I've got a few nits to pick with your first method. I'd pick different nits with your second method but, as you point out, your second method doesn't handle overlaps and, because of that, probably doesn't fit the requirements. So I'll focus on your first one.

while (<DATA>) {
    for my $seq (keys %seqs) {
        $seqs{$seq}->{'count'}++ for m/$seqs{$seq}->{'re'}/g;
    }
}
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What if the file is one 100MB line? (I'm not a biologist or anything but I am under the impression that strands of DNA are very long.) If the data you are searching through is a 100 megs, you've just gone through 100 megs N times, where N is the number of patterns you are searching for. Additionally, optimizing your regex buys you nothing if you are only searching for the pattern once in one long string of input.

Ok, maybe I'm wrong about the number of lines. He said it was a "very large file" but he didn't specify much more than that. So, is your method better if you have a file with many shorter lines? Not very. Compiling the regex patterns ahead of time buys you a little. But consider 100 lines, each 1MB long. In that case, you search each of those lines N times. In other words, you again search through all 100MB N times.

I don't propose that the solution I posted above at Re: Quickest method for matching is at all the best but I suspect it would be noticeably more efficient than your method with real input.

Of course, there are many optimizations that could be used to improve my code too. I could read in a larger buffer at once, thereby reducing the number of reads. I could stop looking for patterns once they've already been found twice. I could refrain from searching across newline boundaries if I expected my DNA data to be composed of many lines. (Notice that newlines don't break the algorithm, they just create a bit of useless work.) Or I could code it up in C because, in this case, Perl is really only buying me a little convenience.

-sauoq
"My two cents aren't worth a dime.";