Published 26 Apr 2019

In 2016, in collaboration with researchers at the the University of Oxford, we generated two of the first human genomes to be sequenced using nanopore technology. The DNA sequencing was a a Herculean effort by the laboratory team, with 107 runs of Oxford Nanopore Technology’s (ONT) MinION device over a four week period. This week our manuscript describing this study has been published in Nature Communications.

The first of the two genomes we sequenced was an established human reference DNA sample known as NA12878. The NA12878 genome has been extensively studied using a range of DNA sequencing technologies and the purpose of sequencing this sample was to enable us to calibrate our approach to the analysis of the long, but error prone, reads that are generated by nanopores. To improve the accuracy of variant calling from nanopore reads we developed a new analytical approach that leveraged the fact that the long reads typically span multiple variant sites and therefore phasing of putative variant alleles enables us to better discriminate between true positive and false positive calls.

The second genome we sequenced was from an individual with ataxia-pancytopenia syndrome and severe immune dysregulation. This individual’s genome had previously been sequenced with Illumina short read technology which had identified two non-synonymous de novo variants in the gene SAMD9L. However there was an unanswered question that the Illumina sequence data was unable to address: were the two de novo mutations disrupting the same parental copy of the gene or were both parental copies of the gene disrupted? The long ONT reads made light work of addressing this particular question demonstrating that the two de novo mutations had occurred on the same copy of the gene that had been inherited paternally.

Our study illustrates one of the potential clinical applications of long-read human genome sequencing with nanopore technology. It also highlights that back in 2016 that there was an inflection point in the scale of data that could be generated on the ONT MinION platform that made human genome sequencing possible. In the intervening three years ONT have continued to develop their technology, with greater data generation capacity and accuracy both through improvements to their chemistry and the development of their PromethION platform. These technological advances combined with type of analytical approach developed by Genomics plc increase the prospect of nanopore-based approaches to human genome sequencing becoming routine.

Bowden et al. Sequencing of human genomes with nanopore technology.

The code developed for phasing of long reads is available in the SEW software available at

Michael Simpson, Head of Human Genetics at Genomics plc describing some initial insights from this study at ONT’s User Event in New York in 2016