The Cystic Fibrosis Heterozygote Advantage: A Synthesis of Ideas

Abstract

Abstract: It has been proposed that the high frequency of Cystic Fibrosis (CF) is due to a selective advantage in the heterozygous state. This research supports this proposition and attempts a holistic perspective in reviewing the various models proposed. The pathophysiology, molecular and population genetics and the epidemiology are all demonstrated to be key components when evaluating the carrier advantage of CF.Various hypotheses are reviewed and critically evaluated. The most recent explanation proposed -- that CF affords protection against cholera -- is a main focus of this research. While this theory has been supported by molecular in vivo experiments, the historical epidemiology of both CF and cholera argue against the acceptance of this model. The conclusion is drawn that while the cholera hypothesis is attractive, further research will be necessary before it can either be accepted or rejected as the explanation for high frequencies of CF.IntroductionCystic Fibrosis is the most common autosomal recessive trait among Caucasians. The term will be used in reference to those individuals of European descent. In Caucasian populations approximately 4 to 5 percent of individuals are heterozygous for CF, i.e., they carry a mutated copy of the cystic fibrosis gene. This results in approximately one in every 2 000 to 2 500 live births being homozygous for CF, i.e., expressing the disorder in full (Gabriel et al., 1994: 107). The frequency of a genetic disorder due to random mutation never exceeds 1 percent. The cystic fibrosis (CF) mutation in the homozygous state is lethal before reproduction. Because homozygous CF individuals have rarely survived to reproduce, the mutations they carry have not been passed on to the next generation. The deleterious nature of the disease should therefore maintain the mutation at a low frequency in the population. However, CF is being maintained at very high frequencies in Caucasian populations. This has led to speculation about a heterozygote (carrier) advantage for the cystic fibrosis mutation. If an additional pressure were selecting for the mutation then the disease would be maintained as a balanced polymorphism, which we may define as a state of equilibrium in which gene frequencies are maintained by a balance between mutation and selection (Saunders, 1994).The prototype for a genetic disease with a heterozygote advantage is, of course, sickle cell anemia. Twenty percent of the population in malarial areas carry the sickle cell allele with up to 40 percent carrying it in some African populations. The explanation for the high frequency is that people who are heterozygous for sickle cell anemia are able to survive and reproduce in areas where malaria is endemic. This is a result of the sickle cell trait in the heterozygous state affording protection against the malaria parasite which matures in the red blood cells (Allison, 1954: 291).This is also the explanation given for the high frequencies of G-6-PD and thalassemia in these areas.The high frequency of CF coupled with the discovery of the location of the gene which causes the disease in 1989 (Rommens et al., 1989), has generated a great deal of interest in this disease among researchers, as well as in the popular press (Glausiusz, 1995: 30-31). The research presented in this paper attempts a holistic synthesis and review of the many disciplines which study this disease. When trying to discover what might be a possible heterozygote advantage for cystic fibrosis, a broad understanding of the disorder is necessary. Researchers must consider how the disease manifests itself clinically, how it works on a molecular level, the historical epidemiology of it and how it is distributed in populations around the world today. Understanding these aspects of the disease provides a strong basis from which inferences may be drawn.Researchers seeking the heterozygote advantage of CF have come up with different hypotheses. …