Why synthesise a yeast genome?

The Synthetic Yeast Genome Project – Sc2.0 for short – is a world-first attempt to build from scratch the genome of the yeast used by bakers and brewers, Saccharomyces cerevisiae.

It’s no small feat. So far a team of about 200 people in 11 research groups in six countries have been working for six years to build 16 synthetic chromosomes encompassing about 12 million base pairs of DNA. Sakkie Pretorius, whose team at Macquarie University has signed on to build two chromosomes, estimates close to $US50 million has already been spent on the project.

The strategy for building Sc2.0 is similar to the one used by Craig Venter to make synthetic bacteria.

Pore over the DNA sequence on a computer and redesign it to streamline and optimise the way the code is read. Old code, as any software engineer will tell you, gets addled by redundancies and glitches. Then punch the new code into a state-of-the-art DNA synthesiser and deliver the synthetic DNA into a living yeast. At first you will have a hybrid cell: synthetic DNA in the shell of a natural yeast. Within a few generations, though, every component of the yeast will be reprogrammed by the synthetic yeast code. There are still some glitches to iron out, but the project expects to unveil its complete synthetic genome by late 2018.

Why do it? Scientists can tinker with nature’s yeast to make all manner of useful things. Pretorius and his collaborators, for example, have tweaked wine-making yeast to make red wine more buttery (thanks to yeast and bacterial genes that convert malic to lactic acid) and white wine fruitier (thanks to a bacterial gene that makes the enzyme beta lyase).

The end game is to create a streamlined chassis organism on which to bolt other synthetic modules. For one thing, a more streamlined and efficient chassis might give yeast-made biofuel the edge it needs to compete with petrochemicals. “If you inherit a suboptimal factory, all you can do is change a few taps,” Pretorius says. “But if you purpose-build it from the ground up, you can design the pipelines and optimise flow-rates the way you want.”

How do you make a yeast chromosome? First synthesize 10,000-letter chunks of DNA code in the lab. Join five chunks to make a ‘megachunk’. Tip the megachunks into a flask of growing yeast with chemicals to solubilise the yeast cell membranes. Some of the megachunks will slip into the cells. Thanks to a natural process of DNA swapping called ‘recombination’, they will insert themselves like a cassette into a matching piece of chromosome, ejecting the natural fragments.

Using this process, the project has swapped out DNA bit by bit. It has removed about 20% of so-called ‘junk DNA’ – stutters in the DNA code that seem to have no function – and pared back the large number of identical copies of so-called rRNA genes. The coding has been arranged more logically – including collecting the dispersed set of so-called tRNA genes, which link code with amino acids, and putting them on a new 17th chromosome.

The synthetic yeast also boasts some state-of-the-art design features. Proteins are made by linking amino acids. More than 100 amino acids are found in nature, but only 20 are naturally used to make proteins. Sc2.0 will create novel, distinctly ‘unnatural’ functions by coding for some of these amino acids that don’t normally make proteins.

More novel functions are expected from a switchable feature built in to the chromosomes called SCRaMbLE. It is a form of accelerated evolution that uses a trigger – say feeding the yeast a chemical – to scramble the chromosomes. This shuffling of DNA may also generate useful new traits.

“The cell’s tolerance for massive change is quite remarkable,” Pretorius says.

“We’ve learned so much from Yeast 2.0,” he enthuses. “Biology is where chemistry was 70 years ago. Anything we can dream up, we can write the DNA to produce.”