Pleiotropy

Pleiotropy describes the biological phenomenon in which a single gene, through the effects of its single protein product, ends up influencing — or is directly responsible for producing — MULTIPLE, and often seemingly quite unrelated, phenotypic characters simultaneously in the same organism. This is, in an important sense, exactly the reverse situation from polygenic inheritance (§4.9), where MANY different genes act together to influence just ONE single character; in pleiotropy, by contrast, it is just ONE single gene that ends up influencing MANY different characters at once. This happens biologically because the one protein product that a pleiotropic gene encodes very often participates in, or is required by, more than one distinct biochemical pathway operating within the body — so that when a mutation disrupts or destroys the gene's normal function, the resulting disruption has multiple, separate knock-on effects, showing up wherever in the body that particular biochemical pathway, or its downstream products, happen to be needed.

Phenylketonuria (PKU) in humans is the standard, and clinically important, textbook example of pleiotropy. PKU is caused by a mutation in a single gene, the gene that codes for the enzyme phenylalanine hydroxylase, whose normal biochemical job is to convert the dietary amino acid phenylalanine into a different amino acid, tyrosine, within the liver. When an individual inherits two copies of the non-functional mutant allele of this one gene and therefore lacks any working phenylalanine hydroxylase enzyme, phenylalanine is no longer efficiently converted to tyrosine and instead accumulates to abnormally high levels in the blood, from where it is diverted into alternative, and in this case harmful, metabolic side-pathways that produce phenylpyruvic acid and several closely related compounds. This single underlying enzyme deficiency, arising from just one mutant gene, ends up producing an entire CLUSTER of seemingly disconnected symptoms simultaneously: severe and progressive mental retardation (caused by the toxic accumulation of phenylalanine and its by-products affecting the developing brain), noticeably reduced pigmentation of the hair and skin (because the missing tyrosine, which PKU patients cannot efficiently produce from phenylalanine, is itself the essential biochemical starting material the body uses to manufacture the dark pigment melanin), and characteristic, medically diagnostic abnormalities detectable by testing the urine, since the excess phenylpyruvic acid and related compounds are excreted there. …