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get-evidence/pharmgkb_stage1.pl
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#!/usr/bin/perl
=head1 SYNOPSIS
Cross-reference PharmGKB database against dbSNP, flip alleles to +
strand where appropriate, and check consistency with dbSNP observed
alleles.
=head1 USAGE
To process all the SNPs regardless of drug or not, and like:
./pharmgkb_stage1.pl Variant_annotation_filtered_allele.txt SNP130.txt.gz \
> Variant_annotation_filtered_allele_flipped.txt \
2> Variant_annotation_filtered_allele_flipped_errs.txt
To produce output for entries containing drug annotations only:
./pharmgkb_stage1.pl Variant_annotation_filtered_allele.txt SNP130.txt.gz Y \
> Variant_annotation_filtered_allele_flipped_drugs.txt \
2> Variant_annotation_filtered_allele_flipped_drugs_errs.txt
=cut
my $drugflag = 0;
my ($pharmfile, $rsfile, $drugflag) = @ARGV;
print STDERR "Command line: $0 $pharmfile $rsfile $drugflag\n";
my $pharmhash = readpharm($pharmfile);
print "\nNucleotide Records\n";
my $rshash = readrsfile($rsfile, $pharmhash);
sub readrsfile {
my ($rsfile, $pharmhash) = @_;
my %rshash = ();
my $fspec = "< $rsfile";
$fspec = "zcat $rsfile |" if ($rsfile =~ /\.gz$/);
open(RS, $fspec) || die("Can't open $rsfile\n");
my $totalrs = 0;
my $badrs = 0;
my $notskipped = 0;
my $goodpharm = 0;
my $badpharm = 0;
while (<RS>) {
$_ =~ s/[\r\n]//;
my $rsrec = $_;
$totalrs++;
my @f = split /\t/, $_;
$f[2]++;
my $key = "$f[1]\t$f[2]\t$f[4]";
if (($f[3] - $f[2]) != 0) {
next;
}
my $pat = '';
$f[9] .= '/';
while ($f[9] =~ s/([ACGT]+)\///) {
next if (length($1) > 1);
$pat .= "$1";
}
next if ($pat eq '');
$notskipped++;
my $pluspat = $pat;
if ($f[6] eq '-') {
$pluspat =~ tr/ACGT/TGCA/;
}
elsif ($f[6] ne '+') {
print STDERR "Error parsing: $_\n";
}
$pluspat = "\[$pluspat\]";
my $minuspat = $pluspat;
$minuspat =~ tr/ACGT/TGCA/;
if ($f[7] !~ /$pluspat/) {
# print STDERR "Disagreement in ref and SNP : $_\n";
$badrs++;
next;
}
if (exists $$pharmhash{$key}) {
my @cols = split /\t/, $$pharmhash{$key};
my $allele = shift @cols;
if ($$pharmhash{$key} =~ /^$pluspat\s+/) {
print "$allele\t$pluspat\t", join("\t", @cols), "\n";
$goodpharm++;
}
elsif ($$pharmhash{$key} =~ /^$minuspat\s+/) {
$allele =~ tr/ACGT/TGCA/;
if ($allele !~ /^$pluspat/) {
die("Weird problem with $$pharmhash{$key} and $pluspat\n");
}
print "$allele (flipped)\t$pluspat\t", join("\t", @cols), "\n";
$flippedpharm++;
}
else {
print STDERR "EXPECTED: $pluspat\t$$pharmhash{$key}\n\t$rsrec\n";
$badpharm++;
}
delete $$pharmhash{$key};
}
}
close(RS);
# print STDERR "Read in " . scalar(keys %rshash) . " rs numbers\n";
print STDERR "GOOD = $goodpharm, FLIPPED = $flippedpharm, BAD = $badpharm, TOTALRS = $totalrs, NOTSKIPPEDRS = $notskipped, BADRS = $badrs\n";
print STDERR "\nLEFTOVERS:\n";
foreach my $p (sort keys %$pharmhash) {
print STDERR "$$pharmhash{$p}\n";
}
# \%rshash;
}
sub readpharm {
my ($pharmfile) = @_;
my %pharmhash = ();
my $ambiguous = 0;
my $unparsed = '';
my $fspec = "< $pharmfile";
$fspec = "zcat $pharmfile |" if ($pharmfile =~ /\.gz$/);
open(PH, $fspec) || die("Can't open $pharmfile\n");
my $header = <PH>;
while (<PH>) {
$_ =~ s/[\r\n]//;
my $l = $_;
my @f = split /\t/, $l;
# print STDERR "DRUG: $f[5]\n";
next if ($drugflag ne '' && $f[5] =~ /^\s*$/);
#for(my $i = 0; $i < @f ; $i++) {
# print "$i\t$f[$i]\n";
# }
my ($chr, $pos, $rsid, $allele) = ();
if ($f[0] =~ /^(chr.*?)\:(\d+)\s/) {
$chr = $1;
$pos = $2;
}
else {
print STDERR "Can't parse chr and loc:\n$_\n";
next;
}
if ($f[0] =~ /\((rs\d+)\)/) {
$rsid = $1;
}
else {
print STDERR "Can't parse rsid:\n$_\n";
next;
}
if ($l =~ /Risk\s+Allele:\s+(rs\d+)\-([ACGT])/i) {
my $rs = $1;
$allele = $2;
if ($rs ne $rsid) {
print STDERR "RSID $rsid <> $rs - skipping\n";
next;
}
}
elsif($l =~ /Risk Allele:\s+([ACGT])/i) {
$allele = $1;
}
elsif ($l =~ /risk allele=([ACGT])/i) {
$allele = $1;
}
elsif ($l =~ /\s(rs\d+)\s*=\s*([ACGT])\s+/) {
my $rs = $1;
$allele = $2;
if ($rs ne $rsid) {
print STDERR "RSID $rsid <> $rs - skipping\n";
next;
}
}
elsif ($l =~ /[\s\(]([ACGT])[\s\-]+allele/i) {
$allele = $1;
}
elsif ($l =~ /[\s\(]allele[\s\-]+([ACGT])[\s\)]/i) {
$allele = $1;
}
elsif ($l =~ /allele\s*\(([ACGT])\)/) {
$allele = $1;
}
elsif ($l =~ /Risk.{0,20}:.{0,20}(rs\d+)\-([ACGT])\)/i) {
my $rs = $1;
$allele = $2;
if ($rs ne $rsid) {
print STDERR "RSID $rsid <> $rs - skipping\n";
next;
}
}
# print "$chr\t$pos\t$rsid\t$allele\n";
$allele =~ s/\s+//g;
$rsid =~ s/\s+//g;
$chr =~ s/\s+//g;
$pos =~ s/\s+//g;
if ($rsid ne '' && $allele ne '') {
# print "$allele\t$_\n";
$pharmhash{"$chr\t$pos\t$rsid"} = "$allele\t$l";
}
elsif ($l =~ /rs\d+\-\?/) {
$ambiguous++;
}
elsif ($l =~ /(ala|arg|asn|asp|cys|glu|gln|gly|his|ile|leu|lys|met|phe|pro|ser|thr|try|tyr|val)(\d+)(ala|arg|asn|asp|cys|glu|gln|gly|his|ile|leu|lys|met|phe|pro|ser|thr|try|tyr|val)/i) {
my $aachange = "$1$2$3";
$pharmhashaa{"$chr\t$pos\t$rsid"} = "$aachange\t\t$l";
}
else {
$unparsed .= "$l\n";
$unparsable++;
}
}
close(PH);
print STDERR "Filtering for drug related records = $drugflag\n";
print STDERR "Read in " . scalar(keys %pharmhash) . " pharm SNPs; $ambiguous ambiguous SNPs\n";
print STDERR "Read in " . scalar(keys %pharmhashaa) . " pharm AA changes\n";
print STDERR "$unparsable Not parsed as follows:\n\n$unparsed\n";
print "Amino Acid Records\n";
foreach my $p (sort keys %pharmhashaa) {
print "$pharmhashaa{$p}\n";
}
\%pharmhash;
}
__END__
Position (RSID) Name(s) Evidence Annotation Genes Drugs Diseases
chr1:12345678 (rs1234) GENE:Val123Met Web Resource:http://www.pharmgkb.org/ This variant is responsible for ..... GENE
SNP database
#bin chrom chromStart chromEnd name score strand refNCBI refUCSC observed molType class valid avHet avHetSE func locType weight
1 chr1 16775073 16781350 rs72059099 0 + ( 6277bp insertion ) ( 6277bp insertion ) (LARGEDELETION)/- genomic named unknown 0 0 unknown range 1
1 chr1 16775613 16788198 rs71260122 0 - ( 12585bp insertion ) ( 12585bp insertion ) ACA/GCG genomic mnp unknown 0 0 unknown range 2
1 chr1 16776311 16782082 rs72496645 0 - ( 5771bp insertion ) ( 5771bp insertion ) -/TCAG genomic in-del unknown 0 0 frameshift rangeInsertion 1
2 chr1 100658226 100667832 rs71808286 0 + ( 9606bp insertion ) ( 9606bp insertion ) (LARGEDELETION)/- genomic named unknown 0 0 frameshift range 1
14 chr1 45080556 45089100 rs71711725 0 + ( 8544bp insertion ) ( 8544bp insertion ) (LARGEDELETION)/- genomic named unknown 0 0 untranslated-5 range 1
26 chr1 149940941 149948891 rs71775793 0 + ( 7950bp insertion ) ( 7950bp insertion ) (LARGEDELETION)/- genomic named unknown 0 0 unknown range 1
30 chr1 177209325 177209347 rs71794609 0 + TGTGTGTGTGTGTGTGTGTGTG TGTGTGTGTGTGTGTGTGTGTG -/TGTGTGTGTGTGTGTGTGTGTG genomic deletion unknown 0 0 unknown range 1
33 chr1 202372482 202380096 rs72451924 0 + ( 7614bp insertion ) ( 7614bp insertion ) (LARGEDELETION)/- genomic named unknown 0 0 frameshift range 1
35 chr1 220190850 220208380 rs72487224 0 - ( 17530bp insertion ) ( 17530bp insertion ) -/TGTTGTCCAA genomic in-del unknown 0 0 near-gene-3 rangeInsertion 1
...
585 chr1 18839 18840 rs60412817 0 - G G C/T genomic single unknown 0 0 unknown exact 3
585 chr1 18847 18848 rs4118001 0 + A A A/G genomic single unknown 0 0 unknown exact 3
585 chr1 18850 18851 rs3878858 0 + C C C/T genomic single unknown 0 0 unknown exact 3
585 chr1 18850 18851 rs62028220 0 - C C A/G genomic single unknown 0 0 unknown exact 3
585 chr1 18876 18877 rs4118011 0 + G G C/G genomic single unknown 0 0 unknown exact 3
585 chr1 18935 18936 rs708634 0 - G G C/T genomic single by-cluster 0 0 unknown exact 3
585 chr1 18935 18936 rs16990161 0 + G G A/G genomic single unknown 0 0 unknown exact 3
585 chr1 19000 19001 rs62028219 0 - G G C/G genomic single unknown 0 0 unknown exact 3
585 chr1 19026 19027 rs2748064 0 - C C C/G genomic single unknown 0 0 unknown exact 3
585 chr1 19027 19028 rs3871716 0 - C C A/G genomic single by-cluster 0 0 unknown exact 3