How do mutations occur

Figure 11.17(a) reminds us how the code in DNA is transcribed into messenger RNA and then translated into a sequence of amino acids. Each time the DNA undergoes replication, this same sequence will be passed on, coding for the same sequence of amino acids. Occasionally, mistakes occur during replication. Cells have repair mechanisms to minimise these errors, but what happens if a mistake still slips through? In Figure 11.17(b), we can see the effect of one nucleotide being inserted into the strand instead of another. When the next round of replication occurs, the modified DNA will act as a template for a newly synthesised strand, which at this position will be made complementary to the new, 'wrong' base, instead of the original one, and thus the mistake will be perpetuated.

This is an example of the simplest type of mutation, a point mutation, where one nucleotide has been substituted by another. The example shown is a missense mutation, which has resulted in the affected triplet coding for a different amino acid; this may or may not have an effect on the phenotype of the organism. RNA polymerase, which transcribes the DNA sequence into mRNA, is unable to tell that an error has occurred, and faithfully

A missense mutation alters the sense of the message encoded in the DNA, and results in an incorrect amino acid being produced at the point where it occurs.

Box 11.6 Settling an argument: the fluctuation test

Luria and Delbrück designed the fluctuation test to show whether resistance in E. coli to the bacteriophage T1 was induced or occurred spontaneously.

Suppose we divide a broth culture of bacteria into two, then inoculate half into a flask of fresh broth, and divide the other half between a large number of smaller cultures in tubes

E. coli culture

E. coli culture

Half of culture grown up in a single large flask.

Half of culture divided between 50 small tubes.

50 samples plated out onto agar pates

Half of culture grown up in a single large flask.

Each sample plated out onto an agar plate.

50 samples plated out onto agar pates

Colony counts quite similar Colony counts highly variable

After allowing the bacteria to grow, samples are taken from tubes and flask, and spread onto a selective agar medium (one covered with T1 phage). All the plates deriving from the single bulk culture have roughly the same number of resistant colonies, but the plates resulting from the smaller, tube cultures show very variable colony counts. Although the average number of colonies across the 50 tubes is similar to that obtained from the bulk culture, the individual plate counts varies greatly, from none on several plates to over a hundred on another.

If the phage-resistance was induced by the presence of the phage, we would expect all plates in the experiment to give rise to approximately the same number of resistant colonies, as all cultures experienced the same exposure. If however, the resistant forms were spontaneously arising all the time at a low level in the population, the numbers of resistant colonies would be dependent on when, if at all, a mutation had taken place in a particular tube culture. A mutant arising early in the incubation period would give rise to more resistant offspring and therefore more colonies than one that arose later.

Figure 11.17 Mutations can alter the sense of the DNA message. (a) A short sequence of DNA is transcribed into mRNA and then transcribed into the corresponding amino acids. (b) A single base change from T to A results in a missense mutation, as a histidine is substituted for a leucine. (c) A silent mutation has altered the DNA (and therefore mRNA) sequence, but has not changed its sense. Both AGG and AGA are mRNA triplets that code for arginine. (d) A nonsense mutation has replaced a tryptophan codon with a STOP codon, hence bringing the peptide chain to a premature end

Figure 11.17 Mutations can alter the sense of the DNA message. (a) A short sequence of DNA is transcribed into mRNA and then transcribed into the corresponding amino acids. (b) A single base change from T to A results in a missense mutation, as a histidine is substituted for a leucine. (c) A silent mutation has altered the DNA (and therefore mRNA) sequence, but has not changed its sense. Both AGG and AGA are mRNA triplets that code for arginine. (d) A nonsense mutation has replaced a tryptophan codon with a STOP codon, hence bringing the peptide chain to a premature end transcribes the misinformation. The machinery of translation is similarly 'unaware' of the mistake, and as a consequence, a different amino acid will be inserted into the polypeptide chain. The consequence of expressing a 'wrong' amino acid in the protein product could range from no effect at all to a total loss of its biological properties. This can be understood in terms of protein structure (Chapter 2), and depends on whether the amino acid affected has a critical role (such as part of the active site of an enzyme), and whether the replacement amino acid has similar or different polar/non-polar properties. You may recall from the beginning of this chapter that the genetic code is degenerate, and that most amino acids are coded for by more than one triplet; this means that some mutations do not affect the amino acid produced; such mutations are said to be silent, as in Figure 11.17(c). These most commonly occur at the third nucleotide of a triplet.

Another type of point mutation is a nonsense mutation. Remember that of the 64 possible triplet permutations of the four DNA bases, three are 'stop' codons, which terminate a polypeptide chain. If a triplet is changed from a coding to a 'stop' codon as shown in Figure 11.17(d), then instead of the whole coding sequence being read, translation will end at this point, and a truncated (and probably non-functional) protein will result.

A nonsense mutation results in a 'stop' codon being inserted into the mRNA at the point where it occurs, and the premature termination of translation.

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