User blog comment:WilliamsonKnox/Villains of Mass Effect 4?/@comment-11209678-20150301172251

Well, the developers have said that the new Mass Effect is going to be in a completely different part of space, so if that's the case I would guess that the villain will probably be of a species we don't even know. My theory is that somehow it's going to end up in the Andromeda Galaxy or another galaxy in general. There are so many things that BioWare does not want to end up contradicting. If they have the game be in a different galaxy, they can avoid some of this problem.

My idea on this is that the game could be set after ME1, possibly in the time that Shepard is in the Lazarus project. A scientist (or team of them) could reverse engineer the conduit and make their own mass relay that would enable them to send a ship into places that were previously unreachable.

By doing this, they avoid a few of the problems that a post-ME3 sequel would have. They avoid the potential issues of some of the ME3 decisions (no quarians/geth, genophage, control/destory/synthesis, etc.) and by having it in an unexplored part of space that has little to no interaction with the galaxy as a whole, you can make it believable that the event of the game had little effect on ME2 and ME3. I know this would frustrate some players, but when ME3 had some decisions that would make the galaxy a very different place, it's difficult to imagine a post ME3 sequel working very well.