I think from a storytelling perspective, having the Arks or at leas the one the Ryder the player chooses is on, leave at the latest moment possible would be my preference. By having them leave at the last possible moment they can have more oportunities to follow up on plot points from ME3. Even if the player choices don't effect the game, it would still be nice to get a few references to the previous games just to cement it's place in the ME universe.
The animosity between races will still be there. I have a feeling the fate of the Milky Way will come into play at some point in the next set of games.