Non-B DNA structure-induced genetic instability and evolution

Abstract

Repetitive DNA motifs are abundant in the genomes of various species and have the capacity to adopt non-canonical (i.e., non-B) DNA structures. Several non-B DNA structures, including cruciforms, slipped structures, triplexes, G-quadruplexes, and Z-DNA, have been shown to cause mutations, such as deletions, expansions, and translocations in both prokaryotes and eukaryotes. Their distributions in genomes are not random and often co-localize with sites of chromosomal breakage associated with genetic diseases. Current genome-wide sequence analyses suggest that the genomic instabilities induced by non-B DNA structure-forming sequences not only result in predisposition to disease, but also contribute to rapid evolutionary changes, particularly in genes associated with development and regulatory functions. In this review, we describe the occurrence of non-B DNA-forming sequences in various species, the classes of genes enriched in non-B DNA-forming sequences, and recent mechanistic studies on DNA structure-induced genomic instability to highlight their importance in genomes.

Fig. 1

Non-B DNA structures. a Cruciform DNA, b Z-DNA, c H-DNA (triplex DNA), d G-quadruplex (tetraplex) DNA, and e slipped DNA

Fig. 2

a Expression profiles of quadruplex-containing genes. Comparison of the gene expression levels between genes containing quadruplex-forming sequences (PG4M_D500-positive, filled squares) and genes without PG4M_D500 (open squares) in each human tissue/cell type. Error bars represent the 95% confidence interval of the mean expression level. (Reprinted with permission from [81].) b Global gene expression profiles of genes containing triplex-forming sequences. Each data point represents the mean ln (x-axis) for all gene expression values falling within 0.5 ln-interval bins, from 0–0.5 to 12.0–12.5. On the y-axis is the percentage of the gene expression values falling within each 0.5 ln-interval bin relative to the total number of gene expression values for either the control genes (open symbols) or the genes harboring ≥18 TR units (set 2) (filled symbols)

Fig. 3

a Y chromosome genealogical tree (left) and identified structural polymorphisms (right). Chromosomes were assigned to one of 47 branches by typing for the stable, biallelic polymorphisms indicated. Red arrows indicate major branches confined to Africa. For each branch, the structure of the Y chromosome sampled is schematized, including (far right) the length of distal-Yq heterochromatin. Within the euchromatin, the presence of a particular structural variant is indicated by a color-coded rectangle. (Reprinted with permission from [92].) b Model for stem-loop-mediated chromosomal inversion and strand exchange. Structure I illustrates the original (ancestral) sequence organization with two inverted repeat (IR) segments. Structure II shows the stem-loop structure containing two Holliday-like junctions originating from strand exchange and the inverting loop. Structure III represents the intermediate DNA species after Holliday junction (HJ) resolution and loop inversion. Structure IV depicts the final DNA configuration with the complementary strands containing DNA bases located originally on the same strand and the inverted loop. (Adapted from [109])

Fig. 4

DNA damage and non-B DNA structures. Unwrapping of a non-B DNA-forming sequence (red box) from the histone core during DNA metabolism (Step 1), facilitates the non-B DNA conformation (Step 2). The non-B DNA conformation may be more susceptible to DNA damage and the damage in the non-B DNA region may be more resistant to repair (Step 3), leading to accumulated damage (blue star) in this region (Step 4). (Adapted from [115])