The rise and fall of the common disease-common variant (CD-CV) hypothesis: How the sickle cell disease paradigm led us all astray (or did it?)

The common disease-common variant (CD-CV) hypothesis requires an explanation for the origin of the variation observed, since substantial neutral, but not deleterious, variation, that is, several alleles each at moderate to high frequency, can be maintained at any gene/locus by mutation. It is argued here that the guiding principle, not always stated, has been balancing selection, influenced by the well-established cases of deleterious alleles maintained through heterozygous advantage in the face of strong malarial selection against normal alleles. It is further argued that, although balanced polymorphisms have indeed arisen and reduced population loss through infectious disease, the history of balance in other contexts should have prevented acceptance of any hypothesis that generalized such a specific mechanism. Finally, it is suggested that in the present state of knowledge no single hypothesis for the genetical contribution to common disorders is justifiable.