I think Karma would be hardly missed if it were removed, but it needs something in its place. The general feeling (which I share) seems to be that there needs to be something that enhances what little roleplaying the karma system provided; i.e. bad karma players will often be known for their cruelty or get more amoral results in conversation. Faction reputations are good and all, but it seems odd that one can essentially become Deputy King of Caesar's glorified fan-club and there will still be factions who have no idea who you are.
A good replacement could be the reputation system they used in PoE, or rather the enhanced one they're planning for PoE II. Each type of response gets you a certain reputation, and you come to be known for those types of attitude; people will recognise as the silent type/cruel despot/complete jackass that you are. On top of that, the enhanced system makes it so one is only known for lying when they are bad at it and will not be recognised by people who have no reason or means to know them.
If a karma system is
absolutely necessary, then it needs to be on two axes instead of one. The most obvious example would be the D&D alignment chart, where a distinction is drawn between what is moral and what is lawful; this would remove one of the most common complaints that killing a raider nets you good boy points, put taking their stuff removes it.
One could also add a perk whose effects change depending on moral standing, like the Lonesome Road coat.
However, regardless of the changes, the karma placements need a serious straightening out. There are multiple instances throughout the game that, due to oversight or a bug, completely break the system, and others that just don't make sense. Making Caesar more complex and interesting by giving him neutral karma is nice and all, but smacks as something of a contradiction when all of the people who follow his orders are marked as evil.
In any event, what about ghouls being healed by radiation or going feral?
I'm fine with ghouls being healed by radiation since
Fallout is based more on what radioactivity was understood to be in the 50's rather than today. Failing that, there's also the other
FoBible chapter that says they might be a result of airborne FEV, so eh.
I would like it more if ferals went back to be what they were; shambling husks of their former selves who might only attack when you get too close. It would be interesting to see them congregate in groups in cordoned-off sections of the Vegas sewers or abandoned towns, and the player having to navigate through them hoping to god they don't provoke any of them. There could also be some who have lost the will to even move, easily confused for corpses; should the player try to loot them, they would be startled and go hostile.
The role of Bethesda's ferals could be taken up by Desert Walkers, banished ghouls who have gone mad from the desert heat. Some of them may be normal ghouls and some of them may be shamblers, who only attack you when you get within their range. The normal ghouls could carry simple meelee weapons and would be tougher than their sane cousins due to the harsh rays of the sun hardening their skin to a leather-like state.
Lastly, Feral Ghouls in the traditional sense could still exist, but it would be explicitly explained that they are not so because of some inevitable part of ghoul ecology; rather, they are unique ghouls who have, for some reason or another, been trapped in various inescapable places or otherwise placed in isolation for an unbearable amount of time, causing them to regress to their more animalistic instincts. They might not even have to be hostile; depending on how they had to adapt to survive and how long they've been isolated, they could be shier, more open to friendship or even speak a tiny bit.