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Easy.
You start in Kanto, after that you go to Johto. You fight an underground version of Team Rocket. They're not as loud and pronounced as they used to be, but you still end up getting involved. Your rival is friendly enough at first but ends up joining them later in order to use their resources as he gets sick and tired of losing to you. After you beat the Kanto and Johto gyms and wipe Rocket out, you fight the Indigo Plateau with new champions and all new members besides Koga.
Once that's done, you explore Sinnoh. This is the post game. You beat the Sinnoh gyms, stumble onto legends, all that. But it's all very exploration oriented, you aren't told where to go too often as the whole Sinnoh section is just you exploring and training just because.
There's also a new Battle Frontier in the old Survival Area, with PWT being one of the parts of it.
I wouldn't mess with any Pokemon. All of Kanto, Johto, and a bit of Hoenn/Sinnoh and Unova mons are in. I don't care about meta.
Returning features:
>Following Pokemon
>BF/PWT(these can easily be squeezed into one)
>multiple regions