New genetic-editing technique to alter the traits and fates of wild populations

A new technique, developed in a collaboration between Caltech and Macquarie University, could allow scientists to more simply and controllably alter the genetic makeup of wild populations than with the current proposed use of gene drives.

Gene drives are a common technology used to insert a novel gene into a population—for example, to make mosquitos resistant to malaria. They can also be used to modify existing genes, such as making herbicide-resistant weeds susceptible to herbicides once again or even to suppress invasive populations. However, gene drives often face social concerns and regulatory challenges because they involve the spread of transgenes (genes that have been transferred and integrated into an organism's DNA) to high frequency.

The new technique, called an Allele Sail, uses the CRISPR/Cas9 genome-editing technology to introduce a targeted "editor" into a population at low frequency. This editor itself does not increase in frequency as organisms reproduce, however, any organism that mates with an editor-carrying organism will become altered at the genomic position targeted by the editor, passing the altered version (called an allele) of the gene down to its own offspring. In this way, the technique mimics the natural genetic process of passing down genes and mutations, and can be used in a wider range of species than traditional gene drive approaches.

"Imagine you have a big room of bouncing balls, most of them white but a few are red," says Bruce Hay, professor of biology and biological engineering. "Any time a red ball—the editor—bumps into a white ball, it turns the white ball pink—the edit. As the balls bounce around, over time, more and more of them turn pink."

The team has likened the system to how the wind catches and pushes a sail or kite in a specific direction. In this case, the editor is the wind, pushing along the altered gene, the sail, to a high frequency within the population.

"Allele Sails offer a simple way to alter the traits and fates of wild populations and may be more acceptable to use because the transgenic component, the editor, is introduced and remains at low frequencies or is actively eliminated if its presence results in a fitness cost," says computational biologist Michelle Johnson, the study's first author and a research technician at Caltech.

The team envisions a variety of applications for Allele Sails to address major global challenges. For example, in the form of what is known as assisted evolution or genetic rescue, corals could be edited to become more resilient to heat in the face of a warming climate. Additionally, species like Australia's invasive and highly poisonous cane toad could be made less toxic and thus kill fewer predators. Finally, for some species (such as certain fish, amphibians, and insects) in which a single gene is responsible for femaleness, the editor can be designed to target that gene, reducing the number of females in the population and leading to the population's elimination. This is especially useful for invasive or harmful species.

Importantly, these types of traits can often be introduced with very minor edits to an organism's genome. Just a single-letter nucleic acid difference is sufficient in many cases. The editor only needs to be introduced into the population at a low level, and combined with its ability to introduce changes that are indistinguishable from natural mutations, the Allele Sail technique could address regulatory challenges frequently associated with alternative gene drive approaches that focus on spreading transgenes to high frequency. This is because small edits of the type an Allele Sail creates are often considered non-transgenic for regulatory purposes.

"Of course, any genetic modification of wild populations will need careful study of potential environmental impacts, but Allele Sails could be an important option in situations where conventional conservation and pest management tools have not been enough on their own," says co-author Maciej Maselko of Macquarie University.

A paper describing the research is titled "Altering traits and fates of wild populations with Mendelian DNA sequence modifying Allele Sails" and appears in the journal Nature Communications on August 13. Funding was provided by the Caltech Center for Evolutionary Science.