DNA Sequence Itself Influences Mutation Rate

In a report published online in Genome Research, researchers have identified intrinsic properties of DNA that influence mutation rate, shedding light on mechanisms involved in genome maintenance and potentially disease.

Some DNA mutations are subject to natural selection, either conferring a biological advantage that is selected for, or a negative effect that is selected against. Mutations not under selection are said to be neutral, and the rate at which neutral mutations accumulate is reflective of the true DNA mutation rate.

Interestingly, the neutral mutation rate can vary significantly between different regions of chromosomes. Sequence high in pairs of the bases C and G (CpGs) where the C's are chemically modified, have been positively correlated with mutation rate.

Walser and Furano compared the CpG content and DNA changes in inactive L1 retrotransposons shared by humans and chimpanzees.
The researchers had previously noted that the older L1s have a lower CpG content than the younger sequences as expected, but here they observed two particularly striking features: "The overall mutation rate in the older fossil sequences dropped dramatically," said Furano, indicating a certain CpG content threshold is required to affect the non-CpG mutation rate. "And most provocatively, the types of mutations changed significantly."

This means that CpGs are not only promoting mutations, but they are also influencing how the non-CpG sequences around them are being mutated, an extension of what the authors call the "CpG effect." These findings strongly support the hypothesis that the co-variation of CpG content and non-CpG mutation rate is a property of the DNA sequence itself, and not a result of the chromosomal location.

"Intriguingly, the CpG effect revealed by our studies mimics the altered mutational state that has been demonstrated for certain cancers," Furano noted.

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http://www.sciencedaily.com/releases/2010/05/100524092348.htm

Raymond Ng (42161040)