The UK government has given nearly £5 million to fund full sequencing of the DNA of 6,000 people with ME using the best available technology. This will help scientists home in on what is really driving the disease. And will probably be the biggest study of its kind for any disease.

The UK government has committed £4.7 million directly to ME/CFS research through an award from its Office for Life Sciences to the landmark study Sequence ME & Long Covid. The award will pay for full sequencing of the DNA of 6,000 people with ME/CFS, using the method of British biotech company Oxford Nanopore Technologies.

This is an extraordinary moment for ME/CFS. It used to get by on the dregs of research funding, but now has a study that will probably be the largest of any single disease using this technique. It Is the result of a lot of work by a lot of people.

The DNA samples are already available through the DecodeME study. Sequence ME & Long Covid ultimately aims to sequence 9,000 people with ME/CFS and 9,000 with Long Covid – as funds permit. The project is led by the University of Edinburgh and Action for ME.

Full sequencing can reveal more

The study will probably be the largest for a single disease using this technique, which gives real depth of genetic detail. DecodeME used older, much cheaper technology looking at common DNA differences at about half a million places in the whole genome. It found a genetic signal in eight small regions of DNA, but these contained dozens of genes, and it isn’t yet clear which ones are involved in ME/CFS.

Using the Oxford Nanopore Technologies approach, Sequence ME & Long Covid will be able to sequence almost all of the 3 billion chemical ‘letters’ in the human genome. As Professor Chris Ponting, scientific lead for the study said,

“This project will allow us to pinpoint individual genes disrupted in ME/CFS… breaking down this complex disease into its underlying biological causes – bringing us closer to more precise diagnosis and, ultimately, targeted treatments.”

The technology

At its heart, the sophisticated Oxford Nanopore technology is simple, as shown in the image above,

1. A strand of DNA is threaded through a tiny hole in a membrane – a nanopore.
2. Each of the four chemical letters (A, T, G and C) creates a distinct electrical signal as it passes through the pore – and the DNA sequence can be read out from the electrical trace, one letter at a time.

Full sequencing can find big-impact genes that can be big clues

DecodeME found genetic differences that are common in the population, and these variants only very slightly increase this risk of disease. They almost always have a subtle role, usually slightly changing gene regulation: how much protein is made, or where exactly, or when. But the gene almost always makes a normal protein.

By contrast, full sequencing will also find rare genetic variants that play a big role, and often make proteins that are faulty in some way – this is likely to be the case for people whose disease tends to run in families, which we know happens in ME/CFS. These big differences in genes are much bigger clues that help scientists home in on biological causes.

Why the long-read approach is so important

Humans have 23 pairs of chromosomes. Each chromosome is a very long strand of DNA with, on average, a bit over 100 million chemical letters. But all sequencing technologies can only sequence much shorter fragments of DNA. The fragments are designed to overlap, but trying to piece them together perfectly is an enormous challenge – a bit like the world’s biggest jigsaw.

Standard short-read technology uses fragments that most often are only a couple of hundred letters long, the length of a tweet. It can be challenging to stitch so many small fragments together, and easy to miss big structural changes, such as a chunk of DNA being added to the chromosome, or lost or flipped around (biology can do these kinds of things).

In contrast, long-read technology used by Sequence ME and Long Covid uses fragments that are often over 10,000 letters long, like a short story. Think of a jigsaw that covers the same picture with far fewer pieces, so it’s possible to put the jigsaw together more accurately and find large structural DNA changes that the short-read approach would miss.

The importance of these structural variants in diseases like ME/CFS is a hot topic of research. With long-read technology and such a large sample, ME/CFS researchers could make key discoveries here.

Long-term gene silencing

On top of this, the Oxford Nanopore technology automatically detects a chemical modification that the body uses to silence genes.  This epigenetic mechanism, where the body adds a chemical tag to the DNA ‘letter’ C, is reversible and is different from the genetic differences we’re born with. It is one way the body regulates things long-term. One of the mysteries of ME/CFS is what maintains it, what locks in the illness? Possibly, it’s this kind of genetic silencing shutting down an important biological mechanism. Sequence ME & Long Covid has a shot at finding this.

We could have results from this initial phase of the study in two years

Full sequencing and analysis of 6,000 DNA samples is an enormous undertaking. But the sequencing will be done by early April 2027. The award covers the cost of all the high-tech kit and materials, with staffing costs covered by donations from the Austrian non-profit organisation WE&ME.

Analysis of so much complex data is a huge piece of work, and the prestigious European Bioinformatics Institute (EBI) has agreed to do it. Like Oxford Nanopore Technologies, the EBI has become a partner in the study, and there’s probably no better organisation in the world to do the work. The analysis will take at least another year and, as yet, it is unfunded

Sequence ME & Long Covid is a £20 million project, and this is just the start

The aim is to sequence and analyse DNA from a further 3,000 ME/CFS cases and 9,000 long Covid cases – 18,000 people in total. Work is already in progress to plan the rest of the study, including efforts to raise funds to complete it. You can donate here.

We’ve only got one shot – Chris Ponting

DecodeME deliberately collected enough saliva DNA from each person for a full sequencing study when the technology became more affordable, and Sequence ME & Long Covid is that study. It will use up the remaining precious DNA samples but will make the most of them with full sequencing to identify rare gene variants, long reads to uncover structural DNA variants and epigenetic changes to find chemical silencing.

As Ponting says of the samples, “we’ve only got one shot”, and this work will convert DNA into genetic insights that will help now and into the future.

Image & video credits:  Main image and video animations, Oxford Nanopore Technologies; video text, this author (any errors are mine); video creation, Adam. 2-part-part graphic Laura Olivares Boldú, Wellcome Connecting Science.