At the end of Snake Eater, the president was confronted briefly with the idea of having Big Boss head a FOX unit, which would handle all "top secret sneaking missions" for the United States. Since Big Boss went his separate way and created Outer Heaven in the PlayStation Portable title Peace Walker, the next best option to run the FOX unit is none other than the man who headed Operation Snake Eater: Major Zero.
Zero will likely be the villain in Ground Zeros, because of two reasons: the tie to the confrontation with Big Boss and Solid Snake in Metal Gear Solid 4; and because Major Zero took the genes from Big Boss for the LesEnfants Terribles Project, which could be done in a similar way that happened to Snake in MGS4 with the new strain of FOXDIE that was sneaked into his system.
At the end of MGS4, Big Boss sought to start back at zero, because "one becomes ten, ten becomes one hundred." Since the title to this next-next-generation installment is Ground Zeros, it must begin with the creation of Liquid Snake and Solid Snake; it could be the uprising of Major Zero and the FOX Unit, but the plural use of zero eludes away from that. If this truly is the case, the game will also take place in 1972, give or take, depending on how Hideo Kojima will develop and deliver his plot.
That could also go one of two ways: either emphasize the looming hatred between Big Boss and Major Zero, or build up the deceit between them with the Les Enfants Terribles Project being the big reveal near the end. Since Solid Snake's history is with the Green Berets and Zero wasn't involved with it at all - Big Boss was the first boss he had to encounter - it'll probably emphasize the events leading up to Les Enfants Terribles. Unless, of course, Kojima makes Major Zero the voice on the radio as Solid Snake infiltrates Outer Heaven in a callback to the original Metal Gear.
Anyway, the Snake brothers are also alluded to in the Ground Zeros reveal as "After FOX, two phantoms were born." Unless this is a spin-off, which Kojima has never done himself before in the MGS series, the closing aspects of the game should involve the creation of Solid and Liquid Snake; personally, I hope it covers exactly how the FOX Unit went about the Super Baby Method mentioned by Liquid in the original MGS.
The story of Big Boss is still very rich, since Peace Walker didn't dabble into the creation of the FOX Unit or Les Enfants Terribles. It would be far less complicated to create a spin-off, but Kojima loves MGS far too much to do that - we hope. Big Boss still has a lot to tell us, and we hope it heads in this direction.