DNA spontaneous mutation and its role in the evolution of GC-content: assessing the impact of the genetic sequence

Abstract

The structure of DNA is not constantly at its equilibrium point but evolves with time. It is generally accepted that evolution induces a decrease of the guanine-cytosine (GC) content and a concomitant increase of the adenine-thymine (AT) ratio through a biased GC → AT mutation process. Unfortunately, the mechanism behind this natural alteration of the stored genetic information is not fully understood. Here, we use a hybrid QM:QM' approach to assess the link between one of the sources of the spontaneous mutation, the so-called G*C* rare tautomers that arise from a double proton exchange between the bases, and the evolution of the GC-content. Our simulations indicate that the G*C* mutation is mainly accumulated in GC-rich regions rather than being randomly spread, and consequently the GC → AT error tends to locate in coding fragments. That specific preference is indirectly induced by the base pairs containing the mutated point, as they tune the structure of the first hydration-shell that solvates the reactive base pair undergoing tautomerisation. The reorganisation of the explicit water molecules eventually modifies the energy barriers as well as the stability of the genetic error during the process.

Next generation sequencing of benzo(a)pyrene-induced lacZ mutants identifies a germ cell-specific mutation spectrum

“…Other proposed mechanisms for the G:C to A:T spontaneous mutation bias include DNA damage from ROS34, or G:C tautomerization caused by proton transfer across the base-pair hydrogen bonds2935. In the present study, there was a marginally significant enrichment (p = 0.066) in the proportion of G:C to A:T transitions that occurred at dipyrimidine sites.…”

Theoretical thermodynamic study of the adenine-thymine tautomeric equilibrium: Electronic structure calculations and steered molecular dynamic simulations

“…Therefore, the canonical and noncanonical forms of these bases will be conditioned by the presence of the aqueous medium capable of modifying the stability and equilibrium constants of these tautomeric processes . It has been shown that other effects such as the base pair stacking in DNA strands have relevance in proton transfer reactions …”

A novel conception for spontaneous transversions caused by homo-pyrimidine DNA mismatches: a QM/QTAIM highlight

“…An intriguing theme of the origin of the spontaneous point mutations has excited researches' mind during several decades suggesting DNA mispairs as their source [1][2][3][4][5][6]. Characterizing current state of this biologically important area of knowledge, it can be certainty stated that one of the stumbling stones in the theory of spontaneous point mutagenesis, which slowly gets on its feet, is understanding of the nature of the spontaneous transversions [7][8][9][10] caused by the homo-pyrimidine DNA base mispairs.…”

“…Their structures are stabilized by strong electrostatic interactions (~ 100 kcal·mol -1 ) and four intermolecular H-bonds [41], whose contribution to the interaction energy is not decisive (Tables S1, S3). High stability of these TSs excludes direct participation in these tautomerisation processes of the endogenous water molecules as active participants of these events [42] and allows to consider the influence of the stacking interactions with neighboring Watson-Crick base pairs [5,6,43,44] on the course of these tautomerisation reactions as slight perturbation. It is important that both Т·Т(w)↔Т·Т*(WC) and Т·Т(w)↔Т* O2 ·Т(WC) tautomerisation processes occur by the non-dissociative mechanism (Figs.…”

“…These TSs are stabilized by strong electrostatic interactions (~ 100 kcal·mol -1 (Table S3)) involving intermolecular H-bonds of medium strength that, similarly to the transformations of the T·T(w) mispair, excludes direct participation of the water molecules in these tautomerisation processes and indicates the negligible impact of the π-π stacking interactions [5,43,44] and sequence [6] on the cosidered tautomerisation processes.…”