I commented earlier, and have read almost all comments.
Many, many great ideas there. I especially liked the specter-detective story idea (*koff* LA Noire in space *koff*) with a sandbox citadel.
What I can gather from the comments, is that the majority doesn't like the idea of a prequel, same here. So, I decided to ponder another framework
for a story:
What about this. Shepards' story is millennia in the past, only something read about in history books. The specific choice of red-green-blue should be completely ret-conned, and the "Mehem" ending is now canon.
If only to prevent all too complex branching stories.
Stage1: An Asari scientist stumbles across Tali Zora's research into the sudden heating of the sun on the planet where she got together with Shep, Haestrum.
There have been reports from far away galaxies about dark matter being syphoned, upsetting the balance, leaving suns to go supernova prematurely (hokum-science, I know, but that has hardly ever hindered enjoyable sci-fi)
A science mission should be deployed. However, the current species, though much more advanced than the Protheans ever were, still do not have the means of travelling the distance, since the galaxies that the reports pertain to, have only been observed by sattelites, space-telescopes etc. and they are, basically, looking eons in the past. And those galaxies are not fitted with mass-effect relays, because the Protheans got wiped-out be
fore they could get to it.
There are rumours, or more like legends, of an interstellar drive that does not need relays, but can manipulate time&space (timey, wimey). Those legends are cautiously/violently guarded by several vaguely known war-like species. (Tons of exploration and negotiating possibilities)
Well, you get my drift. Get small ship. Get soldier crew. Gather blueprints, fight
for them or solve puzzles to get at them in creepy ancient ruins (think KOTOR, afa puzzles go) or talk
your way to them. Gather resources. Finally fight one seriously dangerous species
for a special fuel, or part.
A species that has been sabotaging
Your attempts to get the blueprints, maybe because of some weird religion, maybe because they want the inter-stellar drive
for themselves, to become all-powerful.. blablabla..whatever. The writers will think of something.
stage 2: Build super-ship. Gather some final scientist crew-members. Go to different galaxies, meet new species. research reason
for dark matter syphoning.
Those reasons, I leave to Bioware to fill-in. They are bound to think of something cool, be it loverly nonsense-science-gobbledygook, be it unimaginable creatures, only observable while in hyper-space, or something. (how to fight a critter that's the size of a single galaxy, living in sub-space "vibrations", with a completely incomprehensible mindset)
Space-Opera sized fun...
So, yeah, go bigger, much. much bigger. Show galactic conciences that consider reapers no more than fleas, or staphilococcae....

Make the player really scrounge planets. Even the standard football-field-sized planets in Kotor felt as much bigger, and with much more to discover, than many a "planet" in ME...
So, BW are, indeed, capable of tickling that "explorer"-nerve of a player. And it got seriously snowed-under in FPS-minded ME1, 2 and 3. Bring that exploration back. The wonder, the running around in the Sith-temple, looking
for as much loot as possible. Stuff like that. Heck, even Jedi-knight Academy had bigger levels and more exploration here&there than ME..
BW should take a looong hard look at KOTOR, and try to ascertain what made it such a glorious
game. Both iterations, despite the 2nd one's peculiar ending.