New split-drive system puts scientists in the driver’s seat (genetics)

Powerful new methods of genetic engineering have given scientists the potential to revolutionize several areas of global emergency.

So-called gene drilling, which takes advantage of CRISPR technology to influence genetic inheritance, promises to rapidly spread specific genetic traits in populations of a given species. Genetic drive technologies applied to insects, for example, are designed to stop the spread of devastating diseases such as malaria and dengue fever by preventing mosquito hosts from becoming infected. In agriculture, genetic drilling is being developed to help control or eliminate economically harmful crop pests.

But alongside the ability to change populations, concerns have been raised about the long-term effects of these new transformative technologies in nature. Researchers and ethicists have questioned how genetic holes, once released in a regional population, could be controlled if necessary.

Now, researchers at the University of California at San Diego, the Tata Institute for Genetics and Society (TIGS) at UC San Diego, and their colleagues at UC Berkeley have developed a new method that allows for better control gene drive rejections. The details of the new “split drive” are published on March 5 in the journals Nature communications and eLife.

Most common gene drilling uses a two-component system that includes a DNA-cutting enzyme (called Cas9) and a guide RNA (or gRNA) that targets cuts at specific sites in the genome. After Cas9 / gRNA is cut, the gene drive, along with the cargo it carries, is copied to the rupture site by a DNA repair process.

While classic genetic drilling is designed to propagate autonomously, the newly developed system is designed with controls that separate the processes of genetic implementation. The split-drive system consists of a non-spillable Cas9 component inserted into one location in the genome and a second genetic element that can be copied – with a beneficial trait – to a separate site. When the two elements are present together in an individual, an “active gene drive” is created which spreads the element carrying the beneficial trait to most of their offspring. Yet when decoupled, the element carrying the beneficial trait is inherited according to typical generational genetic rules, or Mendelian frequencies, rather than spreading without restriction.

As described in the Nature communications paper, by creating slight shaping costs that ultimately eliminate the Cas9 enzyme from the population, the split drive system dramatically increases the control and safety of genetic deployments.

“The study of essential gene readers is not a new idea in itself, but we have observed that certain fractionation situations allow a cargo to be distributed efficiently during a first introduction without leaving a trace of Cas9 after a few generations, as well as some errors in the repair process of the rapidly diluted DNA, ”said Gerard Terradas, first author of the Nature communications article and a postdoctoral researcher in the Division of Biological Sciences at UC San Diego.

The Nature communications The article also discusses the benefits on how gene drive is viewed by the public, as efforts to modify wild populations could be flexibly designed in a variety of ways depending on the desired outcome.

The new split drive system follows research announced in September in which UC San Diego researchers led the development of two new active genetics neutralization strategies designed to stop or inactivate gene bores released in the nature.

“We hope that the flexible design features we have developed will be widely applicable in enabling customized approaches to control insect vectors and pests in a variety of settings,” said UC San Diego Distinguished Professor Ethan Bier, main author of Nature communications director of studies and science for TIGS-UC San Diego.

“These pioneering papers reflect a huge effort and fruitful collaborations between UC, to demonstrate novel gene drive architectures to mitigate the formation of resistant alleles while providing a safe confinable means for modification of wild populations,” said Omar Akbari , associate professor at UC San Diego, senior author of eLife to study.