Century-Old Mystery of Robertsonian Chromosomes Solved
Scientists pinpointed the DNA sequence where human chromosomes fuse, solving a century-old mystery in genome biology.
Scientists have finally uncovered the exact DNA sequence where human chromosomes fuse to form Robertsonian chromosomes, a mystery that has puzzled researchers for over a century.
Using advanced genome sequencing at the Stowers Institute for Medical Research, the team revealed how these fusions occur within repetitive DNA.
“This is the first time anyone has shown where this exact DNA breakpoint occurs,” said corresponding author Dr. Jennifer Gerton, a Stowers Institute investigator and the dean of the graduate school.
Understanding Robertsonian chromosomes
Chromosomes come in pairs. In humans, we normally carry 46 chromosomes (23 pairs), and during meiosis, they line up in matching pairs, so each gamete receives 1 copy. However, in ~1 in 800 people, something unusual happens: two chromosomes fuse. These fused forms are known as Robertsonian chromosomes (ROBs).
“Robertsonian chromosomes are chromosomes in which the long arms of two different chromosomes fuse together,” Gerton told Technology Networks. The short arms of these chromosomes are lost.
The carrier ends up with 45 chromosomes, and although many carriers show no obvious symptoms, ROBs can cause fertility issues, miscarriages or raise the risk of trisomies such as Down syndrome.
“They are a mechanism of speciation in nature across many animals and plants,” said Gerton.
Despite being known for over a century, how exactly these fusions occur has remained unknown, until now. The challenge has often been that the fusion point lies in highly repetitive DNA, notably near chromosome centers (the acrocentric “short arm” regions). These regions were poorly mapped by older sequencing methods and were even missing from past genome assemblies.
Now, with complete genome assemblies that can capture those repetitive regions, Gerton and her team have finally been able to pinpoint where the fusions occur. Their new study maps the exact DNA sequence at the fusion site and shows how those rearranged chromosomes can stay stable across generations.
Pinpointing the DNA breakpoints in Robertsonian chromosomes
The researchers analyzed three human cell lines that each carried a common fusion – two joining chromosomes 13 and 14, and one joining 14 and 21. Using long-read sequencing technologies, along with Hi-C data and advanced assembly tools, the team generated complete, telomere-to-telomere sequences of these unusual chromosomes. This level of resolution had never been possible before.
When the data came together, a clear pattern appeared. In all three chromosomes, the fusion occurred within a repetitive DNA sequence known as SST1, located near the chromosome centre. On chromosome 14, that region was found to be inverted. The inversion allows either chromosome 13 or 21 to attach, facilitating the formation of Robertsonian chromosomes.
“That’s never been shown before – in humans or in any other species,” said Gerton.
“SST1 is a repetitive DNA that is special because it seems to be a recombination hotspot, a place where frequent DNA exchange happens. SST1 is shared between multiple chromosomes, and is oriented back to front on chromosome 14, which allows Robertsonian fusions to happen,” said Gerton.
The team also found that, during fusion, the short arms of the chromosomes – home to ribosomal DNA – are lost, leaving the carrier with 45 chromosomes. Each fused chromosome carries two centromeres, but only one is active, preventing the structure from being torn apart during cell division.
Further comparisons with chimpanzee and bonobo genomes revealed that the inversion on chromosome 14 is unique to humans.
“The arrangement of sequences on human chromosomes that allow for the Robertsonian fusion event to occur does not exist in the chimpanzee or bonobo genomes,” Gerton added.
Microscopy and 3D imaging confirmed that SST1 lies precisely between the two centromeres.
Implications of Robertsonian chromosomes for genome evolution and stability
By pinpointing the precise DNA break and fusion site, the team has turned repetitive “junk DNA” into a new focus of genome biology. These sequences, long overlooked, appear to be active players in how chromosomes are organized, repaired and passed on.
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As Gerton noted, “The fusion point happens in repetitive DNA that was left unresolved in the first human genome project. The region was only assembled for the first time in the second human genome project in 2022.”
Knowing exactly how these fusions arise could improve genetic counseling for Robertsonian carriers, who face a higher risk of infertility and trisomies such as Down or Patau syndrome. The work also explains why fused chromosomes remain stable, offering new insight into chromosome segregation and stability mechanisms.
At a broader level, the study links repetitive DNA to chromosome evolution across species.
“Now that we know how these chromosomes form in humans, it gives us insight into how they occur broadly in nature,” said Gerton. “It opens the door to understanding how chromosomes evolve in a way that we had no appreciation for before.”
“As the first group to identify the precise breakpoint at which Robertsonian chromosomes combine, Gerton and her colleagues have lit a flame that could ignite a broader understanding of how these chromosomes function,” said genome scientist Dr. Glennis Logsdon, an assistant professor of genetics from the University of Pennsylvania, who was not involved in the work.
“It really got us thinking about the role these repetitive DNA sequences play in shaping the genome and potentially creating new species. It’s clear that there’s a story there, and that’s what we plan to study next,” said Gerton.
“One day, we may be able to give carriers better genetic counseling and better options,” she added.
Reference: De Lima LG, Guarracino A, Koren S, et al. The formation and propagation of human Robertsonian chromosomes. Nature. 2025. doi: 10.1038/s41586-025-09540-8
About the interviewee:
Dr. Jennifer Gerton is an investigator and the Dean of the Graduate School of the Stowers Institute for Medical Research. Gerton is a chromosome biologist who earned her BA in human biology and PhD in microbiology and immunology from Stanford University. She completed postdoctoral training at the University of North Carolina at Chapel Hill and the University of California, San Francisco, focusing on yeast genetics, genomics and recombination. In 2002, she launched her independent research program at the Stowers Institute for Medical Research.
