One of the comments in my post on animal models prompts me to write a bit more on mutations. I stated that the mutant animal models that we use all have something wrong with them, but I didn't mean to imply that all mutations will do that. There are plenty of so-called "silent" mutations out there, single amino-acid changes in large proteins that basically make no difference. If you switch, say, valine for isoleucine, most of the time it's not going to hurt much (or help much.) (The reason our mutant animals have something wrong with them is that we're trying to mimic a diseased human; if they weren't defective, we wouldn't be interested.)
Billions of years of evolution have honed things down pretty well. If a protein gets altered, it's a lot easier to have a sudden loss of function than it is to have a sudden gain. It's like popping your hood and throwing rocks at your car engine - you have a better chance of damaging the thing than you have of whacking it in a way that increases your gas mileage.
I wrote about a particularly vivid example of this a couple of years ago on my old Lagniappe site. (That material seems to be succumbing to bit-rot when I try to pull it out via Google, so I'm going to rescue some of it every so often.) Here's a slightly reworked version of what I had to say about a famous Alzheimer's mutation:
One of the things that gives me the willies about biochemistry is the nonlinearity. If anyone were to ever come up with a set of equations to model all the ins and outs ofa living organism, there would be all these terms - way out in the boonies of the expression - with things to the eighth and tenth powers in them.
Of course, the coefficients in front of those terms would usually be zero, or close to it, so you'd hardly know they were out there. But if anything tips over and gives a little weight to that part of the equation. . .suddenly something unexpected wakes up, and a buried biological effect comes roaring to life out of nowhere.
Here's the real-world example that got me thinking in that direction. When I used to work on Alzheimer's disease, I first learned the canonical Amyloid Hypothesis of the disease. Briefly put, at autopsy, the brains of Alzheimer's patients always show plaques of precipitated protein, surrounded by dying neurons. It's always the same protein, a 42-amino-acid number called beta-amyloid. A good deal of work went into finding out where it came from, namely, from a much larger protein (751 amino acids) called APP. That stands for "amyloid precursor protein," in case you thought that acronym was going to tell you something useful
The ever-tempting hypothesis has been that an abnormal accumulation of beta-amyloid is the cause of Alzheimer's. This isn't the time to get into the competing hypotheses, but amyloid has always led the pack, notwithstanding a vocal group of detractors who've claimed that Alzheimer's gives you amyloid deposits, not the other way around. (Note from 2004: I wrote recently about developments in the amyloid field here and here.)
So what's APP, and what's it good for? It took all of the 1990s to answer that one, and the answers are still coming in. It's found all over the place, and seems to have a role in cellular (and nuclear) signaling. Normally, it's cleaved to give smaller protein fragments other than the 42-mer that causes all the trouble.
One of the stronger arguments for amyloid as an Alzheimer's cause came from the so-called "Dutch mutation," which is what got me to thinking. As was worked out in 1990, there's a family in Holland with a slightly different version of APP. One of the 751 amino acids is changed - where the rest of the world has glutamic acid, they have glutamine - almost the same size and shape, but lacking the acidic side chain.
So. . .there's one amino acid out of 751 that's been altered. And that's in one protein out of. . .how many? A few hundred thousand seems like the right order of magnitude for the proteome, maybe more. And what happens if you kick over that particular grain of sand on the beach? Well, what happens is, you die - with rampaging early-onset Alzheimer's (and a high likelihood of cerebral hemorrhage) before you're well into your 40s.
As it happens, that amino acid is right in the section of the protein that becomes beta-amyloid. Altering it makes it much easier for proteases to come and break the amide bond in the protein backbone, so you start accumulating beta-amyloid plaques early. Much too early. Bad luck - the change of just a few atoms - snowballs into metabolic disaster. Since then, many other mutations have been found in APP, and many of them are bad news for similar reasons.
But it's not like every amino acid substitution in some random protein causes death, of course. There are any number of silent mutations, and plenty that are relatively benign. Most of the time, those high-exponent terms out there in the mathematics sleep on undisturbed. And it's better that way.