Generating Synthetic DNA Sequence with Subtitution Rate

Question

Given these inputs:

my $init_seq = "AAAAAAAAAA" #length 10 bp 
my $sub_rate = 0.003;
my $nof_tags = 1000;
my @dna = qw( A C G T );

I want to generate:

1. One thousand length-10 tags

2. Substitution rate for each position in a tag is 0.003

Yielding output like:

AAAAAAAAAA
AATAACAAAA
.....
AAGGAAAAGA # 1000th tags

Is there a compact way to do it in Perl?

I am stuck with the logic of this script as core:

#!/usr/bin/perl

my $init_seq = "AAAAAAAAAA" #length 10 bp 
my $sub_rate = 0.003;
my $nof_tags = 1000;
my @dna = qw( A C G T );

    $i = 0;
    while ($i < length($init_seq)) {
        $roll = int(rand 4) + 1;       # $roll is now an integer between 1 and 4

        if ($roll == 1) {$base = A;}
        elsif ($roll == 2) {$base = T;}
        elsif ($roll == 3) {$base = C;}
        elsif ($roll == 4) {$base = G;};

        print $base;
    }
    continue {
        $i++;
    }

Answer 1

EDIT: Assuming substitution rate is in the range 0.001 to 1.000:

As well as $roll, generate another (pseudo)random number in the range [1..1000], if it is less than or equal to (1000 * $sub_rate) then perform the substitution, otherwise do nothing (i.e. output 'A').

Be aware that you may introduce subtle bias unless the properties of your random number generator are known.

Answer 2

As a small optimisation, replace:

    $roll = int(rand 4) + 1;       # $roll is now an integer between 1 and 4

    if ($roll == 1) {$base = A;}
    elsif ($roll == 2) {$base = T;}
    elsif ($roll == 3) {$base = C;}
    elsif ($roll == 4) {$base = G;};

with

    $base = $dna[int(rand 4)];

Answer 3

Not exactly what you are looking for, but I suggest you take a look at BioPerl's Bio::SeqEvolution::DNAPoint module. It does not take mutation rate as a parameter though. Rather, it asks what the lower bound of sequence identity with the original you want.

use strict;
use warnings;
use Bio::Seq;
use Bio::SeqEvolution::Factory;

my $seq = Bio::Seq->new(-seq => 'AAAAAAAAAA', -alphabet => 'dna');

my $evolve = Bio::SeqEvolution::Factory->new (
   -rate     => 2,      # transition/transversion rate
   -seq      => $seq
   -identity => 50      # At least 50% identity with the original
);


my @mutated;
for (1..1000) { push @mutated, $evolve->next_seq }

All 1000 mutated sequences will be stored in the @mutated array, their sequences can be accessed via the seq method.

Answer 4

In the event of a substitution, you want to exclude the current base from the possibilities:

my @other_bases = grep { $_ ne substr($init_seq, $i, 1) } @dna;
$base = @other_bases[int(rand 3)];

Also please see Mitch Wheat's answer for how to implement the substitution rate.

Answer 5

I don't know if I understand correctly but I'd do something like this (pseudocode):

digits = 'ATCG'
base = 'AAAAAAAAAA'
MAX = 1000
for i = 1 to len(base)
  # check if we have to mutate
  mutate = 1+rand(MAX) <= rate*MAX
  if mutate then
    # find current A:0 T:1 C:2 G:3
    current = digits.find(base[i])
    # get a new position 
    # but ensure that it is not current
    new = (j+1+rand(3)) mod 4        
    base[i] = digits[new]
  end if
end for