DNA preparation laboratory. Image credit: Greg Moss / Wellcome Sanger Institute
The Wellcome Sanger Institute has one of the world’s largest genome sequencing facilities. Over the past year, the Institute has taken delivery of four of the latest sequencing platforms – new and upgraded technologies that increase the speed, capacity and precision of DNA and RNA sequencing.
Ultima Genomics UG 100
Potentially cheaper high-throughput short-read sequencing
The UG 100 is one of a new generation of sequencers that are helping to slash the cost of sequencing a genome and creating new research opportunities. The machine arrived at the Sanger Institute in March 2023 and, along with other sequencers, will be trialled over the next few months using samples from across Sanger’s six scientific programmes to determine how well it is suited to particular applications.
This Ultima platform is one of only a handful of the machines in operation worldwide and the first outside of the US. Currently, it costs the Institute around $500 to sequence a human genome. If the UG100 delivers on its promise, this figure could be dramatically reduced to around $100 at commercial launch. There is a good chance it could fall further than that, opening up new possibilities to carry out genomics at scale.
The cost of a single human genome has fallen dramatically since the first was completed in 2003. That original assembly cost around $3 billion. The arrival of next-generation sequencers in 2007 saw the cost fall from millions of dollars to thousands, with the $1,000 milestone reached in the late 2010s. By 2022, the Sanger Institute could sequence a human genome for around $500.
“My career at Sanger began working with John Sulston on the first human genome and key pathogens like malaria and tuberculosis. It’s been incredible to see the advances in sequencing technology since then and we’re excited to put the UG 100 through its paces over the next few months. A lower price per genome will open up wider population-scale studies and deeper sequencing to detect even the rarest genetic variants.
“One of the benefits of this new technology is its ability to perform deeper sequencing. This could support many projects at the Institute, including metagenomic approaches where researchers need to identify multiple organisms in a single sample, single-cell sequencing and somatic variation studies.”
Dr Mike Quail,
Principal Scientist for Sequencing Research, Wellcome Sanger Institute
PacBio Revio
High-throughput long-read sequencing
This long-read DNA sequencing technology will be used to determine the genome sequences of all eukaryotes (animals, plants, fungi and protists) in Britain and Ireland. The new system has a much higher throughput than its predecessor, enabling teams to scale up their biodiversity sequencing programmes.
At the Sanger Institute, the Revio machines are primarily used by researchers seeking to unravel an organism’s genome for the first time. These projects are part of a global effort to determine the genome sequences of all life on Earth. Long-read sequencing data are particularly useful for building reference genomes.
The Revio system produces highly accurate data, with a documented output of 360 billion base pairs (360 Gigabase pairs/Gbp) per day, with read lengths of 15–20,000 base pairs (15–20 kbp).
The system also boasts high accuracy for determining genetic variation; from single letter changes (SNPs) to structural variant calling and methylation status. Recently PacBio introduced a new sample preparation kit, enabling cDNA (complementary DNA synthesised from an RNA template) to be linked together. This allows for economic full-length RNA-Seq, enabling researchers to characterise transcript isoforms.
Dr Kerstin Howe, Head of Production Genomics, Wellcome Sanger Institute said, “The Revio system is a much-welcomed addition to our sequencing portfolio and will allow us to scale up even further to deliver thousands of high-quality reference genomes for a variety of the Earth BioGenome biodiversity genomics projects we are involved in.”
Illumina NovaSeq X
High-throughput short-read sequencing
NovaSeq X enables sequencing at a much lower cost compared to the previous Nova 6000 from Illumina. The NovaSeq X machines also have a new chemistry that will deliver the same output as the NovaSeq 6000 in just 24 hours, compared to 48 hours previously. These benefits will enable Sanger researchers to undertake larger sequencing projects, which could prove especially valuable for large population studies as part of the Human Genetics research programme, as well as detecting rare genetic variants within Cancer, Ageing and Somatic Mutation.
The NovaSeq X is Illumina’s most powerful sequencer, and Sanger’s sequencing research teams envisage it will become the main workhorse for all sequencing applications currently being performed on the current NovaSeq 6000 platforms. They have a documented output of up to 16 Tb per run and up to 26 billion single-reads per flow cell.
Element AVITI
Mid-throughput short-read sequencing
The most recent sequencer to arrive is Element AVITI, which represents a significant advancement in sequencing technology. It is a benchtop mid-throughput sequencer capable of delivering up to 360Gb sequence (1 billion reads) in 48 hours. Sequencing costs are comparable to those achieved on the NovaSeq 6000.
Through rigorous evaluation, the system shows improved mapping rates, genome coverage, and variant detection. The instrument has several potential technical advantages over other short-read technologies, including: superior accuracy (Q40), up to 300 base read lengths, greater tolerance for low complexity, lower duplication rates, no index hopping (enabling the use of combinatorial barcoding and larger inserts of up to 3000 bases), which also provides longer mate pair information and higher mapping rates.
Element have recently announced that AVITI will be able to perform multi-omic analysis and sequencing in cells, profiling RNA, protein, morphology and within-cell DNA sequencing on up to 1 million cells.
Expanding the scope of genomic technologies
All four of these cutting-edge sequencers complement other genomic technologies from companies including Oxford Nanopore, BioNano and others. Data from all these technologies, often combined, allow researchers to push the boundaries of knowledge across diverse scientific fields.
Research teams are sequencing the genomes of thousands of organisms for the first time, as well as sequencing millions of individual human cells to determine their form and function. Other groups are surveying pathogens including drug-resistant bacteria, the agents of malaria, and the COVID-19 virus. Sequencing hundreds of thousands of human genomes also continues, powering research into cancer and a range of other diseases.
“Since the first human genome was completed twenty years ago, the cost and speed of sequencing has fallen dramatically. This facilitated a greater diversity of genomic research and you can see genomics beginning to deliver on its early promise in the scientific and medical advances that we read about in the news each week.
“Each of these new technologies take another leap forward, allowing genomic research to have an even greater impact on human health and disease.”
Director of Scientific Operations, Wellcome Sanger Institute
