How much will the synthesis cost?
We have run several simulations of the costs of the synthesis, assuming this will be outsourced. Assuming that we do “single coverage” (i.e. we never have to go back and resynthesize anything) we modeled the costs assuming a 20%, 35%, and 50% price drop in synthesis per year. To finish the project within a 5 year period we estimate a budget of $2-5 million will be required for outsourced synthesis alone. Hoever radical changes such as adoption of oligonucleotide synthesis libraries (OLS) could change this formula dramatically.
What are the expected outcomes of this project?
Since this type of experiment has never been done it is very difficult to predict the outcomes indeed! However, our work thus far shows that the strategy we have developed, taking into consideration both the designer alternations, all of which have been proven to be consistent with viability, as well as the assembly strategy, which allows regular fitness assessments of small segments of synthetic DNA, produces high fitness yeast. When we do find fitness defects, we can find out quickly which megachunk causes a fitness defect or even lethality. When this happens, we can back up and define which DNA sequences are is responsible until the problem is identified.
What kind of biological questions can be answered with this approach?
This project will bring an engineering perspective into yeast chromosome biology. What can we do and what can’t we do to the structure of a eukaryotic genome and still maintain a living cell? Can we mine the depths of biological databases to predict which cell will live and which will die?
This project will answer some questions never before approachable in biology, including evolutionary aspects of how transposons evolve and spread throughout a host genome, and which combinations of gene deletions/rearrangements can and cannot support viability. Questions to be answered include — What is the set of trajectories to a minimal genome? Can we build transposon-free genome? What happens when transposons are introduced into such genomes? How do engineered genomes perform in meiosis? Will synthetic and native yeast genomes make fertile hybrids? Can we build better biofuels strains? Etc.
Aren’t you changing multiple variables in one experiment?
Yes. In an ideal world, we would make 10’s or hundreds of different synthetic yeasts, each systematically change in a single way. However, given current budgetary and other practical constraints, this simply is not feasible.