The first Mutant on Earth was the Egyptian immortal En Sabah Nur, aka The First One. The prophecies of his time told of the day when a being from the sky will come to warn us of the Apocalypse, and the world will be devoured. En Sabah Nur believed he was this being. He was wrong.
S.H.I.E.L.D was formed around the time of WWII by the U.S. Government as a means to place special agents deep behind enemy lines for reconnaissance missions. The members of S.H.I.E.L.D would need to be extremely highly trained and experts of all forms of combat. Because of this, the government turned to using people whom were born with genetic gifts, such as heightened senses or special abilities, aka "Mutants". The government was the first to know about these Mutants and their existence was not yet known to the public. The first Mutant S.H.I.E.L.D tried to recruit was a Canadian man named James Howlett, who was born with an enhanced healing factor, bone claws, and an animalistic appearance, he was drugged and captured and forced to work for S.H.I.E.L.D. Howlett soon escaped and killed many of his government handlers and S.H.I.E.L.D was shut down.
Super Soldier Project
As the War progressed and the Axis powers became stronger because of the success of their genetic experiments in their "HYDRA" program, S.H.I.E.L.D was reactivated with the intent to create their own mutants through genetic enhancements. Their test subject was a frail Army Private named Steve Rogers. The experiments were a success and Rogers gained enhanced physical strength and stamina. But, a Nazi spy murdered the scientists responsible for the project and the "Super Soldier Serum" was lost forever. Millionaire weapons designer Howard Stark was made the public face of the project to cover up the fact that the real scientists were murdered, and Steve Rogers was made into a propaganda mascot named "Captain America", while he was really running reconnaissance missions for S.H.I.E.L.D as part of their agents the "Howling Commandos".
On one mission in Russia towards the end of the war, the enemy command post was bombed and Rogers plunged into the freezing waters surrounding the base to save himself. He was frozen but remained alive because of the Super Soldier Serum in his blood.
After WWII was over, S.H.I.E.L.D, under the new leadership of Director William Stryker Sr., started a new program to create Super Soldiers. Following the tracking down and recapture of James Howlett in Japan, his memory was wiped and he was implanted with a skeleton coated with adamantium, the strongest metal in the world. He was them placed in a team of other genetically altered mutants (which included the de-evolved animalistic Victor Creed and the psychopathic unkillable mercenary Wade Wilson) called Weapon X. The team was soon deactivated because of the members unstable mutations and William Stryker's son's intolerance of mutantkind. The Mutants in Weapon X soon went feral and rebelled, escaping from their government handlers. The Weapon X program was shut down in S.H.I.E.L.D and was transferred to Canada's Department K, where it's genetic experiments were gruesome failures.
When Mutantkind began making itself known to the world, it was either as peaceful demonstrators and protestors for Mutant rights or as violent Mutant supremest terrorist groups such as the Brotherhood (led by the former Nazi concentration camp prisoner Erik Lehnsherr, aka Magneto). Around this time, William Stryker Jr. was appointed Director of S.H.I.E.L.D and ordered the creation of a series of drones designed by a former Weapon X scientist named Bolivar Trask, called Sentinels, to control the Mutant population. Unfortunately, this only made The Brotherhood more violent, causing some of the members to grow angry at Magneto's violent ways, and started a school for young Mutants led by Magneto's old friend Charles Xavier, and they vowed to stop the Brotherhood's terrorism and restore peace within Mutantkind. The media dubbed them the X-men.
The Fantastic Four
The X-men decreased the need for Sentinels and William Stryker was fired as Director of S.H.I.E.L.D. and replaced with war hero Nick Fury. Fury's first act as Director was to restart the Super Soldier project. But, the project was rushed and the first result was a failure, when scientist Bruce Banner injected himself with the unfinished serum. The serum overloaded his body and he went on a rampage, only to be stopped by a man claiming to be the Norse god Thor. Bruce Banner was locked in a S.H.I.E.L.D testing facility but soon escaped when the serum caused him to transform again, causing S.H.I.E.L.D to inject one of their best agents, Emil Blonsky, with the unfinished serum to track Banner down. But, S.H.I.E.L.D had bigger problems when the ruler of the European nation Latveria, Victor Von Doom, went to war with the powerful African nation Wakanda over their large deposits of Vibranium. Fury put together a team of Superhumans to stop the war, four humans whom S.H.E.L.D experimented on named Reed Richards, Susan and Johnny Storm, and Ben Grimm. They soon broke from S.H.I.E.L.D control and became the world famous team of do-gooders the "Fantastic Four".
Following word that Steve Rogers was found alive and well, preserved by the Super Soldier serum, Nick Fury set out to create a new team of superhumans under S.H.I.E.L.D's control, as Earth is threatened by a seemingly cosmic, silver being that floats on a board, claiming that his master, a being called Galactus, is going to devour the world.