Dominance (genetics) - Dominant and Recessive Genetic Diseases in Humans

Dominant and Recessive Genetic Diseases in Humans

In humans, many genetic traits or diseases are classified simply as "dominant" or "recessive." Especially with respect to so-called recessive diseases, this can oversimplify the underlying molecular basis and lead to misunderstanding of the nature of dominance. For example, the genetic disease phenylketonuria (PKU) results from any of a large number (>60) of alleles at the gene locus for the enzyme phenylalanine hydroxylase (PAH). Many of these alleles produce little or no PAH, as a result of which the substrate phenylalanine and its metabolic byproducts accumulate in the central nervous system and can cause severe mental retardation if untreated.

The genotypes and phenotypic consequences of interactions among three alleles are shown in the following table:

Genotype PAH activity conc PKU ?
AA 100% 60 uM No
AB 30% 120 uM No
CC 5% 200 ~ 300 uM Hyperphenylalaninemia
BB 0.3% 600 ~ 2400 uM Yes

In unaffected persons homozygous for a standard functional allele (AA), PAH activity is standard (100%), and the concentration of phenylalanine in the blood is about 60 uM. In untreated persons homozygous for one of the PKU alleles (BB), PAH activity is close to zero, ten to forty times standard, and the individual manifests PKU.

In the AB heterozygote, PAH activity is only 30% (not 50%) of standard, blood is elevated two-fold, and the person does not manifest PKU. Thus, the A allele is dominant to the B allele with respect to PKU, but the B allele is incompletely dominant to the A allele with respect to its molecular effect, determination of PAH activity level (0.3% < 30% << 100%). Finally, the A allele is an incomplete dominant to B with respect to, as 60 uM < 120 uM << 600 uM. Note once more that it is irrelevant to the question of dominance that the recessive allele produces a more extreme phenotype.

For a third allele C, a CC homozygote produces a very small amount of PAH enzyme, which results in a somewhat elevated level of in the blood, a condition called hyperphenylalaninemia, which does not result in mental retardation.

That is, the dominance relationships of any two alleles may vary according to which aspect of the phenotype is under consideration. It is typically more useful to talk about the phenotypic consequences of the allelic interactions involved in any genotype, rather than to try to force them into dominant and recessive categories.

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