However, there is an important trade-off to consider, as an increased mutation rate will come at the cost of increased mutational load [ 52], in which the random deleterious mutations accumulate in the genome, conferring a large fitness cost.
Therefore, our model predicts that if tumour growth is initiated without an increased mutation rate (Bodmer et al. 2008), then a mutator phenotype is likely to feature only later in progression, which is again consistent with the data from Barrett's oesophagus (Maley et al. 2004, 2006).
Our observation of a higher number of genetic changes in tumors of lower grade could be a consequence of an increased mutation rate in early tumorigenesis due to acquisition of a mutator phenotype.
Thus, there was no evidence of an increased mutation rate or microsatellite instability in Msh2−/− murine embryonic fibroblast (MEF) clones overexpressing hNOX1, despite an increased level of 8-oxodG [ 16].
Genetic changes in bacterial genomes come from either random mutation during replication or "stress-directed mutation", where genes involved in a particular growth-limiting process have an increased mutation rate.
Firstly, the integrity of replication will be relatively impaired and the variant will exhibit an increased mutation rate.
First, an increased mutation rate should lead to a simple increase in the rate at which cheating mutations are generated.
The presence of readily melting DNA correlates with a higher AT content compared to the genome average and suggests that this region may be less thermodynamically stable and likely subject to an increased mutation rate [37].
The question of mutation rate optimization is compounded by the problem of causality, to the extent that an increased mutation rate cannot be selected for in a current organism on the basis of that organism's descendants' increased ability to radiate into new ecological niches.
We determine the circumstances that select for an increased mutation rate and the circumstances when an increased mutation rate accelerates tumour progression.
Some statistical problems relevant to the detection of an increased mutation rate are also discussed.
