The technical achievement at the heart of the study is considerable. Building a truly complete genome has long been one of genomics’ most stubborn challenges, because repetitive DNA sequences near the centers and ends of chromosomes resist standard sequencing methods. The research team overcame this by combining PacBio HiFi long-read sequencing, which produces highly accurate reads spanning tens of thousands of DNA letters, with Hi-C technology, which captures the physical contacts between distant stretches of chromosomes and allows the sequences to be anchored into their correct chromosomal positions. The final assembly spans 2.42 gigabases, with a scaffold N50 of 72.35 megabases and a contig N50 of 66.56 megabases, meaning that half of the assembled genome resides in stretches longer than those figures. The guanine-cytosine content of the assembly sits at 42.36 percent. In practical terms, the contiguity of this assembly approaches the ideal of a single gap-free sequence per chromosome, giving researchers an unprecedented view of the bear’s genome architecture.

With that high-resolution reference in hand, the team turned to comparative genomics, aligning the Tibetan brown bear’s chromosomes against those of its closest living relative, the polar bear. The analysis revealed high chromosomal synteny between the two species, meaning that large blocks of genes retain the same order and orientation across both genomes despite millions of years of separate evolution. This structural conservation is scientifically valuable for two reasons. It confirms that the assembly is accurate, since genuine chromosome-scale structure should be preserved between closely related ursids, and it provides a stable framework for pinpointing the regions that have instead diverged, which are precisely the locations where adaptation to very different environments, Arctic sea ice versus high-altitude steppe, is most likely to leave its mark.

The genomic record also preserves a vivid portrait of the species’ demographic turbulence. By reconstructing changes in effective population size through time, the researchers found that the Tibetan brown bear expanded during the early Pleistocene, a period of dynamic climate and habitat change. That expansion, however, was followed by two severe population bottlenecks. The first occurred approximately two million years ago, coinciding with the pre-Poyang Glaciation, and the second struck around one hundred thousand years ago during the Last Glacial Period. Together, these crashes reduced the bear’s cumulative effective population size by nearly eighty percent. For a species that today persists only on the Qinghai-Xizang Plateau, this history of repeated near-collapses carries a sobering message about the genetic fragility that may still lurk beneath its wild, unbroken landscape.

Yet survival through those bottlenecks suggests the species carries more than vulnerability. Enduring glacial cycles on a plateau whose average elevation exceeds 4,000 meters demands a physiology unlike that of lowland relatives, and the most striking discovery of the study concerns exactly that. When the researchers examined candidate hibernation-related pathways, they found that the Tibetan brown bear displays a distinctly carbohydrate-dominated metabolic signature. This stands in sharp contrast to the hibernation strategy documented in North American brown bears, which rely primarily on lipid, or fat-based, metabolism to fuel their long winter dormancy. In other words, two populations of the same widespread species appear to have evolved fundamentally different biochemical approaches to the same survival problem.

The implications of that finding extend well beyond bears. Fat is the standard fuel of hibernation across most studied mammals, because it stores more energy per gram and spares blood sugar during months of fasting. A sugar-first strategy on the Tibetan Plateau hints at selective pressures unique to that environment, where the short growing season, the composition of available foods, and the metabolic demands of life at low oxygen levels may have favored a different balance of carbohydrate and lipid pathways. The authors emphasize that this distinct metabolic adaptation highlights the bear’s unique mechanisms for surviving the extreme plateau environment, and it gives physiologists a natural experiment in alternative hibernation biochemistry encoded within a single species.

For conservation biologists, the new genome arrives at a critical moment. The Tibetan brown bear sits at the top of the plateau’s food web, playing a crucial ecological role, yet high-quality genomic resources for the species have been scarce until now. A chromosome-level reference genome transforms what conservation managers can do: it enables accurate estimates of genetic diversity and inbreeding, allows the tracking of gene flow between populations, and provides the resolution needed to identify locally adapted lineages that deserve special protection. Given the roughly eighty percent historical reduction in effective population size documented in the study, such tools are not a luxury. They are the baseline data upon which any serious plan for the species’ long-term management on the plateau must rest.

The study also strengthens the broader evolutionary picture of the bear family. Ursids have long fascinated evolutionary biologists because the family contains species with radically different ecologies, from the omnivorous brown bear to the hypercarnivorous, ice-bound polar bear. A near telomere-to-telomere assembly for the Tibetan brown bear adds a critical high-quality data point for reconstructing the phylogenomic relationships within Ursus and for dating the divergences that produced today’s brown bear lineages. Because structural variants, gene duplications, and regulatory regions can now be examined in their full chromosomal context rather than through fragmented assemblies, questions about how bears colonized and adapted to some of Earth’s harshest habitats can be addressed with far greater precision than before.

The research was carried out by Muran Zhao, Anmin Wang, Hai Liu, Chenxing Yu, Yanlin Liu, Nan Sun, and Guogang Li of Qinghai Normal University, with fieldwork, sample collection, and laboratory analysis conducted under permits granted by the university. The work was supported by the National Natural Science Foundation of China. The team notes that the new assembly is intended as a resource for the wider community, facilitating future studies of ursid evolutionary history and supporting conservation and management of the plateau’s wildlife. Because the genome is derived from a female bear, it also enables improved analysis of the sex chromosomes, an area where earlier fragmented assemblies often fell short.

What began as a technical sequencing project has ended with a discovery that may echo well beyond the Qinghai-Xizang Plateau. If a close relative of the brown bears studied across North America and Eurasia can hibernate on a carbohydrate-dominated metabolic program, then hibernation is not a single fixed solution that evolution produced once and reused everywhere. It is a flexible toolkit, and different populations have assembled it from different parts. As climate change alters the length and severity of winters across the world’s mountains, understanding that flexibility, and the genes that underpin it, could prove essential not only for protecting the Tibetan brown bear but for predicting which hibernating species can adjust and which cannot. The near-complete genome of this high-altitude survivor is now available as the roadmap for answering those questions.

Subject of Research: Chromosome-level genome assembly and hibernation-related evolution of the Tibetan brown bear (Ursus arctos pruinosus)

Article Title: Near telomere-to-telomere genome reveals the phylogenomics and hibernation-related evolution in Tibetan brown bear (Ursus arctos pruinosus)

Article References: Zhao, M., Wang, A., Liu, H., Yu, C., Liu, Y., Sun, N., & Li, G. (2026). Near telomere-to-telomere genome reveals the phylogenomics and hibernation-related evolution in Tibetan brown bear (Ursus arctos pruinosus). BMC Genomics. https://doi.org/10.1186/s12864-026-13324-3

Image Credits: AI Generated

DOI: 10.1186/s12864-026-13324-3

Keywords: Tibetan brown bear, telomere-to-telomere genome, genomics, hibernation, Qinghai-Xizang Plateau, population bottlenecks, PacBio HiFi, Hi-C sequencing, phylogenomics, conservation genomics, carbohydrate metabolism, Ursidae evolution

Since the first draft of the human genome was published in 2001, genomics has faced the formidable challenge of resolving highly repetitive DNA sequences. These regions, which often form unusual secondary structures, eluded complete characterization because short-read sequencing technologies could not reliably assemble them. Traditional methods fragmented the genome into countless small pieces, making it virtually impossible to reconstruct repetitive stretches. As a result, approximately 8% of the human genome remained unresolved for nearly two decades, veiling crucial parts of the genome—including telomeres and centromeres—from genetic scrutiny.

The advent of T2T sequencing marks a turning point. This long-read technology reads uninterrupted DNA segments spanning hundreds of thousands of base pairs, bypassing the confounding puzzle of identical repeat units imposed by previous approaches. The Telomere-to-Telomere Consortium successfully completed the human genome sequence in 2022 and 2023, and more recently, the complete genomes of all great apes, including chimpanzee, bonobo, gorilla, orangutans, and siamang, have been fully elucidated at this level of detail. This monumental achievement provides an unprecedented window into repetitive DNA landscapes and the curious non-B DNA structures they harbor.

Non-B DNA refers to DNA conformations deviating from the classic right-handed Watson-Crick double helix. These structures include bent DNA, hairpins, G-quadruplexes (G4s), and Z-DNA, each formed by specific sequence motifs frequently found in repetitive regions. They have been implicated in regulating critical cellular functions, such as initiating DNA replication, modulating gene expression, and maintaining chromosome integrity through telomeres and centromeres. However, until now, the full extent and distribution of these motifs in primate genomes had not been systematically surveyed.

The study, led by Kateryna Makova, Professor of Biology and Verne M. Willaman Chair of Life Sciences at Penn State, deployed computational and experimental approaches to chart these motifs across the newly assembled T2T genomes of six great ape species and the siamang as an outgroup. Their findings reveal non-B DNA motifs are significantly enriched in the recently resolved segments of the genomes, notably within the telomeric and centromeric regions which play pivotal roles during cell division.

Importantly, patterns of non-B DNA accumulation were remarkably conserved across the apes, highlighting a shared evolutionary blueprint amidst species diversity. The gorilla genome stands out with a notably higher load of repetitive DNA and correspondingly more non-B DNA motifs, suggesting species-specific nuances that may inform the understanding of genomic stability and adaptation. The enrichment of these motifs within complex repetitive sequences underscores their potential functional significance and evolutionary relevance.

Beyond their structural intrigue, non-B DNA conformations are prone to higher mutation rates and genomic instability, phenomena that can precipitate chromosomal rearrangements. Such rearrangements have profound implications, sometimes underpinning genetic disorders and cancer. The researchers pinpointed Z-DNA motifs as strikingly overrepresented—up to 97-fold—in satellite DNA regions corresponding to known chromosomal breakpoints, for instance in the translocation event associated with Down Syndrome on chromosome 21. This correlation hints at a mechanistic link between non-B DNA structures and chromosomal fragility.

While only a subset of non-B DNA motifs have been experimentally validated in this study, these findings ignite vital questions about the context-dependent formation of these structures in living cells. Factors such as cell type, developmental stage, and epigenetic modifications (e.g., DNA methylation) are likely to influence their stability and biological roles. This nuanced view shifts the paradigm from thinking of the genome as a static sequence to appreciating it as a dynamic, structurally complex entity.

The researchers emphasize that harnessing the power of complete genomes to characterize non-B DNA landscapes offers a powerful springboard for future inquiries. Integrating genome-wide structural predictions with experimental validation will be key to uncovering how these DNA structures participate in gene regulation, genome stability, and evolutionary innovation. The tangible link to diseases underscores the urgency of this line of research within biomedicine.

Interdisciplinary collaboration was pivotal to this project. Alongside Makova and first author Linnea Smeds, the team included experts in computer science, statistics, and biophysics from Penn State and the Czech Academy of Sciences. Such a blend of computational prowess and experimental biology sets a new standard for genomic research, especially when tackling complex, repetitive sequences long regarded as genomic "dark matter."

This pioneering work, published in the journal Nucleic Acids Research, propels the frontier of genomics into uncharted territory by exposing the intricate dance between DNA sequence, structure, and function in primates. As researchers continue to unravel the roles of non-B DNA, these insights promise to illuminate fundamental mechanisms of genome evolution and open novel avenues for diagnosing and treating human diseases linked to genomic instability.

The journey from fragmented puzzles to complete genomic portraits of great apes underscores the transformative impact of technological innovation on biological discovery. In unlocking the mysteries of non-B DNA, the field moves closer to decoding the full complexity of the genome and harnessing its potential for human health and evolutionary understanding.

Subject of Research: Animals
Article Title: Non-canonical DNA in human and other ape telomere-to-telomere genomes
News Publication Date: 14-Apr-2025
Web References: http://dx.doi.org/10.1093/nar/gkaf298
Image Credits: Dani Zemba and Makova laboratory, Penn State
Keywords: non-B DNA, genome assembly, telomere-to-telomere sequencing, great apes, repetitive DNA, DNA secondary structures, genome evolution, chromosomal rearrangements, genetic diseases, G-quadruplex, Z-DNA, genome instability