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A British-based team of scientists, led by experts from the University of Nottingham and Imperial College London, has completed the construction of a synthetic chromosome as part of a major international project to build the world’s first synthetic yeast genome.
The work, published today in Cell Genomics, represents the British team’s completion of one of the 16 chromosomes of the yeast genome, part of the largest project ever in synthetic biology; the international collaboration in the field of synthetic yeast genome.
The collaboration, known as ‘Sc2.0’, has been a 15-year project involving teams from around the world (UK, US, China, Singapore, UK, France and Australia), working together to create synthetic versions of all to make yeast chromosomes. . In addition to this article, 9 publications from other teams describing their synthetic chromosomes have been released today. Final completion of the genome project – the largest synthetic genome ever – is expected next year.
This effort is the first to build a synthetic genome of a eukaryote – a living organism with a nucleus, such as animals, plants and fungi. Yeast was the organism of choice for the project because it has a relatively compact genome and the innate ability to stitch DNA together, allowing the researchers to build synthetic chromosomes in the yeast cells.
Humans have a long history with yeast: domesticating it for thousands of years for baking and brewing and, more recently, using it to produce chemicals and as a model organism for the way our own cells work. This relationship means we know more about the genetics of yeast than any other organism. These factors made yeast the obvious candidate.
The British team, led by Dr Ben Blount from the University of Nottingham and Professor Tom Ellis from Imperial College London, has now reported the completion of their chromosome, synthetic chromosome XI. The project to build the chromosome took ten years and the constructed DNA sequence consists of approximately 660,000 base pairs – the ‘letters’ that make up the DNA code.
The synthetic chromosome has replaced one of a yeast cell’s natural chromosomes and, after a painstaking debugging process, now allows the cell to grow at the same fitness level as a natural cell. The synthetic genome will not only help scientists understand how genomes function, but it will also have many applications.
Rather than being a direct copy of the natural genome, the synthetic Sc2.0 genome is designed with new features that give cells new capabilities not found in nature. One of these features allows researchers to force the cells to shuffle their gene content, creating millions of different versions of the cells with different characteristics. Individuals can then be selected with improved properties for a wide range of applications in medicine, bioenergy and biotechnology. The process is in fact a form of supercharged evolution.
The team also showed that the chromosome can be repurposed as a new system to study extrachromosomal circular DNAs (eccDNAs). These are free-floating DNA circles ‘looped’ from the genome and are increasingly recognized as factors in aging and as a cause of malignant growth and resistance to chemotherapeutic drugs in many cancers, including glioblastoma brain tumors.
Dr. Ben Blount, one of the lead scientists on the project, is an assistant professor at the School of Life Sciences at the University of Nottingham. He said: “The synthetic chromosomes are a huge technical achievement in themselves, but will also open up a huge range of new possibilities for the way we study and apply biology. This can range from creating new microbial strains for greener bioproduction to helping us understand and combat diseases.
The synthetic yeast genome project is a fantastic example of large-scale science accomplished by a large group of researchers from around the world. It was an amazing experience to be part of such a monumental effort, with everyone involved working towards the same common goal.”
Professor Tom Ellis from the Center for Synthetic Biology and Department of Bioengineering at Imperial College London said: “By constructing a redesigned chromosome from telomere to telomere, and showing that it can perfectly replace a natural chromosome, the work of our team provided the basis for designing and creating synthetic chromosomes and even genomes for complex organisms such as plants and animals.”
In addition to leaders from Nottingham and Imperial College London, the UK team also includes scientists from the Universities of Edinburgh, Cambridge and Manchester in the UK, as well as John Hopkins University and New York University Langone Health in the US and Universidad Nacional Autónoma de México, Querétaro in Mexico.
The full study can be found here.
The work was funded by the BBSRC.
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