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In Genesis, players are taken back to the origins of the Biohazard franchise - taking the role of Jill Valentine as she investigates the disappearance of the S.T.A.R.S. Bravo Team and uncovers the secrets hidden in the mansion of the eccentric Lord Spencer.

Genesis takes a turn away from the other storylines established by adaptations of the original game, as protagonist Chris Redfield has absolutely no mention in the game and does not exist in any scenes. It is also not possible to play as him, so this automatically rules out Rebecca Chambers as well. With this there are a lot of story changes, including design changes within the mansion itself and other areas in the surrounding facility. Such changes include that there is no way to save Barry Burton, as he will be attacked by Lisa Trevor in the second floor Garden and is presumed dead (his body completely vanishes after this point). Lisa Trevor will also chase after your character at an amazing speed, with no real closure to her character aside from running away. Included in that change, comes the finale where Wesker meets his end at the hands of the Tyrant and you must fight him here in the lab (and strangely, anywhere else within the "laboratory" complex as he can chase you from room to room. After killing the Tyrant, the game ends and the credits start to roll...there is no rooftop battle or rocket launcher.