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I think the big main themes (space, castle, pirate, etc) would have a base set of buildings units with swappable skins for the major themes, then have optional "allied" themes which don't have to match your main theme. So islanders from the pirate theme, could be picked as allies to any major theme to supplement some special abilities.
Skins could be stuff like: Castle has Classic, Black Knights, Dragon Knights, Ninja, Knights Kingdom - as your main force. Allied sub-themes from castle could be wolfpack, Bat knights or whatever.
Pirates has Pirates, or Imperials (or whatever they were called) because if you want to mix ALL lego themes they just wouldn't be distinct enough from eachother in that context.
Space could be Classic, Mtron, Ice planet, Space Police, Blacktron, Futuron. Allied themes spyrius, UFO, exploriens, rock raiders.
Town/city might be hard.
But since the advent of licenses it gets way too muddy, modern themes like ninjago and chima with more named characters make it more like DOW3 vs DOW 1/2 in the way the game is structured.
