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Exploiting a Y chromosome-linked Cas9 for sex selection and gene drive

Gamez, Stephanie and Chaverra-Rodriguez, Duverney and Buchman, Anna and Kandul, Nikolay P. and Mendez-Sanchez, Stelia C. and Bennett, Jared B. and Sánchez C., Héctor M. and Yang, Ting and Antoshechkin, Igor A. and Duque, Jonny E. and Papathanos, Philippos A. and Marshall, John M. and Akbari, Omar S. (2021) Exploiting a Y chromosome-linked Cas9 for sex selection and gene drive. Nature Communications, 12 . Art. No. 7202. ISSN 2041-1723. PMCID PMC8664916. doi:10.1038/s41467-021-27333-1.

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CRISPR-based genetic engineering tools aimed to bias sex ratios, or drive effector genes into animal populations, often integrate the transgenes into autosomal chromosomes. However, in species with heterogametic sex chromsomes (e.g. XY, ZW), sex linkage of endonucleases could be beneficial to drive the expression in a sex-specific manner to produce genetic sexing systems, sex ratio distorters, or even sex-specific gene drives, for example. To explore this possibility, here we develop a transgenic line of Drosophila melanogaster expressing Cas9 from the Y chromosome. We functionally characterize the utility of this strain for both sex selection and gene drive finding it to be quite effective. To explore its utility for population control, we built mathematical models illustrating its dynamics as compared to other state-of-the-art systems designed for both population modification and suppression. Taken together, our results contribute to the development of current CRISPR genetic control tools and demonstrate the utility of using sex-linked Cas9 strains for genetic control of animals.

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URLURL TypeDescription CentralArticle ItemData
Gamez, Stephanie0000-0003-0665-0066
Chaverra-Rodriguez, Duverney0000-0001-8068-7436
Buchman, Anna0000-0002-8775-6147
Kandul, Nikolay P.0000-0001-7347-5558
Mendez-Sanchez, Stelia C.0000-0002-2402-3632
Bennett, Jared B.0000-0003-4718-257X
Sánchez C., Héctor M.0000-0001-7378-8853
Yang, Ting0000-0001-7201-4231
Antoshechkin, Igor A.0000-0002-9934-3040
Duque, Jonny E.0000-0003-2245-0558
Papathanos, Philippos A.0000-0001-8508-4554
Marshall, John M.0000-0003-0603-7341
Akbari, Omar S.0000-0002-6853-9884
Additional Information:© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit Received 11 August 2021; Accepted 3 November 2021; Published 10 December 2021. This work was supported in part by funding from a DARPA Safe Genes Program Grant (HR0011-17-2-0047) and an NIH award (R01AI151004) to O.S.A., and an award from the Innovative Genomics Institute at UC Berkeley to J.M.M. Data availability: Complete sequence and plasmid DNA for vector SGyA are available at Addgene (#160292). All RNA-sequencing data are available for download at NCBI with BioProject: PRJNA748400. Source data are provided with this paper. These authors contributed equally: Stephanie Gamez, Duverney Chaverra-Rodriguez. Author Contributions: O.S.A. conceived and designed experiments. S.G., D.C.R., S.C.M., and N.K. obtained genetic cross data; I.A. performed and analyzed RNA-Seq experiments; A.B. designed and T.Y. generated the SGyA, SGyB, and SGyC constructs; S.G., D.C.R., and J.E.D. performed molecular analyses; J.B., H.M.S.C., and J.M.M. performed mathematical modeling; O.S.A., S.G., and D.C.R. analyzed all the data. All authors contributed to writing and approved the final manuscript. Competing interests: O.S.A. is a founder of Agragene, Inc., and has an equity interest. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. S.G. is currently affiliated with Agragene Inc. A.B. is currently affiliated with Verily Life Sciences. All other authors declare no competing interests. Ethical conduct of research: We have complied with all relevant ethical regulations for animal testing and research and conformed to the UCSD institutionally approved biological use authorization protocol (BUA #R2401). Gene drive safety measures: All crosses using gene drive genetics were performed in accordance with a protocol approved by the Institutional Biosafety Committee at UCSD, in which full gene drive experiments were performed in a high-security ACL2 barrier facility and split drive experiments were performed in an ACL1 insectary in plastic vials that were autoclaved prior to being discarded, in accordance with currently suggested guidelines for the laboratory confinement of gene drive systems. Peer review information: Nature Communications thanks Roberto Galizi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
Funding AgencyGrant Number
Defense Advanced Research Projects Agency (DARPA)HR0011-17-2-0047
Innovative Genomics InstituteUNSPECIFIED
Subject Keywords:CRISPR-Cas9 genome editing; Genetic engineering; Synthetic biology
PubMed Central ID:PMC8664916
Record Number:CaltechAUTHORS:20211213-660916200
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Official Citation:Gamez, S., Chaverra-Rodriguez, D., Buchman, A. et al. Exploiting a Y chromosome-linked Cas9 for sex selection and gene drive. Nat Commun 12, 7202 (2021).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:112381
Deposited By: Tony Diaz
Deposited On:13 Dec 2021 21:00
Last Modified:03 Jan 2022 17:04

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