I'm glad to see your wife has an interest in shooting. I'd suggest you have her shop for a handgun just like she shops for shoes. Go to the gun shop/gunshow and have her handle (try on) all of the handguns she can get her hands on. Most she won't comment on, but a few, will feel "just right". Pursue those. Make sure she can work the action. Many manufacturers make different calibers on the same, or similar frames. Starting with a .22 is a sound idea, but the same holds true.... she needs to try it on. A person can be taught to shoot many calibers, in different actions, but it's extremely difficult in my experience, to teach someone to be comfortable with a handgun that doesn't feel right in their hands. If it doesn't feel right, they won't shoot it enough to become proficient with it. If they're not proficient with it, they should carry a ball bat. :no:
Besides, gun shopping is fun....... just my two cents......