Scientists have synthesized first artificial yeast chromosome

Technology Review reports that 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.

Six years ago, the J. Craig Venter Institute built the first artificial chromosome, which encompassed the complete genome of a bacterium.

Two years later, that 582,970 base pair manmade genome was transplanted into a cell which successfully began to carry out its instructions.

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

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.

Careful planning is what allowed the researchers, along with 60 undergraduate students, to painstakingly string chunks of DNA together and insert them into living yeast cells. It’s also what allowed them to introduce over 500 changes to the chromosome’s native sequence — a process that yielded yeast cells endowed with what Boeke referred to as “unusual properties.

The researchers hope to use the scrambling method to come up with yeast that can tolerate a wider range of environmental conditions, and that can carry out fermentation more efficiently. If they can do that, the applications will be countless, because these microorganisms do a lot more than help us make beer and bread. “I think we will see all kinds of biosynthetic products made in bacteria and yeast over the next 10 years,” Boeke says. This advancement will make the production of things like antimalarial drugs and diesel fuel-like compounds a lot more cost-effective, he says. “Pretty much anything made in yeast could benefit from this scrambling approach.”

here is a lot more work to do before researchers can truly explore the treasure trove of applications that this technique will engender, because yeast has more than one chromosome. In fact, it has 16. “It’s unlikely that we will revolutionize an industry by rearranging a single chromosome,” says Boeke. But the scientists might be able to revolutionize a number of industries if they can synthesize the whole set. “Ultimately we want to do this with all 16,” Boeke says, which should take the researchers another two to three years. “That’s when it will become really interesting and powerful, because we will be able to do a lot more when we can control all of its genes.”

Journal Science – Total Synthesis of a Functional Designer Eukaryotic Chromosome

he 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).

Sc2.0 is the synthetic yeast genome web site. This is the site where you will learn about our ongoing project to synthesize the genome – from oligos to chromosomes, and the design features of the new version of Saccharomyces cerevisiae which we fondly refer to as Sc2.0.

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.

ABSTRACT

Rapid advances in DNA synthesis techniques have made it possible to engineer viruses, biochemical pathways and assemble bacterial genomes. Here, we report the synthesis of a functional 272,871–base pair designer eukaryotic chromosome, synIII, which is based on the 316,617–base pair native Saccharomyces cerevisiae chromosome III. Changes to synIII include TAG/TAA stop-codon replacements, deletion of subtelomeric regions, introns, transfer RNAs, transposons, and silent mating loci as well as insertion of loxPsym sites to enable genome scrambling. SynIII is functional in S. cerevisiae. Scrambling of the chromosome in a heterozygous diploid reveals a large increase in a-mater derivatives resulting from loss of the MATα allele on synIII. The complete design and synthesis of synIII establishes S. cerevisiae as the basis for designer eukaryotic genome biology.

Supplemental materials 72 pages

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