=head1 LICENSE Copyright [1999-2015] Wellcome Trust Sanger Institute and the EMBL-European Bioinformatics Institute Copyright [2016-2022] 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 =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 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() { 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" ; } # Check assembly my $assembly = $self->{config}->{assembly}; if ($assembly ne "GRCh37") { die "ERROR: Assembly is not GRCh37, LOEUF only works with GRCh37. \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;