DNA itself regulates the frequency of mutations
Genetic variants resulting from DNA mutations are not only the driving force of adaptation and evolution, but also the cause of many diseases. The data published on May 24 in the preliminary on-line version of the journal Genome Research in the article "The mutational spectrum of non-CpG DNA variations with CpG content" shed light on the little-studied mechanisms of regulating the frequency of mutations. The authors of the work, Jean-Claude Walser and Anthony Furano from the US National Institutes of Health, identified the "innate" features of DNA itself that affect this indicator.
Mutations that provide biological advantages to the organism, or, conversely, negatively affect its viability, are preserved or removed from the genes of the population under the influence of natural selection. Therefore, an indicator of the actual frequency of mutations is the rate of accumulation of so-called neutral mutations that are not subject to selection.
To assess the frequency of mutations, the researchers compared such neutral nucleotide sequences in species with a common ancestor – chimpanzees and humans.
The fact that the level of neutral mutations varies significantly depending on the region of the chromosome indicates the influence of the features of the DNA sequence itself on the rate of accumulation of mutations. Sequences containing a very large number of nucleic base pairs of guanine (G) and chemically modified (for example, methylated) cytosine (C), designated as CpG, are characterized by a high mutation rate. However, the mere fact of chemical modification of CpG duplets increases their susceptibility to mutations, which leads to their gradual disappearance from the genome.
The authors used this feature to study the effect of CpG duplets on the frequency of mutations in nucleotide sequences containing a small number of these duplets by carefully comparing "old" and "young" sequences.
They compared the content of CpG duplets and the number of DNA changes in inactive L1 transposons that make up the genomes of humans and chimpanzees. These ancient mobile DNA sequences, self-copied and propagated through the genome of our common ancestor, are currently passive "DNA fossils", mutations in which are neutral.
Researchers noticed even earlier that the older the L1 transposon, the fewer CpG duplets it contains. However, a more thorough comparison of the composition of the transposon sequences showed that there is a certain threshold for the content of CpG duplets, the achievement of which leads to a sharp decrease in the frequency of mutations. Even more interesting was the fact that reaching this threshold significantly changes the nature of mutations.
This means that CpG duplets not only increase the frequency of mutations of the surrounding sequence, but also affect the mechanisms of mutation occurrence. The authors dubbed this phenomenon the "CpG effect". Identification of this effect confirms the hypothesis that the frequency of mutations is determined not by the localization of a DNA fragment on a chromosome, but by the features of the DNA sequence itself.
The authors note that the CpG effect they found is very similar to the abnormal mutational status characteristic of a number of malignant tumors. They also believe that the data they have obtained will initiate work to study the mechanisms by which CpG duplets affect the frequency of mutations and the participation of these mechanisms in maintaining genome stability.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on ScienceDaily: DNA Sequence Itself Influences Mutation Rate, New Research Indicates.
28.05.2010