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Continuous development and improvement

Continuous integration of multiple technology upgrades drives ongoing improvements

MinION was launched into the MinION Access Programme in Spring 2014 and made commercially available in May 2015. Since that time, Oxford Nanopore has delivered continual improvement in performance, usability and other metrics. The format of the hardware, software and chemistry is continuously improved; typically through upgrades in the consumable and so requiring no device change.

This iterative improvement process will continue throughout the lifetime of all Oxford Nanopore products, however in 2020 the Company will release a “Q” line in Jan 2020, which will be ISO 9001 accredited.

Updates across different parts of the technology can combine to produce specific, measurable improvements. This has been achieved through a combination of software updates, changes in the library preparation kits and protocols, changes in the flow cell design and changes in the flow cell chemistries.

Updates across different parts of the technology can combine to produce specific, measurable improvements. This has been achieved through a combination of software updates, changes in the library preparation kits and protocols, changes in the flow cell design and changes in the flow cell chemistries.

Examples of developments to date

Library preparation kits

  • Many elements of the library preparation process have been improved over time to deliver enhanced performance. Additional kits and protocols have been introduced to enable new applications, for example cDNA sequencing and barcoding of genomic DNA and amplicons.
  • We have also made several changes to our library preparation kits to improve the user experience. These include reducing the number of steps and consequently the time taken, and improving robustness and performance. The Rapid Sequencing kit prepares a library in 5-10 minutes.
  • VolTRAX, an automated library preparation device, is designed for ease of use, anywhere, and to make it easier to prepare high quality libraries for the best sequencing results.

Sequencing chemistry

Nanopore sequencing takes place in consumables called flow cells, which contain bespoke nanopore sensors, motor proteins and associated chemistries. Multiple upgrades in the sequencing apparatus have been delivered over time, for enhanced yields and accuracy.

Three flow cells: MinION, GridION and PromethION, are available. While different scales, the same sequencing chemistry is used across these consumables.

  • In the summer of 2016, 'R9' was released to supercede the previous R7 flow cell. This was designed to improve sequencing accuracy.
  • In October 2016, new flow cells containing R9.4 were shipped, increasing sequencing speeds to 450 bases per second and enabling 10Gb DNA sequencing data to be obtained from a MinION Flow Cell.
  • In May 2017, R9.5 was shipped, to be compatible with the new 1D squared method of sequencing. Oxford Nanopore was at this stage producing more than 20Gb from a single Flow Cell.
  • In June 2019, more than 50Gb had been achieved on a single MinION flow cell internally, with many users outside the company generating 30Gb.
  • In 2019, R10 flow cells were shipped to users in early access. Early results indicate enhanced consensus accuracy and accurate variant calling with this novel nanopore.
  • In 2020, R10.3 – an updated version of the R10 nanopore, was introduced, for further enhanced performance.
  • Continuous improvements to all parts of the technology including the software continue to be delivered.

Device iteration

  • In May 2015 the second version of the MinION, the MinION Mk was introduced. The MinION MkI was a full production device featuring improvements of performance and ease of use.
  • In May 2016, the MinION Mk 1B was introduced. Preparing for future iterations of nanopore chemistry it included improvements such as greater temperature control of the flow cell.
  • In 2019, the GridION X5 transitioned to the matured GridION Mk1. The beta PromethION also transitioned to P24 and P48; these upgrades included improved computational power, temperature control and a variety of other performance-enhancing qualities.

Driving yields: Speed of individual nanopore processing

DNA can translocate a nanopore at a variety of speeds. The faster the DNA passes through, the faster the data is generated and the higher the yields. Speed is affected by multiple factors including buffers, temperature and the motor enzyme deployed. In combination with other improvements, increasing translocation speed means that flow cells have gone from being able to produce hundreds of megabases of data in 2014, to tens of gigabases in 2020.

1.

  • During the first year, Oxford Nanopore recommended a translocation speed of around 30 bases per second per nanopore.
  • By 2015 users could run at 70bps.
  • With the introduction of R9 in the summer of 2016, DNA was passed through the nanopore at 250+bps.

2.

  • From October 2016, processing speeds have been ~400-450 bases per second for DNA sequencing.

Driving yields: Duration of use

  • Nanopore devices do not have a fixed run time; users may run the flow cell for as long as it takes to accumulate sufficient data for their needs. The total available life time of a flow cell does not need to be consumed in a single experiment.
  • More recent releases of flow cells and software have enabled flow cells to be run for longer (at a constant price), enabling resulting in increased overall yields.

Driving yields and performance: the instrument control software (MinKNOW)

  • New versions of MinKNOW have been released to improve MinION performance for all applications. For example, adjusting the frequency of data sampling can improve yield and accuracy.
  • In February 2017, MinKNOW 1.4.2 was released, enabling larger data yields.
  • Further upgrades have included features such as progressive unblock, allowing enhanced yields by allowing longer run times, and improvement in 'MUX' processes to select the most productive channels early in an experiment – these have all contributed to higher yields.

The right throughput for the right project

  • Following on from the success of the MinION, the GridION X5 was launched in 2017. This can run up to five MinION Flow Cells with onboard compute and has now been upgraded to the GridION Mk1, with enhanced compute power.
  • The PromethION 48 is now available and offers nearly 300 times the power of a MinION, except modular and on-demand. The PromethION is designed to operate up to 48 Flow Cells individually or together.
  • The Flongle was introduced in 2019, for rapid, smaller tests.
  • Oxford Nanopore continues to develop SmidgION, a smartphone sequencer.

Analysis tools

Based on electronics rather than optics, nanopore technology can scale to any size:

  • Continuous iteration of basecalling algorithms, device control software and the availability of a broad range of analysis tools from Oxford Nanopore or the community, have contributed to improvements in accuracy of raw and consensus data, and improved variant detection.
  • In 2020, the current R9.4.1 nanopore can generate more than Q40 accuracy (99.99%) on selected genomes, with further work ongoing to expand the range of genomes and further improve accuracy. R10 has demonstrated >Q50 on similar genomes. Read more here about analysis methods.
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