With a strategy known as “population modification” that involves using a CRISPR-Cas9 gene propulsion system to introduce genes to prevent parasite transmission into mosquito chromosomes, University of California researchers have made a great leap forward in the use of genetic technologies to control the transmission of malaria parasites made.
Postdoctoral fellow Adriana Adolfi of the University of California at Irvine, working with colleagues from UC Irvine, UC Berkeley and UC San Diego, continued the group’s pioneering work to develop CRISPR-based gene drive systems that make mosquito vectors resistant to the transmission of malaria parasites can increase the effectiveness of the gene drive in female mosquito progeny.
“This work alleviates a major problem with early gene propulsion systems, namely the build-up of propulsion-resistant mosquitoes that can still transmit malaria parasites,” said Anthony James, UC Irvine vector biologist, Anthony Bren, professor of microbiology and molecular genetics and molecular research at Donald Bren Biology & Biochemistry, who was a co-primary investigator on the study.
This work alleviates a major problem with early gene propulsion systems, namely the buildup of propulsion-resistant mosquitoes that can still transmit malaria parasites, ”said Anthony James, vector biologist at UC Irvine.
Photo credit: Steve Zylius / UC Irvine
“The second generation gene propulsion system described in this article can be applied to any of the thousands of genes that are essential to insect survival or reproduction,” said Ethan Bier, co-author of the study at UC San Diego Scientific Director at Tata Institute of Genetics and Society. “While this system was developed in fruit flies, it can be easily transported to a wide variety of insect species that act as vectors for devastating diseases such as Chagas disease, sleeping sickness, leishmaniasis, and arbovirus diseases.”
The study results appear in Nature Communications. They describe a highly efficient version of the team’s second generation of the original gene drive that was developed for the Indopakistani malaria vector mosquito Anopheles stephensi. The work, published in 2015 in Proceedings of the National Academy of Sciences, was the first demonstration of a CRISPR-based gene drive in mosquitoes.
In this first study, the gene drive was transmitted to about 99 percent of the offspring if the parent the gene drive was inserted into was a male, but only 60 to 70 percent of the offspring if the parent who the gene drive was inserted into was a male. was female. A significant number of drive-resistant chromosomes are created in women; This could, in principle, allow these women to continue transmitting parasites.
Adolfi, lead author of the new study, and coworkers solved the failure to drive efficiently by women by equipping the gene engine with a functional copy of the target gene into which the engine was inserted. The normal function of this target gene in this species of mosquito is necessary for the survival and fertility of the woman after it has fed on blood, and its functionality is usually disrupted when the drive system is introduced into the gene.
The resulting female mosquitoes showed strong and persistent drive and negligible production of drive-resistant chromosomes in a population cage study. This strategy of inserting a gene drive into a gene essential to viability or fertility while including a functional gene that rescues the loss of viability or fertility offers a general solution to promoting resistance in women. As with a catalytic converter that removes combustion pollution from automobiles, the new system also eliminates genetic defects that occur in propulsion.
This gene propulsion system can now – in combination with genes to block parasite transmission – be used to develop field-ready mosquito strains. Thorough testing is required to demonstrate safety and effectiveness before proceeding with field testing.
Nijole Jasinskiene, Hsu-Feng Lee, Arunachalam Ramaiah, JJ Emerson, and Kristy Hwang from UC Irvine; Valentino Gantz, Gerard Terradas, and Emily Bulger from UC San Diego; Jared Bennett and John Marshall of UC Berkeley also participated in the study, which resulted from collaborations between the UC Irvine Malaria Initiative and the UC San Diego Tata Institute of Genetics and Society.
Research support was provided by the Tata Institute of Genetics and Society, the UC Irvine Malaria Initiative, the National Institutes of Health (AI29746, DP5OD023098, and GM123303), and the DARPA Safe Genes program (HR0011-17-2-0047).