University of Manchester - Oxford Nanopore PromethION

Lead Research Organisation: University of Manchester
Department Name: School of Biological Sciences


Technological developments in how we identify, characterise and count molecules (e.g. DNA) in cells has been fundamentally altered through the development of a new technique by Oxford Nanopore Technologies. This approach works by moving molecules through a small channel (or nanopore) and measuring changes in electrical energy as it does so. Through sophisticated computational techniques, we can identify precisely what the molecule looked like from these changes in energy, which are 'sequence-specific'. This is possible because specific disturbances of energy currents are characteristic of a unique combination of nucleotides, or letters, that make up our DNA. This new approach to generating information about our complete genetic composition has many advantages, including an ability to generate data in really large pieces (usually 10-1000x larger than other approaches that are widely used) and to go beyond identifying just the specific sequence of letters in our DNA but also to identify any modifications/attachments to individual nucleotides, or letters - this is analogous to an e being accented to a é and gives a slightly altered meaning or emphasis to a sequence.

These advantages will enable new types of research which are addressing important areas of human health, including the study of diseases where genetics is a key driver (e.g. rare disorders and cancer), and will provide a step change in the identification of exact quantities and precise compositions of pathogens, e.g. bacteria. We will use the technology in Manchester to expand and accelerate an array of fundamental and clinical biomedical research programmes that are already funded, and these unique insights will enable advanced understanding and ultimately improvements to how we diagnose, treat and understand human diseases. We will focus on areas of strength for The University of Manchester, including through collaboration with the NHS Manchester Centre for Genomic Medicine to study genetic disease, collaboration with the Manchester Cancer Research Centre to track how a cancer develops over time, and with the NIHR Manchester Biomedical Research Centre to study how particular types of bacteria develop resistance to antibiotics. We will also continue to develop the technology as part of other important core facilities at The University of Manchester - this will include integration with core teams that make specific genetic edits in cells to observe impact, and approaches that identify precisely where a molecule was at the time of the experiment, a technique known as single cell research. These approaches will use both DNA, and RNA (a molecule that contains the key message to turn DNA to protein).

This technology is important for a diverse range of biological applications, including human genomics, cancer research, microbiology, plant science, environmental research, and agriculture. As a result, we will place the technology in a purpose-built core facility at the University of Manchester and we will make it accessible to all researchers and external partners. The core facility is staffed by specialists who work exclusively with cutting-edge genomics technology, and will be trained by Oxford Nanopore to become experts in operation and data generation. Moreover, all data analyses will be supported by teams of computational specialists to ensure researchers have access to high-powered supercomputers and specialist software required to work with the data that is generated. The University of Manchester regards this as a high value asset to future strategies and it will receive full support and integration to ensure ease-of-use and accessibility.

Technical Summary

An Oxford Nanopore PromethION will be hosted in the Genomic Technologies Core Facility (GTCF) at the University of Manchester (UoM), and made available for use as a genomic service by internal, and external, research groups. The PromethION will be hosted in a purpose built laboratory space, alongside other high-throughput sequencing instruments, and operated by specialist Research Technical Professionals, with a cost-recovery operating model in the facility to ensure long-term accessibility and maintenance.

The ONT PromethION is a high-throughput, direct, real-time, single molecule sequencer that leverages sequence-specific disruptions in ionic current as molecules pass through a nanopore. The sequencing methodology provides a step-change in biological insights across diverse research areas. This is largely underpinned by unrestricted read lengths, and a capability to directly sequencing native DNA/RNA molecules, with added advantages of monitoring and interpreting sequencing data in real-time.

The PromethION will be immediately utilised across a diverse programme of biomedical research at UoM aligned to MRC priorities, with projects assembled into four key themes: (1) clinical genomics: diagnosis and discovery; (2) genomics and therapeutics; (3) insights into rare disease mechanisms and cell biology, and (4) cancer evolution. In addition, the PromethION will be integrated as a routine service associated with other core facilities at UoM, including the Genome Editing Unit (for CRISPR on-/off-target variant identification) and with the Single Cell Facility (as an approach for single cell sequencing). This will develop novel understanding of genomic diseases through a capability to characterise full-length transcripts, to assemble and detect variation in complex genomes, to identify complex structural genomic variation, to survey otherwise intractable genomic regions, and to simultaneously identify single-nucleotide level modifications at a genome-wide scale.


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