January 30, 2012
Variation in the DNA that results in natural selection does not come about randomly. Where a piece of DNA is in the genome and how it is used affects its chances for being mutated. The end result is that the genomes we see today are the product of these nonrandom mutation rates.
One of the first places this became apparent was in transcribed genes. Scientists found that the transcribed strand of active genes has fewer mutations than the nontranscribed strand. They found the major reason for this was transcription-coupled repair.
Now in a new study in yeast, Agier and Fischer have shown that when a piece of DNA is replicated affects its chance of being mutated too. They compared the genomes of 39 different strains of Saccharomyces cerevisiae and found that late replicating DNA is 1.3 times more likely to be mutated compared to early replicating DNA. This is consistent with a recent study by Chen and coworkers that showed a similar result in the human genome.
This means that if a piece of DNA happens to be further away from an origin of replication, it will build up more mutations over time. And while a 1.3 fold increase in mutation rate might seem small, it is predicted to have a significant impact on genomic variation and natural selection on an evolutionary time scale.
There are a number of potential models for why late replicating DNA is more likely to be mutated. One hypothesis is that cells use different repair mechanisms at different times during S phase: cells in early S-phase repair replication errors with relatively error-free repair mechanisms like template switching with newly formed sister chromatids, while cells in late S-phase tend to rely on more error-prone translesion repair pathways.
Other possible models rely on potential differences between the cellular environment in early and late S-phase. They include altered metabolism, increased presence of single stranded DNA, or even a slow decrease in DNA repair as S-phase progresses. The researchers do not know which, if any, of these mechanisms is responsible for the change in mutation rate.
It may even be that different mechanisms are responsible in yeast and humans. Agier and Fischer found that in yeast, the leading strand had higher rates of substitution towards C and A than did the lagging strand. Chen et. al. found the opposite to be true in human cells. Either they use different mechanisms or similar mechanisms can end up with opposite results.
These findings suggest that the genomes observed today are at least partly the result of the nonrandom nature of neutral mutations. Highly expressed genes near an origin of replication are much less likely to be mutated than are genes with low expression more distant from an origin of replication.
And there are other known and yet to be discovered ways that certain DNA ends up more mutated than other DNAs. Just like in real estate, the key to mutation rate is location, location, location.
Categories: Research Spotlight
Tags: DNA replication, mutation, S phase, translesion, yeast