Chapter 4: Gene Function and Protein Structure

Gene Function and Protein Structure begins with the early work of Archibald Garrod, who formulated the concept of inborn errors of metabolism through his study of alkaptonuria, suggesting that genetic diseases result from the absence of specific metabolic enzymes. The core of the chapter focuses on the landmark experiments of Beadle and Tatum using the haploid fungus Neurospora crassa. By inducing mutations with X-rays and isolating auxotrophic mutants—strains unable to grow on minimal medium without specific nutritional supplements—they successfully genetically dissected biochemical pathways. This work led to the formulation of the one-gene-one-enzyme hypothesis, which posited that each gene encodes a specific enzyme. The narrative explains how this hypothesis was subsequently modified to the one-gene-one-polypeptide hypothesis to account for proteins composed of multiple subunits and non-enzymatic structural proteins. The text explores various human genetic disorders to illustrate these concepts, including Phenylketonuria (PKU), caused by a defect in phenylalanine hydroxylase, and Tay-Sachs disease, a lysosomal storage disorder involving hexosaminidase A. It also details defects in non-enzymatic proteins, such as the hemoglobin mutation responsible for sickle-cell anemia (a glutamic acid to valine substitution) and the CFTR chloride channel defect in cystic fibrosis (specifically the Delta F508 deletion). Furthermore, the chapter covers the pleiotropic effects of these mutations and the use of electrophoresis to analyze protein variants. Finally, the discussion extends to practical applications in medical genetics, including genetic counseling, carrier detection, and fetal analysis methods such as amniocentesis and chorionic villus sampling, alongside emerging fields like metabolomics which study the entirety of metabolic intermediates in an organism.