DISCLAIMER: This might make no sense whatsoever, since I never played Bioshock. :(
Samus Aran, Master Chief AND Isaac Clarke are trapped inside USG Ishimura, with a bunch of things that are made from a combination of Flood, Metroids and Necromorphs.
Also, Ishimura has been taken over by GlaDOS, who used Portal technology to create an wormhole system connecting all worlds, and is using Suiseiseki as an energy source, since GlaDOS needs A.D.A.M. to maintain the fusion between the "races" since she made it using a derivate of plasmids (somehow slugs that live in deep sea can fuse races from different plans of existence).
The final plot twists are that Samus is a special kind of Big Sister that has free will, which was created to protect Suiseiseki, who is not only a "super" Little Sister(all dolls are prototype versions of Little Sisters, and Rozen was a high-ranked employee at Aperture Labs), but also part the metroid who used to be Samus's "daughter"; Cortana is an updated version of GlaDOS; the Monolith is actually a different kind of Halo; Isaac Clarke (and his girlfriend) created portal technology (way before the necromorph incidents), but they accidentaly teleported the device capable of controlling it to another universe, where a crazy dude found it, and the events of Portal played out. Oh, and Rapture was funded by Aperture Labs.
And USG Ishimura is jumping from universe to universe while this happens.
And the game allows you to play after the story ends, because after they destroy USG Ishimura, they somehow end up in the Zone(the one from S.T.A.L.K.E.R.).
Did I mentioned everyone in the ship is going insane(including GlaDOS)?
I challenge you guys to make this plot more confusing(or awesome).
TL;DR: Blame GlaDOS.