Three-dimensional genome structure shapes complex traits in cephalopods

Octopuses, squid and cuttlefish, collectively known as coleoid cephalopods, have evolved exceptionally large and elaborately structured nervous systems capable of complex behaviours such as problem-solving and rapid camouflage. A new study by scientists at The University of Vienna suggests that the origins of this complexity may lie not just in the genes themselves, but in how the genome is organized in 3D. The researchers found that ancient, extensive reorganization of the genome altered how DNA is arranged inside the cell. These shifts brought previously distant regions of DNA into contact, changing the way genes are regulated. Understanding this process could change how we think about how new traits emerge during evolution. The findings are currently published in the renowned journal Nature Communications. 

The team studied the 3D structure of the genome across octopus, squid and cuttlefish, combining data on DNA structure with gene activity.

The genome isn't just a sequence of genes. It's folded into a complex three-dimensional structure. Understanding how that structure evolves is becoming increasingly important for understanding how new forms of biological complexity arise."

Dr. Thea Rogers, lead author

"Regulatory entanglement" as a consequence of genome reorganization

In cephalopods, a large-scale burst of genome reorganization, which occurred hundreds of millions of years ago, dramatically reshuffled the genome and brought previously distant regions of chromosomes into close proximity.

The researchers found that when regions of DNA are brought into contact, they can begin to interact and influence each other's activity. Over time, these interactions can become embedded, forming increasingly interconnected regulatory networks. 

"Regulatory entanglement" balances innovation and stability in genome evolution 

This process, described by the researchers as "regulatory entanglement", may allow genomes to generate new patterns of gene expression while maintaining essential functions. 

Not all aspects of genome structure appear to respond to genome reorganization in the same way. The researchers found that large structural units of the genome, known as chromatin domains, remained largely stable over evolutionary time.

In contrast, finer-scale connections known as chromatin loops were far more dynamic. These loops bring distant regions of DNA into contact. They varied widely across species, tissues and developmental stages, and were often found near genes involved in key cephalopod traits, including those linked to the nervous system. This suggests that these more flexible regions may be particularly affected by large-scale changes in DNA organization.

3D structure of DNA shapes evolutionary processes actively 

Together, these findings challenge the idea that genome architecture is a passive consequence of evolution. Instead, they suggest that the 3D organization of DNA actively shapes how evolution unfolds. In cephalopods, this may have played a key role in the emergence of their unusually complex nervous systems.

Summary

• Scientists at the University of Vienna reconstructed the 3D organization of the genome in octopus, squid and cuttlefish to investigate how genome architecture evolved following an ancient burst of genome reorganization.
• The study found that this large-scale reorganisation brought previously distant regions of DNA into contact, creating new networks of regulatory interactions that became embedded over evolutionary time.
• The researchers describe this process as "regulatory entanglement", whereby new DNA interactions become increasingly interconnected, allowing genomes to generate novel patterns of gene regulation while maintaining essential biological functions.
• The researchers found that not all aspects of the 3D genome respond to genome reorganization in the same way. Large chromatin domains remained remarkably stable, whereas finer-scale chromatin loops were far more dynamic.
• The findings challenge the view of genome architecture as a passive consequence of evolution and instead suggest that the 3D organization of DNA can actively influence evolutionary change.