Functional Designer Yeast Chromosome Synthesized

543 Functional Designer Yeast Chromosome Synthesized
Positions of "designer changes" are indicated by pins and white diamonds, and deleted segments are indicated in yellow, using the native chromosome as a reference. Illustration by Lucy Reading-Ikkanda
Scientists have designed and synthesized a fully functional chromosome of baker’s yeast from scratch. And when they placed the synthetic chromosome into living cells, the yeast happily took it up. 
The is the first time anyone has produced a eukaryotic chromosome -- the kind that’s found in all animals and plants. In contrast, scientists have already assembled prokaryotic (bacteria) genomes. Craig Venter’s team famously synthesized the genome of a bacterial parasite in 2010 -- although that genome is orders of magnitude smaller than that of yeast, and it was more or less copied from the original genome (and not designer). 
Here, simply put, they fused together tiny snippets of synthetic DNA to build a computer-designed derivative of the chromosome. So far, the team has only synthesized one of yeast’s 16 chromosomes -- the smallest one, chromosome III -- but the work makes it possible to build an entire eukaryotic genome. They call it synIII.
One of the best-studied organisms on the planet, baker’s or brewer's yeast (Saccharomyces cerevisiae) is used to make beer, biofuel, and medicine. Their genome comprises 12 million nucleotides (the genetic letters, ATCG), which are strung together in matching sets, called base pairs (the rungs of the helical ladder). Once these single-celled organisms are equipped with a full set of synthetic and changeable chromosomes -- like the one designed here -- yeast could produce better versions of all of these things, and faster. 
A huge international team with about 60 undergrads led by Jef Boeke of New York University Langone Medical Center and Srinivasan Chandrasegaran from Johns Hopkins University focused on yeast chromosome III, which comprises 2.5 percent of those nucleotides. Using software, they made small changes to the chromosome, getting rid of repetitive and less used regions of DNA between genes. They made more than 500 alterations to the genetic base, removing: repeating sections of some 47,841 DNA base pairs, “junk DNA” that doesn’t encode for any particular proteins, and "jumping gene" segments that randomly move around, introducing mutations.
Then they built an actual version of the chromosome by stringing together individual nucleotides. Over the course of 7 years, they tied together some 273,871 base pairs of DNA, which is shorter than its native yeast counterpart of 316,667 base pairs. They put little markers called loxPsym sites alongside the genes they thought would be nonessential -- so that they could later on change or delete them and see if the yeast survives. Basically, they stripped the genome of certain features in order to test their importance. 
"So what we're doing is, in some sense, a risky business," Boeke tells Popular Mechanics. "There's not a flag on each segment saying ‘this one's not important'. It's really a judgment call at a certain stage." One wrong change could kill the cell.
Finally, they put their artificial chromosome in living yeast cells to test the ability of the altered cells to survive and grow under various conditions. In each case, yeast equipped with a synthetic chromosome functioned just like normal yeast, “only they now possess new capabilities and can do things that wild yeast cannot,” Boeke explains in a statement
When they activated various loxPsym sites to alter or delete genes, they found that some cells grew slowly, while others with different gene recombinations grew very quickly. “We have made over 50,000 changes to the DNA code in the chromosome and our yeast still live,” Boeke adds. “It shows that our synthetic chromosome is hardy, and it endows the yeast with new properties." Namely, the scientists’ ability to rearrange yeast genome in millions of different ways on command. They call this “genome scrambling.”
By recombining the DNA in different ways, they hope to engineer yeast that can make more ethanol, for example, or grow better in difficult environments; maybe turn them into tiny factories for artemisinin for malaria or a hepatitis B vaccine. Their ultimate goal is to create a whole synthetic yeast genome. Now it’s just a matter of time and money. 
The work was published in Science this week. 
Illustration by Lucy Reading-Ikkanda


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