In the year 2050, a mad scientist was shut down by his superiors after conducting bizarre biological experiments but soon after, his lab exploded and the scientist seemingly disappeared. Several years later, there are new buildings put right on top of the forgotten slum where the experiments took place and this time, a genetic virus has started to spread among the tenants, turning them into vicious and dangerous mutants. Two young fighters of the local city, Ricky Jones and Johnny Hart, return after having been away for several years and upon seeing the chaos that's happening, the two of them take it upon themselves to clean up this new nation of mutants before it spreads any further. Along the way they come across not only mutants but also mechanically modified freaks that the mad scientist created to stop them.
One or two players (Player 1 as Ricky and Player 2 as Johnny) fight their way through the six levels of various mutated and mechanic enemies, each level containing one or more sub-bosses before the real boss appears. The gameplay is pretty standard for the genre but rather than allowing the players to pick up objects to use as weapons against the enemy, Mutation Nation instead uses a system where the player can pick up one of four elemental spheres. The spheres can be used to create devastating attacks by holding down the attack button to power up a special meter and letting go once it’s full. If the players don’t have any spheres or run out of spheres to use they can still fill up their special meter to unleash a flurry of attacks at the cost of their life meter which will be drained partially.
These are the various elemental spheres that can be picked up by the player and used for special attacks. Each sphere is represented by a letter and color that helps the player tell them apart. Note that there are also neutral, orange, spheres without an element alignment that instead add to the players life and increases the amount of special attacks he can do.
- Light - The light sphere is blue and has the letter A on it, it has the fastest but also least damaging special attack where the player is split into two bodies of light that dash horizontally across the screen before coming back together in the same place again.
- Fire - This sphere is represented by the letter B and has a reddish color. It unleashes a very powerful attack where the player punches in the air and creates a large fireball which damages everything on the screen.
- Wind - The wind sphere is the most powerful of all the spheres as it turns the player into a green cyclone that travels across the screen for a long time and can hit enemies twice which causes tremendous damage. The wind sphere is green and can be recognized by the letter D.
- Lightning - The last sphere has by far the slowest special attack of all the spheres. The players leaps high into the air outside of the screen and comes down moments later with a ground pound that causes blue streaks of lightning to appear everywhere on the screen. The lightning sphere has a blue color with the letter C on it.
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