Scientists create synthetic yeast after massive genome development

A global consortium of scientists has successfully combined 7.5 synthetic chromosomes into a single yeast cell which is more than 50% synthetic, and replicates in a similar way to wild yeast.

Re-writing a yeast genome from the bottom up could create a strain that works faster, is more tolerant to harsh conditions and has higher yields.

The work is presented in a collection of 8 papers across the journals Cell, Molecular Cell, and Cell Genomics, detailing the monumental effort of synthesising and debugging all 16 yeast chromosomes.

This research is part of a 15-year project called the Synthetic Yeast Genome Project (Sc2.0). It involves teams from around the world – in the UK, US, China, Singapore, UK, France and Australia – working together to develop the first synthetic eukaryote genome from scratch. 

Eukaryotes are organisms whose cells have a nucleus, they include all animals, plants, fungi, and unicellular organisms like yeast.

The final stage of the project, combining all 16 chromosomes into the largest synthetic genome ever, is expected to be completed next year.

A synthetic genome has been artificially designed and constructed by scientists to carry out new functions or functions not found in nature.

Bacterial and viral genomes have been synthesised from scratch before, but eukaryotic cells – the ones in plants, animals, and fungi – are much more complicated because they contain multiple chromosomes. Chromosomes are the long DNA molecules that contain all of the genetic information of an organism.

“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,” says Professor Patrick Cai, Chair in Synthetic Genomics at The University of Manchester, UK, who is the international coordinator of Sc2.0 project.

“This work is fundamental to our understanding of the building blocks of life and has the potential to revolutionise synthetic biology.”

The synthetic yeast’s genome is very different from the natural Saccharomyces cerevisiae (brewer’s or baker’s yeast) genome on which it is based.

Scanning electron micrographs of the syn6. 5 strain of yeast which has 31 synthetic dna and displays normal morphology and budding behavior 1 credit cell zhao et al 850
Scanning electron micrographs of the syn6.5 strain of yeast which has ~31% synthetic DNA and displays normal morphology and budding behavior 1. Credit: Cell Zhao et al

“We decided that it was important to produce something that was very heavily modified from nature’s design,” says Dr Jef Boeke, a synthetic biologist at New York University Langone Health in the US, and Sc2.0 leader.

“Our overarching aim was to build a yeast that can teach us new biology.”

For example, the researchers removed chunks of non-coding DNA and repetitive elements that could be considered “junk” from the chromosomes.

To increase genome stability, they also removed many of the genes that encode transfer RNA (tRNA) – a small RNA molecule that plays a key role in protein synthesis – and relocated them to a “neochromosome” made of only of tRNA genes. A chromosome like this is entirely new and does not exist in nature.

They also introduced a build-in genetic diversity generator called “SCRaMbLE” that forces the cells to shuffle the order of genes within and between chromosomes. This results in millions of different versions of the cells, each with different characteristics. Individual cells with improved properties can then be cherry-picked for a wide range of applications.

Yeast is commonly known for its uses in bread-making and beer brewing, but also has applications in industrial biotechnological processes, and often in the production of biofuels, pharmaceuticals, flavours, and fragrances.

“Now we’re just this far from the finish line of having all 16 chromosomes in a single cell,” says Boeke.

“I like to call this the end of the beginning, not the beginning of the end, because that’s when we’re really going to be able to start shuffling that deck and producing yeast that can do things that we’ve never seen before.”

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