Harpers

362 / CHAPTER 38Hemoglobin Illustrates the Effects ofSingle-Base Changes in Structural GenesSome mutations have no apparent effect. The genesystem that encodes hemoglobin is one of the beststudiedin humans. The lack of effect of a single-basechange is demonstrable only by sequencing the nucleotidesin the mRNA molecules or structural genes.The sequencing of a large number of hemoglobinmRNAs and genes from many individuals has shownthat the codon for valine at position 67 of the β chainof hemoglobin is not identical in all persons who possessa normally functional β chain of hemoglobin. HemoglobinMilwaukee has at position 67 a glutamicacid; hemoglobin Bristol contains aspartic acid at position67. In order to account for the amino acid changeby the change of a single nucleotide residue in thecodon for amino acid 67, one must infer that themRNA encoding hemoglobin Bristol possessed a GUUor GUC codon prior to a later change to GAU orGAC, both codons for aspartic acid. However, themRNA encoding hemoglobin Milwaukee would haveto possess at position 67 a codon GUA or GUG inorder that a single nucleotide change could provide forthe appearance of the glutamic acid codons GAA orGAG. Hemoglobin Sydney, which contains an alanineat position 67, could have arisen by the change of a singlenucleotide in any of the four codons for valine(GUU, GUC, GUA, or GUG) to the alanine codons(GCU, GCC, GCA, or GCG, respectively).Substitution of Amino Acids CausesMissense MutationsA. ACCEPTABLE MISSENSE MUTATIONSAn example of an acceptable missense mutation (Figure38–4, top) in the structural gene for the β chain of hemoglobincould be detected by the presence of an electrophoreticallyaltered hemoglobin in the red cells of anapparently healthy individual. Hemoglobin Hikari hasbeen found in at least two families of Japanese people.This hemoglobin has asparagine substituted for lysineat the 61 position in the β chain. The correspondingProtein molecule Amino acid CodonsHb A, β chain61 LysineAAAorAAGAcceptablemissenseHb Hikari, β chainAsparagineAAUorAACPartiallyacceptablemissenseHb A, β chain6 GlutamateGAAorGAGHb S, β chainValineGUAorGUGHb A, α chain58 HistidineCAUorCACUnacceptablemissenseHb M (Boston), α chainTyrosineUAUorUACFigure 38–4. Examples of three types of missense mutations resulting in abnormal hemoglobinchains. The amino acid alterations and possible alterations in the respective codons are indicated.The hemoglobin Hikari β-chain mutation has apparently normal physiologic propertiesbut is electrophoretically altered. Hemoglobin S has a β-chain mutation and partial function; hemoglobinS binds oxygen but precipitates when deoxygenated. Hemoglobin M Boston, anα-chain mutation, permits the oxidation of the heme ferrous iron to the ferric state and so willnot bind oxygen at all.