5 Synthetic Yeast Chromosomes Created
Scientists recently created five synthetic chromosomes in yeast, a step towards a completely synthetic yeast genome.
Credit: Chris Bickel/Science 2017

The world is one step closer to a new synthetic organism.

Scientists have created five synthetic yeast chromosomes and placed them inside yeast cells. The chromosomes are composed of the normal letters, or base pairs, that make up DNA, but the sequence is slightly different from those found naturally in yeast.

The new chromosomes could help answer basic science questions, such as what is the purpose of portions of DNA that don't code for genes; they could also be useful for producing drugs like cancer antibodies on a massive scale, said study co-author Joel Bader, a bioinformatics professor at Johns Hopkins University in Baltimore.   

The findings were published today (March 9) in the journal Science in seven separate papers.  [Unraveling the Human Genome: 6 Molecular Milestones]

In 2010, scientists succeeded in creating the first live organism with a completely synthetic genome, a bacterium called Mycoplasma mycoides. Other labs have tweaked the genes needed for life, creating bacteria with synthetic genomes containing the fewest genes needed for life. In 2014, researchers synthesized the first artificial yeast chromosome. [Infographic: How Scientists Created a Semi-Artificial Life Form]

 

The new effort is part of a larger project called the Synthetic Yeast Genome Project (Sc2.0), which aims to replace all 16 yeast chromosomes with synthetic versions. Once those synthetic versions are swapped with the natural ones, they could be modified so that the resulting yeast produce industrial chemicals, antibiotics or even tastier fake meat, Bader said.

To construct the synthetic genomes, the teams first looked at computer files containing all the genetic data from natural Baker's yeast. Next, they looked at the designer genomes they hoped to replicate and made changes to the reference genomes in the computer files. From there, the files are chopped up into smaller sequences that correspond to what can be made in the lab.

From there, the team synthesized the individual base pairs, or letters of DNA, in a dish, then used the templates to assemble small fragments of DNA, which were then put together. These slightly larger fragments were then placed in yeast. The yeast cells use a method called homologous recombination to repair damaged DNA, and the team took advantage of this ability to have the cell swap out its real genetic code and replace it with synthetic snippets of DNA. By doing this process over and over, the team eventually replaced the five of the yeast chromosomes with synthetic copies, Bader said.

"One of the amazing things is that we are just putting DNA into the cells, and the yeast cells are organizing it in chromosomes," Bader told Live Science.

This makes the process of creating synthetic chromosomes significantly easier, considering that chromosomes are made up of DNA tightly wound around little spools known as histones, which are also modified by separate chemicals. Because mammalian cells lack homologous recombination, it would likely be trickier to assemble a mammalian chromosome, Bader said.

The synthetic genomes are very similar to the natural ones, but the researchers removed some of the genes they suspect are unneeded. They also removed one of the three-letter sequences that tell the cell to stop reading a snippet of DNA and translating it into a protein, known as a stop codon. The goal is to ultimately repurpose this stop codon to potentially make completely new forms of amino acids, Bader said.

The team hopes that by creating a completely synthetic yeast, they can answer basic questions about the role of DNA. For instance, there are often repetitive sequences of DNA that many scientists believe are the debris left from viral infections in yeast's past. By deleting these fragments, researchers can effectively test these ideas. Scientists could also build complicated molecules, such as the sugar-tipped antibody proteins used in newer cancer treatments, which normally must be made in expensive mammalian cell cultures, Bader said.

While the new work uses essentially the same gene-assembling techniques as the 2014 project, the development of new computer programs enabled large groups to collaborate on the project, said George Church, a geneticist at Harvard University who is working on a separate synthetic E. coli genome project, called the rE.coli project. He is also working on a project to create humanized pigs that could provide transplants that wouldn't be rejected by the immune system.

In addition, translating the lessons learned in yeast could be a challenge, said Church, who was not involved in the current research.

"Whether we learn from this in the bigger genome-writing projects in pig and human, that remains to be seen," Church told Live Science.

Interestingly, the project used the much-vaunted cut-and-paste editing tool called CRISPR for only 31 genetic changes out of more than 5 million letters assembled in the project. While CRISPR has been promoted as a revolutionary way to make point-by-point edits in the genome, it has a fairly high error rate, of around 50 percent for each change made, Church said.

"If you do 10 of those [CRISPR changes] you have a 1-in-1,000 chance of getting the right thing, and if you do 20 of those you have a 1-in-1-billion chance of getting the right thing," Church said.

Given that, in the future scientists may be more likely to synthesize large swaths of the genome using this technique and then just swap it out, because the overall error rate is lower than making many tiny letter-based changes using CRISPR, Church said. That may be especially true for things like humanized pigs, which scientists know will require many genetic changes, he added.

Originally published on Live Science.