Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes.
Bottom Line: 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.
Affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, Dell Pediatric Research Institute, The University of Texas at Austin, 1400 Barbara Jordan Boulevard, Austin, TX 78723, USA.Show MeSH
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Mentions: We also extracted the mutated A- and G-tracts from the Human Gene Mutation Database (HGMD), a collection of >150,000 germline gene mutations associated with human inherited disease. A total of 1519 genes were mutated at A- or G-tracts out of a total of 3972 (38%); 3480 SBSs and 2866 slippage events were noted within these tracts, 85 and 46% of which were predicted to be disease-causing, respectively (Figure 7A and Supplementary Table S1). Ranking genes by the number of literature reports indicated that among the top 10 entries three were associated with cancer (BRCA1, BRCA2 and APC), two with hemophilia (F8 and F9), four with debilitating lesions of the skin (COL71A), muscle (DMD), lung (CFTR) and kidney (PKD1), with one causing hypercholesterolemia (LDLR) (Figure 7B). Thus, mutations within A- and G-tracts carry a high social burden by contributing to some of the most common human pathological conditions.
Affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, Dell Pediatric Research Institute, The University of Texas at Austin, 1400 Barbara Jordan Boulevard, Austin, TX 78723, USA.