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

Powerful new genetic engineering methods have given scientists the potential to revolutionize various sectors of global urgency.

So-called gene drives, which leverage CRISPR technology to influence genetic inheritance, hold the promise of quickly spreading specific genetic characteristics across populations of a given species. Genetic technologies applied to insects, for example, are being designed to stop the spread of devastating diseases like malaria and dengue, preventing host mosquitoes from becoming infected. In agricultural fields, gene drivers are being developed to help control or eliminate pests from economically damaging crops.

But along with the ability to change populations, concerns have been raised about the long-term effects of these new transformative technologies on nature. Researchers and ethics experts have raised questions about how genetic impulses, once released in a regional population, could be controlled, if necessary.

Now researchers at the University of California, San Diego, UC San Diego’s Tata Institute for Genetics and Society (TIGS) and colleagues at UC Berkeley have developed a new method that provides more control over the release of genes. Details of the new “split unit” are published on March 5 in the magazines Nature Communications and eLife.

The most common genetic units employ a two-component system that features a DNA cutting enzyme (called Cas9) and a guide RNA (or gRNA) that targets cuts at specific locations in the genome. Following the Cas9 / gRNA cut, the drive gene, along with the charge it carries, is copied to the site of the break through a DNA repair process.

While classic genetic impulses are designed to spread autonomously, the newly developed system is designed with controls that separate the processes of genetic implementation. The split-drive system consists of a non-propagable Cas9 component inserted in one location in the genome and a second genetic element that can be copied – along with a beneficial trait – in a separate location. When the two elements are present together in an individual, an “active gene unit” is created that spreads the element that carries the characteristic beneficial to most of its progeny. However, when decoupled, the element that carries the beneficial trait is inherited according to the genetic rules typical of generations, or Mendelian frequencies, instead of spreading without restrictions.

As described in Nature Communications role, by creating small costs of adaptation that eventually eliminate the Cas9 enzyme from the population, the split-drive system greatly increases the control and safety of genetic implantations.

“Studying drives in essential genes is not a new idea in itself, but we found that certain division situations were able to spread a charge effectively in a first introduction, without leaving any traces of Cas9 after a few generations, as well as some errors in the DNA repair process that quickly diluted, “said Gerard Terradas, first author of the Nature Communications article and a postdoctoral fellow in the Division of Biological Sciences at UC San Diego.

THE Nature Communications The article also describes the advantages of how genetic impulses are perceived by the public, since efforts to alter wild populations can be flexibly conceived in several ways, according to the desired outcome.

The new split-drive system follows research announced in September, in which researchers at UC San Diego led the development of two new active genetic neutralization strategies that are designed to interrupt or inactivate the genetic units released into nature.

“We hope that the flexible design features we’ve developed will be widely applicable, allowing for personalized approaches to control insect vectors and pests in a variety of contexts,” said Ethan Bier, distinguished professor at UC San Diego, senior author of the Nature Communications director of studies and sciences at TIGS-UC San Diego.

“These seminal articles reflect tremendous efforts and fruitful collaborations between UCs to demonstrate new gene targeting architectures to mitigate the formation of resistant alleles, while providing a safe and confined means of modifying wild populations,” said Omar Akbari , associate professor at UC San Diego, senior author of the eLife study.