The double helix is one of the most recognized symbols in biological science, representing the spiral structure of DNA molecules. However, not all DNA fits this familiar pattern. Alternative structures of DNA are indeed present, and advancements in technology are uncovering them.
In research conducted last year, scientists pinpointed the locations of these “non-canonical” DNA forms (also known as non-B DNA) within human and other primate genomes. The findings, published in Nucleic Acids Research, enhance our comprehension of the diverse DNA structures within our genome.
Biologist Kateryna Makova from Pennsylvania State University noted that “when the human genome was first published in 2001, it actually wasn’t complete,” adding that “approximately 8 percent of the genome, mainly repetitive DNA, was not determined.”
Subsequent extensive research efforts, culminating in the Telomere-to-Telomere (T2T) consortium, aimed to fill these gaps, resulting in the most exhaustive human genome reference in 2022, with the final segment sequenced in 2023.
By 2025, T2T scientists expanded their work to complete the reference genomes for six ape species: chimpanzee, bonobo, gorilla, Bornean orangutan, Sumatran orangutan, and siamang. In a new study, Makova’s team examined the T2T reference genomes of humans and these ape species to find genetic patterns indicating non-B DNA sequences.
Penn State biologist Linnéa Smeds, the study’s first author, stated, “We now have a complete picture of the motifs that are prone to non-B DNA formation for these genomes.”
The discoveries, along with the T2F datasets, were enabled by long-read sequencing technologies, which sequence genomes in longer, fewer segments, making assembly easier than with shorter snippets.
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This ability to expand the view and analyze more genetic code facilitates the detection of functional genome elements, including previously unnoticed non-B DNA sequences. Analysis of the human reference genome with long-read data uncovered more non-canonical DNA patterns than previously identified.
The researchers report, “We found an overrepresentation of most types of non-B DNA motifs in the newly added sequences of the human T2T genome.” They further explain that investigating previously inaccessible genome regions, rich in non-B DNA motifs, allowed them to map out the complete genome-wide repertoire of these motifs in humans and non-human apes with available T2T genomes.
Non-B DNA motifs in the human genome were primarily found in satellite DNA, which involves repeating sections of non-coding DNA that play a role in chromosome organization and stability. In ape genomes, non-B motifs showed an uneven distribution.
These non-canonical DNA formations can manifest in various shapes, such as bent DNA, hairpins, G-quadruplexes (G4s), and Z-DNA. They are estimated to occupy 13 percent of the human genome and could affect various cellular processes, including DNA replication, chromosome protection, transcription regulation, and methylation.
While some studies suggest that non-B DNA can drive genome evolution, others indicate potential harmful impacts. “Non-B structures may impede replication and elevate mutagenesis and genome instability,” the researchers write, adding they are believed to contribute to cancers, neurodegenerative diseases, and genetic disorders like Werner syndrome.
Expanding knowledge of non-B DNA’s presence in the human genome is expected to deepen understanding of how these structures influence health. “There has been a recent shift in how we think about the function of the genome to go beyond sequence to include structure,” Makova states. “We hope our study will serve as a springboard for additional studies of the function of these novel structural characteristics in the genome.”
The research findings are detailed in Nucleic Acids Research.
This article was fact-checked by Clare Watson and edited by Clare Watson. While we pride ourselves on our process, we are only human. If you spot a mistake, please let us know.
