A friend of mine once had an encounter with a fairly prominent geneticist* who thought that there was only one clear example of heterozygote advantage in humans – sickle-cell. Of course that is not the case: we know of a number of genetic malaria defenses that work in similar ways – alpha-thalassemia, beta-thalassemia, G6PD deficiency, Melanesian ovalocytosis, etc. Not all such are malaria defenses: cystic fibrosis has some advantage, nature unclear, but it’s not malaria resistance.
CF is mostly a European disease, particularly in northern Europeans and their diaspora. The gene frequency for CFTR mutations is around 2%, mostly one mutation, delta-508. It’s easy to show that CFTR mutations have some sort of heterozygote advantage, although that same fairly prominent geneticist didn’t think this had been established. Realize that the input of new mutations per generation is insignificant. Without any advantage in carriers , the frequency of mutated CFTR genes should slowly decline, since the mutation used to be lethal in homozygotes and is still very, very unpleasant. The rarer these mutant alleles get, the slower the decline, since a smaller fraction of them run into each other.
But if you run time backward, the frequency should increase more and more rapidly. If there was no advantage in carriers, a frequency of 2% today implies a frequency of 50% 1200 years ago. Takes a code of several lines to show this!
The scenario is ridiculous. This would require a super-tight bottleneck, in which Europe was first wiped out and then refounded by a population of 2 about 1200 years ago, but that never happened – although it might seem reasonable to some young geneticists. When John Hawks and I talked about the genetic impact of the big population expansion in the Neolithic, which greatly increased effective population size, I remember a person like that saying that we didn’t really know that there was a large ( >> 10,000) population in Pharaonic Egypt. I guess he thought that Paul Bunyan built the Pyramids. By the way, another very prominent geneticist, upon hearing our idea, asked “Why would there be more mutations with a larger population?” I got a million of ‘em!
I think I don’t know what the advantage was. This puts me ahead of many people, including Wikipedia, because they think that it’s a cholera defense. It may well protect against cholera in carriers, but that’s not why it became common, because cholera was never seen in any part of Europe until 1817. Better to know nothing than to know what ain’t so. The people who proposed that in Nature weren’t stupid – they had evidence that it protected against cholera in vitro. They were merely deeply ignorant of history. Which is stupid.
* although I have never quite been able to figure out what he is famous for. I have another, much funnier anecdote about him, by the way.