Mass Effect 4 Leak Promises New Frontiers, Smaller Squad
A leaked survey discussing Mass Effect 4's key plot and gameplay elements seems to confirm that it takes place after the trilogy.
The game is apparently situated in the 'Helius Cluster', far from the (presumably Mass Relay-less) Milky Way and the events of Shepard's story. Apparently a human on a mission to colonise new worlds, you'll recruit seven new teammates, develop settlements and launch Inquisition-esque 'strike team missions'.
Another ancient race, the Remnant, will be the key to unlocking new technologies, with artefacts and ruins dotted across 'hundreds of systems'. There's also mention of an antagonistic race of aliens called the 'Khet' who will attempt to hinder your efforts.
While not officially acknowledged, the survey is well written and chimes with what we know so far. More tellingly, it echoes an earlier survey on Dragon Age: Inquisition, the details of which were later confirmed.
If you're fretting over how to explore this colossal cluster, let me allay your fears: Mass Effect 1's Mako returns with a revamp, and can be upgraded and repainted to purpose. Space dicks it is then.
The full post from Mass Effect's subreddit - and it is gargantuan - can be found here.