You make a fair point that using optimized numerical libraries instead of string methods will be ridiculously fast because they're compiled anyway. For example, scikit-bio does just this for their reverse complement operation [1]. However, they use an 8 bit representation since they need to be able to represent the extended IUPAC notation for ambiguous bases, which includes things like the character N for "aNy" nucleotide [2]. One could get creative with a 4 bit encoding and still end up saving space (assuming you don't care about the distinction between upper versus lowercase characters in your sequence [3]). Or, if you know in advance your sequence is unambiguous (unlikely in DNA sequencing-derived data) you could use the 2 bit encoding. When dealing with short nucleotide sequences, another approach is to encode the sequence as an integer. I would love to see a library—Python, Nim, or otherwise—that made using the most efficient encoding for a sequence transparent to the developer.

[1] https://github.com/biocore/scikit-bio/blob/b470a55a8dfd054ae...

[2] https://en.wikipedia.org/wiki/Nucleic_acid_notation

[3] https://bioinformatics.stackexchange.com/questions/225/upper...