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Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes

Single base substitutions (SBSs) and insertions/deletions are critical for generating population diversity and can lead both to inherited disease and cancer. Whereas on a genome-wide scale SBSs are influenced by cellular factors, on a fine scale SBSs are influenced by the local DNA sequence-context,...

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Autores principales: Bacolla, Albino, Zhu, Xiao, Chen, Hanning, Howells, Katy, Cooper, David N., Vasquez, Karen M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446427/
https://www.ncbi.nlm.nih.gov/pubmed/25897114
http://dx.doi.org/10.1093/nar/gkv364
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author Bacolla, Albino
Zhu, Xiao
Chen, Hanning
Howells, Katy
Cooper, David N.
Vasquez, Karen M.
author_facet Bacolla, Albino
Zhu, Xiao
Chen, Hanning
Howells, Katy
Cooper, David N.
Vasquez, Karen M.
author_sort Bacolla, Albino
collection PubMed
description Single base substitutions (SBSs) and insertions/deletions are critical for generating population diversity and can lead both to inherited disease and cancer. Whereas on a genome-wide scale SBSs are influenced by cellular factors, on a fine scale SBSs are influenced by the local DNA sequence-context, although the role of flanking sequence is often unclear. Herein, we used bioinformatics, molecular dynamics and hybrid quantum mechanics/molecular mechanics to analyze sequence context-dependent mutagenesis at mononucleotide repeats (A-tracts and G-tracts) in human population variation and in cancer genomes. SBSs and insertions/deletions occur predominantly at the first and last base-pairs of A-tracts, whereas they are concentrated at the second and third base-pairs in G-tracts. These positions correspond to the most flexible sites along A-tracts, and to sites where a ‘hole’, generated by the loss of an electron through oxidation, is most likely to be localized in G-tracts. For A-tracts, most SBSs occur in the direction of the base-pair flanking the tracts. We conclude that intrinsic features of local DNA structure, i.e. base-pair flexibility and charge transfer, render specific nucleotides along mononucleotide runs susceptible to base modification, which then yields mutations. Thus, local DNA dynamics contributes to phenotypic variation and disease in the human population.
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spelling pubmed-44464272015-06-15 Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes Bacolla, Albino Zhu, Xiao Chen, Hanning Howells, Katy Cooper, David N. Vasquez, Karen M. Nucleic Acids Res Genomics Single base substitutions (SBSs) and insertions/deletions are critical for generating population diversity and can lead both to inherited disease and cancer. Whereas on a genome-wide scale SBSs are influenced by cellular factors, on a fine scale SBSs are influenced by the local DNA sequence-context, although the role of flanking sequence is often unclear. Herein, we used bioinformatics, molecular dynamics and hybrid quantum mechanics/molecular mechanics to analyze sequence context-dependent mutagenesis at mononucleotide repeats (A-tracts and G-tracts) in human population variation and in cancer genomes. SBSs and insertions/deletions occur predominantly at the first and last base-pairs of A-tracts, whereas they are concentrated at the second and third base-pairs in G-tracts. These positions correspond to the most flexible sites along A-tracts, and to sites where a ‘hole’, generated by the loss of an electron through oxidation, is most likely to be localized in G-tracts. For A-tracts, most SBSs occur in the direction of the base-pair flanking the tracts. We conclude that intrinsic features of local DNA structure, i.e. base-pair flexibility and charge transfer, render specific nucleotides along mononucleotide runs susceptible to base modification, which then yields mutations. Thus, local DNA dynamics contributes to phenotypic variation and disease in the human population. Oxford University Press 2015-05-26 2015-04-20 /pmc/articles/PMC4446427/ /pubmed/25897114 http://dx.doi.org/10.1093/nar/gkv364 Text en © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Genomics
Bacolla, Albino
Zhu, Xiao
Chen, Hanning
Howells, Katy
Cooper, David N.
Vasquez, Karen M.
Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes
title Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes
title_full Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes
title_fullStr Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes
title_full_unstemmed Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes
title_short Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes
title_sort local dna dynamics shape mutational patterns of mononucleotide repeats in human genomes
topic Genomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446427/
https://www.ncbi.nlm.nih.gov/pubmed/25897114
http://dx.doi.org/10.1093/nar/gkv364
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