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

Fabrizio Pucci,Marianne Rooman

doi:10.1186/s12864-019-5867-y

Abstract

BackgroundIt is nowadays clear that single base substitutions that occur in the human genome, of which some lead to pathogenic conditions, are non-random and influenced by their flanking nucleobase sequences. However, despite recent progress, the understanding of these "non-local" effects is still far from being achieved.ResultsTo advance this problem, we analyzed the relationship between the base mutability in specific gene regions and the electron hole transport along the DNA base stacks, as it is one of the mechanisms that have been suggested to contribute to these effects. More precisely, we studied the connection between the normalized frequency of single base substitutions and the vertical ionization potential of the base and its flanking sequence, estimated using MP2/6-31G* ab initio quantum chemistry calculations. We found a statistically significant overall anticorrelation between these two quantities: the lower the vIP value, the more probable the substitution. Moreover, the slope of the regression lines varies. It is larger for introns than for exons and untranslated regions, and for synonymous than for missense substitutions. Interestingly, the correlation appears to be more pronounced when considering the flanking sequence of the substituted base in the 3’ rather than in the 5’ direction, which corresponds to the preferred direction of charge migration. A weaker but still statistically significant correlation is found between the ionization potentials and the pathogenicity of the base substitutions. Moreover, pathogenicity is also preferentially associated with larger changes in ionization potentials upon base substitution.ConclusionsWith this analysis we gained new insights into the complex biophysical mechanisms that are at the basis of mutagenesis and pathogenicity, and supported the role of electron-hole transport in these matters.

Highlights

It is nowadays clear that single base substitutions that occur in the human genome, of which some lead to pathogenic conditions, are non-random and influenced by their flanking nucleobase sequences
Mutation frequencies in the SBS dataset We have set up a dataset of single base substitutions which occur in genes, i.e. in exons, introns or untranslated regions (UTRs), and are annotated as pathogenic, benign, of unclear significance, etc, as described in Methods
Let us start by analyzing which of the base pairs and which of the dinucleotide or trinucleotide stacks mutate significantly more or less frequently than expected from random substitutions in the different gene regions

Summary

Introduction

It is nowadays clear that single base substitutions that occur in the human genome, of which some lead to pathogenic conditions, are non-random and influenced by their flanking nucleobase sequences. The effects of these mutation processes are potentially responsible for a range of diseases such as cancer and various neurodevelopment disorders. The rationalization of these mechanisms is very complex, since single base substitutions (SBSs) can be triggered by a wide range of factors, e.g. chemical species, physical agents or enzymes, through mechanisms such as base deamination, base depurination, or tautomeric shifts. These effects depend on the nucleotide sequence context [1, 2]. One of the wellknown mutational signatures observed in cancer genomes

Methods

Results

Conclusion