I'm going to go against the grain here in light of your (and I'll assume your wife's) inexperience w/ handguns.
Cliff's Notes version:
Since your inexperienced w/ handguns, I'd suggest a full size (4-6" barrel), steel frame, 6 shot (or more) revolver w/ fixed sights chambered in 357 Mag. Start off shooting mild 38 Special rounds, advancing to +P 38 Spec loads when you can handle them. Advance to full 357 Mag loads ONLY once you've mastered the +P 38 Spec loads. If you can't make it to 357 Mag loads, just stay w/ the +P 38 Spec loads, which are still very formidable self defense rounds. A similar sized gun in 38 Special w/ +P rounds is good too if you don't have any interest in the recoil/muzzle blast of the 357 Mag.
If you'd rather have a semi-auto, I'd suggest a full size 9mm from a reputable manufacturer, e.g. S&W (M&P series), Springfield Armory (XD series), Ruger (SR series), Glock, Sig, CZ or Beretta. I prefer DAO or SAO, but you may well prefer SA/DA type. Likewise, I mostly prefer no external safeties, but you may want a safety. If you're experienced and comfortable w/ the platform, a reliable 1911 is appropriate, as well. Try to handle, and shoot, a number of semi-autos before deciding which one to buy. Some of the bigger cities have shooting ranges that will let you rent a handgun and shoot for a period of time.
As already mentioned, for home use, the best self defense weapon is not a handgun, but a shotgun, usually a 12 gauge, but 20 gauge is a good choice, as well.
Full Version:For a self defense gun that is NOT going to be used in concealed carry, you don't want, nor need a compact or subcompact gun; get a full size gun w/ a steel frame. All things being equal, a smaller and lighter gun is generally more difficult to shoot well than is a larger and heavier gun, especially for newbies. Personally, I think revolvers are easier for most newbies to learn w/ than are semi-autos. OTOH, some newbies start out w/ semi-autos w/o any problems. No one can know but you which category you'll fall in to.
The best self defense calibers are 9mm, 357 Mag, 357 Sig, 40 S&W and 45 ACP; the 38 Special also has a good track record, but not like the above.
The semi-auto vs revolver debate always generates a lot of interest. Ruger, Colt, Chiappa and Smith & Wesson are top notch makers of revolvers; other makers that seem to have spotty quality control include Charter Arms, Rossi and Taurus.
Given your inexperience, I recommend some formal training in handgun handling and safety.
Last, if you can swing it, I'd strongly consider buying a 22 LR to learn the basics of handgun handling and to practice w/. If you want a revolver for self defense, make the 22 LR a revolver; if the SD gun is a semi auto, get a semi auto 22 LR.
Good luck. Let us know what you buy and be sure and include PICS. :-)