Revolutionizing biology: the semisynthetic yeast genome reveals new horizons in genetic engineering

Synthetic DNA may seem like the stuff of science fiction, but it is quickly becoming a reality. Researchers have created a yeast cell containing more than 50% artificial genome, including the world’s first fully artificial chromosome.

Scientists had previously produced artificial bacterial and viral genomes, but the next step was eukaryotes, a cell in which the entire genome is located within a membrane-bound nucleus. Yeast may have been the natural choice for this, such as baker’s yeast (Wine yeast) has a compact genome of only 16 chromosomes and has an innate ability to link DNA together.

However, researchers involved in the Synthetic Yeast Genome (Sc2.0) project wanted to do something a little different than simply synthesize DNA, by giving yeast a “designer” genome. “We decided it was important to produce something that was very closely modified by nature’s design,” lead author and Sc2.0 lead Jeff Buckey said in the paper. statement. “Our overarching goal was to build a yeast that could teach us new biology.”

Making an artificial genome

The team first removed so-called “junk” DNA from the genome and replaced it with fresh DNA snippets to help them distinguish between synthetic and original genes, and then reshuffled the gene order. There was also another major removal to be made – tRNA genes.

While the proteins they encode play a crucial role inside cells, tRNA genes also make the yeast genome unstable. In a revolutionary step, the researchers removed it and transferred it to an entirely new ‘new chromosome’ based on t-RNA genes. “The new tRNA chromosome is the world’s first completely artificial chromosome,” said co-author Patrick Yezi Cai. “There is nothing like this in nature.”

Along with the new chromosome, the researchers assembled each chromosome independently, before creating 16 partially artificial yeast strains, each containing 15 normal and one artificial chromosomes.

Put the pieces together

Then came the hard part: gathering all the artificial chromosomes into a single yeast cell. This involved a combination of the classic genetic technique – hybridization – and some entirely new approaches. Hybridization was slow, and while the resulting yeast contained more than 30% synthetic genomes, researchers were seeking more.

After using a new method called chromosome replacement and a technology similar to CRISPR/Cas9 to repair genetic defects, they were able to obtain a single yeast cell containing more than 50% synthetic DNA. Manipulating its genome could have made the yeast grow or look abnormal, but thanks to careful manufacturing, the yeast survived and reproduced similarly to wild yeast.

“The team has now rewritten the operating system of budding yeast, opening a new era of engineering biology — moving from tinkering with a handful of genes to de novo designing and building entire genomes,” Kay said.

Next steps

Yeast has long been a staple in food and drink production – it’s the reason we have decent bread and beer, everyone says “Thank you, yeast” – and in science, for producing chemicals and as a model organism. Using synthetic DNA, we can make many strides in these areas, as Ben Blunt, one of the leading scientists, explained in his article. statement.

“Artificial chromosomes are tremendous technical achievements in their own right, but they will also open up a host of new capabilities for how we study and apply biology. This could range from creating new microbial strains for greener biological production, to helping us understand and control diseases.”

The next step will be to combine all 16 artificial chromosomes into a single yeast cell. This is not easy, but researchers are optimistic. “We are now far from the finish line of having all 16 chromosomes in one cell,” Bucky said.

“I like to call this the end of the beginning, not the beginning of the end, because then we’ll really be able to start mixing up that surface and producing yeast that can do things we’ve never seen before.”

The study is published in the journal cell.