Mutation and Genetic Code

Comparing mutations, sudden heritable changes in a gene, against the resulting changes in the amino acid sequence of the corresponding protein has provided some of the strongest confirmation available for the validity of the genetic code, and this comparison is in fact how the close relationship between genes and DNA has been most convincingly demonstrated. The simplest kind of mutation at the molecular level is a base substitution, in which one nucleotide base is simply swapped for a different one, occurring either spontaneously or as a result of exposure to mutagenic agents. Sickle-cell anaemia in humans is the textbook example of a base-substitution mutation with a dramatic phenotypic consequence: normal human haemoglobin is built from four polypeptide chains of two distinct types, two identical alpha chains and two identical beta chains, each carrying an oxygen-binding heme group; in sickle-cell disease, a single base substitution at the sixth codon of the beta-globin gene changes that codon from GAG to GTG, which in turn changes the amino acid placed at the sixth position of the beta chain from glutamic acid to valine. This single amino-acid substitution alone is enough to make the resulting abnormal haemoglobin polymerise under low-oxygen conditions, distorting red blood cells from their normal, flexible biconcave disc shape into a rigid, sickle shape that impairs blood flow and oxygen delivery -- a single point mutation with an outsized physiological effect. A second, structurally very different category of mutation involves the insertion or deletion, rather than the substitution, of one or more bases. Because the genetic code is read in continuous, non-overlapping groups of exactly three bases starting from a fixed point, inserting or deleting any number of bases that is not an exact multiple of three shifts every codon boundary downstream of that point, garbling the entire remainder of the reading frame from the mutation site onward; this class of mutation is accordingly called a frameshift mutation. A short illustrative analogy makes the effect vivid: reading the letters 'ABC DEF GHI JKL' in fixed three-letter groups, inserting a single extra letter O between DEF and GHI shifts every subsequent group, producing the nonsensical 'ABC DEF OGH IJK L'; inserting two extra letters, OQ, at the …