So I’ve been extremely busy the last few weeks trying to get everything wrapped by the deadlines that always come with the end of the semester. I just completed working on a paper for Molecular Biology about cystic fibrosis. Before I go any further, let me define just a few genetic concepts using the analogy of shoes, so that I don’t have to worry about readers being completely lost. Thirty seconds of biology won’t kill you, I promise.
- allele – alternative version of gene. If shoes are a gene, then cowboy boots, sandals, and tennis shoes would be alleles. For any given gene, you’ve got two alleles – one from mom and one from dad.
- homozygous – you’ve got the same two alleles for a given gene. You’re wearing matching tennis shoes.
- homozygous dominant – both of your alleles make the same working protein. You’re wearing matching tennis shoes.
- homozygous recessive – both of your alleles either don’t make a protein or make a protein that doesn’t work. You’re not wearing any shoes and have two bare feet.
- heterozygous – you’ve got different alleles for a given gene. You’re wearing one cowboy boot and one sandal, or one cowboy boot and one bare foot.
Cystic fibrosis is a homozygous recessive trait. You’ve got to get two CF alleles that don’t work right to get the disease.
Enough of the background information. I was focusing on one thing in particular. The allele that causes CF is a lot more common in European populations than one might expect for such a seemingly detrimental allele. In fact in Caucasian populations, the frequency of carriers can reach as high as 1 in 25 people! That’s pretty darn high when you consider that if two copies of those alleles end up in a child, that child’s dead before they’re three years old. How do you explain that? The likely explanation is what’s called heterozygous advantage, where heterozygous are better fit for their environment than homozygotes.
The classic example of this is sickle-cell anemia and malaria. It turns out that heterozygotes are much less likely to get malaria than homozygotes. I was looking on the internet for a reference to the scientific literature that discusses heterozygous advantage with sickle-cell anemia, when I came across this page from the website of a medical doctor at Harvard. (Incidentally, it’s a nice lengthy discussion if you want to learn more about natural selection favoring a detrimental allele through heterozygous advantage.) But it contained one little illustration that immediately caught my eye and made me laugh out loud.
Figure 2. Schematic representation of the effect of the sickle cell hemoglobin gene on survival in endemic malarial areas. People with normal hemoglobin (left of the diagram) are susceptible to death from malaria. People with sickle cell disease (right of the diagram) are susceptible to death from the complications of sickle cell disease. People with sickle cell trait, who have one gene for hemoglobin A and one gene for hemoglobin S, have a greater chance of surviving malaria and do not suffer adverse consequences from the hemoglobin S gene.
Oh, okay. I get it. But still, it’s a rather odd and comical choice for the illustration. It tickled my funny bone so much that I had to share.
So getting back to cystic fibrosis, the main evidence for heterozygous advantage comes from a study1 which showed that the bacteria which cause typhoid fever use the protein that the cystic fibrosis gene creates. Thus, if you’re heterozygous (one good copy, one bad) then you have less of that protein on the surface of your cells lining your digestive tract. Using mice as a model, they showed that typhoid bacteria are 86% less successful at infecting cells of heterozygotes. They also showed that mice containing two bad copies of the CF gene were not infected by any typhoid bacteria. Thus typhoid are using that protein as their entries into the cell.
As typhoid is a disease that has ravaged Europe for many years in premodern time, it now becomes understandable why selection would increase the frequency of the CF allele in European populations.
1 Pier, G.B., M. Grout, T. Zaidi, G. Meluleni, S.S. Mueschenborn, G. Banting, R. Ratcliff, M.J. Evans, W.H. Colledge. 1998. Salmonella typhi uses CFTR to enter intestinal epithelial cells. Nature 393: 79–82.