Cheating evolution: engineering gene drives to manipulate the fate of wild populations

Journal name:
Nature Reviews Genetics
Year published:
Published online


Engineered gene drives — the process of stimulating the biased inheritance of specific genes — have the potential to enable the spread of desirable genes throughout wild populations or to suppress harmful species, and may be particularly useful for the control of vector-borne diseases such as malaria. Although several types of selfish genetic elements exist in nature, few have been successfully engineered in the laboratory thus far. With the discovery of RNA-guided CRISPR–Cas9 (clustered regularly interspaced short palindromic repeats–CRISPR-associated 9) nucleases, which can be utilized to create, streamline and improve synthetic gene drives, this is rapidly changing. Here, we discuss the different types of engineered gene drives and their potential applications, as well as current policies regarding the safety and regulation of gene drives for the manipulation of wild populations.

At a glance


  1. Mechanisms of homing drives.
    Figure 1: Mechanisms of homing drives.

    a | A homing endonuclease gene (HEG) works by encoding an endonuclease, which cleaves at a target site on the homologous chromosome opposite the HEG. Homology-directed repair (HDR) results in the HEG being copied to the homologous chromosome. b | A homing element may be generated using an RNA-guided CRISPR (clustered regularly interspaced short palindromic repeats) endonuclease together with one or more small guide RNAs (gRNAs). Resistance alleles can be minimized by targeting the homing-based RNA-guided drive to a conserved critical gene at multiple locations using several gRNAs. The gene would only be reformed to functionality if HDR takes place, precluding successful repair and induction of resistance alleles by non-homologous end joining (NHEJ). c | A homing-based RNA-guided drive may be removed from a population by designing a reversal drive encoding a gRNA that targets the previous generation drive. d | A homing drive may be utilized to suppress a population by homing into a critical gene, the disruption of which induces recessive sterility (in this example, female infertility) or lethality.

  2. Spread of homing drives.
    Figure 2: Spread of homing drives.

    a | A homing drive results in most or all progeny of heterozygotes receiving the homing element, which allows the drive to spread rapidly throughout the population. b | A second-generation reversal drive can overwrite a first-generation homing drive, replacing its payload gene. Progeny of heterozygotes with this drive will all inherit the second-generation drive. This homing drive may be configured to home into wild-type alleles as well, immunizing the population against the first-generation homing drive. c | A suppression drive targeting a recessive gene required for viability or fertility will spread rapidly from heterozygotes with the drive, but would create an increasing number of sterile or unviable homozygotes, eventually resulting in a population crash.

  3. Designs for Y-drive systems.
    Figure 3: Designs for Y-drive systems.

    a | An X-chromosome shredder (X-shredder) system works by expressing an endonuclease from the Y chromosome, in an X-Y heterogametic species, that cleaves the X chromosome at many locations. This destroys the X chromosome, so all viable sperm have only Y chromosomes, leading to all male offspring and, eventually, population suppression. A red background denotes lethality. b | An RNA-guided CRISPR (clustered regularly interspaced short palindromic repeats) endonuclease with one or more small guide RNAs (gRNAs) may be used as the X-shredder. c | An RNA-guided endonuclease X-shredder can be reversed using an X chromosome containing multiple gRNAs targeting the gRNAs of the original X-shredder. These X-chromosome-localized gRNAs would be activated before the gRNAs on the Y chromosome, resulting in removal of the gRNAs on the Y chromosome before the X chromosome is shredded. This permanently inactivates the X-shredder, resulting in increased production of female offspring, which have a major fitness advantage compared to male offspring when X-shredder alleles remain in the population.

  4. Characteristics of Medea selfish genetic elements.
    Figure 4: Characteristics of Medea selfish genetic elements.

    a | The Medea system consists of a microRNA (miRNA) toxin expressed during meiosis that takes effect during embryonic development. The antidote consists of a protein expressed zygotically with an altered transcript sequence so as to be immune to the toxin. The system operates by killing offspring of a Medea-bearing female that fail to inherit Medea from either parent, resulting in frequency-dependent spread through a population. A red background denotes lethality. b | In lieu of an miRNA toxin, an RNA-guided CRISPR (clustered regularly interspaced short palindromic repeats) endonuclease may be used to cleave the mRNA of the target gene. c | A fixed Medea element can be reversed using a reversal Medea with a new toxin, a recoded antidote to both toxins (previous and new), and new payload. +, wild-type element; gRNA, guide RNA; M, original Medea element; RM, reversal Medea element.

  5. Underdominance systems.
    Figure 5: Underdominance systems.

    a | Several variants of underdominance systems exist, including double toxin–antidote systems and reciprocal chromosomal translocations. These systems function by reducing the fitness of heterozygotes to a greater extent than that of homozygotes. A red background denotes lethality. b | In two-locus toxin–antidote systems, each element contains a toxin–antidote pair, requiring both to be present for an organism to be viable. c | These toxins can consist of RNA-guided CRISPR (clustered regularly interspaced short palindromic repeats) endonucleases that are designed to destroy an mRNA of an essential gene, whereas the antidote consists of resistant forms of the gene expressing mRNA that cannot be cleaved. d | RNA-guided CRISPR endonucleases may also be used to engineer chromosomal rearrangements to be used in underdominance systems. In part a, the numbers 1 and 2 refer to chromosomes, '+' denotes wild types, and * indicates transgenic organisms from reciprocal chromosomal translocations or the two-locus toxin–antidote system. In part d, lowercase letters a–d refer to chromosome arms. gRNA, guide RNA.

  6. Wolbachia inheritance.
    Figure 6: Wolbachia inheritance.

    Wolbachia are intracellular parasites that are inherited maternally. They spread through a population by killing offspring of Wolbachia-infected males unless they have mated with a female infected with the same strain of Wolbachia.


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Author information

  1. These authors contributed equally to this work.

    • Jackson Champer &
    • Anna Buchman


  1. Department of Entomology, University of California, Riverside, Center for Disease Vector Research, Institute for Integrative Genome Biology, University of California, Riverside, California 92521, USA.

    • Jackson Champer,
    • Anna Buchman &
    • Omar S. Akbari

Competing interests statement

The authors declare no competing interests.

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Author details

  • Jackson Champer

    Jackson Champer is a postdoctoral scholar in the Department of Entomology at the University of California, Riverside, USA. He is interested in developing and mathematically modelling new gene drive systems and creating novel architectures for existing systems.

  • Anna Buchman

    Anna Buchman received her B.S. and M.S. at Sam Houston State University in Huntsville, Texas, USA, and her Ph.D. at the California Institute of Technology (Caltech) in Pasadena, USA. She is currently a postdoctoral scholar in the Department of Entomology at the University of California, Riverside, USA, where she is working to develop Medea systems outside the fruitfly and is also investigating novel ways to generate chromosomal translocations for use as gene drives.

  • Omar S. Akbari

    Omar S. Akbari is an assistant professor in the Department of Entomology at the University of California, Riverside, USA. He was previously at the California Institute of Technology (Caltech), Pasadena, USA, and worked on developing Medea and underdominance-based drive systems. His research group is inspired by synthetic biology and is currently working to further develop several types of gene drive systems in multiple organisms.

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