Metabolic interference and the + - heterozygote. A hypothetical form of simple inheritance which is neither dominant nor recessive

Another form of simple inheritance is possible which is neither dominant nor recessive and in which the heterozygote alone is affected. In this system, homozygosity for the normal allele AA, and the mutant allele A'A', give a normal phenotype. Only the heterozygous condition AA' (+ - heterozygote) produces an abnormal phenotype because the two alleles, when present together, interact to produce a harmful effect. This metabolic interference may occur because the two allelic genes code for different subunits of a multisubunit enzyme or structural protein. The two genes may interact in other ways and need not be allelic. The various matings result in pedigrees, which in some cases resemble those of dominant or recessive inheritance, and in other cases are unique. Certain unusual pedigrees in the literature are compatible with the predictions of metabolic interference and are difficult to explain by other means. Metabolic interference is most likely to be recognized as: (1) a disorder limited to females, apparently dominant or recessive, especially a disorder passed to affected females through unaffected males; (2) a disorder occurring in all members of a large sibship with normal parents; (3) a disorder occurring in all members of a large sibship with one parent similarly affected; (4) an apparently dominant disorder with females more severely affected than males; (5) an apparently X-linked dominant disorder in which males are not more severely affected; or (6) any autosomal dominant disorder. Examples of possible metabolic interference exist among disorders of animals, and the mechanism could be a factor in speciation. Tissue culture methods could be used to demonstrate metabolic interference.