Chromosome by chromosome, the researchers artificially recreated the Saccharomyces cerevisiae genome and created a yeast strain whose genome is more than half synthetic. The semi-synthetic strain survives and grows as well as natural yeast. On the one hand, the research helps better understand the basics of the genome. On the other hand, it can help create improved strains for industrial use. The target is a completely artificial object whose properties can be modified as needed.
People have been using Saccharomyces cerevisiae yeast for thousands of years to bake bread, brew beer, or ferment the juice into wine. In modern biotechnology, yeast is now also used to produce fuels, medicines or perfumes, and is a popular model organism in medical research. Their genome is therefore well known and has been modified several times, at least partially.
Variations in the natural model
A team led by Yu Zhao of New York University has now created a yeast strain for the first time, more than half of which has a synthetic genome. This research is part of a large-scale international research project, the Synthetic Yeast Genome Project, which is developing a fully synthetic yeast. While the genomes of some viruses and bacteria have already been fully manufactured, yeast will be the first eukaryotic organism to have a designed genome.
In order to create something truly new, researchers not only recreated natural chromosomes, they diversified them. They left out several non-coding regions and added new sections of DNA instead. The researchers removed all regions encoding so-called transfer RNAs, which are essential for assembling new proteins, from the original chromosomes and transferred them to an entirely new chromosome, which they called a tRNA neochromosome. “The new tRNA chromosome is the world’s first completely artificial chromosome,” says co-author Yezi Cai from the University of Manchester. “There is nothing like this in nature.”
Artificial chromosomes have crossed over
Towards a fully artificial yeast, the team assembled synthetic variants of all 16 yeast chromosomes in the laboratory and introduced each individually into a yeast strain in which the remaining 15 chromosomes were of natural origin. Through trial and error, they discovered the variables that each made an organism possible. “Our motivation is to understand the basic principles of genomics by building synthetic genomes,” Kay explains.
The researchers crossed the working strains, each of which contained one artificial chromosome, and selected the offspring that contained several artificial chromosomes. They continued to hybridize them together until they combined six complete artificial chromosomes and one chromosome arm into a single strain. They then inserted the larger artificial chromosomes using a newly developed method called chromosome replacement. The genetic makeup of the strain created in this way is more than 50 percent synthetic.
To learn from mistakes
However, this strain showed growth deficits compared to wild-type yeast. The researchers identified many small genetic errors in the artificial DNA sections that would not have been noticeable as long as only one chromosome was replaced. “We knew in principle that something like this could happen, that we could have a large number of small effects that, when you add them together, could pile up and magnify,” says Jeff Buckey, Zhao’s colleague. Using genetic engineering methods, researchers were able to find and correct some of these errors, thus increasing the survival and reproduction of semi-synthetic yeast. “We have now shown that we can integrate half the genome well,” says Bucky. “By troubleshooting we learn new things about the rules of life.”
In the next step, the scientists also plan to integrate the remaining artificial chromosomes. “This is an exciting breakthrough in engineering biology,” Kay says. “Although we have been able to edit genes for some time, we have never been able to rewrite the eukaryotic genome from scratch. This work is fundamental to our understanding of the building blocks of life and has the potential to revolutionize synthetic biology.”
Sources: Yu Zhao (New York University) et al., Cell, doi: 10.1016/j.cell.2023.09.025; Daniel Schindler (University of Manchester) et al., Cell, doi: 10.1016/j.cell.2023.10.015
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