#!/usr/local/bin/perl

# 
# Perl script treefam_genelosses.pl
# Written by Avril Coghlan (alc@sanger.ac.uk).
# 28-Aug-06.  
#
# For the TreeFam project.
#
# This perl script connects to the MYSQL database of
# TreeFam families and prints out a list of gene losses from
# fully sequenced genomes. This script uses Jean-Karim's TreeFam
# API. Finds losses in TreeFam-A clean trees (not seed, as misses fully sequenced genomes,
# and not full trees, as are sometimes wrong). xxx use TreeFam-B too? 
# 
# The command-line format is:
# % perl <treefam_genelosses.pl> 
#
#------------------------------------------------------------------#

# CHECK IF THERE ARE THE CORRECT NUMBER OF COMMAND-LINE ARGUMENTS:

$num_args                  = $#ARGV + 1;
if ($num_args != 0)
{
   print "Usage of treefam_genelosses.pl\n\n";
   print "perl -w treefam_genelosses.pl\n";
   print "For example, >perl -w treefam_genelosses.pl\n";
   exit;
}

# DECLARE MYSQL USERNAME AND HOST:

use strict;
use Treefam::DBConnection;

my $VERBOSE                = 0; # IF $VERBOSE==1, PRINT OUT EXTRA DETAILS.
my $dbc                    =  Treefam::DBConnection->new();

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

# GET ALL THE TREEFAM-A FAMILIES IN THE CURRENT RELEASE:
my $famh                   = $dbc->get_FamilyHandle();    # GET A FAMILY HANDLE.
my @families               = $famh->get_all_by_type('A'); # GET ALL TREEFAM-A FAMILIES.
my $no_families            = 0;
foreach my $family(@families)
{
   my $AC                  = $family->ID();         # GET THE FAMILY ID.  
   $no_families++; 
   print "\n$no_families: reading family $AC...\n"; 
   my $tree                = $family->tree('clean'); # GET THE TREEFAM-A CLEAN TREE. xxx look at treefam-b too?
   # GET THE NAMES OF ALL THE GENES IN THIS TREE:
   my @leaves              = $tree->get_leaf_nodes;
   foreach my $leaf(@leaves) 
   {
      my @tags             = $leaf->get_all_tags();
      my $is_gene_loss     = 0;
      my $loss             = "none";
      foreach my $tag(@tags) 
      {
         # THE TAGS ARE:
         # G: GENE ID, eg. SPBC12D12.06 OR ENSG00000112237 
         # O: TREEFAM ID. eg. SPBC12D12.06 OR ENST00000326298.2
         # S: SPECIES, eg. SCHP0 OR HUMAN
         # E: GENE LOSS
         # B: BOOTSTRAP VALUE
         for my $value ($leaf->get_tag_values($tag)) 
         {                
            if    ($tag eq 'E')
            {
               $loss          = $value;
               $is_gene_loss  = 1;
               my @temp       = split(/\$\-/,$loss);
               $loss          = $temp[1];
               if ($loss ne 'HUMAN' && $loss ne 'Homo') { goto NEXT_LEAF;} # xxx JUST LOOKING AT LOSES OF HUMAN GENES WHERE THERE IS A CHIMP GENE.
               # NOTE THAT IF CHIMP AND HUMAN WERE LOST, THEN $loss WOULD BE 'HUMAN,PANTR'.
               print "___ $AC: ID ",$leaf->id(),"\n";  # THIS IS SYMBOL."_".SPECIES, eg. CCNC_HUMAN
               print "___ GENE LOSS $loss (AC $AC)\n";
            }
         }           
      }

      # IF THIS NODE $leaf->id() HAS A GENE LOSS ASSOCIATED WITH IT, CHECK WHETHER
      # THE CLADE THAT IT IS IN IS GOOD EVIDENCE FOR THE LOSS:
      my $parent              = 'none';
      if ($is_gene_loss == 1)
      {
         #---------------------------------------------------------#
         FIND_PARENT:
         # FIND THE PARENT NODE OF NODE $leaf:
         if ($parent eq 'none')
         {
            if (defined($leaf->ancestor))  { $parent = $leaf->ancestor;  }
            else                           { goto ALL_PARENTS_FOUND;     }
         }
         else # GET THE PARENT NODE OF NODE $parent:
         {
            if (defined($parent->ancestor)){ $parent = $parent->ancestor;}
            else                           { goto ALL_PARENTS_FOUND;     }
         }
         if ($VERBOSE == 1) { print "___ PARENT OF CURRENT NODE is", $parent->internal_id(),"\n";} 
         # FIND THE DESCENDENTS OF NODE $parent, AND CHECK IF THE CLADE OF DESCENDENTS
         # IS GOOD EVIDENCE FOR THE GENE LOSS $loss:
         my %SPECIES          = ();         # HASH TABLE TO RECORD SPECIES IN THIS CLADE.
         for my $descendent ($parent->get_all_Descendents())
         {
            if (defined($descendent->id())) # IF THIS IS A LEAF.
            {
               my $id         = $descendent->id();
               if ($VERBOSE == 1) { print "___ WHICH HAS DESCENDENT $id\n";}
               my @temp       = split(/_/,$id);
               my $species    = $temp[$#temp];
               $SPECIES{$species} = 1;
            }
         }
         # CHECK WHETHER THE CLADE OF DESCENDENTS IS GOOD EVIDENCE FOR THE GENE LOSS $loss:
         my $evidence_for_loss= &check_evidence_for_loss($loss,\%SPECIES); 
         if ($VERBOSE == 1) { print "___ EVIDENCE FOR LOSS IN $loss: $evidence_for_loss\n";}
         if ($evidence_for_loss == 1) { goto ALL_PARENTS_FOUND;}
         # FIND THE PARENT OF NODE $parent:
         goto FIND_PARENT;
         #---------------------------------------------------------#

         ALL_PARENTS_FOUND:
         if ($VERBOSE == 1) { print "___ ALL PARENTS FOUND\n\n";}
         # IF THE CLADE OF DESCENDENTS IS GOOD EVIDENCE FOR GENE LOSS $loss, CHECK IF THERE
         # ARE ANY OTHER LOSSES IN THAT CLADE THAT MAY MAKE $loss LESS BELIEVABLE:
         print "___ EVIDENCE FOR LOSS IN $loss: $evidence_for_loss\n";
         if ($evidence_for_loss == 1)
         {
            for my $descendent ($parent->get_all_Descendents())
            {
               if (defined($descendent->id())) # IF THIS IS A LEAF.
               {
                  my $id         = $descendent->id(); 
                  my ($loss2)    = $descendent->get_tag_values('E');
                  if (defined($loss2))
                  {
                     my @temp2   = split(/\$-/,$loss2);
                     my $species2= $temp2[1];
                     print "descendent $id -> loss $loss2\n";
                     if (($loss eq 'HUMAN' || $loss eq 'Homo') && ($species2 =~ /PANTR/ || $species2 =~ /Pan/)) # xxx add other cases
                     {
                        $evidence_for_loss = 0;
                     }
                  }
               }
            }
         }
         print "___ FINAL EVIDENCE FOR LOSS IN $loss: now $evidence_for_loss\n";
         #---------------------------------------------------------#
      }
      NEXT_LEAF: # xxx
   }
}
print "\n\n";

print STDERR "FINISHED.\n";


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

# SUBROUTINE TO CHECK WHETHER A CLADE OF GENES IS GOOD EVIDENCE FOR A GENE LOSS:

sub check_evidence_for_loss
{
   my $loss                   = $_[0]; # THE SPECIES IN WHICH THE PUTATIVE GENE LOSS OCCURRED.
   my $SPECIES                = $_[1]; # POINTER TO HASH TABLE OF SPECIES IN THE CLADE THAT SPECIES $species IS MISSING FROM.
   my $evidence               = 1;     # SAYS WHETHER THE EVIDENCE FOR GENE LOSS IS STRONG.
   my @all                    = ('HUMAN','PANTR','MACMU','BOVIN','CANFA','MOUSE','RAT','MONDO',
                                 'CHICK','XENTR','TETNG','FUGRU','BRARE','CIOIN','DROME','DROPS',
                                 'CAEEL','CAEBR','CAERE','APIME','ANOGA','YEAST','SCHPO','ARATH','SCHMA');
                                       # ALL THE FULLY SEQUENCED SPECIES.
   my @expect;                         # THE SPECIES THAT WE EXPECT TO SEE IN THE CLADE.
   my $i;                              #
   my %EXPECT                 = ();    #
   my $expecti;                        #
   my @expecti;                        #
   my $j;                              #
   my $found_expecti          = 0;     #
   my $loss2;                          #

   # CHECK WHETHER THERE IS STRONG EVIDENCE FOR A GENE LOSS: # xxx ADD MORE CASES
   # FOR EXAMPLE, WE CAN BE SURE OF A HUMAN GENE LOSS IF THE CLADE CONTAINS AT LEAST
   # ONE CHIMP OR ONE MACAQUE, AT LEAST ONE RAT OR ONE MOUSE, AT LEAST ONE COW, AND
   # AT LEAST ONE DOG GENE:
   if ($loss eq 'HUMAN') { @expect = ('PANTR','MACMU','MOUSE/RAT','BOVIN/CANFA'); }

   # CHECK THAT WE SEE ALL THE SPECIES THAT WE EXPECT IN THE CLADE, AND NO OTHER SPECIES:
   for ($i = 0; $i <= $#expect; $i++)
   {
      $expecti                = $expect[$i];
      @expecti                = split(/\//,$expecti);
      $found_expecti          = 0;
      # CHECK WHETHER WE SEE AT LEAST ONE OF PANTR/MACMU FOR EXAMPLE:
      for ($j = 0; $j <= $#expecti; $j++)
      {
         $EXPECT{$expecti[$j]} = 1;
         if ($SPECIES->{$expecti[$j]}) { $found_expecti = 1;}  
      }
      if ($found_expecti == 0) { $evidence = 0;} # WE DON'T FIND A SPECIES THAT WE EXPECT TO SEE IN THE CLADE.
   } 
   # CHECK IF WE SEE ANY SPECIES IN THE CLADE THAT WE DON'T EXPECT TO SEE:
   for ($i = 0; $i <= $#all; $i++)
   {
      if (!($EXPECT{$all[$i]}) && $all[$i] ne $loss) 
      {
         if ($SPECIES->{$all[$i]}) { $evidence = 0;} # WE FIND A SPECIES THAT WE DON'T EXPECT TO SEE IN THE CLADE.
      }
   }   
  
   return($evidence);
}

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