Integral gene drives for population replacement.

Alexander Nash,George K Christophides,Andrea K Beaghton,Nikolai Windbichler,Philippos Aris Papathanos,Astrid Hoermann,Giulia Mignini Urdaneta

doi:10.1242/bio.037762

Alexander Nash, George K Christophides + Show 5 more

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https://doi.org/10.1242/bio.037762

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Abstract

ABSTRACTA first generation of CRISPR-based gene drives has now been tested in the laboratory in a number of organisms, including malaria vector mosquitoes. Challenges for their use in the area-wide genetic control of vector-borne disease have been identified, including the development of target site resistance, their long-term efficacy in the field, their molecular complexity, and practical and legal limitations for field testing of both gene drive and coupled anti-pathogen traits. We have evaluated theoretically the concept of integral gene drive (IGD) as an alternative paradigm for population replacement. IGDs incorporate a minimal set of molecular components, including drive and anti-pathogen effector elements directly embedded within endogenous genes – an arrangement that in theory allows targeting functionally conserved coding sequences without disrupting their function. Autonomous and non-autonomous IGD strains could be generated, optimized, regulated and imported independently. We performed quantitative modeling comparing IGDs with classical replacement drives and show that selection for the function of the hijacked host gene can significantly reduce the establishment of resistant alleles in the population, while drive occurring at multiple genomic loci prolongs the duration of transmission blockage in the face of pre-existing target site variation. IGD thus has potential as a more durable and flexible population replacement strategy.

Highlights

Homing gene drives were first proposed 15 years ago as potential tools for enabling the genetic engineering of natural populations (Burt, 2003), in particular of disease vectors
Gene drive research is currently focused on two main areas: (1) studying the nature of target site resistance (Champer et al, 2017; Hammond et al, 2017; KaramiNejadRanjbar et al, 2018) to mitigate its eventual rise; and, (2) reducing or counteracting the invasive potential of gene drives, in order to minimize the perceived or actual risk associated with the technology
The former strand of research is centered on improving regulatory elements to contain/confine nuclease activity to homing-relevant cell types, identifying target sites that are intolerant to drive-inactivating mutations (Kyrou et al, 2018), and on the addition of further components to the drive constructs, such as multiple guide RNAs (Champer et al, 2018; Marshall et al, 2017; Noble et al, 2017) or factors that bias repair towards the desired homology-directed pathway (Basu et al, 2015)

Summary

Introduction

Homing gene drives were first proposed 15 years ago as potential tools for enabling the genetic engineering of natural populations (Burt, 2003), in particular of disease vectors. Gene drive research is currently focused on two main areas: (1) studying the nature of target site resistance (Champer et al, 2017; Hammond et al, 2017; KaramiNejadRanjbar et al, 2018) to mitigate its eventual rise; and, (2) reducing or counteracting the invasive potential of gene drives, in order to minimize the perceived or actual risk associated with the technology The former strand of research is centered on improving regulatory elements to contain/confine nuclease activity to homing-relevant cell types, identifying target sites that are intolerant to drive-inactivating mutations (Kyrou et al, 2018), and on the addition of further components to the drive constructs, such as multiple guide RNAs (gRNAs) (Champer et al, 2018; Marshall et al, 2017; Noble et al, 2017) or factors that bias repair towards the desired homology-directed pathway (Basu et al, 2015). For limiting gene drive invasiveness, a number of schemes have been proposed; for example, linking multiple driving and nondriving CRISPR/Cas transgenes into a chain in which the spread of each construct depends on the prior link in the chain (Esvelt and Gemmell, 2017; Noble et al, 2016)

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