New genetic systems created by biologists to neutralize gene drives


Active genetic system

UC San Diego scientists and their collaborators have developed two new genetic systems that inhibit or eliminate gene drives after release. Sincerely: Ana Silva

Two active genetics strategies help address concerns about gene-drive release in the wild.

Over the past decade, researchers have produced a table of new tools that control the balance of genetic inheritance. Based on the CRISPR technique, such gene drives are induced to be transported from the laboratory to the forest, where they are engineered to suppress devastating diseases such as mosquito-borne malaria, dengue, Zika, chikungunya, yellow fever and the West Nile. Used to be. Gene drives carry the power to immunize mosquitoes against malarial parasites, or act as genetic pesticides that reduce mosquito populations.

Although the latest gene drives have been proven to spread efficiently designed in laboratory settings, concerns have been raised about the safety of releasing such systems into wild aggregates. Questions have emerged about the predictability and controllability of gene drives and whether, once loose, they can be called back into the field if they extend beyond their intended application area.

Now, University of California scientists San Diego and their partners have developed two new active genetic systems that address such risks by preventing or eliminating gene drives in the wild. On September 18, 2020 in Journal Molecular cellThe research, led by Jiang-Ru Xu, Emily Bulger and Valentino Gantz in the Department of Biological Sciences, provided two new solutions based on the elements developed in the mango fruit fly.

New genetic system

“One way to reduce the perceived risks of gene drives is to develop approaches to prevent or remove their spread,” said Distinguished Professor Ethan Biere, senior author and science director of the paper at the Tata Institute for Genetics and Society. “There is a lot of concern that there are so many unknowns associated with gene drives. Now we have saturated the possibilities at both the genetic and molecular levels, and the elements that develop. ”

The first neutralizing system, called E-CHSR (erasing hitchhiking on autocatalytic chain reaction), is designed to prevent the spread of gene drive “by shooting with your gun”. e-CHACRs use the CRISPR enzyme Cas9 carried on a gene drive to self-copy, while simultaneously mutating and inactivating the Cas9 gene. Xu states that E-CHCR can be placed anywhere in the genome.

“Without the source of Cas9, it is inherited like any other common gene,” Xu said. “However, once an e-CHACR encounters a gene drive, it deactivates the gene drive in its tracks and continues to propagate for several generations chasing the drive element until its function is lost from the population. go.”

E CHACRs and ERACRs

A second neutralizing system, called ERACR (Element Elementing Elemental Chain Reaction), is designed to completely eliminate gene drive. ERACRs are inserted in place of gene drives, where they use Cas9 from gene drives to attack from either side of Cas9. Once the gene drive is removed, the ERACR copies itself and replaces the gene-drive.

“If the ERACR is given an edge by carrying a functional copy of the gene, which is interrupted by the gene drive, it runs across the finish line, eliminating the gene drive altogether.”

Researchers rigorously test and analyze e-CHACRs and ERACRs, as well as results DNA At the molecular level, in meticulous detail. Beer estimates that the research team, which includes UC Berkeley’s mathematical models, spent an estimated 15 years of effort extensively developing and analyzing new systems. Nevertheless, he cautioned that there are unpredictable scenarios that may emerge, and neutral systems for field-acting gene drives should not be used with false protection.

“Such breaking elements must now be developed and reserved in the case, as it is not known whether some seemingly extraordinary interactions between these elements and the gene drive are designed for unethical activities,” he said. .

According to Bulger, gene drives have a lot of potential to reduce misery, but deploying them responsibly depends on the fact that having control mechanisms should produce unexpected results. ERACRs and eCHACRs give ways to prevent gene drives from spreading and, in the case of ERACRs, can potentially revert the engineered DNA sequence to a state very close to the naturally occurring sequence.

“Because ERACRs and e-CHACRs do not possess their own source of Cas9, they will only spread as gene drives and not edit wild-type populations,” Bulger said. “These technologies are not perfect, but we now have a more comprehensive understanding of why and how unintended consequences affect their function and we believe they have the potential to be powerful gene drive control mechanisms.

References: “Active Genetic Neutralizing Elements for Healthy and Deleting Gene Drives” by Jiang-Ru Shannon Xu, Emily Bulger, Valentino Gantz, Carissa Klencek, Stephanie Hemler, Ankush Hemdkar, Jared Bennett, Lauren Ashley Miller, Sarah Liège, Sarah Sainz Justi. Anna Buchman, Omar Akbari, John M. Marshall and Ethan Bier, 18 September 2020, Molecular cell.
DOI: 10.1016 / j.molcel.2020.09.003

Support for the research includes: National Institutes of Health (R01 GM117321; DP5OD023098); One Paul. Alan Frontiers Group District Investigator Award; DarpaSafe Gene Program (HR0011-17-2- 0047); And TIGS-UC San Diego, a gift from Tata Trusts in India.

Bier and Gantz serve on the State Equity Interest and the Director of Synbal Inc. and the Scientific Advisory Board. Bier, Gantz and Akbari serve on the State Equity Interest and Agragene Inc.’s Scientific Advisory Board. Akbari also receive income from Agragene. These companies could potentially benefit from research results.

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