Usually when there is variation within a series it is simply because the desired numbers are not available. See, for example, AA's 757 fleet. They are mostly N6XXAA, but there is a smattering of -AM's, and even a few -AN's and -A's, even though the planes themselvs are identical.
On the other hand, sometimes the numbers correspond to the manufacturer's serial number, rather than the airline's fleet number, resulting in gaps in the numeric sequence. The old CCAir Jetstreams were registered N9XXAE, where 9XX was BAe's serial number.
Note that, in cases where someone REALLY wants a particular registration, it might be possible to obtain it by paying (or maybe just asking nicely) whoever owns it. This is what a certain athletic shoe manufacturer did when they wanted to register their aircraft N1KE. However, to most airlines, it's not worth the hassle.
Moving even farther off topic, the subtle humor (to an airplane geek, anyway) is not limited to aircraft registered in the U.S. Letter-based registrations offer much more room for creativity: I think the prize goes to Virgin Atlantic for such registrations as G-VRUM ("Calypso Queen"), G-VELD ("African Queen"), and 747's G-VAST, G-VBIG, and G-VXLG, not to mention what is perhaps the most appropriate name ever, "Maiden Toulouse" for an A340.