Scientists one step closer to rewriting world’s first synthetic yeast genome

Researchers in the Manchester Institute of Biotechnology (MIB), based at The University of Manchester, and at the Earlham Institute have created the tRNA Neochromosome – a chromosome that is new to nature.

It forms part of a wider project (Sc2.0) that has now successfully synthesised all 16 native chromosomes in Saccharomyces cerevisiae, common baker’s yeast, and aims to combine them to form a fully synthetic cell.

The international team has already combined six and a half synthetic chromosomes in a functional cell. It is the first time scientists have written a eukaryotic genome from scratch.

Yeasts are a common workhorse of industrial biotechnological processes as they allow valuable chemicals to be produced more efficiently, economically, and sustainably. They are often used in the production of biofuels, pharmaceuticals, flavours and fragrances, as well as in the more well-known fermentation processes of bread-making and beer-brewing.

Being able to rewrite a yeast genome from scratch could create a strain that is stronger, works faster, is more tolerant to harsh conditions and has a higher yield.

The process also sheds light on the traditionally problematic genome fundamentals, such as how genomes are organised and evolved.

The findings of both projects, published as two research articles in the journals Cell and Cell Genomics respectively, are the culmination of 10 years of research from an international consortium of scientists and mark a new chapter in engineering biology. 

The consortium is led by Professor Patrick Cai at The University of Manchester, and includes Earlham Institute Group Leader Dr Conrad Nieduszynski.

Dr Nieduszynski said: “It was a major challenge to design a neochromosome that could both express hundreds of tRNA genes and be faithfully replicated in cells. 

“We’re delighted to have contributed to the design and demonstrated stable DNA replication for the tRNA neochromosome.”

Prof Cai, Chair in Synthetic Genomics at The University of Manchester who is the international coordinator of Sc2.0 project, said: “This is an exciting milestone when it comes to engineering biology. While we have been able to edit genes for some time, we have never before been able to write a eukaryote genome from scratch. 

“This work is fundamental to our understanding of the building blocks of life and has the potential to revolutionise synthetic biology which is fitting as Manchester is the home of the Industrial Revolution. Now, we’re at the forefront of the biotechnological revolution too.

“What’s remarkable about this project is the sheer scale of collaboration and the interdisciplinarity involved in bringing it to fruition. We’ve brought together not only our experts here in the MIB, but also experts from across the world in fields ranging from biology and genomics to computer science and bioengineering.

The tRNA neochromosome is used to house and organise all 275 nuclear tRNA genes from the yeast and will eventually be added to the fully synthetic yeast where the tRNA genes have been removed from the other synthesised chromosomes.

Unlike the other synthetic chromosomes of the Sc2.0 project, the tRNA neochromosome has no native counterpart in the yeast genome.

It was designed using AI assisted, computer-assisted design, manufactured with state-of-the-art roboticized foundries, and completed by comprehensive genome-wide metrology to ensure the high fitness of the synthetic cells.

Next, the researchers will work together to bring all the individual synthetic chromosomes together into a fully synthetic genome. The final Sc2.0 strain will not only be the world’s first synthetic eukaryote, but also the first one to be built by the international community.

“The potential benefits of this research are universal – the limiting factor isn’t the technology, it’s our imagination”, says Prof Cai.