Undergraduates built a synthetic chromosome with cheap DNA-making technology

                                             SYNTHETIC CHROMOSOME: 

                                     The yeast chromosome is represented snake-like, with

                                     the positions of "designer changes" indicated by pins

                                       and white diamonds,

                                     and the deleted segments indicated in yellow, using the 

                                     native chromosome sequence as a reference.  

                                      Illustration by Lucy Reading-Ikkanda

The humble baker's yeast has been enlisted to serve the needs of humanity, responsible for beer, wine and bread, among other staples. A domesticated servant for at least millennia, the microscopic fungus has now had one of its chromosomes swapped out by a host of undergraduate students in favor of a pared-down, synthetic version.

A chromosome is a twisted strand of DNA, the genetic code that tells an organism's cellular machinery what proteins to produce, among other vital functions. There are 16 in baker's yeast (compared to 23 in humans), and the so-called Synthetic Yeast 2.0 project focused on chromosome number three, a "sentimental favorite of yeast geneticists," according to biologist Jef Boeke of Johns Hopkins University, who helped lead the research. That's because it contains the genetics that control the yeast's sexual behavior. As a fungus, Saccharomyces cerevisiae can reproduce both sexually and asexually, and the genes in chromosome number three control mating, which makes it easy to track through the generations. It was also the first chromosome to have its code fully transcribed by scientists and happens to be third shortest of the yeast's 16 chromosomes.

In the early years of the 21st century, Boeke and his colleagues were musing over coffee at a Johns Hopkins University café and hatched a scheme that became Synthetic Yeast 2.0, a full-fledged effort to build a synthetic genome for yeast that would allow near complete control of the organism, whether to boost biofuel production or air pockets in bread. By 2011, Boeke and his colleagues could report success in building one arm of a chromosome, chromosome number nine. That required meticulously synthesizing some 90,000 pairs of the letters of DNA—A for adenine, G for guanine, C for cytosine and T for thymine—that make up the genetic code.


But that effort proved too slow. So Boeke and his colleagues enlisted what he called "an army of undergrads in our 'Build a Genome' course" to build a yeast chromosome—the entirety of baker's yeast chromosome number three, which contains more than 316,000 base pairs. Fortunately, there was a shortcut: synthesizing only those sections considered essential or non-repetitive and cutting down the chromosome to a more manageable 272,871 pairs.

"The organism itself is the workhorse of modern biotechnology and biomanufacturing," says biological engineer Drew Endy of Stanford University, who was not involved in the research or the Synthetic Yeast 2.0 project. "It's a great example of 'do it together' biotechnology."

The undergrads synthesized the DNA—thanks to the ever-decreasing costs of DNA manufacturing enabled by new technology—in roughly 750 pair chunks. The yeast's cellular machinery viewed those chunks as strand breaks in the DNA, so it knit the new, synthetic code in with the old. Over time, the entire chromosome was replaced with the new, pared-down, synthetic version.

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