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

Bacolla, A., Zhu, X., Chen, H., Howells, Katy, Cooper, David Neil and Vasquez, K. M. 2015. Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes. Nucleic Acids Research 43 (10) , pp. 5065-5080. 10.1093/nar/gkv364

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
Uncontrolled Keywords: phenotype , oxidation , mutation , cancer , genetic disorder , base pairing , dna , genome , genome, human , mutagenesis , nucleotides , dna structure , transfer technique , bioinformatics
Publisher: Oxford University Press
ISSN: 0305-1048
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 7 April 2015
Last Modified: 17 Sep 2019 09:22
URI: http://orca.cf.ac.uk/id/eprint/84068

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