Evidence Concerning the Inadequacy of Mutation as an Explanation of the Frequency of the Sickle Cell Gene in the Belgian Congo

Abstract

It is pointed out that there are two outstanding (and not mutually exclusive) possible explanations for the persistence of the sickle cell gene in the face of strong negative natural selection. These are (1) "balanced polymorphism," and (2) a high spontaneous mutation rate. In Léopoldville, Belgian Congo, approximately 25 per cent of the natives exhibit the sickling phenomenon. Over a two and one-half year period 261 patients with sickle cell disease, distributed among 243 families, were seen at the Institute of Tropical Medicine in Léopoldville. A total of 233 of the 243 mothers of the patients in this series was tested for the sickling phenomenon. Only two failed to sickle. Hemoglobin from these two women was normal on paper electrophoresis. The occurrence of these two exceptional mothers can be explained on the basis of mutation at some stage of oogenesis resulting in a sickle cell gene. Alternate possible explanations include (1) transmission by the mother of some other abnormal gene affecting hemoglobin synthesis, (2) occurrence in the mother of a genetic modifier of the effects of the sickle cell gene, (or its normal allele), and (3) unreported adoption. These data make possible a preliminary calculation of the extent to which mutation may be responsible for maintaining the sickle cell gene. Calculations based on the assumption that both these exceptional mothers indicate the occurrence of a mutation will lead to maximal estimates of the rate of mutation of the sickle cell gene. This maximal estimate is 1.7 x 10^-3 per gene per generation. This rate, although very high by the usual standards of human mutation rates, is only approximately one-tenth that necessary to offset natural selection in a population with 25 per cent sickling.