str_finder.c

/*  str_finder.c -- Short Tandem Repeat finder.
    Originally from Crumble (https://github.com/jkbonfield/crumble)

    Copyright (C) 2015-2016, 2021-2022 Genome Research Ltd.

    Author: James Bonfield <jkb@sanger.ac.uk>

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 <stdio.h>
#include <stdlib.h>
#include <string.h>
#include <stdint.h>
#include <ctype.h>

#include "str_finder.h"
#include "utlist.h"

#define MAX(a,b) ((a)>(b)?(a):(b))
#define MIN(a,b) ((a)<(b)?(a):(b))

typedef unsigned char uc;

static void add_rep(rep_ele **list, char *cons, int clen, int pos, int rlen,
		    int lower_only, unsigned int w) {
    rep_ele *el, *tmp, *prev;
    char *cp1, *cp2, *cp_end;
    int i;

    // Already handled this in previous overlap?
    if (*list) {
	tmp = DL_TAIL(*list);
	if (tmp->start <= pos-rlen*2+1 && tmp->end >= pos)
	    return;
    }

    // Find current and last occurence of repeated word.

    cp2 = &cons[pos+1];
    // If unpadded, this is quicker: cp1 = &cons[pos+1-rlen];

    for (cp1 = &cons[pos], i = 1; i < rlen; cp1--) // compensate for pads
	if (*cp1 == '*')
	    continue;
	else
	    i++;
    while (*cp1 == '*')
	cp1--;


    // Scan ahead to see how much further it goes.
    cp_end = &cons[clen];
    while (cp2 < cp_end) {
	if (*cp1 != *cp2)
	    break;

	w<<=2;
	w|=*cp2;
	cp1++;
	cp2++;
    }

    if (!(el = malloc(sizeof(*el))))
	return;

    el->end   = pos + cp2-&cons[pos+1];
    el->rep_len = rlen;
    pos++;
    while (rlen--) {
	while (cons[--pos] == '*');
	while (cons[--pos] == '*');
    }
    //pos++;
    while (pos > 1 && cons[pos-1] == '*') pos--;
    el->start = pos;

    // Check it meets the lower-case only criteria
    if (lower_only) {
	int lc = 0;
	for (i = el->start; i <= el->end; i++) {
	    if (islower(cons[i])) {
		lc = 1;
		break;
	    }
	}

	if (!lc) {
	    free(el);
	    return;
	}
    }

    // Remove any older items on the list that are entirely contained within el
    if (*list) {
	tmp = DL_TAIL(*list);
	do {
	    prev = tmp->prev;
	    if (tmp->end < el->start)
		break;

	    if (tmp->start >= el->start) {
		DL_DELETE(*list, tmp);
		free(tmp);
	    }

	    if (tmp == DL_HEAD(*list))
		break;
	    tmp = prev;
	} while (*list);
    }

    DL_APPEND(*list, el);

    return;
}

/*
 * Finds repeated homopolymers up to 8-mers.
 * Note this assumes cons is 0-3, so N of 4 may rarely give false hits.
 *
 * Returns a list of rep_ele structs holding the start,end tuples of repeats;
 *         NULL on failure.
 */
rep_ele *find_STR64(char *cons, int len, int lower_only) {
    int i, j;
    uint64_t w = 0;
    rep_ele *reps = NULL;

    for (i = j = 0; i < len && j < 26; i++) {
	if (cons[i] == '*') continue;

	w <<= 2;
	w |= cons[i];
	//printf("%3d %c w=%08x\n", i, cons[i], w);
	if (j>= 1 && (w&0x0003) == ((w>> 2)&0x0003))
	    add_rep(&reps, cons, len, i, 1, lower_only, w);
	if (j>= 3 && (w&0x000f) == ((w>> 4)&0x000f))
	    add_rep(&reps, cons, len, i, 2, lower_only, w);
	if (j>= 5 && (w&0x003f) == ((w>> 6)&0x003f))
	    add_rep(&reps, cons, len, i, 3, lower_only, w);
	if (j>= 7 && (w&0x00ff) == ((w>> 8)&0x00ff))
	    add_rep(&reps, cons, len, i, 4, lower_only, w);
	if (j>= 9 && (w&0x03ff) == ((w>>10)&0x03ff))
	    add_rep(&reps, cons, len, i, 5, lower_only, w);
	if (j>=11 && (w&0x0fff) == ((w>>12)&0x0fff))
	    add_rep(&reps, cons, len, i, 6, lower_only, w);
	if (j>=13 && (w&0x3fff) == ((w>>14)&0x3fff))
	    add_rep(&reps, cons, len, i, 7, lower_only, w);
	if (j>=15 && (w&0xffff) == ((w>>16)&0xffff))
	    add_rep(&reps, cons, len, i, 8, lower_only, w);
	if (j>=17 && (w&0x003ffff) == ((w>>18)&0x003ffff))
	    add_rep(&reps, cons, len, i, 9, lower_only, w);
	if (j>=19 && (w&0x00fffff) == ((w>>20)&0x00fffff))
	    add_rep(&reps, cons, len, i,10, lower_only, w);
	if (j>=21 && (w&0x03fffff) == ((w>>22)&0x03fffff))
	    add_rep(&reps, cons, len, i,11, lower_only, w);
	if (j>=23 && (w&0x0ffffff) == ((w>>24)&0x0ffffff))
	    add_rep(&reps, cons, len, i,12, lower_only, w);
	if (j>=24 && (w&0x3ffffff) == ((w>>26)&0x3ffffff))
	    add_rep(&reps, cons, len, i,13, lower_only, w);

	j++;
    }

    for (; i < len; i++) {	
	if (cons[i] == '*') continue;

	w <<= 2;
	w |= cons[i];
	//printf("%3d %c w=%08x\n", i, cons[i], w);
	if      ((w&0xfffffff) == ((w>>28)&0xfffffff))
	    add_rep(&reps, cons, len, i, 14, lower_only, w);
	else if ((w&0x3ffffff) == ((w>>26)&0x3ffffff))
	    add_rep(&reps, cons, len, i, 13, lower_only, w);
	else if ((w&0x0ffffff) == ((w>>24)&0x0ffffff))
	    add_rep(&reps, cons, len, i, 12, lower_only, w);
	else if ((w&0x03fffff) == ((w>>22)&0x03fffff))
	    add_rep(&reps, cons, len, i, 11, lower_only, w);
	else if ((w&0x00fffff) == ((w>>20)&0x00fffff))
	    add_rep(&reps, cons, len, i, 10, lower_only, w);
	else if ((w&0x003ffff) == ((w>>18)&0x003ffff))
	    add_rep(&reps, cons, len, i, 9, lower_only, w);
	else if ((w&0xffff) == ((w>>16)&0xffff))
	    add_rep(&reps, cons, len, i, 8, lower_only, w);
	else if ((w&0x3fff) == ((w>>14)&0x3fff))
	    add_rep(&reps, cons, len, i, 7, lower_only, w);
	else if ((w&0x0fff) == ((w>>12)&0x0fff))
	    add_rep(&reps, cons, len, i, 6, lower_only, w);
	else if ((w&0x03ff) == ((w>>10)&0x03ff))
	    add_rep(&reps, cons, len, i, 5, lower_only, w);
	else if ((w&0x00ff) == ((w>> 8)&0x00ff))
	    add_rep(&reps, cons, len, i, 4, lower_only, w);
	else if ((w&0x003f) == ((w>> 6)&0x003f))
	    add_rep(&reps, cons, len, i, 3, lower_only, w);
	else if ((w&0x000f) == ((w>> 4)&0x000f))
	    add_rep(&reps, cons, len, i, 2, lower_only, w);
	else if ((w&0x0003) == ((w>> 2)&0x0003))
	    add_rep(&reps, cons, len, i, 1, lower_only, w);
    }

    return reps;
}

rep_ele *find_STR(char *cons, int len, int lower_only) {
    int i, j;
    uint32_t w = 0;
    rep_ele *reps = NULL;

    for (i = j = 0; i < len && j < 15; i++) {
	if (cons[i] == '*') continue;

	w <<= 2;
	w |= cons[i];
	//printf("%3d %c w=%08x\n", i, cons[i], w);
	if (j>= 1 && (w&0x0003) == ((w>> 2)&0x0003))
	    add_rep(&reps, cons, len, i, 1, lower_only, w);
	if (j>= 3 && (w&0x000f) == ((w>> 4)&0x000f))
	    add_rep(&reps, cons, len, i, 2, lower_only, w);
	if (j>= 5 && (w&0x003f) == ((w>> 6)&0x003f))
	    add_rep(&reps, cons, len, i, 3, lower_only, w);
	if (j>= 7 && (w&0x00ff) == ((w>> 8)&0x00ff))
	    add_rep(&reps, cons, len, i, 4, lower_only, w);
	if (j>= 9 && (w&0x03ff) == ((w>>10)&0x03ff))
	    add_rep(&reps, cons, len, i, 5, lower_only, w);
	if (j>=11 && (w&0x0fff) == ((w>>12)&0x0fff))
	    add_rep(&reps, cons, len, i, 6, lower_only, w);
	if (j>=13 && (w&0x3fff) == ((w>>14)&0x3fff))
	    add_rep(&reps, cons, len, i, 7, lower_only, w);

	j++;
    }

    for (; i < len; i++) {	
	if (cons[i] == '*') continue;

	w <<= 2;
	w |= cons[i];
	//printf("%3d %c w=%08x\n", i, cons[i], w);
	if ((w&0xffff) == ((w>>16)&0xffff))
	    add_rep(&reps, cons, len, i, 8, lower_only, w);
	else if ((w&0x3fff) == ((w>>14)&0x3fff))
	    add_rep(&reps, cons, len, i, 7, lower_only, w);
	else if ((w&0x0fff) == ((w>>12)&0x0fff))
	    add_rep(&reps, cons, len, i, 6, lower_only, w);
	else if ((w&0x03ff) == ((w>>10)&0x03ff))
	    add_rep(&reps, cons, len, i, 5, lower_only, w);
	else if ((w&0x00ff) == ((w>> 8)&0x00ff))
	    add_rep(&reps, cons, len, i, 4, lower_only, w);
	else if ((w&0x003f) == ((w>> 6)&0x003f))
	    add_rep(&reps, cons, len, i, 3, lower_only, w);
	else if ((w&0x000f) == ((w>> 4)&0x000f))
	    add_rep(&reps, cons, len, i, 2, lower_only, w);
	else if ((w&0x0003) == ((w>> 2)&0x0003))
	    add_rep(&reps, cons, len, i, 1, lower_only, w);
    }

    return reps;
}

/* -----------------------------------------------------------------------------
 * Computes repeat regions in the consensus and then provides a bit mask
 * indicating the extend of the STRs.
 *
 * The purpose of this is to identify where a read needs to span the entire
 * region in order to validate how many copies of a repeat word are present.
 * This only really has a major impact when indels are involved.
 *
 * For example, given this multiple alignment:
 *
 * S1 GATCGGACGAGAG
 * S2 GATCGGACGAGAGAGAGAGAGT
 * S3 GATCGGACGAGAGAGAGAG**TCGGAC
 * S4     GGACGAGAGAGAGAGAGTCGGAC
 * S5        CGAGAGAGAGAG**TCGGAC
 * S6              AGAGAGAGTCGGAC
 *
 * We have subseq of GAGAGAGAGAG** vs GAGAGAGAGAGAG. The first and last
 * (S1 and S6) sequences do not span and so we do not know which allele they
 * match. Specifically as the pad is at the right hand end, the alignment of
 * S6 gives incorrect weight to the consensus as it is stating AG when it
 * may actually be ** at that point.
 *
 * By identifying the repeats we can soft clip as follows:
 *
 * S1 GATCGGACgagag
 * S2 GATCGGACGAGAGAGAGAGAGT
 * S3 GATCGGACGAGAGAGAGAG**TCGGAC
 * S4     GGACGAGAGAGAGAGAGTCGGAC
 * S5        CGAGAGAGAGAG**TCGGAC
 * S6              agagagagTCGGAC
 *
 * Returns an array of STR vs no-STR values.
 *         0  => non repetitive.
 *         1+ => repeat with consecutive bit-number for repeat size.
 *
 * Eg:  AGGGGAGGAGAAGAC
 *       1111  1111
 *         2222222
 *              444444
 * =>   011331137754440
 */
char *cons_mark_STR(char *cons, int len, int lower_only) {
    rep_ele *reps, *elt, *tmp;
    char *str;

    str = calloc(1, len);
    reps = find_STR(cons, len, lower_only);

    DL_FOREACH_SAFE(reps, elt, tmp) {
	int i, v = 0;
	
	//printf("%2d .. %2d %.*s\n", elt->start, elt->end,
	//       elt->end - elt->start+1, &cons[elt->start]);

	// What is there?
	for (i = MAX(elt->start-1,0); i <= MIN(elt->end+1,len-1); i++)
	    v |= str[i];

	for (i = 0; i < 8; i++) {
	    if (!(v&(1<<i)))
		break;
	}
	v = (i == 8) ? 1 : (1<<i);

	// Add new if available, or just overload 1 if not
	for (i = elt->start; i <= elt->end; i++)
	    str[i] |= v;

	DL_DELETE(reps, elt);
	free(elt);
    }

    return str;
}