Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Oct 19;46(5):1203-1212.
doi: 10.1042/BST20180076. Epub 2018 Sep 6.

Recent advances in threshold-dependent gene drives for mosquitoes

Philip T Leftwich  1 , Matthew P Edgington  1 , Tim Harvey-Samuel  1 , Leonela Z Carabajal Paladino  1 , Victoria C Norman  1 , Luke Alphey  2   3
Affiliations
Review

Recent advances in threshold-dependent gene drives for mosquitoes

Philip T Leftwich et al. Biochem Soc Trans. .

Abstract

Mosquito-borne diseases, such as malaria, dengue and chikungunya, cause morbidity and mortality around the world. Recent advances in gene drives have produced control methods that could theoretically modify all populations of a disease vector, from a single release, making whole species less able to transmit pathogens. This ability has caused both excitement, at the prospect of global eradication of mosquito-borne diseases, and concern around safeguards. Drive mechanisms that require individuals to be released at high frequency before genes will spread can therefore be desirable as they are potentially localised and reversible. These include underdominance-based strategies and use of the reproductive parasite Wolbachia Here, we review recent advances in practical applications and mathematical analyses of these threshold-dependent gene drives with a focus on implementation in Aedes aegypti, highlighting their mechanisms and the role of fitness costs on introduction frequencies. Drawing on the parallels between these systems offers useful insights into practical, controlled application of localised drives, and allows us to assess the requirements needed for gene drive reversal.

Keywords: Aedes aegypti; Wolbachia; frequency dependent; gene drive; genetic modification; underdominance.

PubMed Disclaimer

Conflict of interest statement

P.T.L., M.P.E. & L.Z.C.P. are funded on a grant researching UD gene drive strategies made to L.A.

Figures

Figure 1.
Figure 1.. Mating outcomes through inbreeding and hybridisation in one and two locus underdominance.
(A) One-locus UD A&B are mutually suppressing dominant genetic elements at the same locus. ‘Parental’ lines are either heterozygous (in blue) for both A and B alleles at the same loci (AB) or wildtype (in red) (++). Crosses between transgenic and wildtype strains (middle stream) produce F1 genotypes which carry unsuppressed lethals (A+ or B+) and are not viable. All inbreeding of wildtype (right stream) produces fully viable offspring (++). All inbreeding of AB strains (left stream) produces 50% viable offspring (AB) and 50% offspring that are homozygous at the same locus (AA or BB) and are inviable, and are highlighted in light grey (see next). For haploinsufficient RNAi, there is only one modified genetic element at the locus, ‘parental’ lines are AA only and no inviable genotypes are produced by inbreeding. In this scenario, the light grey highlighted box is viable. (B) Two-locus UD A&B are mutually suppressing unlinked dominant genetic elements, ‘parental’ lines are either homozygous for both A and B (AA,BB) or wildtype (++,++). All inbreeding of either wildtype or AA,BB strains (right and left streams, respectively) produces fully viable homozygous offspring. F1 hybrids between these strains (A+,B+) (middle stream) are also viable; however, some of the F2 progeny are non-viable. F1 hybrids therefore have reduced fitness compared with either parental homozygote. As all F1 hybrids are viable, here we illustrate crosses of these F1 hybrids to each other and both parental strains. Genotypes carrying unsuppressed lethals are highlighted in dark grey. If a single copy of a suppressor were insufficient to suppress two copies of a lethal, then these genotypes would also be inviable, these genotypes are highlighted in light grey. (C) The relationship between levels of hybridsation and fitness at the population level for interbreeding between modified populations and wildtype. Fitness is highest when individuals from either population inbreed, as the frequency of hybridisation increases, the relative fitness of the population falls.
Figure 2.
Figure 2.. Comparison of predicted introduction threshold frequencies for Wolbachia, single-locus UD, haploinsufficient RNAi and two-locus UD systems.
For each fitness cost parameter (relative to wildtype), a population genetics mathematical model is repeatedly simulated for different introduction frequencies with the first (lowest) frequency giving successful introgression being output to form the threshold lines seen here. For two-locus UD, the dotted portion of the line indicates a maximum fitness cost beyond which introgression cannot be achieved. In the case of haploinsufficient RNAi, it is assumed that fitness costs affect only heterozygotes, i.e. wildtype and homozygotes are of equal fitness. The four mathematical models used here are adapted from those of Marshall and Hay [31] except that for haploinsufficient RNAi which is from Reeves et al. [29].
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Alphey L. (2014) Genetic control of mosquitoes. Annu. Rev. Entomol 59, 205–224 10.1146/annurev-ento-011613-162002 - DOI - PubMed
    1. Burt A. (2003) Site-specific selfish genes as tools for the control and genetic engineering of natural populations. Proc. Biol. Sci. 270, 921–928 10.1098/rspb.2002.2319 - DOI - PMC - PubMed
    1. NASEM (2016) Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values, National Academies Press (US), Washington (DC) - PubMed
    1. Moreira L.A., Iturbe-Ormaetxe I., Jeffery J.A., Lu G., Pyke A.T., Hedges L.M. et al. (2009) A Wolbachia symbiont in Aedes aegypti limits infection with dengue, Chikungunya, and Plasmodium. Cell 139, 1268–1278 10.1016/j.cell.2009.11.042 - DOI - PubMed
    1. Wang S. and Jacobs-Lorena M. (2013) Genetic approaches to interfere with malaria transmission by vector mosquitoes. Trends Biotechnol. 31, 185–193 10.1016/j.tibtech.2013.01.001 - DOI - PMC - PubMed

Publication types

LinkOut - more resources