For more than two decades, scientists have known the full sequence of the human genome, the approximately three billion DNA letters that form the biological blueprint of every human being. That achievement reshaped medicine, biology, and our understanding of inherited disease, but it also exposed a deep limitation. Knowing the sequence alone did not explain how cells actually use that information. Genes are not read like words on a page. They are selectively activated, suppressed, or ignored depending on cell type, timing, and biological context. Two people can share nearly identical DNA yet experience vastly different health outcomes, and for years, researchers have struggled to explain why. The missing piece was not the code itself, but how that code behaves inside the crowded, dynamic environment of a living cell.

That mystery has now moved into focus. Scientists from Oxford’s Radcliffe Department of Medicine have achieved the most detailed view yet of how DNA folds and functions inside human cells, mapping the genome down to a single base pair, effectively one pixel per nucleotide. Using a newly developed technique called MCC ultra, the team has revealed the physical structures that control when and how genes are switched on or off. This work goes beyond sequencing and into mechanics, showing how the genome is arranged in real space and how that arrangement governs biological outcomes. The breakthrough offers a powerful new way to understand how genetic differences lead to disease and opens new paths toward drug discovery by exposing regulatory failures that were previously invisible.

Many people think of the genome as a string of "letters." The human genome, say, has 3.2 billion base pairs of DNA organized across 23 pairs of chromosomes.

But the genome is a 3D object. Genes located on entirely different chromosomes might be clustered together. Mutations in… pic.twitter.com/pyrGzIhzJr

— Niko McCarty. (@NikoMcCarty) December 23, 2025

Why knowing the genome was never enough

When the Human Genome Project was completed, it was often described as having read the entire instruction manual for the human body. Scientists finally had access to every genetic letter, but they quickly realized that this knowledge answered only part of the puzzle. It explained what instructions existed, but not how cells decided which instructions to follow. This gap became especially clear when researchers discovered that many disease associated genetic variants did not alter genes themselves, yet still had profound biological effects.

Inside every human cell, roughly two metres of DNA must be compressed into a nucleus measuring only one hundredth of a millimetre across. To achieve this, DNA is wrapped around proteins and folded into an intricate three dimensional structure. These folds are not passive or incidental. They determine which genes are physically accessible, which regulatory regions can interact, and which genetic instructions remain silent. In effect, structure dictates function.

Until now, scientists could only study this folding at relatively low resolution. They could see general regions interacting, but not the precise, base by base contacts that drive gene control. This limitation meant that gene regulation was often inferred indirectly, leaving critical questions unanswered about how subtle changes in DNA structure could lead to major disease outcomes.

A technique that sees DNA at its smallest scale

The MCC ultra technique developed by the Oxford team overcomes this barrier by capturing genome interactions at single base pair resolution. This unprecedented level of detail allows researchers to see exactly how individual DNA units participate in folding and regulation inside living cells. Rather than relying on averaged signals or broad approximations, scientists can now observe genome architecture at its most fundamental level.

“For the first time, we can see how the genome’s control switches are physically arranged inside cells,” said Professor James Davies, lead author of the study. “This changes our understanding of how genes work and how things go wrong in disease.” His statement reflects a fundamental shift in genetics, from studying DNA as static information to understanding it as an active physical system shaped by forces and movement.

The resulting maps resemble highly detailed circuit diagrams, revealing how distant regions of DNA loop together to activate or suppress genes. This clarity allows researchers to trace direct cause and effect relationships in gene regulation, making it possible to identify precisely where and how regulatory failures begin.

The hidden switches behind common diseases

One of the most significant implications of the research lies in the location of disease related genetic changes. More than ninety percent of genetic variants associated with common diseases are found outside of genes themselves. Instead, they occur in regulatory regions that act as switches, determining when and where genes are activated.

Without the ability to see how these switches physically interact with genes, scientists have struggled to explain why small genetic changes can have such large biological consequences. MCC ultra now makes it possible to observe these interactions directly, revealing how regulatory elements contact genes inside the nucleus.

This insight helps explain the origins of conditions such as heart disease, autoimmune disorders, and cancer. It shifts the focus of genetic disease research away from faulty genes alone and toward faulty regulation, offering a more accurate framework for understanding how disease develops and progresses.

How DNA folds into functional islands

The study also revealed that DNA inside cells forms clusters of regulatory activity, grouping genes and their control elements into physical islands. These structures, previously invisible to scientists, appear to be central to how cells organize and execute genetic instructions.

“We now have a tool that lets us study how genes are controlled in exquisite detail,” said Hangpeng Li, the doctoral researcher who led the experimental work. “That’s a critical step toward understanding what goes wrong in disease, and what might be done to fix it.” His work highlights how fine scale structural changes can ripple outward to affect entire biological systems.

To validate the findings, the Oxford team collaborated with Professor Rosana Collepardo-Guevara at the University of Cambridge. Her computer simulations confirmed that the folding patterns observed arise naturally from the physical properties of DNA and its packaging proteins, supporting a unified model of gene regulation grounded in both biology and physics.

From structural insight to future treatments

Understanding genome structure at this resolution carries major implications for medicine. By identifying exactly where regulatory interactions fail, scientists can move closer to diagnosing disease at its root rather than responding only after symptoms appear.

The research also opens new routes for drug discovery. Instead of targeting genes or proteins alone, future therapies might aim to correct faulty genome architecture, restoring proper folding and regulation inside the nucleus. This represents a shift in how disease intervention is conceptualized.

“This changes our understanding of how genes work and how things go wrong in disease,” Professor Davies explained. With this framework, future studies can focus on preventing regulatory errors before they escalate into irreversible damage.

What this breakthrough means going forward

This discovery does not promise immediate cures, but it fundamentally changes how scientists approach genetics. Sequencing revealed what the genome contains. Mapping its structure reveals how cells actually read and interpret that information in real time.

As researchers apply this technique to different cell types and disease states, it may explain why genetic risks behave differently across individuals and over a lifetime. Subtle disruptions in genome structure could help explain delayed disease onset, variable severity, and unpredictable progression.

Funded by the Medical Research Council and the Lister Institute, with support from the Wellcome Trust and the NIHR Oxford Biomedical Research Centre, the research was published in the journal Cell. It marks a turning point in genetics, moving the field beyond reading the code and toward understanding how life physically uses it inside every cell.

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