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Yeast 2.0

Designer changes in the first artificial yeast chromosome could help advance synthetic biology.

Scientists have synthesized an entire yeast chromosome, the first artificial chromosome for the kingdom of life that includes humans, plants, and fungi. Yeast with the artificial chromosome appeared to be just as happy as their “natural” counterparts, reports the team. The methods developed to create the designer genomic structure could help synthetic biologists better use the single-celled fungi as biological factories for chemicals like biofuels and drugs.

Scanning electrograph image of a yeast cell budding off a daughter cell.

Humans have been manipulating yeast for thousands of years, first turning wild strains of the fungus into the life-affirming fermenters that give us beer and bread. Yeast also has long been a lab organism for studying molecular biology and genetics; in fact, a lot of what we know about cancer genetics comes from research on our fungal friends.  In recent years, scientists have figured out how to engineer new biochemical pathways into yeast, creating living factories for medicines, biofuels, and more (see “Microbes Can Mass-Produce Malaria Drug” and “Biofuel Plant Opens in Brazil”). The report of the first artificial, designer yeast chromosome suggests ways for researchers to produce new chemicals in the microbes or potentially make their biological production more efficient.  

Six years ago, the J. Craig Venter Institute built the first artificial chromosome, which encompassed the complete genome of a bacterium (see “Synthesizing a Genome from Scratch”). Two years later, that 582,970 base pair manmade genome was transplanted into a cell which successfully began to carry out its instructions (see “Synthetic Genome Reboots Cell”).

The first synthetic yeast chromosome, reported in Science on Thursday, represents just part of that organism’s complete genome and is 272,871 base pairs long. The Johns Hopkins University-led team first designed the chromosome on a computer, streamlining the natural chromosome sequence so that it had less repetitive sequences and other tweaks. Undergraduate students in a class called “Build-A-Genome” at Johns Hopkins used molecular biology tricks to string together snippets of DNA around 70 nucleotides (A’s, T’s, G’s and C’s) long into 750-base pair blocks. Then, other researchers continued to assemble those blocks into longer stretches of the chromosome, and eventually the largest chunks were delivered into yeast cells, which took over the last assembly steps to create the whole, artificial chromosome.

The artificial chromosome is a designer version of just one of the yeast’s 16 chromosomes, and the smallest one at that. But the work is an important step forward for synthetic biology and a milestone in an international effort to build a completely synthetic yeast genome, project Sc2.0 (from the scientific name for baker’s yeast, Saccharomyces cerevisiae).

In addition to deleting some unnecessary sequences from the code of their designer chromosome, the researchers also flanked many genes on the chromosome with tiny bits of DNA that act as landing sites for a protein that can be used to create on-demand mutations. With these designer changes, the researchers say they will be able to test how many mutations a yeast genome can tolerate at once and potentially discover beneficial mutations that could give rise to strains that can survive in a wider range of conditions or perhaps be better factories for useful molecules like fuels and drugs.  Already, the researchers have shown that inducing mutation in yeast using the designer sites led to some cells that grow more slowly, and yet others that grow more quickly.

Lead researcher Jef Boeke tells The Verge that the team plans to create these mutation-ready additions in all 16 chromosomes. That fountain of variability could be key to finding ways to push our fermenting friends to more efficiently create biofuels and other chemicals.

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