Certain DNA sequences can form structures beyond the classic double helix, known as non-B DNA. These alternative conformations, often found in repetitive DNA regions, have been linked to cellular processes and genome evolution, but sequencing their structures has long been challenging.
Now, a team led by Penn State biologists has predicted the locations of non-B DNA structures across the genomes of great apes, marking an important step in understanding their roles in health and evolution. Their findings, published in Nucleic Acids Research, reveal that non-B DNA is enriched in newly sequenced parts of the genome and suggest possible new functions for these structures.
"When the human genome was first released in 2001, it was incomplete," said Kateryna Makova, Verne M. Willaman Chair of Life Sciences and leader of the project. "About 8% of the genome, mostly repetitive regions, was missing because the technology couldn't reconstruct it. In 2022 and 2023, the Telomere-to-Telomere (T2T) consortium finally completed the human genome, and this year, we achieved the same for all great apes."
Traditional short-read sequencing techniques break DNA into small fragments that are difficult to reassemble when dealing with repetitive sequences. The new T2T genomes use long-read sequencing, capturing larger sections at once and allowing researchers to explore previously inaccessible regions.
"Repetitive DNA can involve hundreds or thousands of copies of the same sequence," explained Linnéa Smeds, first author of the study and a postdoctoral researcher at Penn State. "T2T genomes give us the ability to finally look into these regions and identify elements like non-B DNA."
Non-B DNA structures—such as bent DNA, hairpins, G-quadruplexes (G4s), and Z-DNA—form from specific sequence motifs. These structures play roles in DNA replication, gene regulation, and the maintenance of telomeres and centromeres, critical for cell division.
The research team scanned T2T genomes from humans, chimpanzees, bonobos, gorillas, two orangutan species, and siamang, identifying all regions likely to form non-B DNA structures.
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"We now have a comprehensive map of non-B DNA-prone motifs across these genomes," said Smeds.
They found that non-B motifs are especially enriched in newly sequenced regions and that distribution patterns are broadly similar among ape species. Interestingly, the gorilla genome, which contains a higher percentage of repetitive DNA, showed a greater number of non-B motifs.
Because non-B DNA structures can promote mutations and genomic instability, they might play a role in chromosomal rearrangements and evolution. For example, a repetitive DNA region associated with a form of Down syndrome showed 97 times more Z-DNA motifs than the genome average, hinting at a potential link between non-B DNA and chromosomal breakpoints.
While the team experimentally confirmed non-B structures for a few motifs, most will need further validation.
"The formation of these structures likely depends on many factors—cell type, developmental stage, DNA modifications like methylation," Makova said. "We're moving beyond just the DNA sequence itself and starting to understand the importance of its structure as well."
Now, a team led by Penn State biologists has predicted the locations of non-B DNA structures across the genomes of great apes, marking an important step in understanding their roles in health and evolution. Their findings, published in Nucleic Acids Research, reveal that non-B DNA is enriched in newly sequenced parts of the genome and suggest possible new functions for these structures.
"When the human genome was first released in 2001, it was incomplete," said Kateryna Makova, Verne M. Willaman Chair of Life Sciences and leader of the project. "About 8% of the genome, mostly repetitive regions, was missing because the technology couldn't reconstruct it. In 2022 and 2023, the Telomere-to-Telomere (T2T) consortium finally completed the human genome, and this year, we achieved the same for all great apes."
Traditional short-read sequencing techniques break DNA into small fragments that are difficult to reassemble when dealing with repetitive sequences. The new T2T genomes use long-read sequencing, capturing larger sections at once and allowing researchers to explore previously inaccessible regions.
"Repetitive DNA can involve hundreds or thousands of copies of the same sequence," explained Linnéa Smeds, first author of the study and a postdoctoral researcher at Penn State. "T2T genomes give us the ability to finally look into these regions and identify elements like non-B DNA."
Non-B DNA structures—such as bent DNA, hairpins, G-quadruplexes (G4s), and Z-DNA—form from specific sequence motifs. These structures play roles in DNA replication, gene regulation, and the maintenance of telomeres and centromeres, critical for cell division.
The research team scanned T2T genomes from humans, chimpanzees, bonobos, gorillas, two orangutan species, and siamang, identifying all regions likely to form non-B DNA structures.
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"We now have a comprehensive map of non-B DNA-prone motifs across these genomes," said Smeds.
They found that non-B motifs are especially enriched in newly sequenced regions and that distribution patterns are broadly similar among ape species. Interestingly, the gorilla genome, which contains a higher percentage of repetitive DNA, showed a greater number of non-B motifs.
Because non-B DNA structures can promote mutations and genomic instability, they might play a role in chromosomal rearrangements and evolution. For example, a repetitive DNA region associated with a form of Down syndrome showed 97 times more Z-DNA motifs than the genome average, hinting at a potential link between non-B DNA and chromosomal breakpoints.
While the team experimentally confirmed non-B structures for a few motifs, most will need further validation.
"The formation of these structures likely depends on many factors—cell type, developmental stage, DNA modifications like methylation," Makova said. "We're moving beyond just the DNA sequence itself and starting to understand the importance of its structure as well."
