If she shoots, is comfortable with and likes the Ruger 22/45 then this is a no-brainer....setup an identical Ruger 22/45 for her for home defense.
Load it with reliable quality 22 LR ammo that you know functions in the gun.
A heavy caliber gun that you cannot function/manipulate/handle/shoot is completely useless compared to a small caliber gun that can be run well.
My "home defense" gun is whatever primary handgun I've been toting around all day...period. Typically it's a 1911 or a Glock. I always have a J-frame (typically a 340PD) around as well as as a backup.
Everyone's home defense scenario is different, but spend some time thinking through what you are going to do.
If it's just you and your wife I wouldn't recommend any room clearing. Room clearing in my world to be done correctly takes at least two or three people depending on the structure. You're more likely to get ambushed and disarmed in your own home. Barricade yourself in your room and call 911. Stay on the phone with the dispatcher on speakerphone. If someone enters your room then shoot them. Otherwise do what the dispatcher tells you to do. If you have children you need to get to that is a different story.
Before we had kids and I worked graveyard religiously, I would turn the house alarm on bypassing only my bedroom. Someone breaks in I have some warning. With kids sleeping in different bedrooms that's not possible.
I don't want multiple guns sitting around in my house. It's more likely they'll be used against me. Guns belong on your person or secured away. For sleeping, leave it in arms reach in a holster. A call early in my career the guy had both his pistol and phone on his nightstand. The phone rang and in his sleep state he picked up the pistol and accidentally blew his brains out. Weird, but weird stuff happens. It left an impression on me. Make sure you have to do some semi-conscious action to be able to operate the gun.
In an urban or suburban environment I don't typically want a long gun. Typically the encounter will be over fast and the goal is to create a defensible area, call the police and stay safe until they arrive. Be realistic about how long it takes for the cops to get there. Depending on the time and location around here it is three to five minutes.
Can an carbine or shotgun be useful? Yes, but a pistol will work just as well for that purpose and only requires one hand to operate. You also can holster it when the police show up. Running around with an AR when a bunch of rookie cops show up in the middle of the night (typically who works on a Saturday night) who just had an adrenaline dump going to a hot call is a good way to get a bunch of guns pointed at your or get shot.
I've gone to more than a few night-time home break-ins in my career. Unless you are growing weed, a dope dealer or move cash to and from your home frequently (then it's always multiple suspects doing a home invasion), typically it's one person breaking into the house at night. If it's a stranger (not a domestic violence thing), usually it's either crazy person, a drunk going to the wrong house or some ridiculously high tweaker. Daytime break-ins are typically financially motivated (they want to steal your stuff) and don't realize that someone is home.
Think heavily about what you would do during different scenarios, how defensible your bedroom is, and arm yourself accordingly.