WMG / Y: The Last Man

Y: The Last Man is a prescient Let's Play Perspective Flip of a more customizable Pandemic clone or sequel.
It makes perfect sense. In the hypothetical Pandemic 3, the Player set up a Y-chromosome linked virus and was very, very careful to limit as many symptoms as possible. Then, after building up its Infection rating to the maximum level, giving the disease enough time to spread to the entire world (including Madagascar, but not including the International Space Station), and saving up a couple dozen Evolution Points, the Player upgraded it to include vomiting, bleeding, ulcers, and hemorrhagic fever. The plan was to give it an X-chromosome fatality effect after another thirty or fifty evolution points. Yorick and & were a result of getting the One In A Million Chance immunity score, like how the Master Ball in the first two generations of Pokémon fails 1/65536 times due to how the Random Number Generator works.

The disease was the result of a godly intervention that decided, because several signs and possible causes happened at once, it/they/he/she may as well set off the Gendercide.
From a Doylist perspective, this is absolutely correct, though with effect and cause reversed.

Agent 355's real name
I'm sure I'm not the first person who thought of this, but I have a good idea of what 355's real name is. From how Yorick says "it's perfect", and the word Peace on her grave marker, her name is probably Irene, derived from the Greek for 'peace'.

Yorick has magic powers
He's a little too insistent about how much he sucks at everything, it could just be covering up. And he gets his levitation trick names mixed up because he's only pretending to use tricks. His skill at annoying people comes from everyone sensing something wrong with him, and he seems to make animals nervous. But mostly he's just way too good at disappearing in thin air. (And he never does explain that trick to 355.)
  • Also explains his preternaturally bad brawling skills: He's a Squishy Wizard.
  • And come to think of it, how on Earth did he track 355 down to a random location in Paris in the same time it took him to run there from Beth?
  • And over the course of the series, he gives himself a hyperactive brain, an enlarged heart and even a ride in a submersible steel balloon. The parallels to The Wizard of Oz are obvious!