The first synthetic yeast genome has been designed

Researchers have designed a fully artificial yeast genome and started the process of constructing it.

The design of the first fully synthetic yeast genome has been unveiled in a study published in Science. The artificial genome, called Sc2.0, is about eight percent smaller than that of natural yeast. Now that the design is complete, the team plans to integrate it into living yeast cells. They have already made significant progress towards this goal, with six complete artificial chromosomes so far. Yeast typically has 16 chromosomes, and the artificial yeast will also feature an additional “neochromosome,” to which all the protein-making machinery has been moved. This makes the genome more easily customizable. Once all 17 synthetic chromosomes are integrated into a single cell, the newly designed genome will be complete.

We asked lead author Joel Bader, a biomedical engineer at Johns Hopkins University, to tell us more about the design and the yeast that will come out of it.

ResearchGate: What motivated this project?

Joel Bader: There are a number of important research questions that can only be answered by designing and synthesizing a completely new genome—questions like how chromosomes are organized, why genes are organized the way we observe them, and what the functions of supposedly non-functional elements are. Then there are applied questions: whether we can make the genome more modular by collecting genes in a single pathway or process on single chromosomes, called neochromosomes. This would make pathways more amenable to study and easier to manipulate and optimize.

RG: What have you and your colleagues accomplished?

Bader: We have designed a synthetic version of the yeast genome, and completed the synthesis and integration of six entire chromosomes. We’ve also completed the synthesis of the DNA required for the remainder of the genome, the ten remaining chromosomes, and a neochromosome with all of the tRNA genes. Within 1-2 years, all the synthetic chromosomes should be integrated into individual strains, and within 2-3 years we should have a cell that has all 16 synthetic chromosomes, plus the neochromosome.

RG: How did you achieve this?

Bader: The design phase took teamwork between yeast biologists and computational biologists to translate high-level design goals into changes in the DNA sequence. When we had the target sequence—essentially a computer file with hundreds of thousands, almost a million, DNA letters—we had to segment it into smaller and smaller pieces that could eventually be synthesized chemically. Thus, the electronic information became physical in the form of DNA molecules, which we ordered and assembled into larger and larger pieces. The last steps involve gradual replacement of a wild-type chromosome by its synthetic counterpart.

RG: How does this genome compare to that of natural yeast?

Bader: Yeast has about 12 million basepairs in its genome. Our synthetic Sc2.0 genome has about 1 million changes at the nucleotide level, although many of these changes are from edits that affect a larger region. It lacks repeats and most introns, which are nucleotide sequences within a gene that are removed by RNA splicing during maturation. tRNA genes have been relocated from their native positions to a special neochromosome. It also has a system called SCRaMbLE that permits individual yeast cells to rearrange their genomes on the fly, which will allow us to do massively parallel genetics experiments.

RG: What’s the ultimate goal of the project?

Bader: Each chromosome is an important intermediate milestone. Having a completely synthetic genome in a viable cell will be another. We also have research goals beyond that of using the Sc2.0 cells to study basic and applied research questions. These will be the next steps for Sc2.0. For the larger research community, other genomes will be targets for genome synthesis.

RG: What applications could synthetic yeast have?

Bader: Yeast is already an important industrial organism. The Sc2.0 strain could be used to help optimize yeast for new products, or to give yeast capabilities that it lacks. For example, many valuable drugs and biopharmaceuticals can’t be made in industrial yeast strains because pathways are missing. The neochromosome technology gives us a new capability to move pathways into yeast in a modular way that could be very valuable.

RG: Could this lead to more complex organisms being synthetically designed from scratch?

Bader: Yes, in that other genomes could potentially be synthesized, leading to individual cells that have synthetic chromosomes.

RG: How does it feel to have reached this milestone in your research?

Bader: One of the great pleasures of this project has been to work with scientists across the world and see the international excitement about the promise of synthetic biology and biotechnology.

Featured image courtesy of Mehmet Pinarci.