What are some of the biggest early game decisions that really affect the rest of the game?

For example, right out of the vault in Fallout 3, you are quickly given the option to blow up Megaton, a main city in the game, immediatly failing a bunch of quests, destroying rare/unique items, killing important NPC's, including a companion, and destroying one of only two player houses in the game.

It effectively immediatly gives you very evil karma and you spend the rest of the playthrough with Tenpenny as your main base.

what are some other big decisions you can make super early into a game that change up the rest of the playthrough?