They could do Red Dead without John or Jack. John has done his bit in the game unless you did a prequel. There were the comments in redemption where John's wife and son both got on to him for being gone all the time. What exactly was John gone doing after the events of Red Dead Revolver and before the events of Red Dead Redemption.
Then again you could do one where you play Landon Ricketts on his climb up the ladder of life to be the best gunslinger in the West.
Otherwise there is much history and examples to choose from in film. I loved the story in the Kevin Costner film Open Range. I know there are copyright issues there but hell, it would be a good story line to adapt.
Honestly though, it is my opinion that the prime template to establish a game on would be to follow the rise and fall of Billy the Kid and the Lincoln County War and it's aftermath. He was both a hero and a villain. Hated and loved. Worshiped and deplored. You could highlight his time when he wore a badge and when he resorted to a bloodbath. You could to the jail break, the cattle rustling and the battles of the war. Most don't know this but Billy got to meet Jessie James as well while Jessie was laying low for awhile. That's a good temporary persona to bring in. Billy met and ran with many other people. Some even more blood thirsty than himself. All in all, Billy's exploits covered New Mexico, parts of Texas and Old Mexico. You could do many areas like they did in Red Dead Redemption just from that. There could be some artistic freedom working with the subject.
Playing as Billy, you would have to keep a low profile as you went from town to town. People would support you or turn on you. You would be wondering which one of your "loyal" friends would stand by you or turn you in. With that in mind there is Pat Garrett. The killer of Billy the Kid was his former running buddy. They stole, killed and lived close together for a long time. That was the reason alone why Garrett was picked to hunt him down. He was the only one who stood a chance of finding Billy. His routes, habits and personality were known to Garrett.
With him in mind you could also have an open ending. Did Pat Garrett really get him or did he grow old as Brushy Bill? Was it a cover up? Did Billy go to Mexico to lay low?
Though I would rather see more of a historical perspective on it, they could possibly cash in on the Young Guns series by working something out with the folks who own the rights to those two old movies.
If Rockstar wanted to go the Young Guns route, that could be an option seeing as the two movies were cult classics. I am willing to bet that Rockstar could get a contract with Emilio Estevez, Kefier Sutherland and others to reprise their roles voice wise. Those guys really are not up to much these days.