New technologies capable of sequencing single molecules in fine detail will help scientists better understand the mechanisms of rare nucleotides thought to play an important role in the progression of some diseases.

A review paper, led by a scientist at the University of Birmingham, describes how emerging sequencing technologies will transform our understanding of these molecules, ultimately leading to new drug targets. The paper is published in the journal Trends in Biotechnology.

Expression of genes to make protein involves making a messenger RNA molecule. Although RNA, like DNA consist of the four nucleotides, some of them carry decorations called the epitranscriptome. These modified nucleotides are important additions to the genetic code whose functions are little understood, but have been linked to disease such as obesity, cancer and neurological disorders.

Although the importance of the epitranscriptome is recognized, its detection is difficult and comes with high error rates.

Scientist have been interested in these rare modified nucleotides since their discovery more than 40 years ago, but they had been very difficult to examine in specific genes due to technical difficulties. However, their importance has been recognized, because many human parasites and viruses have them. Even more, some viruses including coronavirus SARS-CoV2 have their own RNA modification enzymes, originally acquired from their hosts, but then adapted to their needs. 

Until recently, the study of these modified nucleotides has been limited because they occur so rarely, and existing technologies have not been sufficiently fine-tuned to detect the modifications.

The new technology, developed by Oxford Nanopore Technologies, is promising to overcome current sequencing limitations, with highly selective sequencing capabilities.  By identifying specific nucleotide targets associated with particular diseases, drug developers will be able to start to investigate inhibitor drugs that can interfere with the molecules and influence the progression of the disease.

Lead author of this multinational study, Dr Matthias Soller from the University of Birmingham, UK, says: “These modified nucleotides are particularly hard to detect and previously it was impossible to examine their occurrence in the entire genome with high confidence”.

First author and Schmidt Science Fellow Dr Ina Anreiter, University of Toronto, Canada, adds: “Previously, it was only possible to look at one modification at a time, but there a more than just one and they likely hiding a yet to discover code.

“This new technology will really enable a step-change in how we approach modified nucleotides, giving us a ‘real-time’ topographic map of where the molecules are within the genome, and how frequently they occur. This will be really important in instructing further research into their function and providing us with new insights into how these molecules lead to human disease.”

Dr Soller added: “There is plenty of work still to be done to further develop these sequencing devices, including improving the machine-learning capability for interpreting the sequencing signals, but progress is happening rapidly and I think we will be seeing some very exciting results emerging from this technology.”

Co-author, Dr Sarath Janga from Indiana University, USA says: “SARS-CoV2 RNA virus responsible for the COVID19 pandemic has about 40 RNA modifications and it is already clear, that they are essential for the virus. Hence, understanding their function in virus replication will provide new directions for combating viral infections”

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• Soller et al (2020). ‘New twists on detecting mRNA modification dynamics’. Trends in Biotechnology https://doi.org/10.1016/j.tibtech.2020.06.002