#!/usr/bin/env perl
#
# Author: petr.danecek@sanger
#

use strict;
use warnings;
use Carp;
use Vcf;
use FaSlice;

my $opts = parse_params();
flanking_sequence($opts);

exit;

#--------------------------------

sub error
{
    my (@msg) = @_;
    if ( scalar @msg ) { confess @msg; }
    die
        "About: Annotate VCF with flanking sequence (INFO/FS tag)\n",
        "Usage: fill-fs [OPTIONS] file.vcf\n",
        "Options:\n",
        "   -b, --bed-mask <file>           Regions to mask (tabix indexed), multiple files can be given\n",
        "   -c, --cluster <int>             Do self-masking of clustered variants within this range.\n",
        "   -l, --length <int>              Flanking sequence length [100]\n",
        "   -m, --mask-char <char|lc>       The character to use or \"lc\" for lowercase. This option must preceed\n",
        "                                       -b, -v or -c in order to take effect. With multiple files works\n",
        "                                        as a switch on the command line, see the example below [N]\n",
        "   -r, --refseq <file>             The reference sequence.\n",
        "   -v, --vcf-mask <file>           Mask known variants in the flanking sequence, multiple files can be given (tabix indexed)\n",
        "   -h, -?, --help                  This help message.\n",
        "Example:\n",
        "   # Mask variants from the VCF file with N's and use lowercase for the bed file regions\n",
        "   fill-fs file.vcf -v mask.vcf -m lc -b mask.bed\n",
        "\n";
}


sub parse_params
{
    my $opts = { length=>100, mask=>[], cluster=>0 };
    my $mask = $$opts{mask_char}{default} = 'N';
    my $mask_changed = 0;
    while (defined(my $arg=shift(@ARGV)))
    {
        if ( $arg eq '-c' || $arg eq '--cluster' ) { $$opts{cluster}=shift(@ARGV); $$opts{mask_char}{default}=$mask; $mask_changed=0; next; }
        if ( $arg eq '-r' || $arg eq '--refseq' ) { $$opts{refseq}=shift(@ARGV); next; }
        if ( $arg eq '-l' || $arg eq '--length' ) { $$opts{length}=shift(@ARGV); next; }
        if ( $arg eq '-m' || $arg eq '--mask' ) { $mask=shift(@ARGV); check_mask_char($mask); $mask_changed=1; next; }
        if ( $arg eq '-b' || $arg eq '--bed-mask' ) { $arg=shift(@ARGV); push @{$$opts{bed_mask}},$arg; $$opts{mask_char}{$arg}=$mask; $mask_changed=0; next; }
        if ( $arg eq '-v' || $arg eq '--vcf-mask' ) { $arg=shift(@ARGV); push @{$$opts{vcf_mask}},$arg; $$opts{mask_char}{$arg}=$mask; $mask_changed=0; next; }
        if ( $arg eq '-?' || $arg eq '-h' || $arg eq '--help' ) { error(); }
        if ( -e $arg && !exists($$opts{file}) ) { $$opts{file}=$arg; next; }
        error("Unknown parameter \"$arg\". Run -h for help.\n");
    }
    if ( !($$opts{length}=~/^\d+$/) ) { error("Expected integer after -l, got $$opts{length}\n"); }
    if ( !exists($$opts{refseq}) ) { error("Missing the -r option.\n"); }
    if ( $mask_changed ) { error("The -m parameter must preceed -b, -v, or the file in order to take effect.\n"); }
    return $opts;
}

sub check_mask_char
{
    my ($mask) = @_;
    if ( $mask eq 'lc' ) { return; }
    if ( length($mask) eq 1 ) { return; }
    error("Currently only \"lc\" or one-character mask is supported, got \"$mask\".\n");
}

sub flanking_sequence
{
    my ($opts) = @_;

    $$opts{faref} = FaSlice->new(file=>$$opts{refseq},size=>1_024,oob=>'N');

    my $vcf = $$opts{vcf} = exists($$opts{file}) ? Vcf->new(file=>$$opts{file}) : Vcf->new(fh=>\*STDIN);
    $vcf->parse_header;
    print $vcf->format_header;

    my (@lines,@mask);
    while (my $line=$vcf->next_data_array)
    {
        my $chr = $$line[0];
        my $pos = $$line[1];
        my $ref = $$line[3];
        my $alt = $$line[4];

        my $off;
        $alt =~ s/,.+$//;   # first allele is used at multiallelic sites
        ($off,$ref,$alt) = $vcf->normalize_alleles_pos($ref,$alt);
        $pos += $off;

        push @lines, { chr=>$chr, pos=>$pos, ref=>$ref, alt=>$alt, line=>$line };
        push @mask, { chr=>$chr, pos=>$pos, ref=>$ref };
        flush_buffers($opts,\@lines,\@mask);
    }

    flush_buffers($opts,\@lines,\@mask,1);
}

sub flush_buffers
{
    my ($opts,$lines,$mask,$force) = @_;

    if ( !@$lines ) { return; }

    if ( !$$opts{cluster} )
    {
        shift(@$mask);
        output_line($opts,shift(@$lines),$mask);
        return;
    }

    while ( @$lines && ($force or $$mask[0]{chr} ne $$lines[-1]{chr} or $$mask[0]{pos}+2*$$opts{cluster}<=$$lines[-1]{pos}) )
    {
        output_line($opts,$$lines[0],$mask);
        shift(@$lines);
        while ( @$mask && @$lines && ($$mask[0]{chr} ne $$lines[0]{chr} or $$mask[0]{pos}+$$opts{cluster}<=$$lines[0]{pos}) )
        {
            shift(@$mask);
        }
    }
}

sub output_line
{
    my ($opts,$hline,$mask) = @_;

    my $chr  = $$hline{chr};
    my $pos  = $$hline{pos};
    my $ref  = $$hline{ref};
    my $alt  = $$hline{alt};
    my $line = $$hline{line};

    my $seq_pos = $$opts{length};
    my $reflen  = length($ref);
    my $from = $pos-$$opts{length};
    my $to   = $pos+($reflen-1)+$$opts{length};
    my $seq  = $$opts{faref}->get_slice($chr,$from,$to);
    $seq = mask_sequence($opts,$seq,$chr,$from,$to,$mask);

    my $reflen_ori = $reflen;
    my ($len,$indel,$off) = $$opts{vcf}->is_indel($ref,$alt);
    if ( $len<0 )
    {
        $seq_pos += $off;
        $ref = $indel;
        $reflen = abs($len);
        $alt = '-';
    }
    elsif ( $len>0 )
    {
        $seq_pos += $off;
        $ref = '-';
        $alt = $indel;
        $reflen = $off-1;
    }

    substr($seq,$seq_pos,$reflen,"[$ref/$alt]");
    if ( $reflen_ori - $reflen > 0 ) 
    { 
        # for redundant pad bases which cannot be removed without changing the position, e.g. ACGT AC
        $seq = substr($seq,$reflen_ori-$reflen); 
    }
    if ( $$line[7] eq '.' or !defined $$line[7] ) 
    { 
        $$line[7] = '';
    }
    else 
    {
        $$line[7] .= ';';
    }
    $$line[7] .= "FS=$seq";

    print join("\t",@$line),"\n";
}

sub mask_sequence
{
    my ($opts,$seq,$chr,$from,$to,$mask) = @_;
    for my $m (@$mask)
    {
        my $reflen = length($$m{ref});
        if ( $$m{chr} ne $chr or $$m{pos}+$reflen<$from or $$m{pos}>$to ) { next; }
        apply_mask($opts,\$seq,$$m{pos}-$from,$$m{ref},$$opts{mask_char}{default});
    }
    for my $file (@{$$opts{vcf_mask}})
    {
        my @tabix = `tabix $file $chr:$from-$to`;
        for my $ret (@tabix)
        {
            my $items = $$opts{vcf}->split_mandatory($ret);
            # In different situations one may want to treat indels differently. For
            #   now, mask the whole REF string as for primer design it is safer to 
            #   mask the whole thing; for example, a 2bp deletion can be reported by 
            #   samtools as REF=GACACACA ALT=GACACA, the script will mask it all.
            apply_mask($opts,\$seq,$$items[1]-$from,$$items[3],$$opts{mask_char}{$file});
        }
    }
    for my $file (@{$$opts{bed_mask}})
    {
        my @tabix = `tabix $file $chr:$from-$to`;
        for my $ret (@tabix)
        {
            my @items = split(/\t/,$ret);
            apply_mask($opts,\$seq,$items[1]-$from+1,$items[2]-$from,$$opts{mask_char}{$file});
        }
    }
    return $seq;
}

sub apply_mask
{
    my ($opts,$seq,$from,$ref,$mask_char) = @_;
    if ( $from<0 ) { $from=0; }
    my $ref_len = $ref=~/^\d+$/ ? $ref-$from+1 : length($ref);
    my $seq_len = length($$seq);
    if ( $from+$ref_len>=$seq_len ) { $ref_len = $seq_len - $from; }
    if ( $ref_len<0 ) { return; }
    if ( $ref_len==1 )
    {
        my $rpl = substr($$seq,$from,1);
        $rpl = $mask_char eq 'lc' ? lc(substr($$seq,$from,1)) : $mask_char;
        substr($$seq,$from,1,$rpl);
        return;
    }
    my $rpl = substr($$seq,$from,$ref_len);
    $rpl = $mask_char eq 'lc' ? lc(substr($$seq,$from,$ref_len)) : ($mask_char x $ref_len);
    substr($$seq,$from,$ref_len,$rpl);
}