As much as I loved Red Dead Redemption the first time I played it, the mission structure does not hold up. THe missions are all really bad and almost all of the side characters just jerk John Marston around for 20 hours. The only two characters who are not annoying thorns in Marston's side are Bonnie McFarlane and the famous gunman who retires to Mexico. Every other character is just some moron who Marston has to run errands for for absolutely no reason, over and over again.
My vision for a future Red Dead, if it's sequential, is one where you follow the great migration north following the cattle herding from the South West up to Chicago, and the second half is set in a 1915-1920 Chicago, introducing the character through the meat/cattle/cowboy industry but settling into a crooked government/early organized crime story.
But, if we've learned anything from Rockstars last game, it's that they're unwilling or unable to write a story. So we'll see.