Non-B DNA: a major contributor to small- and large-scale variation in nucleotide substitution frequencies across the genome
Wilfried M. Guiblet, Marzia A Cremona, Robert S Harris, Di Chen, Kristin A Eckert, Francesca Chiaromonte, Yi-Fei Huang, Kateryna D Makova Author Notes
Nucleic Acids Research, gkaa1269, https://doi.org/10.1093/nar/gkaa1269
Published: 15 January 2021
Schematic of different types of non-B DNA structures. (A) G-quadruplex, (B) H-DNA, (C) Z-DNA, (D) cruciform, (E) slipped strands and (F) A-tract bending.
INTRODUCTION
Mutation rates vary across the genome (1,2), and this phenomenon contributes to differences in the levels of intra- and interspecific genetic variation (henceforth called ‘diversity’ and ‘divergence’, respectively). As a result, certain genomic regions may be at a higher (or at a lower) risk of acquiring mutations important for adaptation and/or genetic diseases (1–3). In a broad sense, deciphering the causes of regional variation in mutation rates is essential to understanding both evolution and diseases (1,2).
Numerous genomic features contribute to regional variation in mutation rates, but those identified to date cannot account for all such variation. Some features are directly related to DNA sequence and usually act at the scale of single nucleotides, e.g. guanines and cytosines are more mutable than adenines and thymines (4,5). Neighboring nucleotides also have an effect, e.g. methylated cytosines in CpG dinucleotides are 10 times more mutable than other sites because of their spontaneous deamination (6), and several other contexts leading to guanine holes and increased mutagenesis were previously identified (7). Other genomic features—such as recombination rate (8), replication timing (9), chromatin accessibility (10,11), histone modifications (12,13), and Lamina Associated Domains (14)—contribute to regional variation in mutation rates through the variable activity of different enzymatic processes along the genome. These frequently act at larger scales, from several hundreds of kilobases to several megabases (Mbs). The magnitude of regional variation in mutation rates decreases with the increase in the genomic scale considered; most such regional variation in fact occurs at the single-nucleotide scale (1). At the 1-Mb scale, which is considered the natural long-range variation scale for mammalian genomes (15), most regions have mutation rates deviating by ∼2-fold (1). Notably, at this scale, several analyses indicated that the genomic features listed above explain only ∼50% of the regional variation in mutation rates (12,16,17). The correlation in regional variation in mutation rates between human and great apes (18) suggests that the unexplained portion of this variation is not random, and that additional factors remain to be discovered. Non-B DNA may be one such factor.
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