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1 #!/usr/bin/perl -w
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2 #use strict;
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3
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4 %arguments=
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5 (
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6 "vcf"=>"", #file mandatory, provided at runtime
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7 "disease"=>"", #name optional
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8 "similarD"=>"", #file optional
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9 "lgenes"=>"", #file optional
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10 "leQTL"=>"qfile", #file mandatory, but default value
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11 "keywords"=>"kfile", #file mandatory, but default value
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12 "effects"=>"efile", #file mandatory, but default value
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13 "disease_clinvar"=>8, #numeric mandadory, but default value
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14 "score_AF"=>4, #numeric mandatory, but default value
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15 "score_functional"=>8, #numeric mandatory, but default value
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16 "score_NS"=>6, #numeric mandatory, but default value
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17 "score_nIND"=>8, #numeric mandatory, but default value
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18 "AF"=>0.0001, #numeric mandatory, but default value
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19 "scoreeQTL"=>1, #numeric mandatory, but default value
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20 "nind"=>5, #numeric mandatory, but default value
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21 "scoreG"=>2, #numeric mandatory, but default value
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22 #####OUTPUT file#############################################
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23 "ofile"=>"final_res.csv", #file #OUTPUT #tabulare
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24 "ovcfile"=>"final_res.vcf" #file #OUTOUT #vcf
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25 );
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26
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27
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28 @arguments=@ARGV;
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29 for ($i=0;$i<=$#ARGV;$i+=2)
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30 {
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31 $act=$ARGV[$i];
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32 $act=~s/-//g;
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33 $val=$ARGV[$i+1];
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34 if (exists $arguments{$act})
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35 {
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36 $arguments{$act}=$val;
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37 }else{
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38 warn("$act: unknown argument\n");
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39 @valid=keys %arguments;
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40 warn("Valid arguments are @valid\n");
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41 die("All those moments will be lost in time, like tears in rain.\n Time to die!\n");
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42 }
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43 #print "$act $val\n";
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44 }
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45
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46 $ofile_name=$arguments{"ofile"};
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47 open(O,">$ofile_name");
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48 $ovcfile=$arguments{"ovcfile"};
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49 open(OV,">$ovcfile");
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50
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51
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52 $file=$arguments{"vcf"} ;
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53 die ("input file $file not found!\n") unless -e $file;
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54
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55 $lgenes=$arguments{"lgenes"};
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56 if (-e $lgenes)
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57 {
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58 open(IN,$lgenes);
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59 while(<IN>)
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60 {
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61 chomp;
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62 $Lgenes{$_}=1;
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63 }
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64 }
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65
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66
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67 $kfile=$arguments{"keywords"};
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68 die ("keyword file $kfile not found!\n") unless -e $kfile;
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69 open(IN,$kfile);
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70 while(<IN>)
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71 {
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72 chomp;
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73 $specialKeys{$_}=1;
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74 }
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75
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76
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77 $diseaseO=$arguments{"disease"} ? $arguments{"disease"} : "GinocchioValgoDellaLavandaiaZoppa";
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78
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79 $sfile=$arguments{"similarD"};
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80 if (-e $sfile)
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81 {
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82 open(IN,$sfile);
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83 while(<IN>)
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84 {
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85 chomp;
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86 push(@kw,$_)
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87 }
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88 }
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89
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90 $efile=$arguments{"effects"};
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91 die ("effect file $efile not found!\n") unless -e $efile;
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92 open(IN,$efile);
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93 while(<IN>)
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94 {
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95 chomp;
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96 $effects{$_}=1;
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97 }
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98
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99 $leQTLfile=$arguments{"leQTL"};
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100 if (-e $leQTLfile)
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101 {
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102 open(IN,$leQTLfile);
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103 while(<IN>)
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104 {
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105 chomp();
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106 $Qlist{$_}=1;
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107 }
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108 }
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109
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110 $disease_clinvar=$arguments{"disease_clinvar"};
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111 $score_AF=$arguments{"score_AF"};
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112 $score_functional=$arguments{"score_functional"};
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113 $score_NS=$arguments{"score_NS"};
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114 $score_nIND=$arguments{"score_nIND"};
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115 $score_QTL=$arguments{"scoreeQTL"};
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116 $scoreG=$arguments{"scoreG"};
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117
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118 print O "CHR\tstart\tgene\tref\talt\tAC\t";
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119 foreach $k (sort keys %specialKeys)
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120 {
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121 print O "$k\t";
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122 }
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123 print O "Score\n";
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124
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125 %damaged=();
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126 open(IN,$file);
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127
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128 #print "$gene_score $disease_HGMD $disease_clinvar $score_functional $score_AF $score_NS $score_eQTL $score_nIND\n";
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129 while(<IN>)
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130 {
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131 if ($_=~/^#/)
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132 {
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133 print OV;
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134 next;
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135 }
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136 chomp();
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137 @val=(split(/\t/));
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138 $chr=$val[0];
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139 $start=$val[1];
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140 $pstart=$val[2];
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141 $b1=$val[3];
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142 $b2=$val[4];
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143 $qscore=$val[5];
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144 $pb2=$val[6];
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145 $gene="na";
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146 $annot=$val[7];
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147 $gt=$val[8];
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148 @samples=@val[9..$#val];
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149 $samples=(join("\t",@samples));
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150 @terms=(split(/\;/,$annot));
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151 $DIS=0;
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152 if ($_=~/;AC=(\d+);/)
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153 {
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154 $nind=$1;
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155 }
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156 if ($_=~/Gene.refGene=(\w+);/)
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157 {
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158 $gene=$1;
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159 }
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160 next if $nind==0;
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161 $gene=(split(/\,/,$gene))[0];
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162 $i=0;
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163 %keep=();
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164 $score=0;
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165 $score+=$scoreG if $Lgenes{$gene};
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166 foreach $t (@terms)
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167 {
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168 ($keep,$value)=(split(/\=/,$t))[0,1];
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169 $keep{$keep}=$value;
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170 }
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171
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172 if ($keep{"CLNSIG"} ne "."){
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173 $scoreO=0;
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174 $scoreC=0;
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175 $add=0;
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176 $add=$disease_clinvar if ($keep{"CLNSIG"} eq "Pathogenic" || $keep{"CLNSIG"} eq "Pathogenic,_other,_risk_factor" || $keep{"CLNSIG"} eq "pathogenic" || $keep{"CLNSIG"} eq "Pathogenic/Likely_pathogenic" );
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177 $add=$disease_clinvar/2 if ($keep{"CLNSIG"} eq "Likely_pathogenic" || $keep{"CLNSIG"} eq "Conflicting_interpretations_of_pathogenicity" || $keep{"CLNSIG"} eq "likely-pathogenic");
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178 $add=-$disease_clinvar/2 if ($keep{"CLNSIG"} eq "Likely_benign" || $keep{"CLNSIG"} eq "Benign/Likely_benign");
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179 $add=-$disease_clinvar if ($keep{"CLNSIG"} eq "Benign");
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180 @diseases=split(/\|/,$keep{"CLNDN"});
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181 @databases=split(/\|/,$keep{"CLNDISDB"});
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182 for ($i=0;$i<=$#diseases;$i++)
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183 {
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184 $dis=lc $diseases[$i];
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185 $dat=$databases[$i];
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186 if ($dis=~ /$diseaseO/)
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187 {
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188 if ($dat=~/OMIM/)
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189 {
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190 $scoreO=$add;
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191 }else{
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192 $scoreC=$add;
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193 }
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194 last;
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195 }else{
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196 foreach $kv (@kw)
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197 {
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198 if ($dis=~/$kv/)
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199 {
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200 $DIS=1 if $add>0;
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201 if ($dat=~/OMIM/)
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202 {
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203 $scoreO=$add;
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204 }else{
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205 $scoreC=$add;
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206 }
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207 }
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208 }
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209 }
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210 }
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211 $score+=$scoreO+$scoreC;
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212 }
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213 $esp=$keep{"esp6500siv2_ea"} eq "." ? 0 : $keep{"esp6500siv2_ea"};
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214 $g1000=$keep{"1000g2015aug_all"} eq "." ? 0 : $keep{"1000g2015aug_all"} ;
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215 $exac=$keep{"ExAC_NFE"} eq "." ? 0 : $keep{"ExAC_NFE"};
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216 $gnomad=$keep{"gnomAD_exome_NFE"} eq "." ? 0 : $keep{"gnomAD_exome_NFE"};
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217 @AF=($esp,$g1000,$exac,$gnomad);
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218 @AF=sort{$a<=>$b} @AF;
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219 $AF=$AF[-1];
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220 # Variante molto rara 0.0001 2 punti
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221 # Variante rara 0.004 1 punto
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222 if ($AF<=$arguments{"AF"}) #0,00002
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223 {
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224 $score+=$score_AF;
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225 }elsif($AF>$arguments{"AF"} && $AF<=$arguments{"AF"}*4){
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226 $score+=$score_AF/2;
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227 }elsif($AF>0.01){ #commonSNP
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228 $score-=$score_AF/2;
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229 }
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230
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231 $effectO=(split(/\;/,$keep{"ExonicFunc.refGene"}))[0];
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232 if ($effects{$effectO})
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233 {
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234 $damaged{$gene}{"D"}++;
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235 $score+=$score_functional;
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236 }
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237 #print "Exon " . $keep{"ExonicFunc.refGene"}. " $score\n";
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238 if ($keep{"ExonicFunc.refGene"} eq "nonsynonymous_SNV"){
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239
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240 if ($keep{"MetaSVM_pred"} eq "D" && $keep{"CADD_raw"}>=5)
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241 {
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242 $score+=$score_NS;
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243 $damaged{$gene}{"D"}++;
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244 }elsif($keep{"MetaSVM_pred"} eq "D" && $keep{"CADD_raw"}<5){
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245 $score+=$score_NS/2;
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246 }elsif($keep{"MetaSVM_pred"} ne "D" && $keep{"CADD_raw"}>=5){
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247 $score+=$score_NS/2;
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248 }
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249 }
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250 #print "NS ". $keep{"ExonicFunc.refGene"} . " $score\n";
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251 $damaged{$gene}{"tot"}++;
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252 if ($keep{"Func.refGene"} eq "splicing"){
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253 $score+=$score_functional;
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254 }
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255 #print "SPL ". $keep{"Func.refGene"} . " $score\n";
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256 foreach $QTL (keys %Qlist)
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257 {
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258 next unless $keep{$QTL};
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259 $score+=$score_QTL if ($keep{$QTL} ne ".");
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260 }
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261 if ($nind>=$arguments{"nind"} && $AF<=0.01)
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262 {
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263 $score+=$score_nIND;
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264 }elsif($nind>=$arguments{"nind"}/2 && $nind<$arguments{"nind"} && $AF<=0.01){
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265 $score+=$score_nIND/2;
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266 }
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267 chomp();
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268 #$scores{$score}++;
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269 chop($_);
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270 $outL="";
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271 foreach $k (sort keys %specialKeys)
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272 {
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273 #die("$k\n") unless $keep{$k};
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274 $outL.="$keep{$k}\t";
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275 }
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276 print O "$chr\t$start\t$gene\t$b1\t$b2\t$nind\t$outL$score\n"; #if $score>=12 || $DIS==1;
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277 print OV "$chr\t$start\t$pstart\t$b1\t$b2\t$qscore\t$pb2\t$annot;COSO_score=$score\t$gt\t$samples\n";
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278 }
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279 #open(O,">$file.gc.list.csv");
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280 #foreach $gene (sort{$a<=>$b} keys %G)
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281 #{
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282 # $pos=$G{$gene}{"GR"} ? $G{$gene}{"GR"} : 0;
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283 # $neg=$G{$gene}{"LW"} ? $G{$gene}{"LW"} : 0;
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284 #print O "$gene $pos $neg\n";
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285 ##$Tscore+=$scores{$score} if $score>=$coff;
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286 #}
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287
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288 #open(D,">$file\_damaged.csv");
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289 #foreach $gene (sort{$a<=>$b} keys %damaged)
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290 #{
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291 # $D=$damaged{$gene}{"D"} ? $damaged{$gene}{"D"} : 0;
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292 # $T=$damaged{$gene}{"tot"};
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293 #print D "$gene $D $T\n";
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294 #}
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295
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296 #print "$Tscore\n";
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