Abstract
We report on a new technique, computational DNA hole spectroscopy, which creates spectra of electron hole probabilities vs. nucleotide position. A hole is a site of positive charge created when an electron is removed. Peaks in the hole spectrum depict sites where holes tend to localize and potentially trigger a base pair mismatch during replication. Our studies of mitochondrial DNA reveal a correlation between L-strand hole spectrum peaks and spikes in the human mutation spectrum. Importantly, we also find that hole peak positions that do not coincide with large variant frequencies often coincide with disease-implicated mutations and/or (for coding DNA) encoded conserved amino acids. This enables combining hole spectra with variant data to identify critical base pairs and potential disease ‘driver’ mutations. Such integration of DNA hole and variance spectra could ultimately prove invaluable for pinpointing critical regions of the vast non-protein-coding genome. An observed asymmetry in correlations, between the spectrum of human mtDNA variations and the L- and H-strand hole spectra, is attributed to asymmetric DNA replication processes that occur for the leading and lagging strands.
Highlights
Tendency of holes to localize on guanine in natural DNA
The results discussed above suggest that: 1) enhanced mutation rates often correlate with hole localization sites; 2) holes on the mitochondrial DNA (mtDNA) L-strand correlate with mutations much more strongly than those on the H-strand; 3) sites where L-strand hole peaks do not coincide with mutation spectrum peaks potentially identify base pairs of critical importance, whose replacements would be lethal or deleterious; and 4) one can potentially identify critical base pairs and disease driver mutations by using variant data to suppress hole peaks and disease mutations when variant frequencies are large
We hypothesize that the observed striking L/H-strand bias in hole-mutation correlations is due to the asymmetry in DNA replication for the leading and lagging strands
Summary
Tendency of holes to localize on guanine in natural DNA. Collectively, the above studies are consistent with the idea that DNA’s electronic fingerprint plays a key if not dominant role in driving the underlying mutation probabilities. The study reported here is intended to: 1) develop a computational method that enables rapid comparisons of hole localization sites on the two DNA strands with peaks in the mutation spectrum; and 2) explore new tools, combining the effects of holes with the pruning effects of natural selection, to identify critical base pairs and likely sites of ‘driver’ mutations, i.e., those which drive a disease state rather than occurring as a ‘passenger,’ e.g., in a growing tumour. The spectra for the two strands, of hole probability peaks vs nucleotide position, depict sites where holes tend to localize These electronic signatures can be correlated with any benign variants, disease mutations, or, for coding DNA, encoded amino acids. The sections discuss our D-Spectrum algorithm and some tests on mitochondrial DNA
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
