The capacity to blunder slightly is the real marvel of DNA. Without this special attribute, we would still be anaerobic bacteria and there would be no music.
— Lewis Thomas
The sources of mutations
DNA replication and unrepaired DNA damage
Mutations arise via two major mechanisms: base misincorporation during replication of non-damaged DNA; and accumulation of DNA damage that has not been properly repaired, leading to mutation.
Deficiencies of co-replicative repair
The rate of nucleotide misincorporation during replication is monitored by the exonuclease activity of major DNA polymerases (Pol \(\delta\) for lagging strand, Pol \(\epsilon\) for leading-strand) and by co-replicative MMR (mismatch repair).
MMR
- more proficient in removing replication errors on the lagging strand than on the leading strand
- activity correlates with the chromatin structure
Deficiencies of other DNA repair mechanisms
Male and female germlines undergo similar numbers of mitotic cell divisions by the onset of puberty (~30 to 35 divisions). Thereafter the ratio of male to female cell divisions increases rapidly with age, because of frequent mitotic divisions of spermatogonial stem cells (an estimated 23 divisions per year) and the absence of mitosis of female germ cells over the same period.
Paternal mutations: 75-80%, no significant effect of paternal age
Variation in mutation rate
Estimation of germline mutation rate
Variation along the genome
CpG to TpG
Deamination of a mC creates a T:G mismatch. Erroneous repair of these by BER to T:A will lead to mutation (independent of replication, track time rather than the number of cell divisions). Mismatches formed immediately before cell division and repaired until replication also lead to mutation (track cell divisions because BER is efficient at short timescales). During replication, the deamination rate is probably increased for single-stranded DNA, and the lagging strand is exposed to the single-strand conformation during replication stress. Moreover, mC may be an inferior template for polymerases and could lead to misincorporation opposite mC.