Influence of Electron–Holes on DNA Sequence-Specific Mutation Rates

Abstract

Biases in mutation rate can influence molecular evolution, yielding rates of evolution that vary widely in different parts of the genome and even among neighboring nucleotides. Here, we explore one possible mechanism of influence on sequence-specific mutation rates, the electron–hole, which can localize and potentially trigger a replication mismatch. A hole is a mobile site of positive charge created during one-electron oxidation by, for example, radiation, contact with a mutagenic agent, or oxidative stress. Its quantum wavelike properties cause it to localize at various sites with probabilities that vary widely, by orders of magnitude, and depend strongly on the local sequence. We find significant correlations between hole probabilities and mutation rates within base triplets, observed in published mutation accumulation experiments on four species of bacteria. We have also computed hole probability spectra for hypervariable segment I of the human mtDNA control region, which contains several mutational hotspots, and for heptanucleotides in noncoding regions of the human genome, whose polymorphism levels have recently been reported. We observe significant correlations between hole probabilities, and context-specific mutation and substitution rates. The correlation with hole probability cannot be explained entirely by CpG methylation in the heptanucleotide data. Peaks in hole probability tend to coincide with mutational hotspots, even in mtDNA where CpG methylation is rare. Our results suggest that hole-enhanced mutational mechanisms, such as oxidation-stabilized tautomerization and base deamination, contribute to molecular evolution.

Relation between DNA ionization potentials, single base substitutions and pathogenic variants

“…Exposure to high-energy radiations or to reactive oxygen species generated as by-products of the cellular metabolism can lead to DNA ionization through the creation of electron holes. These holes then migrate along the DNA stack until they remain (more or less) localized in a potential well [11–13].…”

“…Although some electron holes have solely a damaging effect and need to be repaired by specific enzymes [14], others seem to have a positive role as suggested more than a decade ago by the finding that the amount of reactive oxygen species likely to create such holes is regulated by specific proteins and is, for example, higher during cell differentiation [15]. The important role played by electron-hole transfer in various biological processes appears increasingly clear [16, 17] and more specifically, in the sequence dependence of the SBSs [2, 12, 13, 18] and their possible pathogenicity [12, 19].…”

Low frequency mitochondrial DNA heteroplasmy SNPs in blood, retina, and [RPE+choroid] of age-related macular degeneration subjects

“…The mechanism behind developing ‘hot-spots’ is not understood. Villagran and Miller have used computational DNA hole spectroscopy to show that a positive charge site is created when an electron is removed and this may trigger mtDNA replication base pair mismatching and possible disease associated mutations [ 60 , 61 ]. Further work is needed to clarify the importance of heteroplasmy SNP ‘hot-spots’ in aging and diseases.…”

Physicochemical Foundations of Life that Direct Evolution: Chance and Natural Selection are not Evolutionary Driving Forces

“…It has been proposed that these mutations (i) are induced by ROS-mediated deamination of (methyl) cytosine, leading to C > T mutations, or incorporation of oxidized guanine during replication, leading to G > A mutations and (ii) protect cancer cells from the high levels of ROS by increasing the global antioxidant capacity of the cancer proteome [81][82][83][84][85]. Interestingly, CGN codons (that encode Arg) seem to be particularly sensitive to oxidation because of their physicochemical properties [81,86]. Furthermore, (methyl)cytosine deamination produces CG > TA mutations, and thereby can increase the nitrogen availability required by proliferative cancer cells, as it reduces the nitrogen-richer C:G pairs in favor of the nitrogen-poorer T:A pairs, as well as the GC-rich sequences that contain codons (e.g., CGN) corresponding to nitrogen-rich amino acids (e.g., Arg) [81].…”