Yeast with 50% synthetic DNA engineered in breakthrough genetic studies

Scientists have hit a major milestone in a 15-year project trying to build a completely synthetic yeast genome. Reporting in a bumper crop of new papers, the team has engineered viable yeast cells with more than 50% synthetic DNA for the first time, and have created synthetic versions of almost all its chromosomes, plus a completely new one.

The world’s first completely synthetic organism was created in 2010, and has been tweaked in the years since to let it grow and divide, and even move around on its own. But this, and others like it, are bacteria, which have very simple genomes contained in a single chromosome.

Other scientists have been working to create synthetic versions of more complex lifeforms, including the Synthetic Yeast Project (Sc2.0). As you may have guessed, their goal is to create a fully synthetic genome of brewer’s yeast, which would make it the first artificial eukaryote – a large group of life that includes all plants and animals.

Yeast packs its DNA into 16 chromosomes, six of which have previously been synthesized by the project. In the new batch of studies, the Sc2.0 scientists have added eight more, and performed a series of experiments that let them explore the biology of yeast and what changes can be safely made in a synthetic version.

One of the main changes made to the genome was deleting large sections of repeating DNA. These areas don’t code for anything in particular, but they can recombine with each other and cause major structural changes. By deleting them, the team says they gain greater control over the genome, making it more stable.

In another of the studies, the researchers created an entirely new chromosome that contained sections of DNA that encode for transfer RNA (tRNA). These DNA sequences are vulnerable to instability, the team says, so snipping them out of their usual places in the genome and lumping them into their own chromosome also helped make the entire genome more stable.

Other groups pushed the viability of the yeast to its limits, by making major structural changes like fusing chromosomes together, inverting their “arms” or deliberately folding chromosomes incorrectly. They found that the yeast cells could tolerate a surprising level of change and still thrive.

Next, the Sc2.0 scientists set out to assemble as many of these synthetic chromosomes as possible into one living yeast cell. They used a gradual technique where they cross-bred strains with one synthetic chromosome each, then selected the offspring that had acquired both of its parents’ mutations. Repeating this process over generations, they ended up with a yeast strain containing 6.5 synthetic chromosomes.

Finally, they used a new technique developed as part of the project to substitute another chromosome into this strain, resulting in yeast with a genome consisting of 7.5 synthetic chromosomes, meaning it’s the first to have more than 50% synthetic DNA.

Although it’s taken 15 years to reach the “halfway” point, the scientists predict that it’ll only take one more year before they’ll have a strain of yeast that’s 100% synthetic. The final two chromosomes have already been synthesized and are expected to be the subject of their own papers in the next few months. After that comes the tedious work of editing them and debugging the changes to make sure the yeast is still viable.

The project isn’t just to “play God” – a completely synthetic strain of yeast could help the world in far more ways than you might think. Already yeast is put to work producing not just food but antibiotics, drugs, biofuels, and a range of other useful molecules. It could be engineered to do so more efficiently, or expand its repertoire to solve other major problems.

The research was published in 10 papers in the journals Cell, Molecular Cell and Cell Genomics [1],[2].

Sources: NYU Langone Health, University of Nottingham, Nature, Science