I watched the quicklook of SimCity and noticed what I would consider a mistake in city design. That would be treating each city in a region as a traditional SimCity city so to speak and only worrying about the RCI. But the regions and specializations are there for a reason. You can build one city as a heavy polluting industry city with lots of power and minimal residents and commercial, while another city in that region fulfills those roles and others. You do not need every city with absolutely everything in it as your Sims will travel to neighboring cities to fulfill needs that aren't provided. This will be the way to optimize your regions as due to the size constraints you clearly cannot make a be all end all city that does everything.
This post isn't intended to be judgmental. If this absolutely blows your mind and you hate it with a burning passion there is still SimCity 4 and Cities XL (I have no experience with Cities games but I'm just throwing it out there). But if you are looking to pick up the new SimCity I think it's best to throw out preconceived notions on how cities work from previous SimCity games as I believe they do not apply for the most part.