Yeast is going digital. Biologists have built two artificial chromosome arms and put them to work in a living yeast. They plan to replace the entire yeast genome over the next five years and then evolve new strains to order.

“Nothing like this has ever been done before,” says Jef Boeke of the Johns Hopkins University School of Medicine in Baltimore, Maryland, who is leading the research. As well as designing and building the new genome from scratch, his team has come up with a way to systematically scramble it to produce new strains.

The artificial yeast are similar to Craig Venter’s synthetic cells, announced last year. Venter replaced the entire genome of a bacterium with a synthetic genome – but the task is far harder in yeast, because it is a more complex organism and has a bigger genome.

Yeast has 16 chromosomes, all of which have been sequenced. Boeke started small, replacing the right arm of chromosome 9 and part of the left arm of chromosome 6. He began by designing the new sequences on a computer, using the known sequence as his starting point. He stripped from this virtual DNA all the meaningless “junk” DNA, which does not code for proteins. Then he added markers called loxPsym at the ends of all non-essential genes – those that could be changed or deleted without killing the yeast. In the real world, these markers can be attacked by an enzyme called Cre, which swaps genes between the marker sites. Finally, he created these new sequences in the lab using the chemical building blocks of DNA, and inserted them into a living yeast in place of its natural chromosome arms.


Shuffling genes

“This is another remarkable example of how synthetic biology can be used to rewrite chromosome sequences at a sizeable scale,” says Daniel Gibson of the J. Craig Venter Institute in Rockville, Maryland. He says it could help us understand the rules governing genome structure.

For instance, the reshuffling technique can test how different arrangements of genes affect the yeast. Boeke has already done this by shuffling the genes on the artificial chromosomes using the Cre enzyme.

“You can take a yeast gene and insert it somewhere else in the genome, and you tend to get a healthy yeast,” Boeke says. That suggests a reshuffle wouldn’t matter, but different yeasts consistently use the same order. “Maybe there are hidden rules of genome structure that we can distil,” Boeke says.

Make your own yeast

Boeke now intends to repeat this re-engineering process with the other chromosomes in yeast. Once the entire genome is laced with loxPsym sites, Boeke plans to use Cre to make wholesale changes. Because the method targets only non-essential genes, and does not interfere with their internal structure, it should mostly produce healthy yeast.

Genomes can be rewritten in a different way using multiplex automated genome engineering (MAGE), which swaps out a particular piece of code and replaces it with another. Ultimately, organisms could be made that use a completely different genetic code.

Both methods could produce useful organisms. Besides bread and beer, ordinary yeast is already used to make vaccines, and researchers have made genetically modified yeast that can make biofuels.

Journal reference: Nature, DOI: 10.1038/nature10403