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Synthetic Yeast Genome Now One Third Complete

NEW YORK (GenomeWeb) – In a big step toward completing the world's first synthetic yeast genome, the Synthetic Yeast Genome Project (Sc2.0) has published seven papers, collectively describing the assembly of five new synthetic yeast chromosomes based on the genome of Saccharomyces cerevisiae, commonly known as baker's yeast.  

"Yeast are particularly interesting organisms because … they are very easy to manipulate genetically," Jef Boeke, a geneticist at New York University's Langone Medical Center and team lead for Sc2.0, said in a video statement. "But unlike most microorganisms, yeast are much more like human cells in the way their genome is wired."

Sc2.0, which began in the early 2010s, is made up of over 200 researchers led by teams at NYU Langone, Tianjin University, Tsinghua University, John Hopkins University, the Institut Pasteur, the University of Edinburgh, and BGI. One of their main goals is to build the first synthetic eukaryotic genome.

Published today in Science, the papers describing the five synthetic yeast chromosomes — synII, synV, synVI, synX, and synXII — follow the first synthetic chromosome, synIII, which was built by a Boeke-led research team in March 2014. The creation of these six synthetic chromosomes means that more than one third of the organism's genetic material has now been swapped out for engineered replacements.

The researchers began by designing their chromosomes using BioStudio, a technology specially designed for eukaryotic genome creation that they developed at the onset of the project.

However, to actually build their synthetic genome, the researchers broke down chromosomes into what they called "megachunks," and labelled them with PCRtag. Then the teams used a process called switching auxotrophies progressively for integration (SwAP-In) to build and recombine the individual chromosomes to suit their needs. The tagged megachunks were then chemically synthesized based on the PCRTagging system.

The teams used different methods to simplify the chromosomes. One method was to put genetic markers, called loxPsym sites, alongside the genes thought to be nonessential in their designed chromosomes. These markers helped the researchers make note of places they could make changes or deletions to determine if their initial conclusions were correct. They dubbed this inducible genome rearrangement system "SCRaMbLE."

In some cases, these site markers created problems for the yeast by reducing the expression of essential genes. In one incidence, the research team from Tsinghua University used CRISPR-Cas9 to attempt some "debugging" particularly when building pieces of synXII. The chromosome was then assembled into a final molecule which was more than a million base pairs in length, making it the largest synthetic chromosome of the bunch.

Another team led by Tianjin University found that when designed effectively, synV and synVI can be circularized and still power yeast cell growth without affecting the organism's fitness, as long as gene content is maintained. The Tianjin-led researchers also built synX, noting that they "chemically synthesized [it] from scratch" and developed an efficient mapping method called PoPM, or pooled PCRTag mapping, that allowed them to "identify bugs during genome synthesis."

The team from BGI, responsible for building the synII chromosome, demonstrated that it could segregate, replicate, and function in a "highly similar fashion compared to its wild type counterpart."

And the researchers from NYU Langone, who worked on synVI, found they were able to determine the existence of "rare bugs" introduced in the genome editing process through analysis of its phenotypes, transcriptomics, and proteomics.

One of the efforts, led by researchers at the Institut Pasteur, described what the synthetic chromosomes looked like in three dimensions. They wrote that "the absences of repeats leads to a smoother contact pattern and more precisely tractable chromosome conformations, and the large-scale genomic organization is globally unaffected by the presence of synthetic chromosome." They further noted the absence of these characteristics in synIII, which lacks the silent mating-type cassettes, and synXII, specifically when the ribosomal DNA was moved to another chromosome.

Overall, however, the researchers wrote that their collective efforts to add synthetic chromosomes to the yeast genome resulted in "a highly modified Saccharomyces cerevisiae genome reduced in size by nearly 8 [percent], with 1.1 megabases of the synthetic genome deleted, inserted, or altered."

"This set of papers described some remarkable changes to the structure of yeast chromosomes, and unexpectedly some of these changes which involved moving huge swaths of DNA from one chromosome to another," Boeke added. "While they did have a big impact on the three-dimensional structure of the chromosomes, inside the nucleus of the cell, those cells still grew remarkably normally .... This work sets the stage for completion of designer, synthetic genomes to address unmet needs in medicine and industry."

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