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LOEUF.pm
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LOEUF.pm
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=head1 LICENSE
Copyright [1999-2015] Wellcome Trust Sanger Institute and the EMBL-European Bioinformatics Institute
Copyright [2016-2024] EMBL-European Bioinformatics Institute
Licensed under the Apache License, Version 2.0 (the "License");
you may not use this file except in compliance with the License.
You may obtain a copy of the License at
http://www.apache.org/licenses/LICENSE-2.0
Unless required by applicable law or agreed to in writing, software
distributed under the License is distributed on an "AS IS" BASIS,
WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
See the License for the specific language governing permissions and
limitations under the License.
=head1 CONTACT
Ensembl <http://www.ensembl.org/info/about/contact/index.html>
=cut
=head1 NAME
LOEUF
=head1 SYNOPSIS
mv LOEUF.pm ~/.vep/Plugins
./vep -i variations.vcf --plugin LOEUF,file=/path/to/loeuf/data.tsv.gz,match_by=gene
./vep -i variations.vcf --plugin LOEUF,file=/path/to/loeuf/data.tsv.gz,match_by=transcript
=head1 DESCRIPTION
This is a plugin for the Ensembl Variant Effect Predictor (VEP) that
adds the LOEUF scores to VEP output. LOEUF stands for the "loss-of-function
observed/expected upper bound fraction."
The score can be added matching by either transcript or gene.
When matched by gene:
If multiple transcripts are available for a gene, the most severe score is reported.
NB: The plugin currently does not add the score for downstream_gene_variant and upstream_gene_variant
Please cite the LOEUF publication alongside the VEP if you use this resource:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334197/
LOEUF scores can be downloaded from
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334197/bin/41586_2020_2308_MOESM4_ESM.zip
For GRCh37:
These files can be tabix-processed by:
Unzip 41586_2020_2308_MOESM4_ESM.zip
cd supplement
zcat supplementary_dataset_11_full_constraint_metrics.tsv.gz | (head -n 1 && tail -n +2 | sort -t$'\t' -k 76,76 -k 77,77n ) > loeuf_temp.tsv
sed '1s/.*/#&/' loeuf_temp.tsv > loeuf_dataset.tsv
bgzip loeuf_dataset.tsv
tabix -f -s 76 -b 77 -e 78 loeuf_dataset.tsv.gz
For GRCh38:
The LOEUF scores are available for assembly GRCh37, to be able to run the plugin for GRCh38
please remap the regions from file supplementary_dataset_11_full_constraint_metrics.tsv
After the remapping the file can be tabix-processed by:
cat supplementary_dataset_11_full_constraint_metrics_grch38.tsv | (head -n 1 && tail -n +2 | sort -t$'\t' -k 76,76 -k 77,77n ) > loeuf_grch38_temp.tsv
sed '1s/.*/#&/' loeuf_grch38_temp.tsv > loeuf_dataset_grch38.tsv
bgzip loeuf_dataset_grch38.tsv
tabix -f -s 76 -b 77 -e 78 loeuf_dataset_grch38.tsv.gz
The tabix utility must be installed in your path to use this plugin.
=cut
package LOEUF;
use strict;
use warnings;
use Bio::EnsEMBL::Variation::Utils::BaseVepTabixPlugin;
use base qw(Bio::EnsEMBL::Variation::Utils::BaseVepTabixPlugin);
use Scalar::Util qw(looks_like_number);
sub new {
my $class = shift;
my $self = $class->SUPER::new(@_);
$self->expand_left(0);
$self->expand_right(0);
my $param_hash = $self->params_to_hash();
# Test tabix
die "ERROR: tabix does not seem to be in your path\n" unless `which tabix 2>&1` =~ /tabix$/;
# Get file
die "ERROR: LOEUF file not provided or not found!\n" unless defined($param_hash->{file}) && -e $param_hash->{file};
$self->add_file($param_hash->{file});
# Get headers from file
my $headers;
open HEAD,"tabix -H $param_hash->{file} 2>&1 | ";
while(<HEAD>) {
chomp;
$_ =~ s/^\#//;
$headers = [split];
}
close HEAD;
# Compare indexes of expected and observed columns
die "ERROR: Could not read headers from $param_hash->{file}\n" unless defined($headers) && scalar @{$headers};
my @obs_columns = @{$headers}[1,30,64] ;
my @exp_columns = ("transcript", "oe_lof_upper", "gene_id");
my @missing_columns;
foreach my $index (0 .. $#exp_columns){
if ($obs_columns[$index] ne $exp_columns[$index]){
push @missing_columns,$exp_columns[$index];
}
}
my $missing_columns_str = join(", ", @missing_columns) if scalar @missing_columns;
die "ERROR: Missing columns: $missing_columns_str\n" if defined($missing_columns_str);
# Check match_by argument and store on self
if(defined($param_hash->{match_by})) {
my $match_by = $param_hash->{match_by};
$self->{match_by} = $match_by;
}
else{
die "ERROR: Argument 'match_by' is undefined\n" ;
}
return $self;
}
sub feature_types {
return ['Transcript'];
}
sub get_header_info {
return { LOEUF => 'Loss-of-function observed/expected upper bound fraction'};
}
sub run {
my ($self, $tva) = @_;
return {} if grep {$_->SO_term eq 'downstream_gene_variant' || $_->SO_term eq 'upstream_gene_variant'} @{$tva->get_all_OverlapConsequences};
my $vf = $tva->variation_feature;
my $transcript = $tva->transcript;
my $end = $vf->{end};
my $start = $vf->{start};
($start, $end) = ($end, $start) if $start > $end;
if ($self->{match_by} eq 'transcript'){
my ($res) = grep {
$_->{transcript_id} eq $transcript->stable_id;
} @{$self->get_data($vf->{chr}, $start, $end)};
return $res ? $res->{result} : {};
}
elsif ($self->{match_by} eq 'gene'){
my @data = grep {
$_->{gene_id} eq $transcript->{_gene_stable_id}
} @{$self->get_data($vf->{chr}, $start, $end)};
# Get min loeuf value for the gene
my $min_loeuf_score;
my $first_entry_flag = 0;
foreach (@data){
if (looks_like_number($_->{result}->{LOEUF})){
if (!$first_entry_flag){
$min_loeuf_score = $_->{result}->{LOEUF};
$first_entry_flag = 1 ;
next;
}
if ($_->{result}->{LOEUF} < $min_loeuf_score){
$min_loeuf_score = $_->{result}->{LOEUF};
}
}
}
return $min_loeuf_score ? {LOEUF => $min_loeuf_score} : {};
}
else{
return {};
}
}
sub parse_data {
my ($self, $line) = @_;
my @values = split /\t/, $line;
my ($transcript_id, $oe_lof_upper, $gene_id) = @values[1,30,64];
return {
gene_id => $gene_id,
transcript_id => $transcript_id,
result => {
LOEUF => $oe_lof_upper,
}
};
}
sub get_start {
return $_[1]->{start};
}
sub get_end {
return $_[1]->{end};
}
1;