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Gene drive and resilience through renewal with next generation Cleave and Rescue selfish genetic elements

Oberhofer, Georg and Ivy, Tobin and Hay, Bruce A. (2020) Gene drive and resilience through renewal with next generation Cleave and Rescue selfish genetic elements. Proceedings of the National Academy of Sciences of the United States of America, 117 (16). pp. 9013-9021. ISSN 0027-8424. PMCID PMC7183144. https://resolver.caltech.edu/CaltechAUTHORS:20191216-141643773

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Abstract

Gene drive-based strategies for modifying populations face the problem that genes encoding cargo and the drive mechanism are subject to separation, mutational inactivation, and loss of efficacy. Resilience, an ability to respond to these eventualities in ways that restore population modification with functional genes, is needed for long-term success. Here, we show that resilience can be achieved through cycles of population modification with “Cleave and Rescue” (ClvR) selfish genetic elements. ClvR comprises a DNA sequence-modifying enzyme such as Cas9/gRNAs that disrupts endogenous versions of an essential gene and a recoded version of the essential gene resistant to cleavage. ClvR spreads by creating conditions in which those lacking ClvR die because they lack functional versions of the essential gene. Cycles of modification can, in principle, be carried out if two ClvR elements targeting different essential genes are located at the same genomic position, and one of them, ClvR^(n+1), carries a Rescue transgene from an earlier element, ClvR^n. ClvR^(n+1) should spread within a population of ClvR^n, while also bringing about a decrease in its frequency. To test this hypothesis, we first show that multiple ClvRs, each targeting a different essential gene, function when located at a common chromosomal position in Drosophila. We then show that when several of these also carry the Rescue from a different ClvR, they spread to transgene fixation in populations fixed for the latter and at its expense. Therefore, genetic modifications of populations can be overwritten with new content, providing an ongoing point of control.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.1921698117DOIArticle
https://www.pnas.org/content/suppl/2020/04/03/1921698117.DCSupplementalPublisherSupporting Information
https://doi.org/10.1101/2019.12.13.876169DOIDiscussion Paper
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183144PubMed CentralArticle
ORCID:
AuthorORCID
Oberhofer, Georg0000-0003-0930-1996
Hay, Bruce A.0000-0002-5486-0482
Additional Information:© 2020 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). Edited by Dana Carroll, University of Utah School of Medicine, Salt Lake City, UT, and approved March 2, 2020 (received for review December 13, 2019). PNAS first published April 3, 2020. Stocks obtained from the Bloomington Drosophila Stock Center (NIH Grant P40OD018537) were used in this study. This work was carried out with support from the US Department of Agriculture (USDA), National Institute of Food and Agriculture (NIFA) specialty crop initiative under USDA NIFA Award 2012-51181-20086, California University of Technology, and a Beaufort Visiting Fellow award from St. John’s College, Cambridge, UK (to B.A.H.). G.O. was supported by a Baxter Foundation Endowed Senior Postdoctoral Fellowship. T.I. was supported by NIH Training Grant 5T32GM007616-39. Data Availability: All data are available in the main text and the supplementary materials. ClvR flies are available on request under the conditions outlined in ref. 25. Author contributions: G.O. and B.A.H. designed research; G.O., T.I., and B.A.H. performed research; G.O., T.I., and B.A.H. analyzed data; G.O. and B.A.H. wrote the paper; and T.I. performed computational modeling. Competing interest statement: The authors have filed patent applications on ClvR and related technologies (U.S. Application No. 15/970,728). This article is a PNAS Direct Submission.
Funders:
Funding AgencyGrant Number
NIHP40OD018537
Department of Agriculture2012-51181-20086
CaltechUNSPECIFIED
St. John’s CollegeUNSPECIFIED
Baxter FoundationUNSPECIFIED
NIH Predoctoral Fellowship5T32GM007616-39
Subject Keywords:gene drive; Cas9; population replacement; selfish genetic element
Issue or Number:16
PubMed Central ID:PMC7183144
Record Number:CaltechAUTHORS:20191216-141643773
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20191216-141643773
Official Citation:Gene drive and resilience through renewal with next generation Cleave and Rescue selfish genetic elements. Georg Oberhofer, Tobin Ivy, Bruce A. Hay. Proceedings of the National Academy of Sciences Apr 2020, 117 (16) 9013-9021; DOI: 10.1073/pnas.1921698117
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100308
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:16 Dec 2019 22:24
Last Modified:05 May 2020 15:48

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