Genetics versus "Reverse Genetics":
Genetics and molecular biology of Alkaptonuria, an inborn error of metabolism:


    Archibald Garrod in 1902 observed the "Black Urine Disease" in his patients (Step 1) . From the pattern of inheritance (pedigree) observed in families under his care (Step 2), he deduced that the disease  was inherited as a simple recessive trait, in the manner described by Mendel, whose work at the time had been recently rediscovered. Chemical analysis of their urine suggested a biochemical basis, that the disease was caused by build-up of the substance alkapton (Step 3). Garrod had no knowledge of the biochemical nature of genes. [We now call alkapton homogentistic acid.]

    Subsequent investigation mapped the gene to a physical location (locus) in a particular band on the long arm of Chromosome 3 (3q2) (Step 4). Isolation of the gene in another organism (Steps 5-7) provided molecular probes to further localize the gene to a  small region within the 3q2 band (Steps 8 & 9). Detailed analysis of the region shows that the enzyme defects are due to specific mutations in particular exons (Step 10). On investigation, some members of the families studied have an unusual phenotype, "Black Urine Disease." DNA sequencing of those individuals in a pedigree similar to those studied by Garrod demonstrates that parents and offspring have the expected phenotypes for their observed genotypes.

    Garrod's analysis is classical Genetics: he observed the pattern of inheritance of the phenotype in order to infer the the nature of the biochemical genotype. The molecular analysis is "reverse Genetics": detailed study of the gene locus genotype predicts how it produces a disease phenotype.

    Homework: Explain the connection between Steps 10 & 11 in detail: How do the alleles identified in Step 10 result in the phenotypes shown in Step 11



Archibald Garrod  (ca. 1908)

Figures ©2002 by Griffiths et al.; All text material ©2011 by Steven M. Carr