By working on tiny worms, scientists can now test the effects of thousands of genetic mutations in one fell swoop.
A new gene-editing technology developed by researchers from the University of Oregon (UO) is compressing what was previously years of work into just a few days, making new types of research possible in animal models. It would allow biologists to run experiments comparing many versions of a gene, looking for mutations that lead to specific traits and tracking their evolution over time.
Such research is often a first step towards identifying mutations relevant to human health, or in unraveling the mechanisms underlying human diseases.
While comprehensive gene-editing tricks have been developed for single-celled organisms such as bacteria and yeast, this is the first time this has been possible on such a scale in an animal.
says Zach Stevenson, a graduate student in the University of Ooo’s Patrick Phillips lab who helped design the technology. “This is a way to get around this suffocation.”
Stevenson and colleagues describe their new method in a preliminary version published in bioRxiv.
They experimented with the system in C. elegans, a small worm common for biology research. Stevenson said a similar approach could eventually work in other lab animals, such as flies or mice.
“Genetic engineering of microbial DNA has served as the basis for the revolution in biotechnology over the past three decades, but it has been difficult to do on a large scale within animal systems,” Phillips said. “The new approach developed in our lab could serve as the platform for an entirely new way to use a simple animal as the basis for synthetic biology in the same way that bacteria and yeast have been used for an entire generation.”
There are many reasons why scientists might want the ability to create several gene mutations at once. For example, they may be looking for a mutation that could make an animal resistant to a particular drug, better able to survive under certain conditions, or less likely to develop a disease. They may need to examine dozens or even hundreds of potential variations on the gene to find the most effective type.
These types of experiments are very slow in animals. Each mutant strain – a group of worms with a specific genetic modification – must be individually engineered. Stevenson said that making one mutant “typically takes seven to ten hours of hands-on training.” With this new system, “For the same work of making three or four mutants, you can make tens of thousands.”
To speed things up, Stevenson and his colleagues designed a way to compress hundreds or even thousands of potential mutations into a single “library.” Each book in the library is a small snippet of genetic code, meaningless and non-functional in and of itself. Each extract fits a geometric gap in the target gene, like the Mad Libs genetic puzzle.
This design means that instead of injecting many individual worms with different copies of a gene individually, researchers can inject the entire mutagenic library into a single worm.
Then, as the worm reproduces, the library expands. In each offspring, one book from the mutation library is randomly selected to complete the target gene. When a portion of a gene library slips inward, it makes the gene active, like flipping a switch to complete an electrical circuit.
The result: a group of worms that all contain different genetic mutations that were selected at random.
The researchers named their method TARDIS – a playful nod to the space and time-traveling police chest of Dr. Who. Here, transgenic matrices resulting from the diversity of the integrated sequences are denoted. Like the fictional TARDIS, Stephenson says, the worm is “bigger on the inside.” (That is, it contains a lot of extra genetic material.)
Researchers tested TARDIS with a gene that gives the worms resistance to antibiotics. But they see broad applications for biology in general, including research in other model organisms.
It might be especially useful for studying interactions between proteins or signaling between cells, suggests UO research professor Stephen Pence, who helped develop TARDIS. Such interactions are often relevant to understanding disease, Pansy said, but scientists lose important context by studying them in yeast or bacteria. “Now we can do these things in an animal model.”
Zachary Christopher Stevenson et al, High-throughput library development in Caenorhabditis elegans via Transgenic Arrays Diversity-Diversity-Integrated Arrays (TARDIS), (2022). DOI: 10.1101 / 2022.10.30.514301
Presented by the University of Oregon
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