Mutation and DNA repair

A mutation is a sudden change in the genetic material.

Chromosomal mutations change a chromosome's structure (aberrations: a piece lost, gained or rearranged) or the number of chromosomes (aneuploidy, polyploidy). They can be seen under the microscope with banding or FISH (fluorescent labelling).

Gene (point) mutations change one or a few nucleotides:

• Addition or deletion of a base shifts the reading frame, so every codon after it is read wrongly.
• Substitution swaps one base for another. If a purine replaces a purine (or a pyrimidine a pyrimidine), it is a transition; if a purine and pyrimidine swap, it is a transversion. Sickle cell anaemia comes from a single substitution.

Spontaneous mutations can happen when a base briefly takes a rare form (a tautomer, enol or imino) and pairs wrongly during copying; after another round, a G-C pair can become A-T.

Induced mutations are caused by outside agents (Muller showed that X-rays cause them):

• X-rays break bonds and can delete bases.
• UV light joins neighbouring pyrimidines into pyrimidine dimers.
• 5-bromouracil, a base analog (it looks like thymine), mispairs with G.
• EMS adds a chemical group to guanine (alkylation), so it pairs with T.

Cells repair most damage, keeping mutation rates low:

• Base excision repair: the enzyme DNA glycosylase removes a damaged base, leaving a gap with no base (an AP site); the gap is cut, filled and sealed.
• Nucleotide excision repair: the Uvr complex cuts out a short stretch of DNA around a UV dimer.
• Mismatch repair: Mut proteins find a wrong base on the new strand (recognised because the new strand is not yet methylated) and replace it.