In 1902, shortly after the rediscovery of Gregor Mendel's work by William Bateson1 and just a few years after the word biochemistry was first coined, Archibald Garrod2, a practicing physician at the Hospital for Sick Children in London, England, proposed that alkaptonuria, a condition characterized by black urine, was inherited in humans as a Mendelian recessive trait. In so doing, he identified the first “inborn error of metabolism”. Like Mendel's work, this finding was largely ignored until the Nobel prize winning work of Beadle and Tatum (Physiology or Medicine, 1958) who proposed the one gene, one enzyme hypothesis, which states that each gene is responsible for directing the building of a single, specific enzyme.
Based on the incidence of alkaptonuria, Garrod argued that there were “good reasons for thinking that alkaptonuria is not the manifestation of a disease but is rather of the nature of an alternative course of metabolism, harmless and usually congenital and lifelong”. The very large proportion of alkaptonuric individuals who were the children of first cousins suggested to Bateson that the law of heredity discovered by Mendel was at work. He wrote, “Now there may be other accounts possible, but we note that the mating of first cousins gives exactly the conditions most likely to enable a rare, and usually recessive, character to show itself. If the bearers of such a gamete mate with individuals not bearing it the character will hardly ever be seen; but first cousins will frequently be the bearers of similar gametes, which may in such unions meet each other and thus lead to the manifestation of the peculiar recessive characters in the zygote”.
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