Letter: Frequency of cystic-fibrosis gene.

An unsolved problem in human population genetics is the high frequency of 
the gene for cystic fibrosis (C.F.) in Caucasians. Whereas the gene 
frequency is probably low enough in non-Caucasians to be maintained by 
recurring mutation, this is not the case in Caucasians, where the 
carrier frequency is approximately 1 in 25. In order to establish 
a stable genetic polymorphism for a gene where the homozygous state 
is lethal, some degree of heterozygote advantage must exist, and it 
has been suggested that C.F. heterozygotes have a higher reproductive fitness 
than normal individuals. It is not possible, of course, to know 
exactly how stable the C.F. polymorphism is, and one cannot exclude 
the possibility that some form of heterozygote advantage has existed at 
some time in the past and no longer exists today. We 
should like to suggest a possible explanation which has much in 
common with the generally accepted explanation for the very high frequency 
of the sickle-cell gene in certain populations. In the latter case, 
heterozygotes have an increased resistance to a particular type of malaria. 
Patients with C.F. and heterozygous carriers have been found to have, 
in their serum, a substance (probably a protein) that agglutinates Proteus 
vulgaris. Immunological cross-reactivity between certain strains of Proteus (e.g., OX 19) 
and Rickettsia prowazeki has long provided the basis of a serological 
test for typhus (Weil-Felix reaction). Thus it is conceivable that the 
C.F. heterozygote might have an increased innate ability to counter infection 
by R. prowazeki. Although typhus is known in many parts of 
the world, it seems to have been predominantly endemic and epidemic 
in the temperate regions inhabited by Caucasian peoples. Some areas where 
it is now endemic, such as South America, first experienced the 
disease after it had been introduced by Europeans. This would seem 
to be compatible with the observed higher C.F. gene frequency in 
Caucasians than in other groups. 