BIO 2311 J. G. Burr
(Just for your interest; “not on the test.”)
What is good about cystic fibrosis?
(Summary of the article by Paul M. Quinton, Current Biology, 1994, vol 4, No. 8, p. 742)
The gene responsible (when mutated) for cystic fibrosis (CF) encodes the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR): a chloride channel regulated by both ATP and phosphorylation (by Protein Kinase-A: “PK-A”). This channel is predominantly responsible for intestinal fluid secretion. Cholera toxin elevates cytoplasmic cAMP levels, thus activating PK-A, which in turn phosphorylates CFTR, thus activating this Cl- channel and causing fluid secretion, leading to diarrhea.
One out of every 2,500 Caucasians of northern European descent suffers from cystic fibrosis (ie, they are “homozygous” for a mutated CFTR gene); this implies that one out of every 20 northern European individuals carries a bad copy of the gene (ie, is “heterozygous” for the gene) (Hardy-Weinberg calculation). This is a much higher frequency than one would expect for a disease-causing gene; interestingly, this relatively high rate of occurrence is not found in other populations around the world. Why have mutated CFTR genes not been selected out of the northern European population? Maybe, as is the case with the sickle cell anemia gene (which encodes a mutant hemoglobin), heterozygotes have some selective advantage? (Individuals who are heterozygous for the sickle cell gene resist malarial infections; hence the prevalence of this gene in African populations where malaria is endemic. It’s not good if you are homozygous [you get anemia]; but many more people will be heterozygous, and that provides protection.) What might be the selective advantage conferred by the CF gene (for a heterozygote)?
Intestinal epithelial cells from CF patients are resistant to cholera toxin. So CF heterozygotes presumably have a better chance to survive cholera-induced diarrhea attacks. A mere 2% increase in the survival rate would be sufficient to maintain the current gene frequency. If this is the case, why is the mutated CF gene not equally common in other areas of the world, especially in populations in Southeast Asia which are frequently exposed to cholera?
Maybe it is because CF heterozygotes lose more salt in their sweat. Salt is historically a rare commodity. In cold climates, individuals sweat less; people sweat more in hot climates. Maybe in hot climates this mild disadvantage for CF heterozygotes (losing more salt in sweat) outweighs the mild advantage (better diarrhea survival) that heterozygotes have?