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1 # Package Align.pl
2 # (c) Johannes Soeding, 2006
3 # Perl functions for Smith-Waterman and Needleman-Wunsch sequence alignment
4
5 # HHsuite version 2.0
6 #
7 # Reference:
8 # Remmert M., Biegert A., Hauser A., and Soding J.
9 # HHblits: Lightning-fast iterative protein sequence searching by HMM-HMM alignment.
10 # Nat. Methods, epub Dec 25, doi: 10.1038/NMETH.1818 (2011).
11
12 # (C) Johannes Soeding and Michael Remmert, 2012
13
14 # This program is free software: you can redistribute it and/or modify
15 # it under the terms of the GNU General Public License as published by
16 # the Free Software Foundation, either version 3 of the License, or
17 # (at your option) any later version.
18
19 # This program is distributed in the hope that it will be useful,
20 # but WITHOUT ANY WARRANTY; without even the implied warranty of
21 # MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the
22 # GNU General Public License for more details.
23
24 # You should have received a copy of the GNU General Public License
25 # along with this program. If not, see <http://www.gnu.org/licenses/>.
26
27 # We are very grateful for bug reports! Please contact us at soeding@genzentrum.lmu.de
28
29 #############################################################################
30 # Subroutine AlignSW
31 # Smith-Waterman local alignment
32 # usage:
33 # 1. Use global variables of package Align.pm:
34 # $score = &AlignSW();
35 # printf(" XSEQ: $Align::xseq\n");
36 # printf(" MATCH: $Align::Sstr\n");
37 # printf(" YSEQ: $Align::yseq\n");
38 # etc.
39 #
40 # 2. Use references and/or global variables
41 # $score = &AlignSW(\$xseq,\$yseq);
42 # $score = &AlignNW(\$xseq,\$yseq,\@i,\@j,\$imin,\$imax,\$jmin,\$jmax,\$Sstr,\@S);
43 # printf(" XSEQ: $xseq\n");
44 # printf(" MATCH: $Sstr\n");
45 # printf(" YSEQ: $yseq\n");
46 #
47 # Input: $xseq, $yseq : sequences x and y as strings
48 # Param: $main::d : gap opening penalty
49 # $main::e : gap extension penalty
50 # Output: return value : bit score
51 # $xseq, $yseq : aligned residues of x and y (with - as gap)
52 # @i : $i[$col],$j[$col] are aligned residues in column $col
53 # @j : (first is 1 (NOT 0!), 0 means gap)
54 # $imin : first aligned residue of sequence x
55 # $imax : last aligned residue of sequence x
56 # $jmin : first aligned residue of sequence y
57 # $jmax : last aligned residue of sequence y
58 # $Sstr : string belonging to $xseq and $yseq showing quality of alignment
59 # $S[$col] : match score for aligning positions $i[$col] and $j[$col]
60 #############################################################################
61
62 #############################################################################
63 # Subroutine AlignNW
64 # Needleman-Wunsch global alignment
65 # usage: $score = &AlignNW();
66 # $score = &AlignNW(\$xseq,\$yseq);
67 # $score = &AlignNW(\$xseq,\$yseq,\@i,\@j);
68 # $score = &AlignNW(\$xseq,\$yseq,\@i,\@j,\$imin,\$imax,\$jmin,\$jmax,\$Sstr,\@S);
69 #
70 # Input: $xseq, $yseq : sequences x and y as strings
71 # Param: $main::d : gap opening penalty
72 # $main::e : gap extension penalty
73 # $main::g : end gap penalty
74 # Output: return value : bit score
75 # $xseq, $yseq : aligned residues of x and y (with - as gap)
76 # @i : $i[$col],$j[$col] are aligned residues in column $col
77 # @j : (first is 1 (NOT 0!), 0 means gap)
78 # $imin : first aligned residue of sequence x
79 # $imax : last aligned residue of sequence x
80 # $jmin : first aligned residue of sequence y
81 # $jmax : last aligned residue of sequence y
82 # $Sstr : string belonging to $xseq and $yseq showing quality of alingment
83 # $S[$col] : match score for aligning positions $i[$col] and $j[$col]
84 #############################################################################
85
86 package Align;
87
88 use strict;
89 use vars qw(@ISA @EXPORT @EXPORT_OK %EXPORT_TAGS $VERSION);
90 use Exporter;
91 our @ISA = qw(Exporter);
92 our @EXPORT = qw(&AlignSW &AlignNW $matrix);
93
94 our $xseq; # first sequence
95 our $yseq; # second sequence
96 our $ri; # reference to input array: $i[$col] -> $ri->[$col]
97 our $rj; # reference to input array: $j[$col] -> $rj->[$col]
98 our $imin; # first aligned residue of sequence x
99 our $imax; # last aligned residue of sequence x
100 our $jmax; # first aligned residue of sequence y
101 our $jmin; # last aligned residue of sequence y
102 our $Sstr; # $Sstr annotates the match quality
103 our $rS; # reference $rS->[$col] -> $S[$col] = match score for aligning positions $i[$col] and $j[$col]
104 our $matrix;
105
106 my $firstcall=1;
107 my @Sab; # Substitution matrix in bit
108 # A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
109 my @ch2i=( 0, 3, 4, 3, 6,13, 7, 8, 9,20,11,10,12, 2,20,14, 5, 1,15,16, 4,19,17,20,18, 6);
110 my @Gonnet = (
111 # A R N D C Q E G H I L K M F P S T W Y V X
112 # The Gonnet matrix is in units of 10*log10()
113 [ 2.4,-0.6,-0.3,-0.3, 0.5,-0.2, 0.0, 0.5,-0.8,-0.8,-1.2,-0.4,-0.7,-2.3, 0.3, 1.1, 0.6,-3.6,-2.2, 0.1,-1.0,-9.9], # A
114 [-0.6, 4.7, 0.3,-0.3,-2.2, 1.5, 0.4,-1.0, 0.6,-2.4,-2.2, 2.7,-1.7,-3.2,-0.9,-0.2,-0.2,-1.6,-1.8,-2.0,-1.0,-9.9], # R
115 [-0.3, 0.3, 3.8, 2.2,-1.8, 0.7, 0.9, 0.4, 1.2,-2.8,-3.0, 0.8,-2.2,-3.1,-0.9, 0.9, 0.5,-3.6,-1.4,-2.2,-1.0,-9.9], # N
116 [-0.3,-0.3, 2.2, 4.7,-3.2, 0.9, 2.7, 0.1, 0.4,-3.8,-4.0, 0.5,-3.0,-4.5,-0.7, 0.5, 0.0,-5.2,-2.8,-2.9,-1.0,-9.9], # D
117 [ 0.5,-2.2,-1.8,-3.2,11.5,-2.4,-3.0,-2.0,-1.3,-1.1,-1.5,-2.8,-0.9,-0.8,-3.1, 0.1,-0.5,-1.0,-0.5, 0.0,-1.0,-9.9], # C
118 [-0.2, 1.5, 0.7, 0.9,-2.4, 2.7, 1.7,-1.0, 1.2,-1.9,-1.6, 1.5,-1.0,-2.6,-0.2, 0.2, 0.0,-2.7,-1.7,-1.5,-1.0,-9.9], # Q
119 [ 0.0, 0.4, 0.9, 2.7,-3.0, 1.7, 3.6,-0.8, 0.4,-2.7,-2.8, 1.2,-2.0,-3.9,-0.5, 0.2,-0.1,-4.3,-2.7,-1.9,-1.0,-9.9], # E
120 [ 0.5,-1.0, 0.4, 0.1,-2.0,-1.0,-0.8, 6.6,-1.4,-4.5,-4.4,-1.1,-3.5,-5.2,-1.6, 0.4,-1.1,-4.0,-4.0,-3.3,-1.0,-9.9], # G
121 [-0.8, 0.6, 1.2, 0.4,-1.3, 1.2, 0.4,-1.4, 6.0,-2.2,-1.9, 0.6,-1.3,-0.1,-1.1,-0.2,-0.3,-0.8,-2.2,-2.0,-1.0,-9.9], # H
122 [-0.8,-2.4,-2.8,-3.8,-1.1,-1.9,-2.7,-4.5,-2.2, 4.0, 2.8,-2.1, 2.5, 1.0,-2.6,-1.8,-0.6,-1.8,-0.7, 3.1,-1.0,-9.9], # I
123 [-1.2,-2.2,-3.0,-4.0,-1.5,-1.6,-2.8,-4.4,-1.9, 2.8, 4.0,-2.1, 2.8, 2.0,-2.3,-2.1,-1.3,-0.7, 0.0, 1.8,-1.0,-9.9], # L
124 [-0.4, 2.7, 0.8, 0.5,-2.8, 1.5, 1.2,-1.1, 0.6,-2.1,-2.1, 3.2,-1.4,-3.3,-0.6, 0.1, 0.1,-3.5,-2.1,-1.7,-1.0,-9.9], # K
125 [-0.7,-1.7,-2.2,-3.0,-0.9,-1.0,-2.0,-3.5,-1.3, 2.5, 2.8,-1.4, 4.3, 1.6,-2.4,-1.4,-0.6,-1.0,-0.2, 1.6,-1.0,-9.9], # M
126 [-2.3,-3.2,-3.1,-4.5,-0.8,-2.6,-3.9,-5.2,-0.1, 1.0, 2.0,-3.3, 1.6, 7.0,-3.8,-2.8,-2.2, 3.6, 5.1, 0.1,-1.0,-9.9], # F
127 [ 0.3,-0.9,-0.9,-0.7,-3.1,-0.2,-0.5,-1.6,-1.1,-2.6,-2.3,-0.6,-2.4,-3.8, 7.6, 0.4, 0.1,-5.0,-3.1,-1.8,-1.0,-9.9], # P
128 [ 1.1,-0.2, 0.9, 0.5, 0.1, 0.2, 0.2, 0.4,-0.2,-1.8,-2.1, 0.1,-1.4,-2.8, 0.4, 2.2, 1.5,-3.3,-1.9,-1.0,-1.0,-9.9], # S
129 [ 0.6,-0.2, 0.5, 0.0,-0.5, 0.0,-0.1,-1.1,-0.3,-0.6,-1.3, 0.1,-0.6,-2.2, 0.1, 1.5, 2.5,-3.5,-1.9, 0.0,-1.0,-9.9], # T
130 [-3.6,-1.6,-3.6,-5.2,-1.0,-2.7,-4.3,-4.0,-0.8,-1.8,-0.7,-3.5,-1.0, 3.6,-5.0,-3.3,-3.5,14.2, 4.1,-2.6,-1.0,-9.9], # W
131 [-2.2,-1.8,-1.4,-2.8,-0.5,-1.7,-2.7,-4.0,-2.2,-0.7, 0.0,-2.1,-0.2, 5.1,-3.1,-1.9,-1.9, 4.1, 7.8,-1.1,-1.0,-9.9], # Y
132 [ 0.1,-2.0,-2.2,-2.9, 0.0,-1.5,-1.9,-3.3,-2.0, 3.1, 1.8,-1.7, 1.6, 0.1,-1.8,-1.0, 0.0,-2.6,-1.1, 3.4,-1.0,-9.9], # V
133 [-1.0,-1.0,-1.0,-1.0,-1.0,-1.0,-1.0,-1.0,-1.0,-1.0,-1.0,-1.0,-1.0,-1.0,-1.0,-1.0,-1.0,-1.0,-1.0,-1.0,+1.0,-9.9], # X
134 [-9.9,-9.9,-9.9,-9.9,-9.9,-9.9,-9.9,-9.9,-9.9,-9.9,-9.9,-9.9,-9.9,-9.9,-9.9,-9.9,-9.9,-9.9,-9.9,-9.9,-9.9,-9.9] # ~
135 );
136
137 # A R N D C Q E G H I L K M F P S T W Y V X
138 my @BLOSUM62 = (
139 [ 4,-1,-2,-2, 0,-1,-1, 0,-2,-1,-1,-1,-1,-2,-1, 1, 0,-3,-2, 0, 0,-9],
140 [-1, 5, 0,-2,-3, 1, 0,-2, 0,-3,-2, 2,-1,-3,-2,-1,-1,-3,-2,-3,-1,-9],
141 [-2, 0, 6, 1,-3, 0, 0, 0, 1,-3,-3, 0,-2,-3,-2, 1, 0,-4,-2,-3,-1,-9],
142 [-2,-2, 1, 6,-3, 0, 2,-1,-1,-3,-4,-1,-3,-3,-1, 0,-1,-4,-3,-3,-1,-9],
143 [ 0,-3,-3,-3, 9,-3,-4,-3,-3,-1,-1,-3,-1,-2,-3,-1,-1,-2,-2,-1,-2,-9],
144 [-1, 1, 0, 0,-3, 5, 2,-2, 0,-3,-2, 1, 0,-3,-1, 0,-1,-2,-1,-2,-1,-9],
145 [-1, 0, 0, 2,-4, 2, 5,-2, 0,-3,-3, 1,-2,-3,-1, 0,-1,-3,-2,-2,-1,-9],
146 [ 0,-2, 0,-1,-3,-2,-2, 6,-2,-4,-4,-2,-3,-3,-2, 0,-2,-2,-3,-3,-1,-9],
147 [-2, 0, 1,-1,-3, 0, 0,-2, 8,-3,-3,-1,-2,-1,-2,-1,-2,-2, 2,-3,-1,-9],
148 [-1,-3,-3,-3,-1,-3,-3,-4,-3, 4, 2,-3, 1, 0,-3,-2,-1,-3,-1, 3,-1,-9],
149 [-1,-2,-3,-4,-1,-2,-3,-4,-3, 2, 4,-2, 2, 0,-3,-2,-1,-2,-1, 1,-1,-9],
150 [-1, 2, 0,-1,-3, 1, 1,-2,-1,-3,-2, 5,-1,-3,-1, 0,-1,-3,-2,-2,-1,-9],
151 [-1,-1,-2,-3,-1, 0,-2,-3,-2, 1, 2,-1, 5, 0,-2,-1,-1,-1,-1, 1,-1,-9],
152 [-2,-3,-3,-3,-2,-3,-3,-3,-1, 0, 0,-3, 0, 6,-4,-2,-2, 1, 3,-1,-1,-9],
153 [-1,-2,-2,-1,-3,-1,-1,-2,-2,-3,-3,-1,-2,-4, 7,-1,-1,-4,-3,-2,-2,-9],
154 [ 1,-1, 1, 0,-1, 0, 0, 0,-1,-2,-2, 0,-1,-2,-1, 4, 1,-3,-2,-2, 0,-9],
155 [ 0,-1, 0,-1,-1,-1,-1,-2,-2,-1,-1,-1,-1,-2,-1, 1, 5,-2,-2, 0, 0,-9],
156 [-3,-3,-4,-4,-2,-2,-3,-2,-2,-3,-2,-3,-1, 1,-4,-3,-2,11, 2,-3,-2,-9],
157 [-2,-2,-2,-3,-2,-1,-2,-3, 2,-1,-1,-2,-1, 3,-3,-2,-2, 2, 7,-1,-1,-9],
158 [ 0,-3,-3,-3,-1,-2,-2,-3,-3, 3, 1,-2, 1,-1,-2,-2, 0,-3,-1, 4,-1,-9],
159 [ 0,-1,-1,-1,-2,-1,-1,-1,-1,-1,-1,-1,-1,-1,-2, 0, 0,-2,-1,-1,+1,-9],
160 [-9,-9,-9,-9,-9,-9,-9,-9,-9,-9,-9,-9,-9,-9,-9,-9,-9,-9,-9,-9,-9,-9]
161 );
162
163 # print("Substitution matrix:\n");
164 # for ($a=0; $a<=20; $a++) {
165 # for ($b=0; $b<=20; $b++) {
166 # printf("%6.1f ",$Sab[$a][$b]);
167 # }
168 # printf("\n");
169 # }
170
171
172 # Set substitution matrix in bits (do only at first call of one of the alignment routines)
173 sub SetSubstitutionMatrix {
174 if ($firstcall) {
175 # Transform to bits;
176 if (defined($matrix) && $matrix eq "Gonnet") {
177 for (my $a=0; $a<=20; ++$a) {
178 for (my $b=0; $b<=20; ++$b) {
179 $Sab[$a][$b] = $Gonnet[$a][$b]*0.3322; # 1*log(10)/log(2);
180 }
181 }
182 } elsif (defined($matrix) && $matrix eq "Blosum62") {
183 {printf("Using Blosum62 matrix...\n");}
184 for (my $a=0; $a<=20; $a++) {
185 for (my $b=0; $b<=20; $b++) {
186 $Sab[$a][$b] = $BLOSUM62[$a][$b];
187 }
188 }
189 } else {
190 for (my $a=0; $a<20; ++$a) {
191 for (my $b=0; $b<20; ++$b) {
192 $Sab[$a][$b] = -1;
193 }
194 $Sab[$a][$a] = 2;
195 }
196 for (my $b=0; $b<=20; ++$b) {
197 $Sab[20][$b] = $Sab[$b][20] = 0;
198 $Sab[21][$b] = $Sab[$b][21] = -10;
199 }
200 $Sab[20][20] = $Sab[20][20] = +1;# if in doubt, match X with X
201 }
202
203 $firstcall=0;
204 }
205 }
206
207 # maxbt(val1,...,valx,\$bt) finds maximum of values and puts index of maximum into $bt
208 sub maxbt {
209 my $rbt=pop @_; # last element of @_ is address of $bt
210 my $max = shift;
211 my $i=0;
212 $$rbt = 0;
213 foreach $_ (@_) {
214 $i++;
215 if ($_>$max) {$max=$_; $$rbt=$i;}
216 }
217 return $max;
218 }
219
220 # max3bt(val1,val2,val3,\$bt) finds maximum of values and puts index of maximum into $bt
221 sub max3bt {
222 if ($_[1] < $_[0]) {
223 if ($_[2] < $_[0]) {
224 ${$_[3]}=0;
225 return $_[0];
226 } else {
227 ${$_[3]}=2;
228 return $_[2];
229 }
230 } else {
231 if ($_[2] < $_[1]) {
232 ${$_[3]}=1;
233 return $_[1];
234 } else {
235 ${$_[3]}=2;
236 return $_[2];
237 }
238 }
239 }
240
241 # max2bt(val1,val2,\$bt) finds maximum of values and puts index of maximum into $bt
242 sub max2bt {
243 if ($_[1] < $_[0]) {
244 ${$_[2]}=0;
245 return $_[0];
246 } else {
247 ${$_[2]}=1;
248 return $_[1];
249 }
250 }
251
252
253 #############################################################################
254 # Subroutien AlignSW
255 # Smith-Waterman local alignment
256 #############################################################################
257 sub AlignSW {
258 if (@_>=1) {$xseq=$_[0];}
259 if (@_>=2) {$yseq=$_[1];}
260 if (@_>=3) {$ri=$_[2];}
261 if (@_>=4) {$rj=$_[3];}
262 if (@_>=5) {$imin=$_[4];}
263 if (@_>=6) {$imax=$_[5];}
264 if (@_>=7) {$jmin=$_[6];}
265 if (@_>=8) {$jmax=$_[7];}
266 if (@_>=9) {$Sstr=$_[8];}
267 if (@_>=10) {$rS=$_[9];}
268
269 if (length($$xseq)<1) {warn ("ERROR in Align.pm: sequence x is empty\n"); return 0;}
270 if (length($$yseq)<1) {warn ("ERROR in Align.pm: sequence x is empty\n"); return 0;}
271
272 my @xchr; # ASCII characters of $xseq
273 my @ychr; # ASCII characters of $yseq
274 my @xres; # internal integer representation of residues of x
275 my @yres; # internal integer representation of residues of y
276
277 $$xseq =~ s/\s//g;
278 $$yseq =~ s/\s//g;
279 @xchr = split(//,$$xseq);
280 @ychr = split(//,$$yseq);
281
282 my $Lx=@xchr; # length of sequence x
283 my $Ly=@ychr; # length of sequence y
284 my @M; # $M[a][b] = score of best alignment of x[1..a] and y[1..b] ending in match state
285 my @A; # $A[a][b] = score of best alignment of x[1..a] and y[1..b] ending in gap in x
286 my @B; # $B[a][b] = score of best alignment of x[1..a] and y[1..b] ending in gap in y
287 my @Mbt; # $Mbt[a][b] = 0:STOP 1:M 2:A 3:B
288 my @Abt; # $Abt[a][b] = 0:A 1:M
289 my @Bbt; # $Bbt[a][b] = 0:B 1:M
290 my $score; # bit score of alignment
291 my $bt; # backtracing variable set by &maxbt: which argument was largest? (first=0)
292 my $state; # STOP:0 M:1 A:2 B:3
293 my ($i, $j); # indices for sequence x and y, respectively
294
295 my $dx = $main::dx;
296 my $dy = $main::dy;
297 if (! defined $dx) {$dx = $main::d;}
298 if (! defined $dy) {$dy = $main::d;}
299
300 # Transform @xres and @yres to integer
301 for ($i=0; $i<@xchr; $i++) {
302 my $a=ord(uc($xchr[$i]));
303 if ($a<65 || $a>90) {
304 if ($a!=ord(".") && $a!=ord("-") && $a!=ord("~")) {
305 printf(STDERR "\nWARNING: invalid symbol '%s' in pos $i of first sequence to be aligned\n",$xchr[$i]);
306 }
307 $xres[$i]=21;
308 } else {
309 $xres[$i]=$ch2i[$a-65];
310 }
311 }
312 for ($j=0; $j<@ychr; $j++) {
313 my $a=ord(uc($ychr[$j]));
314 if ($a<65 || $a>90) {
315 if ($a!=ord(".") && $a!=ord("-") && $a!=ord("~")) {
316 printf(STDERR "\nWARNING: invalid symbol '%s' in pos $j of second sequence to be aligned\n",$ychr[$j]);
317 }
318 $yres[$j]=21;
319 } else {
320 $yres[$j]=$ch2i[$a-65];
321 }
322 }
323 unshift (@xres,21); unshift (@xchr," "); # insert dummy 0'th element
324 unshift (@yres,21); unshift (@ychr," "); # insert dummy 0'th element
325
326 &SetSubstitutionMatrix;
327
328 # Initialization
329 for ($i=0; $i<=$Lx; $i++) {
330 $M[$i][0]=-999; $A[$i][0]=-999; $B[$i][0]=-999;
331 }
332 for ($j=1; $j<=$Ly; $j++) {
333 $M[0][$j]=-999; $A[0][$j]=-999; $B[0][$j]=-999;
334 }
335
336 # Iteration
337 for ($i=1; $i<=$Lx; ++$i) {
338 my $Mi =$M[$i];
339 my $Mi1=$M[$i-1];
340 my $Ai =$A[$i];
341 my $Ai1=$A[$i-1];
342 my $Bi =$B[$i];
343 my $Bi1=$B[$i-1];
344 my $Sabx=$Sab[$xres[$i]];
345 my $j1=0;
346 for ($j=1; $j<=$Ly; ++$j, ++$j1) {
347 ${$Mi}[$j] = max3bt(${$Mi1}[$j1], ${$Ai1}[$j1], ${$Bi1}[$j1], \$Mbt[$i][$j]) + ${$Sabx}[$yres[$j]];
348 ${$Ai}[$j] = max2bt(${$Ai}[$j1]-$main::e, ${$Mi}[$j1]-$dx, \$Abt[$i][$j]);
349 ${$Bi}[$j] = max2bt(${$Bi1}[$j]-$main::e, ${$Mi1}[$j]-$dy, \$Bbt[$i][$j]);
350 }
351 }
352
353 # Finding maximum
354 $score = -1000;
355 for ($i=1; $i<=$Lx; $i++) {
356 my $Mi =$M[$i];
357 for ($j=1; $j<=$Ly; $j++) {
358 if (${$Mi}[$j]>$score) {$score=${$Mi}[$j]; $$imax=$i; $$jmax=$j;}
359 }
360 }
361
362 # Backtracing
363 @$ri=();
364 @$rj=();
365 @$rS=();
366 $state=1; # last state is M
367 $i=$$imax; $j=$$jmax;
368 $$xseq=""; $$yseq="";
369 while ($state) {
370 if ($state==1) {
371 # current state is M (match-match)
372 unshift(@$ri,$i);
373 unshift(@$rj,$j);
374 $state = $Mbt[$i][$j];
375 $$xseq=$xchr[$i].$$xseq;
376 $$yseq=$ychr[$j].$$yseq;
377 unshift(@$rS, $Sab[$xres[$i]][$yres[$j]]);
378 $$imin=$i; $$jmin=$j;
379 $i--; $j--;
380 } elsif ($state==2) {
381 # current state is A (gap in x)
382 unshift(@$ri,0);
383 unshift(@$rj,$j);
384 $$xseq="-".$$xseq;
385 $$yseq=$ychr[$j].$$yseq;
386 $bt = $Abt[$i][$j--];
387 if ($bt) {
388 # previous state was M
389 unshift(@$rS,-$dx);
390 $state = 1;
391 } else {
392 # previous state was A
393 unshift(@$rS,-$main::e);
394 }
395 } else {
396 # current state is B (gap in y)
397 unshift(@$ri,$i);
398 unshift(@$rj,0);
399 $$xseq=$xchr[$i].$$xseq;
400 $$yseq="-".$$yseq;
401 $bt = $Bbt[$i--][$j];
402 if ($bt) {
403 # previous state was M
404 unshift(@$rS,-$dy);
405 $state = 1;
406 } else {
407 # previous state was B
408 unshift(@$rS,-$main::e);
409 }
410 }
411 }
412
413 # Set annotation string representing match quality
414 $$Sstr="";
415 for (my $col=0; $col<@$ri; $col++) {
416 if ($xres[$ri->[$col]] eq $yres[$rj->[$col]]) {
417 $$Sstr.=uc($xchr[$ri->[$col]]);
418 } elsif ($rS->[$col] > 0 ) {
419 $$Sstr.="+";
420 } else {
421 $$Sstr.=".";
422 }
423 }
424 return $score;
425 }
426
427
428 #############################################################################
429 # Subroutien AlignNW
430 # Needleman-Wunsch global alignment
431 #############################################################################
432 sub AlignNW {
433 if (@_>=1) {$xseq=$_[0];}
434 if (@_>=2) {$yseq=$_[1];}
435 if (@_>=3) {$ri=$_[2];}
436 if (@_>=4) {$rj=$_[3];}
437 if (@_>=5) {$imin=$_[4];}
438 if (@_>=6) {$imax=$_[5];}
439 if (@_>=7) {$jmin=$_[6];}
440 if (@_>=8) {$jmax=$_[7];}
441 if (@_>=9) {$Sstr=$_[8];}
442 if (@_>=10) {$rS=$_[9];}
443
444 if (length($$xseq)<1) {warn ("ERROR in Align.pm: sequence x is empty\n"); return 0;}
445 if (length($$yseq)<1) {warn ("ERROR in Align.pm: sequence x is empty\n"); return 0;}
446
447 my @xchr; # ASCII characters of $xseq
448 my @ychr; # ASCII characters of $yseq
449 my @xres; # internal integer representation of residues of x
450 my @yres; # internal integer representation of residues of y
451
452 $$xseq =~ s/\s//g;
453 $$yseq =~ s/\s//g;
454 @xchr = split(//,$$xseq);
455 @ychr = split(//,$$yseq);
456
457 my $Lx=@xchr; # length of sequence x
458 my $Ly=@ychr; # length of sequence y
459 my @M; # $M[a][b] = score of best alignment of x[1..a] and y[1..b] ending in match state
460 my @A; # $A[a][b] = score of best alignment of x[1..a] and y[1..b] ending in gap in x
461 my @B; # $B[a][b] = score of best alignment of x[1..a] and y[1..b] ending in gap in y
462 my @Mbt; # $Mbt[a][b] = 0:STOP 1:M 2:A 3:B
463 my @Abt; # $Abt[a][b] = 0:A 1:M
464 my @Bbt; # $Bbt[a][b] = 0:B 1:M
465 my $score; # bit score of alignment
466 my $bt; # backtracing variable set by &maxbt: which argument was largest? (first=0)
467 my $state; # STOP:0 M:1 A:2 B:3
468 my ($i, $j); # indices for sequence x and y, respectively
469
470 my $dx = $main::dx;
471 my $dy = $main::dy;
472 if (! defined $dx) {$dx = $main::d;}
473 if (! defined $dy) {$dy = $main::d;}
474 printf("dx=%f dy=%f\n",$dx,$dy); ##############DEBUG#############
475
476 # Transform @xres and @yres to integer
477 for ($i=0; $i<@xchr; $i++) {
478 my $a=ord(uc($xchr[$i]));
479 if ($a<65 || $a>90) {
480 if ($a!=ord(".") && $a!=ord("-") && $a!=ord("~")) {
481 printf(STDERR "\nWARNING: invalid symbol '%s' in pos $i of first sequence to be aligned\n",$xchr[$i]);
482 }
483 $xres[$i]=21;
484 } else {
485 $xres[$i]=$ch2i[$a-65];
486 }
487 }
488 for ($j=0; $j<@ychr; $j++) {
489 my $a=ord(uc($ychr[$j]));
490 if ($a<65 || $a>90) {
491 if ($a!=ord(".") && $a!=ord("-") && $a!=ord("~")) {
492 printf(STDERR "\nWARNING: invalid symbol '%s' in pos $j of second sequence to be aligned\n",$ychr[$j]);
493 }
494 $yres[$j]=21;
495 } else {
496 $yres[$j]=$ch2i[$a-65];
497 }
498 }
499 unshift (@xres,21); unshift (@xchr," "); # insert dummy 0'th element
500 unshift (@yres,21); unshift (@ychr," "); # insert dummy 0'th element
501
502 &SetSubstitutionMatrix;
503
504 # Initialization
505 $M[0][0]=$A[0][0]=$B[0][0]=0;
506 for ($i=1; $i<=$Lx; $i++) {
507 $M[$i][0] = -999;
508 $A[$i][0] = -999;
509 $B[$i][0] = -$i*$main::g;
510 $Bbt[$i][0] = 0; # previous state was B as well (gap in y)
511 }
512 for ($j=1; $j<=$Ly; $j++) {
513 $M[0][$j] = -999;
514 $A[0][$j] = -$j*$main::g;
515 $B[0][$j] = -999;
516 $Abt[0][$j] = 0; # previous state was A as well (gap in x)
517 }
518
519 # Iteration
520 for ($i=1; $i<=$Lx; ++$i) {
521 my $Mi =$M[$i];
522 my $Mi1=$M[$i-1];
523 my $Ai =$A[$i];
524 my $Ai1=$A[$i-1];
525 my $Bi =$B[$i];
526 my $Bi1=$B[$i-1];
527 my $Sabx=$Sab[$xres[$i]];
528 my $j1=0;
529 for ($j=1; $j<=$Ly; ++$j, ++$j1) {
530 ${$Mi}[$j] = max3bt(${$Mi1}[$j1], ${$Ai1}[$j1], ${$Bi1}[$j1], \$Mbt[$i][$j]) + ${$Sabx}[$yres[$j]];
531 ${$Ai}[$j] = max2bt(${$Ai}[$j1]-$main::e, ${$Mi}[$j1]-$dx, \$Abt[$i][$j]);
532 ${$Bi}[$j] = max2bt(${$Bi1}[$j]-$main::e, ${$Mi1}[$j]-$dy, \$Bbt[$i][$j]);
533 }
534 }
535
536 # Finding maximum
537 $score = -1000;
538 for ($i=1; $i<=$Lx; $i++) {
539 my $endgappenalty = ($Lx-$i)*$main::g;
540 if ($M[$i][$Ly]-$endgappenalty > $score) {
541 $score=$M[$i][$Ly]-$endgappenalty; $$imax=$i; $$jmax=$Ly; $state = 1;
542 }
543 if ($A[$i][$Ly]-$endgappenalty > $score) {
544 $score=$A[$i][$Ly]-$endgappenalty; $$imax=$i; $$jmax=$Ly; $state = 2;
545 }
546 if ($B[$i][$Ly]-$endgappenalty > $score) {
547 $score=$B[$i][$Ly]-$endgappenalty; $$imax=$i; $$jmax=$Ly; $state = 3;
548 }
549 }
550 for ($j=1; $j<$Ly; $j++) {
551 my $endgappenalty = ($Ly-$j)*$main::g;
552 if ($M[$Lx][$j]-$endgappenalty > $score) {
553 $score=$M[$Lx][$j]-$endgappenalty; $$imax=$Lx; $$jmax=$j; $state = 1;
554 }
555 if ($A[$Lx][$j]-$endgappenalty > $score) {
556 $score=$A[$Lx][$j]-$endgappenalty; $$imax=$Lx; $$jmax=$j; $state = 2;
557 }
558 if ($B[$Lx][$j]-$endgappenalty > $score) {
559 $score=$B[$Lx][$j]-$endgappenalty; $$imax=$Lx; $$jmax=$j; $state = 3;
560 }
561 }
562
563 # Make sure the end gapped regions are also backtraced
564 if ($$jmax<$Ly) {
565 $Abt[$Lx][$$jmax+1] = $state;
566 for ($j=$$jmax+2; $j<=$Ly; $j++) {$Abt[$Lx][$j] = 0;}
567 $state = 2;
568 } elsif ($$imax<$Lx) {
569 $Bbt[$$imax+1][$Ly] = $state;
570 for ($i=$$imax+2; $i<=$Lx; $i++) {$Bbt[$i][$Ly] = 0;}
571 $state = 3;
572 } else {
573 $state = 1;
574 }
575
576
577
578 # Backtracing
579 @$ri=();
580 @$rj=();
581
582 @$rS=();
583 $i=$Lx; $j=$Ly;
584 $$xseq=""; $$yseq="";
585 while ($i || $j) {
586 if ($state==1) {
587 # current state is M (match-match)
588 unshift(@$ri,$i);
589 unshift(@$rj,$j);
590 $state = $Mbt[$i][$j]+1; # previous state
591 $$xseq=$xchr[$i].$$xseq;
592 $$yseq=$ychr[$j].$$yseq;
593 unshift(@$rS, $Sab[$xres[$i]][$yres[$j]]);
594 $$imin=$i; $$jmin=$j;
595 $i--; $j--;
596 } elsif ($state==2) {
597 # current state is A (gap in x)
598 unshift(@$ri,0); # $ri->[$col]=0 for gap in $x
599 unshift(@$rj,$j);
600 $$xseq="-".$$xseq;
601 $$yseq=$ychr[$j].$$yseq;
602 $bt = $Abt[$i][$j--];
603 if ($bt) {
604 # previous state was M
605 if ($i==$Lx || $i==0) {
606 unshift(@$rS,-$main::g); # end gap
607 } else {
608 unshift(@$rS,-$dx); # gap opening
609 }
610 $state = 1;
611 } else {
612 # previous state was A
613 if ($i==$Lx || $i==0) {
614 unshift(@$rS,-$main::g); # end gap
615 } else {
616 unshift(@$rS,-$main::e); # gap extension
617 }
618 }
619 } else {
620 # current state is B (gap in y)
621 unshift(@$ri,$i);
622 unshift(@$rj,0); # $j[$col]=0 for gap in $y
623 $$xseq=$xchr[$i].$$xseq;
624 $$yseq="-".$$yseq;
625 $bt = $Bbt[$i--][$j];
626 if ($bt) {
627 # previous state was M
628 if ($j==$Ly || $j==0) {
629 unshift(@$rS,-$main::g); # end gap
630 } else {
631 unshift(@$rS,-$dy); # gap opening
632 }
633 $state = 1;
634 } else {
635 # previous state was B
636 if ($j==$Ly || $j==0) {
637 unshift(@$rS,-$main::g); # end gap
638 } else {
639 unshift(@$rS,-$main::e); # gap extension
640 }
641 }
642 }
643 }
644
645 # Set annotation string representing match quality
646 $$Sstr="";
647 for (my $col=0; $col<@$ri; $col++) {
648 if ($xres[$ri->[$col]] eq $yres[$rj->[$col]]) {
649 $$Sstr.=uc($xchr[$ri->[$col]]);
650 } elsif ($rS->[$col] > 0 ) {
651 $$Sstr.="+";
652 } else {
653 $$Sstr.=".";
654 }
655 }
656 return $score;
657 }
658
659 1;