DNA molecule Gene 1 Gene 2 Gene 3 DNA template strand TRANSCRIPTION TRANSLATION mRNA Protein Codon Amino acid 1

Second mRNA base First mRNA base (5 end of codon) Third mRNA base (3 end of codon) 2

Wild-type 3 DNA template strand Stop Carboxyl end Amino end Protein mRNA A instead of G U instead of C Silent (no effect on amino acid sequence) Stop T instead of C A instead of G Stop Missense A instead of T U instead of A Stop Nonsense No frameshift, but one amino acid missing (3 base-pair deletion) Frameshift causing extensive missense (1 base-pair deletion) Frameshift causing immediate nonsense (1 base-pair insertion) Stop missing Stop Extra U Extra A (a) Base-pair substitution(b) Base-pair insertion or deletion 3

Wild-type hemoglobin DNA mRNA Mutant hemoglobin DNA mRNA CCTT T T G G A A A A AA A GG U Normal hemoglobinSickle-cell hemoglobin Glu Val 4

Primary structure Secondary and tertiary structures Quaternary structure Normal hemoglobin (top view) Primary structure Secondary and tertiary structures Quaternary structure Function  subunit Molecules do not associate with one another; each carries oxygen. Red blood cell shape Normal red blood cells are full of individual hemoglobin moledules, each carrying oxygen. 10 µm Normal hemoglobin     Val His Leu ThrPro Glu Red blood cell shape  subunit Exposed hydrophobic region Sickle-cell hemoglobin   Molecules interact with one another and crystallize into a fiber; capacity to carry oxygen is greatly reduced.   Fibers of abnormal hemoglobin deform red blood cell into sickle shape. 10 µm Sickle-cell hemoglobin GluPro Thr Leu His Val