Oxford spinout spies the hidden mechanics of DNA and disease with single-pair resolution method

A spinout from the University of Oxford is using a newly invented method to depict and analyze DNA with super-fine resolution, allowing them to peer into what they describe as “the dark matter of the human genome” and the molecular basis of many diseases.

Nucleome Therapeutics is working on a method known as micro-capture-C, or MCC, to provide a three-dimensional view of the famously twisting double-helix structure, with the ability to zoom in on individual base pairs.

“Previous methods of determining the large-scale 3D genome structure within cells have been unable to resolve it much below 500 to 1,000 base pairs,” said co-founder James Davies, who helped develop the technology at Oxford’s MRC Weatherall Institute of Molecular Medicine alongside Danuta Jeziorska, who serves as Nucleome’s CEO.

Academic researchers are using this technique to identify the genes at play behind severe COVID—while Nucleome also plans to find new drug targets for autoimmune diseases. The latest work on 3D genome mapping was published this week in Nature.

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The researchers equate the process with looking at a city’s skyline, representing the full strand of DNA within a cell. While before they could only make out the shape of small buildings from a distance, now they can see how it’s built up from individual bricks—with all 6 billion of them representing a single letter of the genetic code.

“3D genome analysis is key to understanding the largely untapped dark matter of the genome,” Jeziorska said. “Better resolution of 3D genome maps improves the accuracy and confidence of linking disease-relevant genetic changes to genes.”

This could include the coronavirus pandemic and may help provide a better understanding of why some people require intensive care while others may show no symptoms at all.

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“For example, at the moment we know that there is a genetic variant which doubles the risk of being severely affected by COVID-19,” Davies said. “However, we do not know how the genetic variant makes people more vulnerable to COVID-19.”

By providing a more detailed view into DNA’s larger structure, drugs aimed at these genetic targets may have a better chance of making it through clinical trials, he added.

In the Nature publication, the researchers report that MCC could spot the physical interactions between gene-regulating proteins and the DNA code itself at base-pair resolution—even though one targeted string may be controlled by genes located tens of thousands to millions of base pairs further along the chain—or maybe a mile away, by bricks in a wall on the other side of the city.