gtc2vcf.h

/* The MIT License

   Copyright (c) 2018-2024 Giulio Genovese

   Author: Giulio Genovese <giulio.genovese@gmail.com>

   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 <dirent.h>
#include <htslib/hfile.h>
#include <htslib/faidx.h>
#include <htslib/sam.h>

#define min(a, b)                                                                                                      \
    ({                                                                                                                 \
        __typeof__(a) _a = (a);                                                                                        \
        __typeof__(b) _b = (b);                                                                                        \
        _a < _b ? _a : _b;                                                                                             \
    })

#define max(a, b)                                                                                                      \
    ({                                                                                                                 \
        __typeof__(a) _a = (a);                                                                                        \
        __typeof__(b) _b = (b);                                                                                        \
        _a > _b ? _a : _b;                                                                                             \
    })

// tests the end-of-file indicator for an hFILE
static inline int heof(hFILE *hfile) {
    if (hgetc(hfile) == EOF) return 1;
    hfile->begin--;
    return 0;
}

// read or skip a fixed number of bytes
static inline void read_bytes(hFILE *hfile, void *buffer, size_t nbytes) {
    if (buffer) {
        if (hread(hfile, buffer, nbytes) < nbytes) {
            error("Failed to read %ld bytes from stream\n", nbytes);
        }
    } else {
        int i, c = 0;
        for (i = 0; i < nbytes; i++) c = hgetc(hfile);
        if (c == EOF) error("Failed to reposition stream forward %ld bytes\n", nbytes);
    }
}

static inline char **get_file_list(const char *pathname, const char *extension, int *nfiles) {
    char **filenames = NULL;
    DIR *d = opendir(pathname);
    if (d) { // check if d is a directory
        struct dirent *dir;
        int mfiles = 0;
        int p = strlen(pathname);
        while ((dir = readdir(d))) {
            const char *ptr = strrchr(dir->d_name, '.');
            if (ptr && strcmp(ptr + 1, extension) == 0) {
                hts_expand0(char *, *nfiles + 1, mfiles, filenames);
                int q = strlen(dir->d_name);
                filenames[*nfiles] = (char *)malloc((p + q + 2) * sizeof(char));
                memcpy(filenames[*nfiles], pathname, p);
                filenames[*nfiles][p] = '/';
                memcpy(filenames[*nfiles] + p + 1, dir->d_name, q + 1);
                (*nfiles)++;
            }
        }
        closedir(d);
    } else {
        filenames = hts_readlines(pathname, nfiles);
        if (!filenames) error("Failed to read from file %s\n", pathname);
    }
    if (*nfiles == 0) error("No .%s files found in %s\n", extension, pathname);
    return filenames;
}

static inline FILE *get_file_handle(const char *str) {
    if (!str) return NULL;
    FILE *ret;
    if (strcmp(str, "-") == 0) {
        ret = stdout;
    } else {
        ret = fopen(str, "w");
        if (!ret) error("Failed to open %s: %s\n", str, strerror(errno));
    }
    return ret;
}

static inline void flank2fasta(const char *name, const char *flank, FILE *stream) {
    if (!flank) return;
    const char *left = strchr(flank, '[');
    const char *middle = strchr(flank, '/');
    const char *right = strchr(flank, ']');
    fprintf(stream, "@%s:1\n", name);
    if (!left && !middle && !right) {
        fprintf(stream, "%s\n", flank);
        return;
    }
    if (!left || !middle || !right) error("Flank sequence is malformed: %s\n", flank);
    if (*(middle - 1) == '-')
        fprintf(stream, "%.*s%s\n", (int)(left - flank), flank, right + 1);
    else
        fprintf(stream, "%.*s%.*s%s\n", (int)(left - flank), flank, (int)(middle - left) - 1, left + 1, right + 1);
    fprintf(stream, "@%s:2\n", name);
    if (*(middle - 1) == '-')
        fprintf(stream, "%.*s%.*s%s\n", (int)(left - flank), flank, (int)(right - middle) - 1, middle + 1, right + 1);
    else
        fprintf(stream, "%.*s%.*s%s\n", (int)(left - flank), flank, (int)(right - middle) - 1, middle + 1, right + 1);
}

static inline int bcf_hdr_name2id_flexible(const bcf_hdr_t *hdr, char *chr) {
    if (!chr) return -1;
    char buf[] = {'c', 'h', 'r', '\0', '\0', '\0'};
    int rid = bcf_hdr_name2id(hdr, chr);
    if (rid >= 0) return rid;
    if (strncmp(chr, "chr", 3) == 0) rid = bcf_hdr_name2id(hdr, chr + 3);
    if (rid >= 0) return rid;
    strncpy(buf + 3, chr, 2);
    rid = bcf_hdr_name2id(hdr, buf);
    if (rid >= 0) return rid;
    if (strcmp(chr, "23") == 0 || strcmp(chr, "25") == 0 || strcmp(chr, "XY") == 0 || strcmp(chr, "XX") == 0
        || strcmp(chr, "PAR1") == 0 || strcmp(chr, "PAR2") == 0) {
        rid = bcf_hdr_name2id(hdr, "X");
        if (rid >= 0) return rid;
        rid = bcf_hdr_name2id(hdr, "chrX");
    } else if (strcmp(chr, "24") == 0) {
        rid = bcf_hdr_name2id(hdr, "Y");
        if (rid >= 0) return rid;
        rid = bcf_hdr_name2id(hdr, "chrY");
    } else if (strcmp(chr, "26") == 0 || strcmp(chr, "MT") == 0 || strcmp(chr, "chrM") == 0) {
        rid = bcf_hdr_name2id(hdr, "MT");
        if (rid >= 0) return rid;
        rid = bcf_hdr_name2id(hdr, "chrM");
    }
    return rid;
}

static inline char rev_nt(char iupac) {
    static const char iupac_complement[128] = {
        0x00, 0x01, 0x02, 0x03, 0x04, 0x05, 0x06, 0x07, 0x08, 0x09, 0x0A, 0x0B, 0x0C, 0x0D, 0x0E, 0x0F,
        0x10, 0x11, 0x12, 0x13, 0x14, 0x15, 0x16, 0x17, 0x18, 0x19, 0x1A, 0x1B, 0x1C, 0x1D, 0x1E, 0x1F,
        0x20, 0x21, 0x22, 0x23, 0x24, 0x25, 0x26, 0x27, 0x28, 0x29, 0x2A, 0x2B, 0x2C, '-',  0x2E, '/',
        0x30, 0x31, 0x32, 0x33, 0x34, 0x35, 0x36, 0x37, 0x38, 0x39, 0x3A, 0x3B, 0x3C, 0x3D, 0x3E, 0x3F,
        0x40, 'T',  'V',  'G',  'H',  0x45, 0x46, 'C',  'D',  0x49, 0x4A, 'M',  0x4C, 'K',  'N',  0x4F,
        0x50, 0x51, 'Y',  'S',  'A',  0x55, 'B',  'W',  0x58, 'R',  0x5A, ']',  0x5C, '[',  0x5E, 0x5F,
        0x60, 't',  'v',  'g',  'h',  0x65, 0x66, 'c',  'd',  0x69, 0x6A, 'm',  0x6C, 'k',  'n',  0x6F,
        0x70, 0x71, 'y',  's',  'a',  0x75, 'b',  'w',  0x78, 'r',  0x7A, 0x7B, 0x7C, 0x7D, 0x7E, 0x7F,
    };
    return iupac_complement[(int)(iupac & 0x7F)];
}

static inline char mask_nt(char iupac) {
    static const char iupac_mask[128] = {
        0, 0, 0,  0, 0,  0, 0, 0, 0,  0, 0, 0,  0, 0, 0,  0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0,  0, 0, 0, 0, 0, 0,
        0, 0, 0,  0, 0,  0, 0, 0, 0,  0, 0, 0,  0, 0, 0,  0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0,  0, 0, 0, 0, 0, 0,
        0, 1, 14, 2, 13, 0, 0, 4, 11, 0, 0, 12, 0, 3, 15, 0, 0, 0, 5, 6, 8, 0, 7, 9, 0, 10, 0, 0, 0, 0, 0, 0,
        0, 1, 14, 2, 13, 0, 0, 4, 11, 0, 0, 12, 0, 3, 15, 0, 0, 0, 5, 6, 8, 0, 7, 9, 0, 10, 0, 0, 0, 0, 0, 0,
    };
    return iupac_mask[(int)(iupac & 0x7F)];
}

#define MAX_LENGTH_LEFT_ALLELE 256
static inline void flank_reverse_complement(char *flank) {
    // swap alleles, but only if first allele is one base pair long
    char *left = strchr(flank, '[');
    char *middle = strchr(flank, '/');
    char *right = strchr(flank, ']');
    if (!left || !middle || !right) error("Flank sequence is malformed: %s\n", flank);

    char buf[MAX_LENGTH_LEFT_ALLELE];
    if (middle - left - 1 > MAX_LENGTH_LEFT_ALLELE) error("Cannot swap alleles in flank sequence %s\n", flank);
    memmove((void *)buf, left + 1, middle - left - 1);
    memmove((void *)left + 1, middle + 1, right - middle - 1);
    *(left + (right - middle)) = '/';
    memmove(left + (right - middle) + 1, (void *)buf, middle - left - 1);

    size_t i, len = strlen(flank);
    for (i = 0; i < len / 2; i++) {
        char tmp = flank[i];
        flank[i] = rev_nt(flank[len - i - 1]);
        flank[len - i - 1] = rev_nt(tmp);
    }
    if (len % 2 == 1) flank[len / 2] = rev_nt(flank[len / 2]);
}

// this is the weird way Illumina left shifts indels
// http://github.com/Illumina/GTCtoVCF/blob/develop/BPMRecord.py
static inline int flank_left_shift(char *flank) {
    char *left = strchr(flank, '[');
    char *middle = strchr(flank, '/');
    char *right = strchr(flank, ']');
    if (!left || !middle || !right) error("Flank sequence is malformed: %s\n", flank);

    int n = 0;
    int len = (int)(right - middle) - 1;
    while ((left - flank >= len) && (strncmp(left - len, middle + 1, len) == 0)) {
        memmove(left - len, left, right - left + 1);
        left -= len;
        middle -= len;
        right -= len;
        memmove(right + 1, middle + 1, len);
        n += len;
    }

    const char *ptr;
    char nt = *(middle + 1);
    for (ptr = middle + 2; ptr < right; ptr++)
        if (*ptr != nt) nt = -1;
    while (nt > 0 && *(left - 1) == nt) {
        memmove(left - 1, left, right - left + 1);
        *right = nt;
        left--;
        middle--;
        right--;
        n++;
    }
    return n;
}

// returns 1 if the first sequence is the best alignment, and 2 if the second sequence is
// if neither sequence is better or neither provides an alignment, it returns 0
// if it fails to read from the hts file, it returns -1
static inline int get_position(htsFile *hts, sam_hdr_t *sam_hdr, bam1_t *b, const char *name, const char *flank,
                               int left_shift, const char **chromosome, int *position, int *strand) {
    const char *left = strchr(flank, '[');
    const char *middle = strchr(flank, '/');
    const char *right = strchr(flank, ']');
    int cnv = !left && !middle && !right;
    if (!cnv && (!left || !middle || !right)) error("Flank sequence is malformed: %s\n", flank);
    const char *chromosome_pair[2];
    int position_pair[2], strand_pair[2];
    int64_t aln_score_pair[2];
    int idx = -1, ret;
    while (idx < 1 - cnv && (ret = sam_read1(hts, sam_hdr, b)) >= 0) {
        const char *qname = bam_get_qname(b);
        if (b->core.flag & BAM_FSECONDARY || b->core.flag & BAM_FSUPPLEMENTARY) continue;
        int qname_l = strlen(qname);
        if (strncmp(qname, name, qname_l - 2) != 0)
            error("Query ID %.*s found in SAM file but %s expected\n", qname_l - 2, qname, name);
        idx = qname[qname_l - 1] == '1' ? 0 : (qname[qname_l - 1] == '2' ? 1 : -1);
        if (idx < 0) error("Query ID %s found in SAM file does not end with :1 or :2\n", qname);

        chromosome_pair[idx] = sam_hdr_tid2name(sam_hdr, b->core.tid);
        position_pair[idx] = 0;
        strand_pair[idx] = -1;
        if (!(b->core.flag & BAM_FUNMAP)) {
            strand_pair[idx] = bam_is_rev(b);
            int n_cigar = b->core.n_cigar;
            const uint32_t *cigar = bam_get_cigar(b);
            position_pair[idx] = b->core.pos;

            int qlen =
                cnv ? (strlen(flank) + 1) / 2 : (bam_is_rev(b) ? strlen(flank) - (right - flank) : left - flank + 1);
            if (strchr(flank, '-')) {
                if (left_shift) {
                    int len = (int)(right - middle) - 1;
                    char nt = toupper(*(middle + 1));
                    const char *ptr;
                    for (ptr = middle + 2; ptr < right; ptr++)
                        if (*ptr != nt) nt = -1;
                    if (bam_is_rev(b)) {
                        ptr = right + 1;
                        while (strncasecmp(middle + 1, ptr, len) == 0) {
                            qlen -= len;
                            ptr += len;
                        }
                        while (nt > 0 && toupper(*ptr) == nt) {
                            qlen--;
                            ptr++;
                        }
                    } else {
                        ptr = left - len;
                        while (ptr >= flank && (strncasecmp(ptr, middle + 1, len) == 0)) {
                            qlen -= len;
                            ptr -= len;
                        }
                        ptr += len - 1;
                        while (nt > 0 && toupper(*ptr) == nt) {
                            qlen--;
                            ptr--;
                        }
                    }
                }
                if (idx == 0) qlen--;
            }

            int k;
            for (k = 0; k < n_cigar && qlen > 1; k++) {
                int type = bam_cigar_type(bam_cigar_op(cigar[k]));
                int len = bam_cigar_oplen(cigar[k]);
                if ((type & 1) && (type & 2)) { // consume reference sequence ( case M )
                    position_pair[idx] += min(len, qlen);
                    qlen -= len;
                } else if (type & 1) { // consume query sequence ( case I )
                    qlen -= len;
                    if (qlen <= 0) // we skipped the base pair that needed
                                   // to be localized
                    {
                        position_pair[idx] = 0;
                    }
                } else if (type & 2) {
                    position_pair[idx] += len; // consume reference sequence ( case D )
                }
            }
            if (qlen == 1) position_pair[idx]++;
        }
        uint8_t *as = bam_aux_get(b, "AS");
        aln_score_pair[idx] = bam_aux2i(as);
    }
    if (ret < -1) return -1;

    if (!cnv
        && ((aln_score_pair[0] == aln_score_pair[1] && position_pair[0] != position_pair[1])
            || (position_pair[0] == 0 && position_pair[1] == 0))) {
        idx = -1;
        *chromosome = NULL;
        *position = 0;
        *strand = -1;
    } else {
        idx = cnv ? 0 : (aln_score_pair[1] > aln_score_pair[0]);
        *chromosome = chromosome_pair[idx];
        *position = position_pair[idx];
        *strand = strand_pair[idx];
    }
    return idx + 1;
}

static inline void strupper(char *str) {
    char *s = str;
    while (*s) {
        *s = toupper((unsigned char)*s);
        s++;
    }
}

static inline float get_gc_ratio(const char *beg, const char *end) {
    int at_cnt = 0, cg_cnt = 0;
    const char *ptr;
    for (ptr = beg; ptr < end; ptr++) {
        int c = toupper(*ptr);
        if (c == 'A' || c == 'T') at_cnt++;
        if (c == 'C' || c == 'G') cg_cnt++;
    }
    return (float)(cg_cnt) / (float)(at_cnt + cg_cnt);
}

static inline int len_common_suffix(const char *s1, const char *s2, size_t n) {
    int ret = 0;
    while (ret < n && *s1 == *s2) {
        s1--;
        s2--;
        ret++;
    }
    return ret;
}

static inline int len_common_prefix(const char *s1, const char *s2, size_t n) {
    int ret = 0;
    while (ret < n && *s1 == *s2) {
        s1++;
        s2++;
        ret++;
    }
    return ret;
}

// http://github.com/Illumina/GTCtoVCF/blob/develop/BPMRecord.py
// For an insertion relative to the reference, the position of the base immediately 5' to the
// insertion (on the plus strand) is given. For a deletion relative to the reference, the
// position of the most 5' deleted base (on the plus strand) is given
static inline int get_indel_alleles(kstring_t *allele_a, kstring_t *allele_b, const char *flank, const char *ref,
                                    int win, int len, int shift) {
    const char *left = strchr(flank, '[');
    const char *middle = strchr(flank, '/');
    const char *right = strchr(flank, ']');
    if (!left || !middle || !right) error("Flank sequence is malformed: %s\n", flank);

    int del_left = len_common_suffix(left - 1, &ref[win], left - flank);
    int del_right = len_common_prefix(right + 1, &ref[win] + 1, strlen(right + 1));
    int ins_match = strncmp(middle + 1, &ref[win], right - middle - 1) == 0; // same as indel_sequence_match
    int ins_left = len_common_suffix(left - 1, &ref[win] - 1, left - flank);
    int ins_right = len_common_prefix(right + 1, &ref[win] + (right - middle) - 1, strlen(right + 1));
    int ref_is_del = (del_left >= ins_left) && (del_right >= ins_right);
    if ((ref_is_del && del_left * del_right == 0) || (!ref_is_del && (!ins_match || ins_left * ins_right == 0))) {
        // computes it again but with shifted coordinates to better match Illumina's _calculate_is_deletion()
        del_left = len_common_suffix(left - 1, &ref[win - shift], left - flank);
        del_right = len_common_prefix(right + 1, &ref[win - shift] + 1, strlen(right + 1));
        ref_is_del = (del_left >= ins_left) && (del_right >= ins_right);
        if ((ref_is_del && del_left * del_right == 0) || (!ref_is_del && (!ins_match || ins_left * ins_right == 0)))
            return -1;
    }
    int allele_b_is_del = allele_b->s[0] == 'D';
    allele_a->l = allele_b->l = 0;
    kputc(ref[win - 1 + ref_is_del], allele_a);
    kputc(ref[win - 1 + ref_is_del], allele_b);
    kputsn(ref_is_del ? middle + 1 : &ref[win], right - middle - 1, allele_b_is_del ? allele_a : allele_b);
    return ref_is_del;
}

static inline int get_allele_b_idx(char ref_base, char *allele_a, char *allele_b) {
    if (*allele_a == '.' && *allele_b == '.') {
        return -1;
    } else if (*allele_a == 'D' || *allele_a == 'I' || *allele_b == 'D' || *allele_b == 'I') {
        return 1;
    } else if (*allele_a == ref_base) {
        return 1;
    } else if (*allele_b == ref_base) {
        return 0;
    } else if (*allele_a == '.') {
        *allele_a = ref_base;
        return 1;
    } else if (*allele_b == '.') {
        *allele_b = ref_base;
        return 0;
    } else {
        return 2;
    }
}

static inline int get_allele_a_idx(int allele_b_idx) {
    switch (allele_b_idx) {
    case 0:
        return 1;
    case 1:
        return 0;
    case 2:
        return 1;
    default:
        return -1;
    }
}

static inline int alleles_ab_to_vcf(const char **alleles, const char *ref_base, const char *allele_a,
                                    const char *allele_b, int allele_b_idx) {
    switch (allele_b_idx) {
    case -1:
        alleles[0] = ref_base;
        return 1;
    case 0:
        alleles[0] = allele_b;
        if (*allele_a == '.') return 1;
        alleles[1] = allele_a;
        return 2;
    case 1:
        alleles[0] = allele_a;
        if (*allele_b == '.') return 1;
        alleles[1] = allele_b;
        return 2;
    case 2:
        alleles[0] = ref_base;
        alleles[1] = allele_a;
        alleles[2] = allele_b;
        return 3;
    default:
        return -1;
    }
}

// Petr Danecek's similar implementation in bcftools/plugins/fixref.c
// http://www.illumina.com/documents/products/technotes/technote_topbot.pdf
static inline int get_strand_from_top_alleles(char *allele_a, char *allele_b, const char *ref, int win, int len) {
    int i;
    char ref_base = ref[win];
    int ia = (int)mask_nt(*allele_a);
    int ib = (int)mask_nt(*allele_b);
    int ir = (int)mask_nt(ref_base);

    // as alleles must be designated on the TOP strand, the only acceptable pairs are (A,C),
    // (A,G), (A, T), (C, G)
    switch (ia | ib) {
    case 1 | 2: // A and C
    case 1 | 4: // A and G
        if (ir == ia || ir == ib)
            return 0;
        else if (ref_base == rev_nt(*allele_a) || ref_base == rev_nt(*allele_b))
            return 1;
        else
            return -1; // Reference allele is not A/C/G/T
        break;
    case 1 | 8: // A and T
    case 2 | 4: // C and G
        for (i = 1; i <= win; i++) {
            int ra = (int)mask_nt(ref[win - i]);
            int rb = (int)mask_nt(ref[win + i]);
            if (ra == 15 || rb == 15 || ra == rb) continue; // N
            switch (ra | rb) {
            case 1 | 2:              // A and C
            case 1 | 4:              // A and G
            case 2 | 8:              // C and T
            case 4 | 8:              // G and T
                return ra & (2 | 4); // A or T
            case 1 | 8:              // A and T
            case 2 | 4:              // C and G
                continue;
            default:
                return -1; // Flanking reference alleles are not valid alleles for TOP/BOT strand determination
            }
        }
        return -1; // Unable to determine reference sequence strand
    default:
        return -1; // Alleles are not TOP alleles
    }
}

// compute BAF and LRR from Theta and R as explained in Peiffer, D. A. et al. High-resolution genomic profiling of
// chromosomal aberrations using Infinium whole-genome genotyping. Genome Res. 16, 1136–1148 (2006)
static inline void get_baf_lrr(float ilmn_theta, float ilmn_r, float aa_theta, float ab_theta, float bb_theta,
                               float aa_r, float ab_r, float bb_r, float r_mean, float *baf, float *lrr) {
    float r_ref;
    if (ilmn_theta == ab_theta) {
        r_ref = ab_r;
        *baf = 0.5f;
    } else if (ilmn_theta < ab_theta) {
        float slope = (aa_r - ab_r) / (aa_theta - ab_theta);
        float b = aa_r - (aa_theta * slope);
        r_ref = (slope * ilmn_theta) + b;
        *baf = 0.5f - (ab_theta - ilmn_theta) * 0.5f / (ab_theta - aa_theta);
    } else if (ilmn_theta > ab_theta) {
        float slope = (ab_r - bb_r) / (ab_theta - bb_theta);
        float b = ab_r - (ab_theta * slope);
        r_ref = (slope * ilmn_theta) + b;
        *baf = 1.0f - (bb_theta - ilmn_theta) * 0.5f / (bb_theta - ab_theta);
    } else {
        *lrr = -NAN;
        *baf = -NAN;
        return;
    }
    // for non-polymorphic (Illumina) markers we compute the LRR using the clusters mean
    *lrr = logf(ilmn_r / (isnan(r_mean) ? r_ref : r_mean)) * (float)M_LOG2E;
}