The ability to sequence entire genomes began in 1977 with the development of Sanger sequencing at the Medical Research Council (MRC) Laboratory of Molecular Biology by Dr Frederick Sanger. Sanger sequencing established genomics as a new area of bioscience research and has underpinned notable scientific projects.
The field of genomics has grown exponentially over the past half-century, with newer sequencing technologies fuelling this growth. These technologies are often faster and cheaper than Sanger sequencing.
One such technology, Illumina sequencing, is one of the most highly used tools for sequencing in bioscience research and industry today. The Biotechnology and Biological Sciences Research Council (BBSRC) has supported the research underlying the development of the technology.
Illumina sequencing: a history
Underpinning research
In the 1990s, University of Cambridge scientists Professor Sir Shankar Balasubramanian and Professor Sir David Klenerman were working on a BBSRC-funded responsive mode project.
The project involved exploring an enzyme involved in DNA synthesis. During the project, they began to consider how visualising the activity of this enzyme also allowed them to read DNA sequences and generate data quickly.
The research evolved into developing sequencing by synthesis (SBS) and the spin-out Solexa, which specialised in the technology. Professor Sir Shankar Balasubramanian won BBSRC’s 2010 Innovator of the Year award for this work. Illumina acquired Solexa in 2007, and SBS became known as Illumina sequencing.
Professor Klenerman said:
The idea for Solexa came from some basic research funded by the BBSRC and was originally sketched out on a sheet of A4 paper.
Optimising the technology
Illumina has continued to optimise the sequencing technology, making whole genome sequencing quicker and more accessible, enabling its application across bioscience. One of Illumina’s newest sequencing systems, NovaSeq X, can generate more than 20,000 whole genomes per year at a cost of $200 per genome.
The cost of sequencing has been reduced substantially by this technology, especially when compared to the cost of the Human Genome Project. This international effort to sequence a single human genome took 13 years and cost $2.7 billion to complete.
Illumina sequencing has allowed us to understand the genomes of species that are important for our environment, economy, industry and human health.
Perhaps one of the most significant sequences to be revealed in the past five years is the COVID-19 virus, with Illumina supporting the sequencing efforts. The technology proved invaluable during the COVID-19 pandemic, allowing rapid characterisation of the virus and its variants. By tracking the distribution and prevalence of these variants, this knowledge could be used to inform global control measures.
BBSRC’s contribution to the genetic revolution
Unveiling the Arabidopsis genome
BBSRC invests in research utilising sequencing platforms to uncover the genomes of, and genomic variation within, a variety of species.
BBSRC-funded research has helped to uncover the genome of the model species Arabidopsis thaliana. Arabidopsis has been adopted by the scientific community as a system in which key biological questions can be explored.
Researchers at the John Innes Centre (JIC), which receives strategic funding from BBSRC, contributed to this sequencing effort as part of the Arabidopsis Genome Initiative, completing the work in 2000.
The genome of this plant has formed the basis of numerous studies into the genetics behind fundamental plant functions. Researchers have gone on to apply learnings from Arabidopsis genomics to other plants, including globally important crops.
Why Arabidopsis thaliana is the key to protecting our plants. Credit: BBSRC
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Understanding crops and livestock
BBSRC-funded researchers have contributed to sequencing a range of crop and livestock species, including:
- chicken (2004): supported by researchers at The Roslin Institute
- rice (2005): supported by researchers at JIC
- Chinese cabbage (2011): supported by researchers at JIC and Rothamsted Research
- oilseed rape (2014): supported by JIC researchers
- potato (2011): supported by University of Dundee and Imperial College London researchers
- tomato (2012): led by researchers at the University of Nottingham, Imperial College London and supported by the Earlham Institute
- barley (2012): supported by Earlham Institute researchers
- bread wheat (2014): supported by researchers at the Earlham Institute and JIC
- pig (2012, 2020): led by researchers at The Roslin Institute
- sheep (2014): led by researchers at The Roslin Institute
- European flat oyster (2022): led by researchers at The Roslin Institute
Knowledge of crop and livestock genomes has informed breeding efforts for higher yield, increased nutrition, greater resistance to disease, and resilience against climate change. For example, BBSRC funded:
- the sequencing of the wheat genome
- the development of improved wheat varieties
- the production of resources with commercial use to breeders
BBSRC’s investment in genomic wheat research and impact is outlined in BBSRC’s revolutionising wheat showcase.
Building the UK’s genomic capabilities
Much of the capacity to sequence and assemble these genomes has come from BBSRC-funded facilities and institutes, which have since become national genomics capabilities.
Edinburgh Genomics
Edinburgh Genomics’ history of BBSRC support is outlined in our case study on farm animal genetics and genomics at The Roslin Institute. It is through Edinburgh Genomics, and its predecessor ARK-Genomics, that reference genomes (example genomes representative of all animals of the species) for sheep, pigs and oysters were generated.
The free availability of high-quality genome sequence annotation in the public domain is critical to making these reference sequences an invaluable resource for bioscience and related communities. BBSRC support for the annotation of farmed animal genomes has been invaluable. BBSRC support came through the Biological and Bioinformatics Resource Fund via a longstanding collaboration between The Roslin Institute and the Ensembl team at the European Bioinformatics Institute.
Edinburgh Genomics provides researchers from academia and industry with agriculturally and biomedically important data (partly using Illumina sequencing technology). BBSRC continues to invest in this capability, awarding funding to Edinburgh Genomics in 2014, alongside the Natural Environment Research Council. The funding was awarded to produce software for analysing Oxford Nanopore MinIOn data and to support the facility in updating their PacBio sequencing technology.
Through the BBSRC ALERT scheme, Edinburgh Genomics acquired the PacBio Sequel IIe in 2020 and the PacBio Revio in 2023. Edinburgh Genomics now offers Illumina, Oxford Nanopore and PacBio sequencing technologies.
The Earlham Institute
The Earlham Institute, previously The Genome Analysis Centre, began its contribution to genome analysis back in 2009 when BBSRC funded its establishment.
Since then, the Earlham Institute has sequenced the genomes of plant, animal and fungal species, and BBSRC has supported these efforts by providing funding to the Earlham Institute as a strategically supported institute.
Beyond sequencing, the Earlham Institute stores genomic data and analyses this information using high performance computing. It has recently applied its expertise to sequencing protist genomes as part of the Darwin Tree of Life Project, which aims to sequence all animals, plants, fungi and protists in Britain and Ireland. Their genomes will help us to trace their evolution and learn how we can protect these species from the threat of climate change, securing biodiversity more widely.
The Earlham Institute continues to improve its capacity in genomics. In 2023, with capital funding from BBSRC, it became the first UK site to receive an Illumina NovaSeq X Plus sequencer, allowing it to further support bioscience research through genome analysis.
In providing this infrastructure, the Earlham Institute has yielded genomic data to support impact through selective breeding in agricultural and aquaculture industries. In particular, they have collaborated with The Roslin Institute and WorldFish to improve genetic resources for tilapia fish. The Illumina NovaSeq X Plus technology has supported this effort, and WorldFish is set to implement genetic improvements to Nile tilapia strains based on this work.
Medical genomics
Sequencing human genomes has become key to the medical sector. As more human genomes have been sequenced, we can identify how small abnormalities in our genomes can result in disease and determine appropriate treatments.
This has underpinned the UK’s 100,000 Genomes Project, a UK government-funded project to sequence the genomes of patients with cancer and rare diseases to facilitate genomic medicine.
BBSRC researchers have supported this effort by developing software for sequence processing. Software from Professor Gerton Lunter made processing human genome data cheaper, faster and more accurate. This has allowed medical researchers to detect genetic markers that may indicate a patient’s predisposition to developing cancer.
Recently, MRC, in collaboration with BBSRC, has provided £28.5 million in funding to establish the Human Functional Genomics Initiative programme. The programme aims to understand how genomic variations can affect human physiology and how it changes over time and in disease. This will support scientists to develop new diagnostics and treatments for patients.
The Streptomyces genome
To tackle infectious diseases, we must look to the genomes of other species, including pathogenic organisms and organisms that synthesise compounds we can use as medications, including antibiotics.
Streptomycetes, a group of soil bacteria, are responsible for producing most antibiotics in use today.
The Streptomyces genetics programme began at JIC in 1968, but it wasn’t until 2002 that the first Streptomyces genome, Streptomyces coelicolor, was sequenced. Researchers at JIC oversaw the sequencing effort.
Additional species of Streptomyces have since been sequenced, including Streptomyces kanamyceticus. In 2011, this allowed JIC scientists to identify repeated motifs within the bacterial genome that resulted in increased antibiotic production. They could exploit this system to increase antibiotic yields from other species. Other similar clusters may represent novel sources of antibiotics. Identifying new antibiotics helps us to combat the challenge of antimicrobial resistance, a global health threat.
The future of genomics
The ability to accurately sequence genomes at speed has transformed the direction and capabilities of bioscience research. BBSRC continues to invest in genomics technologies, including:
- improvements to existing sequencing methods
- the development of novel sequencing tools
- innovative applications of sequencing technologies
BBSRC-funded researchers at JIC, led by Professor Diane Saunders, in collaboration with Dr Dave Hodson at CIMMYT have built on Oxford Nanopore sequencing to produce MARPLE diagnostics. MARPLE (Mobile and Real-time PLant disEase) diagnostics is a wheat yellow rust disease detection system.
The technology is designed for field use, gives results in only two days, and allows fast detection and decision making to protect crop harvests from the fungal pathogen. To date, MARPLE has been rolled out in Ethiopia, Kenya and Nepal. In 2019, Professor Saunders and Dr Dave Hodson were named BBSRC’s Innovator of the Year for international impact.
At the Earlham Institute, researchers have developed and optimised single-cell and spatial sequencing approaches using next generation sequencing technologies. The Earlham Institute has been supported in its efforts through BBSRC’s Tools and Resources Development Fund and strategic institute funding. Earlham Institute’s single-cell and spatial sequencing platforms enable progress within their strategic programmes.
The Earlham Institute also provides access to innovative tools and technologies to the UK bioscience community, strengthening its position as a national capability.
Uses of genetic information
BBSRC programmes, such as ALERT, help to ensure that regional genomics capabilities are available to bioscientists. This will allow researchers to continue to generate informative genomic data. In agriculture, more genomic data enables a greater understanding of how the genes of agricultural organisms link to desirable characteristics.
At present, this genetic data informs selective breeding. The Genetic Technology (Precision Breeding) Act 2023, which will enable gene-edited products to be brought to market, may accelerate the speed at which genetic information can be translated into application going forward. Gene editing can make agricultural products available quicker than possible through traditional breeding as precise changes to plant and animal genomes can be made.
BBSRC has already funded research into genome editing, including work by Professor Alan Archibald and Professor Bruce Whitelaw at The Roslin Institute. They have successfully engineered pigs with resistance to porcine reproductive and respiratory syndrome virus.
At JIC, Professor Cathie Martin has led work on gene-editing tomatoes to produce vitamin D. Professor Graham Moore has used gene editing to understand the importance of a wheat ZIP4 gene copy in grain yield and genome stability, opening the door for breeding beneficial traits into wheat from wild relatives. These gene editing efforts support livestock and human health, as well as food security, but would not have been possible without initial sequencing efforts revealing the genomes of these organisms.
The UK is a global leader in genomics. As sequencing costs reduce, making whole genome sequencing more accessible, this opens the possibility for the UK’s genomics expertise to be used in an ever-growing number of sectors.
Top image: Credit: nicolas_, E+ via Getty Images