Well, I am a lady, and I am pretty comfortable shooting whatever. But, it would really depend on what your wife's comfortable with. Has she tried all of the handguns you currently own? If so, what did she think of them? and how well did she shoot with them?
My personal favorite, is a springfield XD9. It's not too expensive, easy to shoot, well balanced, and I make a nice little grouping with it on a target at 25 yards. I guess I don't know if the XD comes in 45...I haven't looked into that.
I've also tried Walther P99, and that would be my second favorite, as they have interchangeable backstraps, so you can fit the grip to your hand. My husband says the grip is too small, so that might be a good option for a lady. Again though, I don't know what calibers are offered, I've only used the 9mm on that one too.
I also shoot well with larger calibers, but I'm really very comfortable with guns. If your wife is, than she can probably learn to shoot anything....and honestly, if you're keeping it in your house, she should learn to shoot everything you have, and be confident with it, because you just never know if she'd need to.
However, if she's not all that comfortable shooting guns, then I'd suggest lots of practice on the range, and actually have her take a local gun training class, even if she knows the basics. I took a class, with a bunch of 12 year olds I might add, and there was alot of history and mechanical knowledge about calibers and differences between types of guns that I didn't know even though I've been shooting since I was a little girl. It was really informational, and it actually helped me be a more confident shooter when I had more knowledge. Once she develops alot of confidence, you'd be better able to make a decision on a caliber and good handgun for her.
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