The self-destruction of malaria-carrying mosquitoes can be driven by gene drives used to manipulate natural populations. In particular, they can be used to reduce the number of individuals in a population or to change its composition; this is particularly useful when such species are disease vectors.
The use of genetic engineering tools is becoming more widespread, allowing the use of natural and synthetic gene drivers that can augment a specific subset of the genetic expression population by influencing Mendelian laws of inheritance.
Photo credit: nechaevkon/Shutterstock.com
Gene drives are selfish genetic elements that can result in a particular DNA sequence or trait being passed between generations through sexual reproduction at a rate that is 50% higher than would occur naturally. The means of achieving it are varied, and the most common include a method of removing a wild-type allele and copying the propulsion system in its place.
This form of gene drive is called homing; a gene can subsequently produce multiple copies of itself in a genome. Consequently, gene drives can be used to suppress populations of target species. This can be achieved through technical features that affect reproduction, e.g. B. male sterility, and cause a population crash. This is because the offspring will be predominantly female and future generations will experience a reduced rate of reproduction. Other gene drives can be used over specific time periods and geographic locations.
So far, no genetically engineered gene drive has been used to combat vector-borne diseases – but there is hope that they will be introduced in the next two years.
How do gene drives work?
Gene drives use CRISPR 2 to insert a genetic modification into a host that is intended to spread through a population at higher than average inheritance rates. Once a gene drive is built into a genome, the organism’s descendants inherit the drive on one of the chromosomes. A normal gene is retained from the other parent. During early development, the CRISPR portion of the gene drive is able to cut the other copy. The cut is then repaired using the gene drive as a template. This leaves the offspring with two copies of the modification.
If a mutant mosquito then mates with one in the wild, the offspring retain a 50% chance of inheriting the mutation, according to standard inheritance theory. With this type of inheritance, the mutation slowly spreads through the population. With gene drive inheritance, when a mutant mosquito mates with an unedited mosquito, nearly 100% of the offspring will inherit the modified gene. This modified gene then spreads rapidly through the population.
Suppression versus modification strategies
Two main strategies are employed for low-threshold gene drive systems to reduce the impact of disease on insect-borne pathogens such as mosquitoes. The first is called population suppression and is the genetic equivalent of insecticide use. The suppressive drives are gene drives that reduce the size of a target population by manipulating the genes required for fertility of one or both sexes.
For example, suppressing the Anopheline mosquito would reduce malaria caused by parasites such as Plasmodium falciparum and Plasmodium vivax. Likewise, suppressing the Aedes mosquito reduces transmission of arboviruses that cause diseases such as dengue fever, yellow fever, Zika virus, and chikungunya virus.
The second approach is to modify the insect vector that prevents them from transmitting the pathogen. This type of modification is called population modification or replacement. In this scenario, the insect population remains intact, but it impairs its ability to participate in disease transmission.
Are gene drives a viable means of self-destruction?
In some cases, the accumulation of mutations can eventually lead to further propagation of gene drives over generations. In test cases of two gene drives introduced into fruit flies, genetic variants often formed that confirmed resistance; this subsequently led to a reduced frequency over several generations as a result of resistant mutations in the target gene.
Some genes are highly conserved, and by selecting those genes as a drive target, fewer mutations and less resistance will occur. In 2018, a population of caged Anopheles mosquitoes successfully crashed with 100% efficiency due to disruption of the doublesex fertility gene. When processed, female mosquitoes cannot bite and lay eggs.
These cage populations failed to produce eggs within 8 to 12 generations. Because of the doublesex gene’s need for reproduction, it was particularly resistant to mutation; A useful trait, since resistance to a drive construct is a barrier to self-destructing mosquitoes.
Can gene drives be controlled?
In the field of CRISPR-based gene drives, reversal drives were introduced to overwrite the original command to prevent the potential corruption of wild-type species. In addition, some drives can be designed to be contained within a target population of mosquitoes. This would require the continuous release of the drive over many generations.
When these releases stop, the gene drive is diluted with the wild-type version of the gene and wipes itself out. To this end, the Target Malaria team is developing a countermeasure to stop the spread of the dual sex drive in a population
Genetic engineering of non-reproductive organs
Outside of controlling fertility, genetic engineering can be used to alter the organ structures and physiology of mosquitoes to make them less than optimal vectors for parasites. For example, the mosquito gut can be engineered to reduce the chances of Plasmodium surviving. In this method, new effector genes are introduced into the mosquito genome, which are expressed in the mosquito gut as anti-Plasmodium proteins.
This subsequently makes the gut an uninhabitable environment for Plasmodium. Fungi, viruses, or bacterial symbionts already known to infect mosquitoes and occupy the gut can be used to introduce these effector genes. Symbiotic gut bacteria can also be genetically modified to allow introduction of the effector genes.
Other methods involve the expression of mosquito anti-Plasmodium immune genes that are built up in the midgut after a blood meal. The strains with this form of genetic manipulation possess increased anti-Plasmodium and antibacterial activity; It is important that this does not entail any disadvantage for the reproductive capacity of mosquitoes.
Another approach used in the species Aedes to combat dengue fever is to ensure that the offspring do not mature. The offspring die before they can transmit the disease. This represents another way in which the occurrence of malaria can be reduced when applied to Anopheles mosquitoes.
- Champer J, Reeves R, Oh SY, et al. (2011) Novel CRISPR/Cas9 gene drive constructs reveal insights into mechanisms of resistance cell formation and drive efficiency in genetically diverse populations. doi: 10.1371/journal.pgen.1006796.
- Kyrou K, Hammond AM, Galizi R, et al. (2018) A CRISPR-Cas9 gene drive targeting dual-sex causes complete population suppression in caged Anopheles gambiae mosquitoes. nat. biotech. doi: 10.1038/nbt.4245.
- Grunwald HA, Gantz VM, Poplawski G, et al. (2020) Super-Mendelian inheritance mediated by CRISPR-Cas9 in the female mouse germline. Nature. doi: 10.1038/s41586-019-0875-2.
- Hammond AM, Kyrou K, Bruttini M, et al. (2017) The creation and selection of mutations resistant to a gene drive over several generations in the malaria mosquito. PLoS Genet. doi: 10.1371/journal.pgen.1007039.
- North AR, Burt A, Godfray HCJ. (2019) Modeling the potential of genetic control of malarial mosquitoes at the national level. BMC Biol. doi: 10.1186/s12915-019-0645-5.
- James S, Collins FH, Welkhoff PA, et al. (2018). Pathway to Deployment of Gene Drive Mosquitoes as a Potential Biocontrol Tool for Elimination of Malaria in Sub-Saharan Africa: Recommendations of a Scientific Working Group†. Bin J Trop Med Hyg. doi: 10.4269/ajtmh.18-0083.
- Hammond AM, Galizi R. (2017) Gene drives to fight malaria: current status and future directions. Pathog Glob health. doi:10.1080/20477724.2018.1438880.