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Five new artificial yeast chromosomes set stage for first synthetic eukaryotic genome

March 09, 2017

In a package featuring seven new studies, scientists of the Synthetic Yeast Genome Project (Sc2.0) who previously constructed a single yeast chromosome now report constructing five more - representing more than one-third of yeast's entire genome, in total. The results are major progress on the road to building the first fully synthetic complex organism, which the Sc2.0 consortium hopes to do in the future (swapping all 16 yeast chromosomes for engineered ones). Baker's yeast, an important model for designer biology, is already used to make beer, biofuel and medicine, but once equipped with a full set of synthetic and changeable chromosomes like those designed here, this single-celled organism could produce better versions of these important commodities, including new antibiotics or more environmentally friendly biofuels. In March 2014, researchers led by Jef Boeke built a yeast eukaryotic chromosome, synIII, for the first time. Now, the research papers in this issue describe the first assembly of yeast chromosomes synII, synV, synVI, synX, and synXII. Their work is accompanied by another paper that lays out, broadly, the procedures and goals of creating a fully synthetic eukaryote genome of Baker's yeast. A seventh study provides the first look at the three-dimensional structure of several synthetic chromosomes, including strains with more than one synthetic chromosome. The chromosome-building work represented in this package involved first using specially designed software, BioStudio, to carefully design the chromosomes of interest. This included making conservative changes (i.e., removing some of the repetitive and less used regions of DNA between genes). Certain cases did involve moving especially large swaths of DNA from one chromosome to another. Despite such changes, the authors report, once the altered chromosomes were placed in living yeast cells, the cells grew normally. This plasticity suggests researchers can make even more dramatic changes, going forward, exploring the limits of genome engineering to have the yeast yield even more useful products. Critically, researchers often put genetic markers called loxPsym sites alongside the genes thought to be nonessential, in their designed chromosomes, so they could change or delete these genes and see if the yeast featuring these engineered chromosomes survived. In some cases, the introduction of loxPsym sites reduced the expression of essential genes, creating problems for the yeast. These results are helping scientists better understand the genetic components required for life. The research package also captures the team's development of new systems for "debugging" rebuilt chromosomes; despite meticulous planning, synthetic chromosomes sometimes malfunction when incorporated into a living cell. Researchers must figure out why, and the consortium's new techniques promise to accelerate those investigations. Among other applications, the approach outlined here paves the way to a new era of gene manipulation, such as in gene therapy, which is currently limited to a delivery of a single gene, but could be expanded to allow for delivery of gene networks or pathways, or multiple genes, for therapeutic ends. A Perspective by Krishna Kannan and Daniel G. Gibson provides additional insights.
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American Association for the Advancement of Science

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