Well, if it is in Shep's lifetime, I'm just hoping that they bring back the psychotic biotic. God, I loved her.
Jack? I'm skeptical of the game taking place when Shepard is active. That was mere speculation a gaming journalist made up taking BioWare's words out of context. I believe it's possible we may see Wrex or Liara, but I'm expecting MENext to take place far enough in the future where Shepard and others with shorter lifespans won't be in the picture. It would tie up more loose ends that way.
Mass Effect is a roleplaying game.For your Shepard Destroy may have been the only in-character decision. It wasn't for mine. My Shepard didn't care about destroying the Reapers; he cared about saving the galaxy.
As for MENext, ideally, I would like to see some reflection of the events of the trilogy if it is going to be a sequel or side-quel. Given how massively game-changing every single one of the endings is, I don't see how they can not refer to them if it is a sequel.
If it's a prequel, then maybe some Easter Eggs.
To be quite honest with you, Mass Effect is a terrible role playing game, compared to other BioWare titles. The reason I say this is because you are either a renegade Shepard, or a paragon Shepard. Choice is illusory as you can only follow the good guy path or the bad ass path. They both have their own methods of dealing with a situation, but they ultimately want the same goal, which was established since ME1: Destroy the Reapers. Also, it's worth pointing out that the only way to truly "save the galaxy" is to destroy the Reapers. Control, Synthesis, and Refuse only create loopholes and the possibility of the Reaper's return. Destroy is the only definitive choice.
MENext will definitely take place after the original trilogy. BioWare has never done a prequel, and certainly it wouldn't make any sense either as we would not be able to import our choices, which has been a standard for BioWare since ME1.