Shannon's Entropy and DNA
I think that genome-wide probabilities (i.e. not 0.25 for each base) should be fine. For a given segment of DNA, the chance that the sequence doesn't appear anywhere else in the genome is fairly high.
There is lots of patchy non-randomness (e.g. at centromeres, STRs, and other tandem repeat regions), but there's not much point in modelling that because it's not random.