flank_detector.cpp

/* The MIT License

   Copyright (c) 2015 Adrian Tan <atks@umich.edu>

   Permission is hereby granted, free of charge, to any person obtaining a copy
   of this software and associated documentation files (the "Software"), to deal
   in the Software without restriction, including without limitation the rights
   to use, copy, modify, merge, publish, distribute, sublicense, and/or sell
   copies of the Software, and to permit persons to whom the Software is
   furnished to do so, subject to the following conditions:

   The above copyright notice and this permission notice shall be included in
   all copies or substantial portions of the Software.

   THE SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR
   IMPLIED, INCLUDING BUT NOT LIMITED TO THE WARRANTIES OF MERCHANTABILITY,
   FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT. IN NO EVENT SHALL THE
   AUTHORS OR COPYRIGHT HOLDERS BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER
   LIABILITY, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM,
   OUT OF OR IN CONNECTION WITH THE SOFTWARE OR THE USE OR OTHER DEALINGS IN
   THE SOFTWARE.
*/

#include "flank_detector.h"

/**
 * Constructor.
 */
FlankDetector::FlankDetector(std::string& ref_fasta_file, bool debug)
{
    //////////////////////
    //initialize variables
    //////////////////////
    this->debug = debug;

    ///////////////////
    //initialize raHMMs
    ///////////////////
    float delta = 0.0001;
    float epsilon = 0.0005;
    float tau = 0.01;
    float eta = 0.01;
    float mismatch_penalty = 3;

    ahmm = new AHMM(false);
    ahmm->set_delta(delta);
    ahmm->set_epsilon(epsilon);
    ahmm->set_tau(tau);
    ahmm->set_eta(eta);
    ahmm->set_mismatch_penalty(mismatch_penalty);
    ahmm->initialize_T();

    lfhmm = new LFHMM(false);
    lfhmm->set_delta(delta);
    lfhmm->set_epsilon(epsilon);
    lfhmm->set_tau(tau);
    lfhmm->set_eta(eta);
    lfhmm->set_mismatch_penalty(mismatch_penalty);
    lfhmm->initialize_T();

    rfhmm = new RFHMM(false);
    rfhmm->set_delta(delta);
    rfhmm->set_epsilon(epsilon);
    rfhmm->set_tau(tau);
    rfhmm->set_eta(eta);
    rfhmm->set_mismatch_penalty(mismatch_penalty);
    rfhmm->initialize_T();

    qual.assign(1000, 'K');

    //////////////////
    //initialize tools
    //////////////////
    fai = fai_load(ref_fasta_file.c_str());
    if (fai==NULL)
    {
        fprintf(stderr, "[%s:%d %s] Cannot load genome index: %s\n", __FILE__, __LINE__, __FUNCTION__, ref_fasta_file.c_str());
        exit(1);
    }
};

/**
 * Destructor.
 */
FlankDetector::~FlankDetector()
{
    fai_destroy(fai);
}

/**
 * Detect repeat region.
 */
void FlankDetector::detect_flanks(bcf_hdr_t* h, bcf1_t *v, Variant& variant, uint32_t mode)
{
    VNTR& vntr = variant.vntr;

    //simple single base pair clipping of ends
    if (mode==CLIP_ENDS)
    {
        if (debug)
        {
            std::cerr << "********************************************\n";
            std::cerr << "CLIP ENDS\n";
            std:: cerr << "\n";
        }

        //in the case of simple indels, it is guaranteed that repeat tract length 
        //is always greater than 2 after exact alignment for deletions. This is 
        //because at least one end of the REF and ALT will end or start in the same base, 
        //and this allows the exact alignment detection of the repeat region to always 
        //increase by at least 1 base.
        //
        //exceptions:
        //
        //    simple insertion
        //    C[G]C  => [GC]
        //      GA
        //
        //    complex substitution
        //    C[G]C  => [G]
        //      TA
        if (vntr.exact_repeat_tract.size()>2) 
        {
            vntr.exact_repeat_tract = vntr.exact_repeat_tract.substr(1, vntr.exact_repeat_tract.size()-2);
            ++vntr.exact_rbeg1;
        }

        vntr.ru = choose_repeat_unit(vntr.exact_repeat_tract, vntr.motif);
        
//        std::cerr << "repeat tract : "
        
        vntr.exact_rend1 = vntr.exact_rbeg1+vntr.exact_rl-1;

        ahmm->set_model(vntr.ru.c_str());
        ahmm->align(vntr.exact_repeat_tract.c_str(), qual.c_str());

        vntr.exact_motif_concordance = ahmm->motif_concordance;
        vntr.exact_no_exact_ru = ahmm->exact_motif_count;
        vntr.exact_total_no_ru = ahmm->motif_count;
        vntr.exact_rl = ahmm->repeat_tract_len;

        if (debug)
        {
            vntr.print();
        }
    }
    else if (mode==FRAHMM)
    {
        if (debug)
        {
            std::cerr << "********************************************\n";
            std::cerr << "DETECTING REPEAT TRACT FUZZILY\n";
        }

        /////////////////
        //exact alignment
        /////////////////
        if (debug)
        {
            std::cerr << "++++++++++++++++++++++++++++++++++++++++++++\n";
            std::cerr << "Exact left/right alignment\n";
        }

        if (vntr.exact_repeat_tract.size()>2)
        {
            //removing the anchor bases
            if (vntr.mlen==1)
            {
                int32_t offset = 0;
                int32_t length = vntr.exact_repeat_tract.size();
                if (vntr.exact_repeat_tract.at(0)!=vntr.motif.at(0))
                {
                    offset = 1;
                    ++vntr.exact_rbeg1;
                }

                if (vntr.exact_repeat_tract.at(vntr.exact_repeat_tract.size()-1)!=vntr.motif.at(0))
                {
                    length -= offset+1;
                    --vntr.exact_rend1;
                }

                vntr.exact_repeat_tract = vntr.exact_repeat_tract.substr(offset, length);
            }
            else
            {
                if (vntr.exact_repeat_tract.size()>=3)
                {
                    vntr.exact_repeat_tract = vntr.exact_repeat_tract.substr(1, vntr.exact_repeat_tract.size()-2);
                    ++vntr.exact_rbeg1;
                    --vntr.exact_rend1;
                }
            }
        }
        //this is for nonexistent repeat units
        // 
        // RU : T
        // repeat_tract : G[T]C where T is an insert
        else if (vntr.exact_repeat_tract.size()==2)
        {
            
        }

        vntr.ru = choose_repeat_unit(vntr.exact_repeat_tract, vntr.motif);
        ahmm->set_model(vntr.ru.c_str());
        ahmm->align(vntr.exact_repeat_tract.c_str(), qual.c_str());

        vntr.exact_motif_concordance = ahmm->motif_concordance;
        vntr.exact_no_exact_ru = ahmm->exact_motif_count;
        vntr.exact_total_no_ru = ahmm->motif_count;
        vntr.exact_rl = ahmm->repeat_tract_len;

        if (debug)
        {
            std::cerr << "\n";
            std::cerr << "repeat_tract              : " << vntr.exact_repeat_tract << "\n";
            std::cerr << "position                  : [" << vntr.exact_rbeg1 << "," << vntr.exact_rend1 << "]\n";
            std::cerr << "motif_concordance         : " << vntr.exact_motif_concordance << "\n";
            std::cerr << "repeat units              : " << vntr.exact_rl << "\n";
            std::cerr << "exact repeat units        : " << vntr.exact_no_exact_ru << "\n";
            std::cerr << "total no. of repeat units : " << vntr.exact_total_no_ru << "\n";
            std::cerr << "\n";
        }

        ///////////////////////
        //fuzzy right alignment
        ///////////////////////
        if (debug)
        {
            std::cerr << "++++++++++++++++++++++++++++++++++++++++++++\n";
            std::cerr << "Fuzzy right alignment\n";
        }

        int32_t slen = 100;

        char* rflank;
        int32_t rflank_len;
        char* lflank;
        int32_t lflank_len;

        int32_t lflank_end1;
        int32_t rflank_beg1;

        char* seq;
        int32_t seq_len;
//        bool encountered_N = false;
        
        while (true)
        {
            //pick 5 bases to the right
            rflank = faidx_fetch_seq(fai, variant.chrom.c_str(), vntr.exact_rend1+1-1, vntr.exact_rend1+5-1, &rflank_len);

            //pick 105 bases for aligning

            seq = faidx_fetch_seq(fai, variant.chrom.c_str(), vntr.exact_rend1-slen-1, vntr.exact_rend1+5-1, &seq_len);
 
            
            rfhmm->set_model(vntr.ru.c_str(), rflank);
            rfhmm->align(seq, qual.c_str());
            if (debug) rfhmm->print_alignment();

            if (rflank_len) free(rflank);
            if (seq_len) free(seq);

            //////////////////////
            //fuzzy left alignment
            //////////////////////
            if (debug)
            {
                std::cerr << "\n";
                std::cerr << "++++++++++++++++++++++++++++++++++++++++++++\n";
                std::cerr << "Fuzzy left alignment\n";
            }

            //this is a hack around rfhmm rigidity in modeling the RUs
            //todo: we should change this to a reverse version of LFHMM!!!!
            if (rfhmm->get_lflank_read_epos1()>2*vntr.ru.size())
            {
                lflank_end1 = vntr.exact_rend1-slen-1+1 + rfhmm->get_lflank_read_epos1() - 1;
                break;
            }
            else if (slen==1000)
            {
                lflank_end1 = vntr.exact_rend1 - 1000 - 1;
                vntr.is_large_repeat_tract = true;
                break;
            }
            else
            {
                slen +=100;
                
                if (debug)
                    std::cerr << "extending the reference sequence for RFHMM : " << slen << "\n";
            }
        }

        slen = 100;

        //pick 5 bases to right
        while(true)
        {
            lflank = faidx_fetch_seq(fai, variant.chrom.c_str(), lflank_end1-5-1, lflank_end1-1, &lflank_len);

            //pick 105 bases for aligning
            seq = faidx_fetch_seq(fai, variant.chrom.c_str(), lflank_end1-5-1, lflank_end1+slen-1-1, &seq_len);

            lfhmm->set_model(lflank, vntr.ru.c_str());
            lfhmm->align(seq, qual.c_str());
            if (debug) lfhmm->print_alignment();

            if (seq_len) free(seq);

            if (lfhmm->get_rflank_read_epos1()!=INT32_MAX)
            {
                rflank_beg1 = lflank_end1 - 5 + lfhmm->get_rflank_read_spos1() -1;
                break;
            }
            else if (slen==1000)
            {
                rflank_beg1 = lflank_end1 + 1000;
                vntr.is_large_repeat_tract = true;
                break;
            }
            else
            {
                slen +=100;
                if (debug)
                    std::cerr << "extending the reference sequence for LFHMM : " << slen << "\n";
            }
        }

        if (lflank_len) free(lflank);

        lflank = faidx_fetch_seq(fai, variant.chrom.c_str(), lflank_end1-10-1, lflank_end1-1, &lflank_len);
        rflank = faidx_fetch_seq(fai, variant.chrom.c_str(), rflank_beg1-1, rflank_beg1 +10 -1 -1, &rflank_len);

        vntr.fuzzy_rbeg1 = lflank_end1+1;
        vntr.fuzzy_rend1 = rflank_beg1-1;
        int32_t repeat_tract_len;
        char* repeat_tract = faidx_fetch_seq(fai, variant.chrom.c_str(), lflank_end1, rflank_beg1-1-1, &repeat_tract_len);
        vntr.fuzzy_repeat_tract.assign(repeat_tract);
        if (repeat_tract_len) free(repeat_tract);
        vntr.fuzzy_motif_concordance = lfhmm->motif_concordance;
        vntr.fuzzy_no_exact_ru = lfhmm->exact_motif_count;
        vntr.fuzzy_total_no_ru = lfhmm->motif_count;
        vntr.fuzzy_rl = rflank_beg1-lflank_end1-1;

        if (lflank_len) free(lflank);
        if (rflank_len) free(rflank);

        if (debug)
        {
            std::cerr << "\n";
            vntr.print();
            std::cerr << "\n";
        }
    }

    //fill in flanks
    const char* chrom = variant.chrom.c_str();
    uint32_t pos1 = vntr.exact_rbeg1;
    int32_t len = 0;
    faidx_fetch_seq(fai, chrom, pos1-10, pos1-1, &len);
};

/**
 * Shifts a string.
 */
std::string FlankDetector::shift_str(std::string& seq, uint32_t i)
{
    std::string sseq = seq;
    if (i)
    {
        sseq = seq.substr(i) + seq.substr(0,i);
    }

    return sseq;
}

/**
 * Chooses a phase of the motif that is appropriate for the alignment
 */
std::string FlankDetector::choose_repeat_unit(std::string& ref, std::string& motif)
{
    for (uint32_t i=0; i<motif.size(); ++i)
    {
        std::string smotif = shift_str(motif, i);
        if (ref.compare(0, smotif.size(), smotif)==0)
        {
            return smotif;
        }
    }

    return motif;
}