Noncanonical DNA structures are drivers of genome evolution

Abstract

In addition to the canonical right-handed double helix, other DNA structures, termed 'non-B DNA', can form in the genomes across the tree of life. Non-B DNA regulates multiple cellular processes, including replication and transcription, yet its presence is associated with elevated mutagenicity and genome instability. These discordant cellular roles fuel the enormous potential of non-B DNA to drive genomic and phenotypic evolution. Here we discuss recent studies establishing non-B DNA structures as novel functional elements subject to natural selection, affecting evolution of transposable elements (TEs), and specifying centromeres. By highlighting the contributions of non-B DNA to repeated evolution and adaptation to changing environments, we conclude that evolutionary analyses should include a perspective of not only DNA sequence, but also its structure.

Keywords: G-quadruplexes; Z-DNA; mutations; natural selection; noncanonical DNA structure.

FIGURE 1.. Non-B DNA structures as a blessing and a curse.

Due to their many functions and molecular effects, non-B DNA structures can be seen as both ‘a blessing’ and ‘a curse’. In this figure, we present schematic examples of vital cellular functions (‘blessing’) as well as of detrimental effects (‘curse’). The former include telomere end protection, where G4 structures may prevent the telomeric 3’ overhang from being degraded by nucleases; the regulation of transcription, in which folded G4s act as transcription factor binding sites in the promoter; and the initiation of replication, where G4s located upstream of replication origins facilitate the firing of the replication machinery. Examples of manifested non-B DNA structures having detrimental effects are cruciform-structure-mediated genome instability leading to deletions and chromosome translocations; and the potential impeding of replication, in which a folded G4 structure on the leading strand stalls the progression of the replication fork. After [18,44,116,118,119].

FIGURE 2.. Evidence suggesting the functionality of G4 motifs in the human genome.

On the x-axis, different genomic regions are shown, with genic regions in bold. The first row depicts the fold-difference between the G-corrected G4 motif density for a particular genomic region as compared to the average genome-wide G4 motif density; a significant increase in representation above 1 indicates overrepresentation and thus potentially functionality. In the second row, median thermostability (as computed by Quadron) is shown; the genome-wide average thermostability is 19.5; a value significantly higher than 19.5 indicates elevated thermostability and thus potentially functionality. The third row depicts the odds ratios of the Hudson-Kreitman-Aquade test used to evaluate purifying selection; odds ratio equal to one is inconsistent with selection; odds ratio significantly higher than one is suggestive of purifying selection. * bold font within tiles denotes a significance level of <0.05 [76]; normal font - not significant; n.a. - not analyzed. Vertical black bars indicate a thermostability value of 19.5, a fold-change of G4 motif density of 1, and an odds ratio of 1, respectively. After [76].