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?