Heterozygote Advantage

One of the important things to realize about heterozygote advantage is that it doesn't matter how disadvantageous the homozygous form is, as long as the heterozygote has an advantage over the other homozygote. Or, as Campbell puts it:

Although the fitness advantage to the heterozygotes is much smaller than the disadvantage to the homozygotes, there are so many more heterozygotes than homozygotes that the aggregate benefit of the allele in the population balances, its aggregate harm.'

The classic example is sickle-cell anemia and malaria and this is the only example that seems to fulfil the criteria for heterozygote advantage and be well understood.

Other possible examples are:

Cholera and Cystic fibrosis. When you have Cholera, a toxin is produced by the bacteria which binds to the small intestine, interfers with fluid channels, and causes the body to pump out large amounts of chloride ions and water. In the absence of medical inervention many individuals die from dehydration. Mice (used here as a model system) that are heterozygous for the Cystic fibrosis gene only pump out half as much water and stay better hydrated during Cholera infection. The hypothesis is that, like sickle cell anemia, the Cystic fibrosis gene will be found at higher concentrations where Cholera was most prevalent in the past. But there are some problems with the hypothesis. Perhaps the largest are that Cholera is not thought to have been around long enough to lead to the relatively high frequencies of cystic fibrosis in caucasian populations and there is some evidence the allele had high frequencies before the emergence of cholera. The same allele has been hypothesized to also confer some protection against other diseases that lead to diarrhea and dehydration (eg Typhoid fever and E.coli)

A third possible example of heterozygote advantage is Tay Sachs disease in European Jews originally from Eastern Europe. Heterozygotes are hypothesized to be more resistant to Tuberculosis, which had a high prevalence in this area in the past.

(Speaking of Tuberculosis, check out yesterday's Doonesbury cartoon)