pos - lastPos);
}
if (verbosity >= 3)
std::cerr << "append(seq, infix(contig, " << svRecord.pos << ", " << svRecord.pos + svRecord.size << ") " << __LINE__ << " (inversion)\n";
reverseComplement(infix(seq, oldLen, length(seq)));
lastPos = svRecord.pos + svRecord.size;
SEQAN_ASSERT_LT(lastPos, (int)length(contig));
// Copy out breakpoints.
breakpoints.push_back(std::make_pair(currentPos, variants.posToIdx(Variants::SV, i)));
breakpoints.push_back(std::make_pair((int)length(seq), variants.posToIdx(Variants::SV, i)));
currentPos = length(seq);
}
break;
case StructuralVariantRecord::TRANSLOCATION:
{
SEQAN_ASSERT_GEQ(svRecord.targetPos, svRecord.pos + svRecord.size);
append(seq, infix(contig, svRecord.pos + svRecord.size, svRecord.targetPos));
if (methSimOptions && methSimOptions->simulateMethylationLevels)
{
appendValue(varPoints, std::make_pair((int)length(seq), false));
append(levelsLargeVariants->forward, infix(levels->forward, svRecord.pos + svRecord.size, svRecord.targetPos));
append(levelsLargeVariants->reverse, infix(levels->reverse, svRecord.pos + svRecord.size, svRecord.targetPos));
}
if (currentPos != length(seq))
appendValue(intervals, GenomicInterval(currentPos, length(seq), svRecord.pos + svRecord.size, svRecord.targetPos,
'+', GenomicInterval::NORMAL));
unsigned tmpCurrentPos = length(seq);
append(seq, infix(contig, svRecord.pos, svRecord.pos + svRecord.size));
if (methSimOptions && methSimOptions->simulateMethylationLevels)
{
appendValue(varPoints, std::make_pair((int)length(seq), false));
append(levelsLargeVariants->forward, infix(levels->forward, svRecord.pos, svRecord.pos + svRecord.size));
append(levelsLargeVariants->reverse, infix(levels->reverse, svRecord.pos, svRecord.pos + svRecord.size));
}
if (tmpCurrentPos != length(seq))
appendValue(intervals, GenomicInterval(tmpCurrentPos, length(seq), svRecord.pos, svRecord.pos + svRecord.size,
'+', GenomicInterval::NORMAL));
if (verbosity >= 3)
std::cerr << "append(seq, infix(contig, " << svRecord.pos + svRecord.size << ", " << svRecord.targetPos << ") " << __LINE__ << " (translocation)\n"
<< "append(seq, infix(contig, " << svRecord.pos << ", " << svRecord.pos + svRecord.size << ") " << __LINE__ << "\n";
lastPos = svRecord.targetPos;
SEQAN_ASSERT_LT(lastPos, (int)length(contig));
// Copy out small variant infos for translocation, shift left to right and righ to left but keep
// center intact.
for (; itSmallVar != smallVarInfos.end() && itSmallVar->pos < svRecord.pos; ++itSmallVar)
{
int offset = (int)currentPos - lastPos;
varInfos.push_back(*itSmallVar);
varInfos.back().pos += offset;
int bpLeft = svRecord.pos + svRecord.size;
int bpRight = svRecord.targetPos;
if (itSmallVar->pos < bpLeft)
varInfos.back().pos -= (svRecord.targetPos - svRecord.pos);
else if (itSmallVar->pos >= bpRight)
varInfos.back().pos += (svRecord.targetPos - svRecord.pos);
}
// Copy out breakpoints.
breakpoints.push_back(std::make_pair(currentPos, variants.posToIdx(Variants::SV, i)));
breakpoints.push_back(std::make_pair(currentPos + svRecord.targetPos - svRecord.pos - svRecord.size, variants.posToIdx(Variants::SV, i)));
breakpoints.push_back(std::make_pair((int)length(seq), variants.posToIdx(Variants::SV, i)));
currentPos = length(seq);
}
break;
case StructuralVariantRecord::DUPLICATION:
{
append(seq, infix(contig, svRecord.pos, svRecord.pos + svRecord.size));
SEQAN_ASSERT_GEQ(svRecord.targetPos, svRecord.pos + svRecord.size);
if (methSimOptions && methSimOptions->simulateMethylationLevels) // first copy
{
appendValue(varPoints, std::make_pair((int)length(seq), false));
append(levelsLargeVariants->forward, infix(levels->forward, svRecord.pos, svRecord.pos + svRecord.size));
append(levelsLargeVariants->reverse, infix(levels->reverse, svRecord.pos, svRecord.pos + svRecord.size));
}
if (currentPos != length(seq))
appendValue(intervals, GenomicInterval(currentPos, length(seq), svRecord.pos, svRecord.pos + svRecord.size,
'+', GenomicInterval::DUPLICATED));
unsigned tmpCurrentPos = length(seq);
append(seq, infix(contig, svRecord.pos + svRecord.size, svRecord.targetPos));
if (methSimOptions && methSimOptions->simulateMethylationLevels)
{
appendValue(varPoints, std::make_pair((int)length(seq), false));
append(levelsLargeVariants->forward, infix(levels->forward, svRecord.pos + svRecord.size, svRecord.targetPos));
append(levelsLargeVariants->reverse, infix(levels->reverse, svRecord.pos + svRecord.size, svRecord.targetPos));
}
if (tmpCurrentPos != length(seq))
appendValue(intervals, GenomicInterval(tmpCurrentPos, length(seq), svRecord.pos + svRecord.size, svRecord.targetPos,
'+', GenomicInterval::NORMAL));
tmpCurrentPos = length(seq);
append(seq, infix(contig, svRecord.pos, svRecord.pos + svRecord.size));
if (methSimOptions && methSimOptions->simulateMethylationLevels) // second copy
{
appendValue(varPoints, std::make_pair((int)length(seq), false));
append(levelsLargeVariants->forward, infix(levels->forward, svRecord.pos, svRecord.pos + svRecord.size));
append(levelsLargeVariants->reverse, infix(levels->reverse, svRecord.pos, svRecord.pos + svRecord.size));
}
if (tmpCurrentPos != length(seq))
appendValue(intervals, GenomicInterval(tmpCurrentPos, length(seq), svRecord.pos, svRecord.pos + svRecord.size,
'+', GenomicInterval::NORMAL));
if (verbosity >= 3)
std::cerr << "append(seq, infix(contig, " << svRecord.pos << ", " << svRecord.pos + svRecord.size << ") " << __LINE__ << " (duplication)\n"
<< "append(seq, infix(contig, " << svRecord.pos + svRecord.size << ", " << svRecord.targetPos << ") " << __LINE__ << "\n"
<< "append(seq, infix(contig, " << svRecord.pos << ", " << svRecord.pos + svRecord.size << ") " << __LINE__ << "\n";
lastPos = svRecord.targetPos;
SEQAN_ASSERT_LT(lastPos, (int)length(contig));
// Write out small variant infos for duplication.
for (; itSmallVar != smallVarInfos.end() && itSmallVar->pos < svRecord.pos + svRecord.size; ++itSmallVar)
{
int offset = (int)currentPos - lastPos;
varInfos.push_back(*itSmallVar);
varInfos.back().pos += offset;
if (itSmallVar->pos < svRecord.pos + svRecord.size)
{
varInfos.push_back(*itSmallVar);
varInfos.back().pos += (svRecord.targetPos - svRecord.pos);
}
}
// Copy out breakpoints.
breakpoints.push_back(std::make_pair(currentPos, variants.posToIdx(Variants::SV, i)));
breakpoints.push_back(std::make_pair(currentPos + svRecord.pos + svRecord.size - svRecord.pos, variants.posToIdx(Variants::SV, i)));
breakpoints.push_back(std::make_pair(currentPos + svRecord.pos + svRecord.size - svRecord.pos + svRecord.targetPos - (svRecord.pos + svRecord.size), variants.posToIdx(Variants::SV, i)));
breakpoints.push_back(std::make_pair((int)length(seq), variants.posToIdx(Variants::SV, i)));
currentPos = length(seq);
}
break;
default:
return 1;
}
}
if (verbosity >= 3)
std::cerr << "append(seq, infix(contig, " << lastPos << ", " << length(contig) << ") "
<< __LINE__ << " (last interim)\n";
append(seq, infix(contig, lastPos, length(contig)));
if (methSimOptions && methSimOptions->simulateMethylationLevels)
{
append(levelsLargeVariants->forward, infix(levels->forward, lastPos, length(contig)));
append(levelsLargeVariants->reverse, infix(levels->reverse, lastPos, length(contig)));
SEQAN_ASSERT_EQ(length(seq), length(levelsLargeVariants->forward));
SEQAN_ASSERT_EQ(length(seq), length(levelsLargeVariants->reverse));
fixVariationLevels(*levelsLargeVariants, *rng, seq, varPoints, *methSimOptions);
}
if (currentPos != length(seq))
appendValue(intervals, GenomicInterval(currentPos, length(seq), lastPos, length(contig),
'+', GenomicInterval::NORMAL));
// Copy out small variant infos for trailing characters.
for (; itSmallVar != smallVarInfos.end(); ++itSmallVar)
{
int offset = (int)currentPos - lastPos;
varInfos.push_back(*itSmallVar);
varInfos.back().pos += offset;
}
// Build the interval trees of the positionMap.
seqan2::String<PositionMap::TInterval> svIntervals, svIntervalsSTL;
for (unsigned i = 0; i < length(intervals); ++i)
appendValue(svIntervals, PositionMap::TInterval(
intervals[i].svBeginPos, intervals[i].svEndPos, intervals[i]));
for (unsigned i = 0; i < length(intervals); ++i)
if (intervals[i].smallVarBeginPos != -1) // ignore insertions
appendValue(svIntervalsSTL, PositionMap::TInterval(
intervals[i].smallVarBeginPos, intervals[i].smallVarEndPos, intervals[i]));
createIntervalTree(positionMap.svIntervalTree, svIntervals);
createIntervalTree(positionMap.svIntervalTreeSTL, svIntervalsSTL);
return 0;
}
// --------------------------------------------------------------------------
// Function PositionMap::overlapsWithBreakpoint()
// --------------------------------------------------------------------------
bool PositionMap::overlapsWithBreakpoint(int svBeginPos, int svEndPos) const
{
std::set<std::pair<int, int> >::const_iterator it = svBreakpoints.upper_bound(std::make_pair(svBeginPos, std::numeric_limits<int>::max()));
return (it != svBreakpoints.end() && it->first < svEndPos);
}
// --------------------------------------------------------------------------
// Function PositionMap::getGenomicInterval()
// --------------------------------------------------------------------------
GenomicInterval PositionMap::getGenomicInterval(int svPos) const
{
seqan2::String<GenomicInterval> intervals;
findIntervals(intervals, svIntervalTree, svPos);
SEQAN_ASSERT_EQ(length(intervals), 1u);
return intervals[0];
}
// --------------------------------------------------------------------------
// PositionMap::getGenomicIntervalSmallVarPos()
// --------------------------------------------------------------------------
// Returns the GenomicInterval on the sequence using a position on the small var reference.
GenomicInterval PositionMap::getGenomicIntervalSmallVarPos(int smallVarPos) const
{
seqan2::String<GenomicInterval> intervals;
findIntervals(intervals, svIntervalTreeSTL, smallVarPos);
return intervals[0];
}
// --------------------------------------------------------------------------
// Function PositionMap::toSmallVarInterval()
// --------------------------------------------------------------------------
std::pair<int, int> PositionMap::toSmallVarInterval(int svBeginPos, int svEndPos) const
{
SEQAN_ASSERT(!overlapsWithBreakpoint(svBeginPos, svEndPos));
GenomicInterval gi = getGenomicInterval(svBeginPos);
if (gi.kind == GenomicInterval::INSERTED)
{
// novel sequence, cannot be projected
return std::make_pair(-1, -1);
}
if (gi.kind != GenomicInterval::INVERTED)
{
// forward
return std::make_pair(gi.smallVarBeginPos + (svBeginPos - gi.svBeginPos),
gi.smallVarBeginPos + (svEndPos - gi.svBeginPos));
}
else
{
// reverse
return std::make_pair(gi.smallVarBeginPos + (gi.svEndPos - svBeginPos),
gi.smallVarBeginPos + (gi.svEndPos - svEndPos));
}
return std::make_pair(-1, -1); // cannot reach here
}
// --------------------------------------------------------------------------
// Function PositionMap::smallVarToLargeVarInterval()
// --------------------------------------------------------------------------
std::pair<int, int> PositionMap::smallVarToLargeVarInterval(int beginPos, int endPos) const
{
// SEQAN_ASSERT(!overlapsWithBreakpoint(svBeginPos, svEndPos));
GenomicInterval gi = getGenomicIntervalSmallVarPos(beginPos);
SEQAN_ASSERT_NEQ(gi.kind, GenomicInterval::INSERTED);
if (gi.kind != GenomicInterval::INVERTED)
{
// forward
return std::make_pair(gi.svBeginPos + (beginPos - gi.smallVarBeginPos),
gi.svBeginPos + (endPos - gi.smallVarBeginPos));
}
else
{
// reverse
return std::make_pair(gi.svBeginPos + (gi.svEndPos - beginPos),
gi.svBeginPos + (gi.svEndPos - endPos));
}
return std::make_pair(-1, -1); // cannot reach here
}
// --------------------------------------------------------------------------
// Function PositionMap::orignalToSmallVarInterval()
// --------------------------------------------------------------------------
std::pair<int, int> PositionMap::originalToSmallVarInterval(int beginPos, int endPos) const
{
// TODO(holtgrew): Project to the left at the end.
// Get anchor gaps objects from anchors.
TGaps refGaps(seqan2::Nothing(), refGapAnchors);
TGaps smallVarGaps(seqan2::Nothing(), smallVarGapAnchors);
// Translate begin and end position.
int beginPos2 = toViewPosition(refGaps, beginPos);
int beginPos3 = toSourcePosition(smallVarGaps, beginPos2);
int endPos2 = toViewPosition(refGaps, endPos);
int endPos3 = toSourcePosition(smallVarGaps, endPos2);
return std::make_pair(beginPos3, endPos3);
}
// --------------------------------------------------------------------------
// Function PositionMap::toOriginalInterval()
// --------------------------------------------------------------------------
std::pair<int, int> PositionMap::toOriginalInterval(int smallVarBeginPos, int smallVarEndPos) const
{
// TODO(holtgrew): Project to the left at the end.
// Get anchor gaps objects from anchors.
TGaps refGaps(seqan2::Nothing(), refGapAnchors);
TGaps smallVarGaps(seqan2::Nothing(), smallVarGapAnchors);
// Translate begin and end position.
int smallVarBeginPos2 = toViewPosition(smallVarGaps, smallVarBeginPos);
int smallVarBeginPos3 = toSourcePosition(refGaps, smallVarBeginPos2);
int smallVarEndPos2 = toViewPosition(smallVarGaps, smallVarEndPos);
int smallVarEndPos3 = toSourcePosition(refGaps, smallVarEndPos2);
return std::make_pair(smallVarBeginPos3, smallVarEndPos3);
}
// --------------------------------------------------------------------------
// Function PositionMap::reinit()
// --------------------------------------------------------------------------
void PositionMap::reinit(TJournalEntries const & journal)
{
// Reset the interval tree and breakpoints.
// TODO(holtgrew): Better API support for IntervalTree?
svIntervalTree = TIntervalTree();
svIntervalTreeSTL = TIntervalTree();
svBreakpoints.clear();
clear(refGapAnchors);
clear(smallVarGapAnchors);
// Convert the journal to two gaps.
//
// Get anchor gaps objects from anchors.
typedef seqan2::Iterator<TGaps, seqan2::Standard>::Type TGapsIter;
TGaps refGaps(seqan2::Nothing(), refGapAnchors);
TGapsIter itRef = begin(refGaps, seqan2::Standard());
TGaps smallVarGaps(seqan2::Nothing(), smallVarGapAnchors);
TGapsIter itVar = begin(smallVarGaps, seqan2::Standard());
// Iterate over the journal.
typedef seqan2::Iterator<TJournalEntries const, seqan2::Standard>::Type TJournalEntriesIt;
TJournalEntriesIt it = begin(journal, seqan2::Standard());
SEQAN_ASSERT_NEQ(it->segmentSource, seqan2::SOURCE_NULL);
SEQAN_ASSERT_EQ(it->virtualPosition, 0u);
unsigned lastRefPos = std::numeric_limits<unsigned>::max(); // Previous position from reference.
for (; it != end(journal, seqan2::Standard()); ++it)
{
SEQAN_ASSERT_NEQ(it->segmentSource, seqan2::SOURCE_NULL);
// The segment is from the reference.
if (it->segmentSource == seqan2::SOURCE_ORIGINAL)
{
// There is a gap at the beginning of the reference.
if (lastRefPos == std::numeric_limits<unsigned>::max() && it->physicalPosition != 0)
{
// Insert gaps in reference.
insertGaps(itRef, it->physicalPosition);
// Jump to position after gaps in reference.
itRef += it->physicalPosition;
// Jump over characters in variant.
itVar += it->physicalPosition;
}
// There is a gap in the variant.
if (it->physicalPosition > lastRefPos)
{
// How many gaps.
int len = it->physicalPosition - lastRefPos;
// Insert gaps in variant.
insertGaps(itVar, len);
// Jump over characters in reference.
itRef += len;
// Jump to position after gaps in variant.
itVar += len;
}
// This is a common segment. Advance both reference and variant.
itRef += it->length;
itVar += it->length;
// The end of the common segment is the last reference position.
lastRefPos = it->physicalPosition + it->length;
}
else // The segment is from the variant.
{
// Insert gaps in reference.
insertGaps(itRef, it->length);
// Jump to position after gaps in reference.
itRef += it->length;
// Jump over characters in variant.
itVar += it->length;
}
}
// std::cerr << "--> done\n";
// typedef seqan2::Gaps<seqan2::CharString, seqan2::AnchorGaps<TGapAnchors> > TGaps2;
// seqan2::CharString seqH;
// seqan2::CharString seqV;
// for (unsigned i = 0; i < 1000; ++i)
// {
// appendValue(seqH, 'X');
// appendValue(seqV, 'X');
// }
// TGaps2 gapsH(seqH, refGapAnchors);
// TGaps2 gapsV(seqV, smallVarGapAnchors);
// std::cerr << "REF\t" << gapsH << "\n"
// << "VAR\t" << gapsV << "\n";
}
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