Designer yeast

September 2011
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A Johns Hopkins University team has built a yeast chromosome from scratch, they report today in the journal Nature. Sarah Richardson used what she learned as a Computational Science Graduate Fellow to help design and monitor the chromosome’s construction.

The tiny white yeast colonies in the right panel interspersed with larger normal colonies are cells that have had a synthetic chromosome inserted and their DNA shuffled by the lab-induced SCRaMbLE system, which introduces changes that slow cell growth. By comparison, all colonies on the left are grown from the standard lab yeast strain and appear uniform. (Click on image to enlarge.)

Last year the J. Craig Venter Institute made waves by creating the first fully synthetic bacterial genome. Now a group from Johns Hopkins University has extended that work to yeast, producing a built-from-scratch chromosome that works just like the natural chromosome it replaced.

The project, described today in the advance online issue of the journal Nature, is the first step in creating a modular, synthetic organism that its makers hope will act as a biological factory for churning out medicines or substances that break down toxic waste.

Led by biologists Joel Bader, Jef Boeke and Srinivasan Chandrasegaran, the team relied on the computational skills of Sarah Richardson, a graduate student in Bader’s lab and an alumna of the Department of Energy Computational Science Graduate Fellowship (DOE CSGF), to design the chromosome and to oversee its construction. Software assisted biologists in fashioning a chromosome containing millions of individual DNA bases and thousands of functioning genes in a highly structured, modular system.

“Probably the most computationally difficult algorithm is the segmentation of a chromosome into assemble-able bits,” Richardson says. To manage such a data-intensive project, Richardson searched for programs she could modify for her team’s task. She spoke to geneticists who wrote widely used gene annotation software but quickly discovered that the tools, which ensure genes are correctly sequenced and labeled, fell flat at breaking the chromosome down and moving genes around.

“The biggest problem was that there are not (publicly available) algorithms to edit chromosomes or genomes,” Richardson says. “So I set out to write those algorithms and create that framework for editing sequence on a large scale.”

The result was a software suite called BioStudio and an associated program called GeneDesign. Together, the software assists in designing genetic constructs and tracking the progress of synthesis and assembly. Richardson specifically designed the programs to be as generic and user friendly as possible. She wove in touches adapted from open-source packages, such as a collaborative wiki-like interface with revision-control systems and color-coding graphics to assist editing tasks.

In yeast, all the essential genes – ones the organism can’t survive without – are known. With that information in place, the visualization software colors all the essential genes red. “The red flag on essential genes,” she says, “really lets you know if you are editing a particular gene, you are potentially affecting the fitness of the yeast.” All genes with known functions follow the color-coding system, enabling the designers to monitor changes they are making.

Although the computer can automate many tasks, deciding which genes to move around requires a scientist’s experienced eye for subtle detail.

“It turns out it is pretty hard for the computer to decide what stays and what goes” in the genome design, she says. “First you need to know what you want. Then you can apply the algorithms.”

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