A confinable home and rescue gene drive for population modification

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Abstract

Homing based gene drives, engineered using CRISPR/Cas9, have been proposed to spread desirable genes throughout populations. However, invasion of such drives can be hindered by the accumulation of resistant alleles. To limit this obstacle, we engineer a confinable population modification Home-and-Rescue (HomeR) drive in Drosophila targeting an essential gene. In our experiments, resistant alleles that disrupt the target gene function were recessive lethal, and therefore disadvantaged. We demonstrate that HomeR can achieve an increase in frequency in population cage experiments, but that fitness costs due to the Cas9 insertion limit drive efficacy. Finally, we conduct mathematical modeling comparing HomeR to contemporary gene drive architectures for population modification over wide ranges of fitness costs, transmission rates, and release regimens. HomeR could potentially be adapted to other species, as a means for safe, confinable, modification of wild populations.

Data availability

All data are represented fully within the tables and figures. The gRNA#1PolG2, gRNA#2PolG2, HomeRPolG2, HomeR(B)PolG2, exuL-Cas9, Rcd1r-Cas9, and βTub-Cas9 plasmids and corresponding fly lines are deposited at Addgene.org (159671-159677) and the Bloomington Drosophila Stock Center (91375-91378), respectively.

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Nikolay P Kandul

Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, United States

Competing interests
Nikolay P Kandul, is a consultant for Agragene..

"This ORCID iD identifies the author of this article:" 0000-0001-7347-5558
Junru Liu

Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, United States

Competing interests
No competing interests declared.
Jared B Bennett

Department of Biophysics, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-4718-257X
John M Marshall

Division of Epidemiology and Biostatistics, School of Public Health, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-0603-7341
Omar S Akbari

Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, United States

For correspondence
oakbari@ucsd.edu

Competing interests
Omar S Akbari, is a founder of Agragene, Inc., has an equity interest, and serves on the company's Scientific Advisory Board..

"This ORCID iD identifies the author of this article:" 0000-0002-6853-9884

Funding

Defense Advanced Research Projects Agency (HR0011-17-2-0047)

Omar S Akbari

National Institutes of Health (R21RAI149161A)

Omar S Akbari

National Institutes of Health (R01AI151004)

Omar S Akbari

National Institutes of Health (DP2AI152071)

Omar S Akbari

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.