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Gene Drive: Evolved and Synthetic

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† Life Sciences, Imperial College, Silwood Park, Ascot, SL5 7PY, United Kingdom
‡ Life Sciences, Imperial College, South Kensington, London, SW7 2AZ, United Kingdom
*E-mail: [email protected]
*E-mail: [email protected]
Cite this: ACS Chem. Biol. 2018, 13, 2, 343–346
Publication Date (Web):February 5, 2018
https://doi.org/10.1021/acschembio.7b01031

Copyright © 2022 American Chemical Society. This publication is licensed under CC-BY.

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Abstract

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Drive is a process of accelerated inheritance from one generation to the next that allows some genes to spread rapidly through populations even if they do not contribute to—or indeed even if they detract from—organismal survival and reproduction. Genetic elements that can spread by drive include gametic and zygotic killers, meiotic drivers, homing endonuclease genes, B chromosomes, and transposable elements. The fact that gene drive can lead to the spread of fitness-reducing traits (including lethality and sterility) makes it an attractive process to consider exploiting to control disease vectors and other pests. There are a number of efforts to develop synthetic gene drive systems, particularly focused on the mosquito-borne diseases that continue to plague us.

SPECIAL ISSUE

This article is part of the Chemical Biology of CRISPR special issue.

Introduction to Gene Drive

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Most genes are thought to spread and persist in populations because they do something useful for the organisms carrying them, increasing survival and/or reproduction, at least on average. That is, most genes spread in populations by positive Darwinian selection and are maintained in the face of recurrent mutation by purifying selection. Some features of a gene may be selectively neutral—such as which nucleotide is found at a particular silent site—but random drift by itself will not lead to long open reading frames and associated control sequences that produce complex proteins performing a particular function.
There are other genes, a minority, which spread and persist not by natural selection, not by increasing organismal survival or reproduction, but instead by distorting their transmission from one generation to the next. For example, some genes manage to be transmitted to more than half of an individual’s gametes, even when that individual only inherited the gene from one of its two parents. In this case, the frequency of the gene increases due to the process of gene transmission from one generation to the next, and it is this unequal genetic transmission that gives the gene its advantage. Genes or genetic elements showing such transmission ratio distortion, or “drive,” include gametic and zygotic killers, meiotic drivers, homing endonuclease genes, B chromosomes, and transposable elements, each of which has evolved several or many times in different taxa. (1, 2) Moreover, drive has been an important process affecting such genomic features as genome size, base composition, chromosome shape, repeat structure, distribution of recombination hotspots, and centromere structure. (1, 3, 4)
Not only can driving genes spread without doing anything useful for the organisms carrying them, they can even spread if they cause some harm, as long as the effect of the transmission distortion is greater than the effect of the reduced survival and reproduction. For this reason, they are often called selfish genes, or selfish genetic elements. (1, 2) And since they can be harmful to the organism, genes that suppress these genes can themselves spread by natural selection (analogous to the spread of genes suppressing any other parasite), which the selfish gene will then be selected to avoid, potentially leading to an arms race. Occasionally, features of a selfish genetic element may be co-opted to do something useful for the host. Classic examples include mating type switching in yeast, antibody diversification in vertebrates, and telomere maintenance in Drosophila (and in eukaryotes more generally)—the evolution of all of these operations has involved the domestication or co-option of functions of selfish genetic elements. (1, 3)

Synthetic Gene Drive Systems

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The fact that gene drive can lead to the spread of fitness-reducing traits makes it potentially useful for controlling disease vectors and other pests. Moreover, the spread can be rapid: in a closed, random mating population, a construct with 100% drive and no fitness effects can increase from 1% to 99% in the population in just nine generations—fast enough to be attractive for public health interventions. Discussions about how to exploit gene drive for pest control date back for decades, long before there was any mechanistic understanding of how they worked, particularly among medical entomologists looking for new ways to control disease vectors. (5-10) However, classical genetic approaches were not sufficiently flexible to be able to construct a useful gene drive system. Now, with the recent progress in molecular biology, there is renewed interest in trying to make synthetic gene drive elements, (11, 12) and preliminary discussions of potential uses have expanded to agriculture and conservation. (13)
In broad outline, two types of intervention have been considered, either to reduce the size of the target population, or to leave numbers more-or-less intact and genetically modify the population such that it is less harmful (e.g., less able to transmit a pathogen). And three main molecular paradigms are being explored, the use of toxin–antidote systems, chromosomal rearrangements, or sequence-specific nucleases. Toxin-antidote systems and chromosomal rearrangements may be useful for introducing and spreading a new “cargo” gene through a population that makes the population less harmful (e.g., an effector gene that makes mosquitoes unable to transmit a pathogen). (14, 15) Nuclease-based drive systems may also be used to introduce novel genes, or they may be used for population suppression. (16, 17)

Toxin-Antidote Systems and Chromosomal Rearrangements

Many naturally occurring gene drive systems act as if they produce a toxin and antidote, though often the molecular details are not known. For example, in mice heterozygous for the t-haplotype, and Drosophila heterozygous for Segregation Distorter, these elements somehow act during spermatogenesis to sabotage spermatids or sperm carrying the wild-type allele, with the result that each is transmitted to over 90% of the progeny (compared to the Mendelian 50%). (18, 19) In Tribolium flour beetles, the medea gene acts in heterozygous females to somehow cause progeny that do not inherit the medea gene to die. (20, 21) Though the underlying molecular mechanisms are not known, this example stimulated the development of a synthetic gene drive construct in Drosophila with the same logic. (22) The construct combined a microRNA-based repressor of myd88 (an important protein normally supplied by the mother into the embryo) with a zygotically expressed myd88 gene that was not affected by the microRNA and supplied the missing protein. As intended, this construct was able to increase in frequency over successive generations in experimental cage populations. Two other medea systems, using different components, have also been developed in Drosophila, (23) as have toxin–antidote systems that display maternal-effect lethal underdominance and threshold-dependent invasion into population cages. (15, 24) Recent descriptions of natural toxin–antidote systems in plants, fungi, and nematodes (25-31) may provide further insights into how these sorts of systems can be engineered.
One way for toxin–antidote systems to work is by generating underdominant fitness interactions, in which the heterozygote is less fit than either of the two homozygotes. Underdominant interactions can also be generated with chromosomal rearrangements such as reciprocal translocations, and if these can be introduced at a sufficient frequency into a population (>50% in the simplest scenario), then they can spread to fixation. (6) Strains of Drosophila with reciprocal translocations have been engineered, and these showed the expected frequency-dependent spread in lab populations. (32)

Nuclease-Based Systems: Chromosome Shredding

In Aedes and Culex mosquitoes, there is a naturally occurring driving Y chromosome that, in some crosses, is transmitted to more than 90% of a male’s progeny. First described in the 1960s, (5, 33) there is still no good understanding of how it works at the molecular level, but cytologically it is associated with breaks of the X chromosome at male meiosis, perhaps having something to do with interrupted crossovers. (34, 35) This observation led to the idea that cleavage of the X chromosome during male meiosis might lead to drive of the Y. (16) In Anopheles gambiae, the most important vector of malaria in Africa, the rRNA genes are found in a single cluster of hundreds of copies on the X chromosome, making it an ideal target, (36) and sure enough, production of a nuclease targeting this sequence during spermatogenesis can produce biased sex ratios, up to 95% males, using both an engineered meganuclease and a CRISPR-based nuclease. (37, 38) A male-biased population sex ratio would be useful because males do not bite people and transmit disease, nor do they contribute as much materially to population productivity, and so total population size is also likely to decline. (39) The constructs reported to date do not yet constitute a fully functional gene drive system, because the nuclease genes have been inserted on an autosome, and so are themselves still transmitted in a Mendelian manner; the next step is to put them on the Y chromosome, which is challenging because it is highly repetitive and largely suppressed at meiosis, though some progress has been made. (40, 41)

Nuclease-Based Systems: Homing

Homing endonuclease genes (HEGs) are a class of natural occurring driving elements for which there is a good understanding about the molecular mechanisms, and these are both simple and general enough to potentially be worth exploiting. HEGs encode a nuclease that recognizes and cuts a sequence that typically occurs just once in the genome. The gene is in the middle of its own recognition sequence, disrupting it and protecting the chromosome it is on from being cut. Therefore, in heterozygotes, only the chromosome not containing the gene is cut; it is then repaired using the HEG-containing homologue as a template, with the result that the HEG is copied across to the chromosome where previously it was absent, converting a heterozygote into a homozygote. (42, 43) This “homing” reaction simply requires a gene encoding a sequence-specific nuclease, with the gene inserted in the middle of its own recognition sequence, and the cell’s DNA repair system takes care of the rest.
HEGs occur naturally in many microbes but have not yet been identified in any insects or vertebrates. Important proof-of-principle experiments demonstrated that the homing reaction can occur in both Drosophila and Anopheles. (44-47) These first experiments used meganucleases, and later experiments showed the reaction could also be catalyzed by zinc finger and TALE nucleases, (48) and, more recently, CRISPR-based nucleases. (49-51) In principle, the homing reaction can be used for both population-wide knockout of target genes, such as those involved in survival, fertility, or pathogen transmission, or for population-wide knock-in of novel effector genes. (17, 52, 53) As with other forms of pest or disease control, due attention must be given to the possibility of resistance evolving. (54-57)

Prospects

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There are a relatively small number of species for which genetic control methods, including gene drive, may be appropriate. Most prominent are those causing or transmitting diseases. Even now, more than 700 000 people die every year from vector-borne diseases, and there is an additional heavy burden of nonlethal morbidity. (58) Much of disease control is, ultimately, chemical, with efficacy largely determined by the degree to which production and delivery can be targeted and affordable. Vaccination can be among the most cost-effective of all health interventions because it uses the adaptive immune system to generate and deliver the active agents. The promise of genetic approaches—and gene drive in particular—is again to use biological processes–mating, meiosis, transcription, translation, etc.—for targeted, cost-effective delivery of appropriate chemicals (e.g., nucleases or antimicrobial peptides) that will substantially reduce disease transmission. Indeed, gene drive may take efficiency a step further, with a single release (perhaps with periodic “booster” releases) giving area-wide, population-level control. Important steps have been made toward realizing this potential, though there remains much more to do.

Author Information

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  • Corresponding Authors
    • Austin Burt - Life Sciences, Imperial College, Silwood Park, Ascot, SL5 7PY, United Kingdom;  Email: [email protected]
    • Andrea Crisanti - Life Sciences, Imperial College, South Kensington, London, SW7 2AZ, United Kingdom;  Email: [email protected]
    • Notes
      The authors declare no competing financial interest.

    Acknowledgment

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    We thank the reviewers for useful comments. Funded by grants from the Bill & Melinda Gates Foundation and the Open Philanthropy Project.

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      Insects act as vectors for diseases of plants, animals, and humans. Replacement of wild insect populations with genetically modified individuals unable to transmit disease provides a potentially self-perpetuating method of disease prevention. Population replacement requires a gene drive mechanism in order to spread linked genes mediating disease refractoriness through wild populations. We previously reported the creation of synthetic Medea selfish genetic elements able to drive population replacement in Drosophila. These elements use microRNA-mediated silencing of myd88, a maternally expressed gene required for embryonic dorso-ventral pattern formation, coupled with early zygotic expression of a rescuing transgene, to bring about gene drive. Medea elements that work through addnl. mechanisms are needed in order to be able to carry out cycles of population replacement and/or remove existing transgenes from the population, using second-generation elements that spread while driving first-generation elements out of the population. Here we report the synthesis and population genetic behavior of two new synthetic Medea elements that drive population replacement through manipulation of signaling pathways involved in cellular blastoderm formation or Notch signaling, demonstrating that in Drosophila Medea elements can be generated through manipulation of diverse signaling pathways. We also describe the mRNA and small RNA changes in ovaries and early embryos assocd. from Medea-bearing females. Finally, we use modeling to illustrate how Medea elements carrying genes that result in diapause-dependent female lethality could be used to bring about population suppression.
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    24. 24
      Akbari, O. S., Matzen, K. D., Marshall, J. M., Huang, H., Ward, C. M., and Hay, B. A. (2013) A synthetic gene drive system for local, reversible modification and suppression of insect populations Curr. Biol. 23, 671– 677 DOI: 10.1016/j.cub.2013.02.059
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      A synthetic gene drive system for local, reversible modification and suppression of insect populations
      Akbari, Omar S.; Matzen, Kelly D.; Marshall, John M.; Huang, Haixia; Ward, Catherine M.; Hay, Bruce A.
      Current Biology (2013), 23 (8), 671-677CODEN: CUBLE2; ISSN:0960-9822. (Cell Press)
      Replacement of wild insect populations with genetically modified individuals unable to transmit disease provides a self-perpetuating method of disease prevention but requires a gene drive mechanism to spread these traits to high frequency [1-3]. Drive mechanisms requiring that transgenes exceed a threshold frequency in order to spread are attractive because they bring about local but not global replacement, and transgenes can be eliminated through diln. of the population with wild-type individuals [4-6]. These features are likely to be important in many social and regulatory contexts [7-10]. Here we describe the first creation of a synthetic threshold-dependent gene drive system, designated maternal-effect lethal underdominance (UDMEL), in which two maternally expressed toxins, located on sep. chromosomes, are each linked with a zygotic antidote able to rescue maternal-effect lethality of the other toxin. We demonstrate threshold-dependent replacement in single- and two-locus configurations in Drosophila. Models suggest that transgene spread can often be limited to local environments. They also show that in a population in which single-locus UDMEL has been carried out, repeated release of wild-type males can result in population suppression, a novel method of genetic population manipulation.
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      Ben-David, E., Burga, A., and Kruglyak, L. (2017) A maternal-effect selfish genetic element in Caenorhabditis elegans Science 356, 1051– 1055 DOI: 10.1126/science.aan0621
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      Hu, W., Jiang, Z. D., Suo, F., Zheng, J. X., He, W. Z., and Du, L. L. (2017) A large gene family in fission yeast encodes spore killers that subvert Mendel’s law eLife 6, e26057 DOI: 10.7554/eLife.26057
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      Nuckolls, N. L., Bravo Nunez, M. A., Eickbush, M. T., Young, J. M., Lange, J. J., Yu, J. S., Smith, G. R., Jaspersen, S. L., Malik, H. S., and Zanders, S. E. (2017) wtf genes are prolific dual poison-antidote meiotic drivers eLife 6, e26033 DOI: 10.7554/eLife.26033
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      Seidel, H. S., Ailion, M., Li, J. L., van Oudenaarden, A., Rockman, M. V., and Kruglyak, L. (2011) A novel sperm-delivered toxin causes late-stage embryo lethality and transmission ratio distortion in C. elegans PLoS Biol. 9, e1001115 DOI: 10.1371/journal.pbio.1001115
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      Yang, J. Y., Zhao, X. B., Cheng, K., Du, H. Y., Ouyang, Y. D., Chen, J. J., Qiu, S. Q., Huang, J. Y., Jiang, Y. H., Jiang, L. W., Ding, J. H., Wang, J., Xu, C. G., Li, X. H., and Zhang, Q. F. (2012) A killer-protector system regulates both hybrid sterility and segregation distortion in rice Science 337, 1336– 1340 DOI: 10.1126/science.1223702
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      Windbichler, N., Papathanos, P. A., Catteruccia, F., Ranson, H., Burt, A., and Crisanti, A. (2007) Homing endonuclease mediated gene targeting in Anopheles gambiae cells and embryos Nucleic Acids Res. 35, 5922– 5933 DOI: 10.1093/nar/gkm632
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      Galizi, R., Doyle, L. A., Menichelli, M., Bernardini, F., Deredec, A., Burt, A., Stoddard, B. L., Windbichler, N., and Crisanti, A. (2014) A synthetic sex ratio distortion system for the control of the human malaria mosquito Nat. Commun. 5, 3977 DOI: 10.1038/ncomms4977
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      A synthetic sex ratio distortion system for the control of the human malaria mosquito
      Galizi, Roberto; Doyle, Lindsey A.; Menichelli, Miriam; Bernardini, Federica; Deredec, Anne; Burt, Austin; Stoddard, Barry L.; Windbichler, Nikolai; Crisanti, Andrea
      Nature Communications (2014), 5 (), 3977CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
      It has been theorized that inducing extreme reproductive sex ratios could be a method to suppress or eliminate pest populations. Limited knowledge about the genetic makeup and mode of action of naturally occurring sex distorters and the prevalence of co-evolving suppressors has hampered their use for control. Here we generate a synthetic sex distortion system by exploiting the specificity of the homing endonuclease I-PpoI, which is able to selectively cleave ribosomal gene sequences of the malaria vector Anopheles gambiae that are located exclusively on the mosquito's X chromosome. We combine structure-based protein engineering and mol. genetics to restrict the activity of the potentially toxic endonuclease to spermatogenesis. Shredding of the paternal X chromosome prevents it from being transmitted to the next generation, resulting in fully fertile mosquito strains that produce >95% male offspring. We demonstrate that distorter male mosquitoes can efficiently suppress caged wild-type mosquito populations, providing the foundation for a new class of genetic vector control strategies.
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      Galizi, R., Hammond, A., Kyrou, K., Taxiarchi, C., Bernardini, F., O’Loughlin, S. M., Papathanos, P. A., Nolan, T., Windbichler, N., and Crisanti, A. (2016) A CRISPR-Cas9 sex-ratio distortion system for genetic control Sci. Rep. 6, 31139 DOI: 10.1038/srep31139
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      A CRISPR-Cas9 sex-ratio distortion system for genetic control
      Galizi, Roberto; Hammond, Andrew; Kyrou, Kyros; Taxiarchi, Chrysanthi; Bernardini, Federica; O'Loughlin, Samantha M.; Papathanos, Philippos-Aris; Nolan, Tony; Windbichler, Nikolai; Crisanti, Andrea
      Scientific Reports (2016), 6 (), 31139CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
      Genetic control aims to reduce the ability of insect pest populations to cause harm via the release of modified insects. One strategy is to bias the reproductive sex ratio towards males so that a population decreases in size or is eliminated altogether due to a lack of females. We have shown previously that sex ratio distortion can be generated synthetically in the main human malaria vector Anopheles gambiae, by selectively destroying the X-chromosome during spermatogenesis, through the activity of a naturally-occurring endonuclease that targets a repetitive rDNA sequence highly-conserved in a wide range of organisms. Here we describe a CRISPR-Cas9 sex distortion system that targets ribosomal sequences restricted to the member species of the Anopheles gambiae complex. Expression of Cas9 during spermatogenesis resulted in RNA-guided shredding of the X-chromosome during male meiosis and produced extreme male bias among progeny in the absence of any significant redn. in fertility. The flexibility of CRISPR-Cas9 combined with the availability of genomic data for a range of insects renders this strategy broadly applicable for the species-specific control of any pest or vector species with an XY sex-detn. system by targeting sequences exclusive to the female sex chromosome.
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      Deredec, A., Godfray, H. C. J., and Burt, A. (2011) Requirements for effective malaria control with homing endonuclease genes Proc. Natl. Acad. Sci. U. S. A. 108, E874– E880 DOI: 10.1073/pnas.1110717108
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      Bernardini, F., Galizi, R., Menichelli, M., Papathanos, P. A., Dritsou, V., Marois, E., Crisanti, A., and Windbichler, N. (2014) Site-specific genetic engineering of the Anopheles gambiae Y chromosome Proc. Natl. Acad. Sci. U. S. A. 111, 7600– 7605 DOI: 10.1073/pnas.1404996111
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      Hall, A. B., Papathanos, P. A., Sharma, A., Cheng, C. D., Akbari, O. S., Assour, L., Bergman, N. H., Cagnetti, A., Crisanti, A., Dottorini, T., Fiorentini, E., Galizi, R., Hnath, J., Jiang, X. F., Koren, S., Nolan, T., Radune, D., Sharakhova, M. V., Steele, A., Timoshevskiy, V. A., Windbichler, N., Zhang, S. M., Hahn, M. W., Phillippy, A. M., Emrich, S. J., Sharakhov, I. V., Tu, Z. J., and Besansky, N. J. (2016) Radical remodeling of the Y chromosome in a recent radiation of malaria mosquitoes Proc. Natl. Acad. Sci. U. S. A. 113, E2114– E2123 DOI: 10.1073/pnas.1525164113
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      Colleaux, L., D'Auriol, L., Betermier, M., Cottarel, G., Jacquier, A., Galibert, F., and Dujon, B. (1986) Universal code equivalent of a yeast mitochondrial intron reading frame is expressed into Escherichia coli as a specific double strand endonuclease Cell 44, 521– 533 DOI: 10.1016/0092-8674(86)90262-X
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      Dujon, B. (1989) Group I introns as mobile genetic elements – facts and mechanistic speculations – a review Gene 82, 91– 114 DOI: 10.1016/0378-1119(89)90034-6
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      Chan, Y.-S., Huen, D. S., Glauert, R., Whiteway, E., and Russell, S. (2013) Optimising homing endonuclease gene drive performance in a semi-refractory species: the Drosophila melanogaster experience PLoS One 8, e54130 DOI: 10.1371/journal.pone.0054130
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      Chan, Y.-S., Naujoks, D. A., Huen, D. S., and Russell, S. (2011) Insect population control by homing endonuclease-based gene drive: an evaluation in Drosophila melanogaster Genetics 188, 33– 44 DOI: 10.1534/genetics.111.127506
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      Chan, Y.-S., Takeuchi, R., Jarjour, J., Huen, D. S., Stoddard, B. L., and Russell, S. (2013) The design and in vivo evaluation of engineered I-OnuI-based enzymes for HEG gene drive PLoS One 8, e74254 DOI: 10.1371/journal.pone.0074254
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      The design and in vivo evaluation of engineered I-Onui-based enzymes for HEG gene drive
      Chan, Yuk-Sang; Takeuchi, Ryo; Jarjour, Jordan; Huen, David S.; Stoddard, Barry L.; Russell, Steven
      PLoS One (2013), 8 (9), e74254CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      The homing endonuclease gene (HEG) drive system, a promising genetic approach for controlling arthropod populations, utilizes engineered nucleases to spread deleterious mutations that inactivate individual genes throughout a target population. Previous work with a naturally occurring LAGLIDADG homing endonuclease (I-SceI) demonstrated its feasibility in both Drosophila and Anopheles. Here we report on the next stage of this strategy: the redesign of HEGs with customized specificity in order to drive HEG-induced 'homing' in vivo via break-induced homologous recombination. Variants targeting a sequence within the Anopheles AGAP004734 gene were created from the recently characterized I-OnuI endonuclease and tested for cleavage activity and frequency of homing using a model Drosophila HEG drive system. We obsd. cleavage and homing at an integrated reporter for all endonuclease variants tested, demonstrating for the first time that engineered HEGs can cleave their target site in insect germline cells, promoting targeted mutagenesis and homing. However, in comparison to our previously reported work with I-SceI, the engineered I-OnuI variants mediated homing with a reduced frequency, suggesting that site-specific cleavage activity is insufficient by itself to ensure efficient homing. Taken together, our expts. take a further step towards the development of a viable HEG-based population control strategy for insects.
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    47. 47
      Windbichler, N., Menichelli, M., Papathanos, P. A., Thyme, S. B., Li, H., Ulge, U. Y., Hovde, B. T., Baker, D., Monnat, R. J., Jr., Burt, A., and Crisanti, A. (2011) A synthetic homing endonuclease-based gene drive system in the human malaria mosquito Nature 473, 212– 215 DOI: 10.1038/nature09937
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      A synthetic homing endonuclease-based gene drive system in the human malaria mosquito
      Windbichler, Nikolai; Menichelli, Miriam; Papathanos, Philippos Aris; Thyme, Summer B.; Li, Hui; Ulge, Umut Y.; Hovde, Blake T.; Baker, David; Monnat, Raymond J.; Burt, Austin; Crisanti, Andrea
      Nature (London, United Kingdom) (2011), 473 (7346), 212-215CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      Genetic methods of manipulating or eradicating disease vector populations have long been discussed as an attractive alternative to existing control measures because of their potential advantages in terms of effectiveness and species specificity. The development of genetically engineered malaria-resistant mosquitoes has shown, as a proof of principle, the possibility of targeting the mosquito's ability to serve as a disease vector. The translation of these achievements into control measures requires an effective technol. to spread a genetic modification from lab. mosquitoes to field populations. The authors have suggested previously that homing endonuclease genes (HEGs), a class of simple selfish genetic elements, could be exploited for this purpose. Here they demonstrate that a synthetic genetic element, consisting of mosquito regulatory regions and the homing endonuclease gene I-SceI, can substantially increase its transmission to the progeny in transgenic mosquitoes of the human malaria vector Anopheles gambiae. The authors show that the I-SceI element is able to invade receptive mosquito cage populations rapidly, validating math. models for the transmission dynamics of HEGs. Mol. analyses confirm that expression of I-SceI in the male germline induces high rates of site-specific chromosomal cleavage and gene conversion, which results in the gain of the I-SceI gene, and underlies the obsd. genetic drive. These findings demonstrate a new mechanism by which genetic control measures can be implemented. The results also show in principle how sequence-specific genetic drive elements like HEGs could be used to take the step from the genetic engineering of individuals to the genetic engineering of populations.
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    48. 48
      Simoni, A., Siniscalchi, C., Chan, Y.-S., Huen, D. S., Russell, S., Windbichler, N., and Crisanti, A. (2014) Development of synthetic selfish elements based on modular nucleases in Drosophila melanogaster Nucleic Acids Res. 42, 7461– 7472 DOI: 10.1093/nar/gku387
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      Gantz, V. M. and Bier, E. (2015) The mutagenic chain reaction: a method for converting heterozygous to homozygous mutations Science 348, 442– 444 DOI: 10.1126/science.aaa5945
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      The mutagenic chain reaction: A method for converting heterozygous to homozygous mutations
      Gantz, Valentino M.; Bier, Ethan
      Science (Washington, DC, United States) (2015), 348 (6233), 442-444CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      An organism with a single recessive loss-of-function allele will typically have a wild-type phenotype, whereas individuals homozygous for two copies of the allele will display a mutant phenotype. We have developed a method called the mutagenic chain reaction (MCR), which is based on the CRISPR/Cas9 genome-editing system for generating autocatalytic mutations, to produce homozygous loss-of-function mutations. In Drosophila, we found that MCR mutations efficiently spread from their chromosome of origin to the homologous chromosome, thereby converting heterozygous mutations to homozygosity in the vast majority of somatic and germline cells. MCR technol. should have broad applications in diverse organisms.
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    50. 50
      Gantz, V. M., Jasinskiene, N., Tatarenkova, O., Fazekas, A., Macias, V. M., Bier, E., and James, A. A. (2015) Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi Proc. Natl. Acad. Sci. U. S. A. 112, E6736– E6743 DOI: 10.1073/pnas.1521077112
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      50
      Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi
      Gantz, Valentino M.; Jasinskiene, Nijole; Tatarenkova, Olga; Fazekas, Aniko; Macias, Vanessa M.; Bier, Ethan; James, Anthony A.
      Proceedings of the National Academy of Sciences of the United States of America (2015), 112 (49), E6736-E6743CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Genetic engineering technologies can be used both to create transgenic mosquitoes carrying antipathogen effector genes targeting human malaria parasites and to generate gene-drive systems capable of introgressing the genes throughout wild vector populations. We developed a highly effective autonomous Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-assocd. protein 9 (Cas9)-mediated gene-drive system in the Asian malaria vector Anopheles stephensi, adapted from the mutagenic chain reaction (MCR). This specific system results in progeny of males and females derived from transgenic males exhibiting a high frequency of germ-line gene conversion consistent with homol.-directed repair (HDR). This system copies an ∼17-kb construct from its site of insertion to its homologous chromosome in a faithful, site-specific manner. Dual anti-Plasmodium falciparum effector genes, a marker gene, and the autonomous gene-drive components are introgressed into ∼99.5% of the progeny following outcrosses of transgenic lines to wild-type mosquitoes. The effector genes remain transcriptionally inducible upon blood feeding. In contrast to the efficient conversion in individuals expressing Cas9 only in the germ line, males and females derived from transgenic females, which are expected to have drive component mols. in the egg, produce progeny with a high frequency of mutations in the targeted genome sequence, resulting in near-Mendelian inheritance ratios of the transgene. Such mutant alleles result presumably from nonhomologous end-joining (NHEJ) events before the segregation of somatic and germ-line lineages early in development. These data support the design of this system to be active strictly within the germ line. Strains based on this technol. could sustain control and elimination as part of the malaria eradication agenda.
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    51. 51
      Hammond, A., Galizi, R., Kyrou, K., Simoni, A., Siniscalchi, C., Katsanos, D., Gribble, M., Baker, D., Marois, E., Russell, S., Burt, A., Windbichler, N., Crisanti, A., and Nolan, T. (2016) A CRISPR-Cas9 gene drive system-targeting female reproduction in the malaria mosquito vector Anopheles gambiae Nat. Biotechnol. 34, 78– 83 DOI: 10.1038/nbt.3439
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      Eckhoff, P. A., Wenger, E. A., Godfray, H. C. J., and Burt, A. (2017) Impact of mosquito gene drive on malaria elimination in a computational model with explicit spatial and temporal dynamics Proc. Natl. Acad. Sci. U. S. A. 114, E255– E264 DOI: 10.1073/pnas.1611064114
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      Godfray, H. C. J., North, A., and Burt, A. (2017) How driving endonuclease genes can be used to combat pests and disease vectors BMC Biol. 15, 81 DOI: 10.1186/s12915-017-0420-4
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      How driving endonuclease genes can be used to combat pests and disease vectors
      Godfray H Charles J; North Ace; Burt Austin
      BMC biology (2017), 15 (1), 81 ISSN:.
      Driving endonuclease genes (DEGs) spread through a population by a non-Mendelian mechanism. In a heterozygote, the protein encoded by a DEG causes a double-strand break in the homologous chromosome opposite to where its gene is inserted and when the break is repaired using the homologue as a template the DEG heterozygote is converted to a homozygote. Some DEGs occur naturally while several classes of endonucleases can be engineered to spread in this way, with CRISPR-Cas9 based systems being particularly flexible. There is great interest in using driving endonuclease genes to impose a genetic load on insects that vector diseases or are economic pests to reduce their population density, or to introduce a beneficial gene such as one that might interrupt disease transmission. This paper reviews both the population genetics and population dynamics of DEGs. It summarises the theory that guides the design of DEG constructs intended to perform different functions. It also reviews the studies that have explored the likelihood of resistance to DEG phenotypes arising, and how this risk may be reduced. The review is intended for a general audience and mathematical details are kept to a minimum.
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    54. 54
      Beaghton, A., Beaghton, P. J., and Burt, A. (2017) Vector control with driving Y chromosomes: modelling the evolution of resistance Malar. J. 16, 286 DOI: 10.1186/s12936-017-1932-7
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      54
      Vector control with driving Y chromosomes: modelling the evolution of resistance
      Beaghton Andrea; Beaghton Pantelis John; Burt Austin
      Malaria journal (2017), 16 (1), 286 ISSN:.
      BACKGROUND: The introduction of new malaria control interventions has often led to the evolution of resistance, both of the parasite to new drugs and of the mosquito vector to new insecticides, compromising the efficacy of the interventions. Recent progress in molecular and population biology raises the possibility of new genetic-based interventions, and the potential for resistance to evolve against these should be considered. Here, population modelling is used to determine the main factors affecting the likelihood that resistance will evolve against a synthetic, nuclease-based driving Y chromosome that produces a male-biased sex ratio. METHODS: A combination of deterministic differential equation models and stochastic analyses involving branching processes and Gillespie simulations is utilized to assess the probability that resistance evolves against a driving Y that otherwise is strong enough to eliminate the target population. The model considers resistance due to changes at the target site such that they are no longer cleaved by the nuclease, and due to trans-acting autosomal suppressor alleles. RESULTS: The probability that resistance evolves increases with the mutation rate and the intrinsic rate of increase of the population, and decreases with the strength of drive and any pleiotropic fitness costs of the resistant allele. In seasonally varying environments, the time of release can also affect the probability of resistance evolving. Trans-acting suppressor alleles are more likely to suffer stochastic loss at low frequencies than target site resistant alleles. CONCLUSIONS: As with any other intervention, there is a risk that resistance will evolve to new genetic approaches to vector control, and steps should be taken to minimize this probability. Two design features that should help in this regard are to reduce the rate at which resistant mutations arise, and to target sequences such that if they do arise, they impose a significant fitness cost on the mosquito.
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      PLoS Genetics (2017), 13 (7), e1006796/1-e1006796/18CODEN: PGLEB5; ISSN:1553-7404. (Public Library of Science)
      A functioning gene drive system could fundamentally change our strategies for the control of vector-borne diseases by facilitating rapid dissemination of transgenes that prevent pathogen transmission or reduce vector capacity. CRISPR/Cas9 gene drive promises such a mechanism, which works by converting cells that are heterozygous for the drive construct into homozygotes, thereby enabling super-Mendelian inheritance. Although CRISPR gene drive activity has already been demonstrated, a key obstacle for current systems is their propensity to generate resistance alleles, which cannot be converted to drive alleles. In this study, we developed two CRISPR gene drive constructs based on the nanos and vasa promoters that allowed us to illuminate the different mechanisms by which resistance alleles are formed in the model organism Drosophila melanogaster. We obsd. resistance allele formation at high rates both prior to fertilization in the germline and post-fertilization in the embryo due to maternally deposited Cas9. Assessment of drive activity in genetically diverse backgrounds further revealed substantial differences in conversion efficiency and resistance rates. Our results demonstrate that the evolution of resistance will likely impose a severe limitation to the effectiveness of current CRISPR gene drive approaches, esp. when applied to diverse natural populations.
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        Champer, J., Buchman, A., and Akbari, O. S. (2016) Cheating evolution: engineering gene drives to manipulate the fate of wild populations Nat. Rev. Genet. 17, 146– 159 DOI: 10.1038/nrg.2015.34
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        12
        Cheating evolution: engineering gene drives to manipulate the fate of wild populations
        Champer, Jackson; Buchman, Anna; Akbari, Omar S.
        Nature Reviews Genetics (2016), 17 (3), 146-159CODEN: NRGAAM; ISSN:1471-0056. (Nature Publishing Group)
        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 lab. thus far. With the discovery of RNA-guided CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR-assocd. 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.
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        NASEM. (2016) Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values, The National Academies Press, Washington, DC.
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        Adelman, Z. N., Basu, S., and Myles, K. M. (2016) Engineering pathogen resistance in mosquitoes, in Genetic Control of Malaria and Dengue (Adelman, Z. N., Ed.), pp 277– 304, Academic Press, London.
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        Marshall, J. M. and Akbari, O. S. (2016) Gene drive strategies for population replacement, in Genetic Control of Malaria and Dengue (Adelman, Z. N., Ed.), pp 169– 200, Academic Press, London.
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        Burt, A. (2003) Site-specific selfish genes as tools for the control and genetic engineering of natural populations Proc. R. Soc. London, Ser. B 270, 921– 928 DOI: 10.1098/rspb.2002.2319
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        16
        Site-specific selfish genes as tools for the control and genetic engineering of natural populations
        Burt, Austin
        Proceedings of the Royal Society of London, Series B: Biological Sciences (2003), 270 (1518), 921-928CODEN: PRLBA4; ISSN:0962-8452. (Royal Society)
        Site-specific selfish genes exploit host functions to copy themselves into a defined target DNA sequence, and include homing endonuclease genes, group II introns and some LINE-like transposable elements. If such genes can be engineered to target new host sequences, then they can be used to manipulate natural populations, even if the no. of individuals released is a small fraction of the entire population. For example, a genetic load sufficient to eradicate a population can be imposed in fewer than 20 generations, if the target is an essential host gene, the knockout is recessive and the selfish gene has an appropriate promoter. There will be selection for resistance, but several strategies are available for reducing the likelihood of it evolving. These genes may also be used to genetically engineer natural populations, by means of population-wide gene knockouts, gene replacements and genetic transformations. By targeting sex-linked loci just prior to meiosis one may skew the population sex ratio, and by changing the promoter one may limit the spread of the gene to neighboring populations. The proposed constructs are evolutionarily stable in the face of the mutations most likely to arise during their spread, and strategies are also available for reversing the manipulations.
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        Burt, A. (2014) Heritable strategies for controlling insect vectors of disease Philos. Trans. R. Soc., B 369, 20130432 DOI: 10.1098/rstb.2013.0432
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        17
        Heritable strategies for controlling insect vectors of disease
        Burt Austin
        Philosophical transactions of the Royal Society of London. Series B, Biological sciences (2014), 369 (1645), 20130432 ISSN:.
        Mosquito-borne diseases are causing a substantial burden of mortality, morbidity and economic loss in many parts of the world, despite current control efforts, and new complementary approaches to controlling these diseases are needed. One promising class of new interventions under development involves the heritable modification of the mosquito by insertion of novel genes into the nucleus or of Wolbachia endosymbionts into the cytoplasm. Once released into a target population, these modifications can act to reduce one or more components of the mosquito population's vectorial capacity (e.g. the number of female mosquitoes, their longevity or their ability to support development and transmission of the pathogen). Some of the modifications under development are designed to be self-limiting, in that they will tend to disappear over time in the absence of recurrent releases (and hence are similar to the sterile insect technique, SIT), whereas other modifications are designed to be self-sustaining, spreading through populations even after releases stop (and hence are similar to traditional biological control). Several successful field trials have now been performed with Aedes mosquitoes, and such trials are helping to define the appropriate developmental pathway for this new class of intervention.
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        Larracuente, A. M. and Presgraves, D. C. (2012) The selfish Segregation Distorter gene complex of Drosophila melanogaster Genetics 192, 33– 53 DOI: 10.1534/genetics.112.141390
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        Beeman, R. W., Friesen, K. S., and Denell, R. E. (1992) Maternal-effect selfish genes in flour beetles Science 256, 89– 92 DOI: 10.1126/science.1566060
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        Lorenzen, M. D., Gnirke, A., Margolis, J., Garnes, J., Campbell, M., Stuart, J. J., Aggarwal, R., Richards, S., Park, Y., and Beeman, R. W. (2008) The maternal-effect, selfish genetic element Medea is associated with a composite Tc1 transposon Proc. Natl. Acad. Sci. U. S. A. 105, 10085– 10089 DOI: 10.1073/pnas.0800444105
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        Chen, C. H., Huang, H. X., Ward, C. M., Su, J. T., Schaeffer, L. V., Guo, M., and Hay, B. A. (2007) A synthetic maternal-effect selfish genetic element drives population replacement in Drosophila Science 316, 597– 600 DOI: 10.1126/science.1138595
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        22
        A Synthetic Maternal-Effect Selfish Genetic Element Drives Population Replacement in Drosophila
        Chen, Chun-Hong; Huang, Haixia; Ward, Catherine M.; Su, Jessica T.; Schaeffer, Lorian V.; Guo, Ming; Hay, Bruce A.
        Science (Washington, DC, United States) (2007), 316 (5824), 597-600CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
        One proposed strategy for controlling the transmission of insect-borne pathogens uses a drive mechanism to ensure the rapid spread of transgenes conferring disease refractoriness throughout wild populations. Here, we report the creation of maternal-effect selfish genetic elements in Drosophila that drive population replacement and are resistant to recombination-mediated dissocn. of drive and disease refractoriness functions. These selfish elements use microRNA-mediated silencing of a maternally expressed gene essential for embryogenesis, which is coupled with early zygotic expression of a rescuing transgene.
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        Akbari, O. S., Chen, C.-H., Marshall, J. M., Huang, H., Antoshechkin, I., and Hay, B. A. (2014) Novel synthetic medea selfish genetic elements drive population replacement in Drosophila; a theoretical exploration of medea-dependent population suppression ACS Synth. Biol. 3, 915– 928 DOI: 10.1021/sb300079h
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        23
        Novel synthetic Medea selfish genetic elements drive population replacement in Drosophila; a theoretical exploration of Medea-dependent population suppression
        Akbari, Omar S.; Chen, Chun-Hong; Marshall, John M.; Huang, Haixia; Antoshechkin, Igor; Hay, Bruce A.
        ACS Synthetic Biology (2014), 3 (12), 915-928CODEN: ASBCD6; ISSN:2161-5063. (American Chemical Society)
        Insects act as vectors for diseases of plants, animals, and humans. Replacement of wild insect populations with genetically modified individuals unable to transmit disease provides a potentially self-perpetuating method of disease prevention. Population replacement requires a gene drive mechanism in order to spread linked genes mediating disease refractoriness through wild populations. We previously reported the creation of synthetic Medea selfish genetic elements able to drive population replacement in Drosophila. These elements use microRNA-mediated silencing of myd88, a maternally expressed gene required for embryonic dorso-ventral pattern formation, coupled with early zygotic expression of a rescuing transgene, to bring about gene drive. Medea elements that work through addnl. mechanisms are needed in order to be able to carry out cycles of population replacement and/or remove existing transgenes from the population, using second-generation elements that spread while driving first-generation elements out of the population. Here we report the synthesis and population genetic behavior of two new synthetic Medea elements that drive population replacement through manipulation of signaling pathways involved in cellular blastoderm formation or Notch signaling, demonstrating that in Drosophila Medea elements can be generated through manipulation of diverse signaling pathways. We also describe the mRNA and small RNA changes in ovaries and early embryos assocd. from Medea-bearing females. Finally, we use modeling to illustrate how Medea elements carrying genes that result in diapause-dependent female lethality could be used to bring about population suppression.
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      24. 24
        Akbari, O. S., Matzen, K. D., Marshall, J. M., Huang, H., Ward, C. M., and Hay, B. A. (2013) A synthetic gene drive system for local, reversible modification and suppression of insect populations Curr. Biol. 23, 671– 677 DOI: 10.1016/j.cub.2013.02.059
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        24
        A synthetic gene drive system for local, reversible modification and suppression of insect populations
        Akbari, Omar S.; Matzen, Kelly D.; Marshall, John M.; Huang, Haixia; Ward, Catherine M.; Hay, Bruce A.
        Current Biology (2013), 23 (8), 671-677CODEN: CUBLE2; ISSN:0960-9822. (Cell Press)
        Replacement of wild insect populations with genetically modified individuals unable to transmit disease provides a self-perpetuating method of disease prevention but requires a gene drive mechanism to spread these traits to high frequency [1-3]. Drive mechanisms requiring that transgenes exceed a threshold frequency in order to spread are attractive because they bring about local but not global replacement, and transgenes can be eliminated through diln. of the population with wild-type individuals [4-6]. These features are likely to be important in many social and regulatory contexts [7-10]. Here we describe the first creation of a synthetic threshold-dependent gene drive system, designated maternal-effect lethal underdominance (UDMEL), in which two maternally expressed toxins, located on sep. chromosomes, are each linked with a zygotic antidote able to rescue maternal-effect lethality of the other toxin. We demonstrate threshold-dependent replacement in single- and two-locus configurations in Drosophila. Models suggest that transgene spread can often be limited to local environments. They also show that in a population in which single-locus UDMEL has been carried out, repeated release of wild-type males can result in population suppression, a novel method of genetic population manipulation.
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        Ben-David, E., Burga, A., and Kruglyak, L. (2017) A maternal-effect selfish genetic element in Caenorhabditis elegans Science 356, 1051– 1055 DOI: 10.1126/science.aan0621
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        Hu, W., Jiang, Z. D., Suo, F., Zheng, J. X., He, W. Z., and Du, L. L. (2017) A large gene family in fission yeast encodes spore killers that subvert Mendel’s law eLife 6, e26057 DOI: 10.7554/eLife.26057
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        Nuckolls, N. L., Bravo Nunez, M. A., Eickbush, M. T., Young, J. M., Lange, J. J., Yu, J. S., Smith, G. R., Jaspersen, S. L., Malik, H. S., and Zanders, S. E. (2017) wtf genes are prolific dual poison-antidote meiotic drivers eLife 6, e26033 DOI: 10.7554/eLife.26033
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        Yang, J. Y., Zhao, X. B., Cheng, K., Du, H. Y., Ouyang, Y. D., Chen, J. J., Qiu, S. Q., Huang, J. Y., Jiang, Y. H., Jiang, L. W., Ding, J. H., Wang, J., Xu, C. G., Li, X. H., and Zhang, Q. F. (2012) A killer-protector system regulates both hybrid sterility and segregation distortion in rice Science 337, 1336– 1340 DOI: 10.1126/science.1223702
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        Windbichler, N., Papathanos, P. A., Catteruccia, F., Ranson, H., Burt, A., and Crisanti, A. (2007) Homing endonuclease mediated gene targeting in Anopheles gambiae cells and embryos Nucleic Acids Res. 35, 5922– 5933 DOI: 10.1093/nar/gkm632
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        Galizi, R., Doyle, L. A., Menichelli, M., Bernardini, F., Deredec, A., Burt, A., Stoddard, B. L., Windbichler, N., and Crisanti, A. (2014) A synthetic sex ratio distortion system for the control of the human malaria mosquito Nat. Commun. 5, 3977 DOI: 10.1038/ncomms4977
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        A synthetic sex ratio distortion system for the control of the human malaria mosquito
        Galizi, Roberto; Doyle, Lindsey A.; Menichelli, Miriam; Bernardini, Federica; Deredec, Anne; Burt, Austin; Stoddard, Barry L.; Windbichler, Nikolai; Crisanti, Andrea
        Nature Communications (2014), 5 (), 3977CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
        It has been theorized that inducing extreme reproductive sex ratios could be a method to suppress or eliminate pest populations. Limited knowledge about the genetic makeup and mode of action of naturally occurring sex distorters and the prevalence of co-evolving suppressors has hampered their use for control. Here we generate a synthetic sex distortion system by exploiting the specificity of the homing endonuclease I-PpoI, which is able to selectively cleave ribosomal gene sequences of the malaria vector Anopheles gambiae that are located exclusively on the mosquito's X chromosome. We combine structure-based protein engineering and mol. genetics to restrict the activity of the potentially toxic endonuclease to spermatogenesis. Shredding of the paternal X chromosome prevents it from being transmitted to the next generation, resulting in fully fertile mosquito strains that produce >95% male offspring. We demonstrate that distorter male mosquitoes can efficiently suppress caged wild-type mosquito populations, providing the foundation for a new class of genetic vector control strategies.
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        Galizi, R., Hammond, A., Kyrou, K., Taxiarchi, C., Bernardini, F., O’Loughlin, S. M., Papathanos, P. A., Nolan, T., Windbichler, N., and Crisanti, A. (2016) A CRISPR-Cas9 sex-ratio distortion system for genetic control Sci. Rep. 6, 31139 DOI: 10.1038/srep31139
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        A CRISPR-Cas9 sex-ratio distortion system for genetic control
        Galizi, Roberto; Hammond, Andrew; Kyrou, Kyros; Taxiarchi, Chrysanthi; Bernardini, Federica; O'Loughlin, Samantha M.; Papathanos, Philippos-Aris; Nolan, Tony; Windbichler, Nikolai; Crisanti, Andrea
        Scientific Reports (2016), 6 (), 31139CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
        Genetic control aims to reduce the ability of insect pest populations to cause harm via the release of modified insects. One strategy is to bias the reproductive sex ratio towards males so that a population decreases in size or is eliminated altogether due to a lack of females. We have shown previously that sex ratio distortion can be generated synthetically in the main human malaria vector Anopheles gambiae, by selectively destroying the X-chromosome during spermatogenesis, through the activity of a naturally-occurring endonuclease that targets a repetitive rDNA sequence highly-conserved in a wide range of organisms. Here we describe a CRISPR-Cas9 sex distortion system that targets ribosomal sequences restricted to the member species of the Anopheles gambiae complex. Expression of Cas9 during spermatogenesis resulted in RNA-guided shredding of the X-chromosome during male meiosis and produced extreme male bias among progeny in the absence of any significant redn. in fertility. The flexibility of CRISPR-Cas9 combined with the availability of genomic data for a range of insects renders this strategy broadly applicable for the species-specific control of any pest or vector species with an XY sex-detn. system by targeting sequences exclusive to the female sex chromosome.
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        Deredec, A., Godfray, H. C. J., and Burt, A. (2011) Requirements for effective malaria control with homing endonuclease genes Proc. Natl. Acad. Sci. U. S. A. 108, E874– E880 DOI: 10.1073/pnas.1110717108
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        Bernardini, F., Galizi, R., Menichelli, M., Papathanos, P. A., Dritsou, V., Marois, E., Crisanti, A., and Windbichler, N. (2014) Site-specific genetic engineering of the Anopheles gambiae Y chromosome Proc. Natl. Acad. Sci. U. S. A. 111, 7600– 7605 DOI: 10.1073/pnas.1404996111
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        Hall, A. B., Papathanos, P. A., Sharma, A., Cheng, C. D., Akbari, O. S., Assour, L., Bergman, N. H., Cagnetti, A., Crisanti, A., Dottorini, T., Fiorentini, E., Galizi, R., Hnath, J., Jiang, X. F., Koren, S., Nolan, T., Radune, D., Sharakhova, M. V., Steele, A., Timoshevskiy, V. A., Windbichler, N., Zhang, S. M., Hahn, M. W., Phillippy, A. M., Emrich, S. J., Sharakhov, I. V., Tu, Z. J., and Besansky, N. J. (2016) Radical remodeling of the Y chromosome in a recent radiation of malaria mosquitoes Proc. Natl. Acad. Sci. U. S. A. 113, E2114– E2123 DOI: 10.1073/pnas.1525164113
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        Chan, Y.-S., Huen, D. S., Glauert, R., Whiteway, E., and Russell, S. (2013) Optimising homing endonuclease gene drive performance in a semi-refractory species: the Drosophila melanogaster experience PLoS One 8, e54130 DOI: 10.1371/journal.pone.0054130
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        Chan, Y.-S., Naujoks, D. A., Huen, D. S., and Russell, S. (2011) Insect population control by homing endonuclease-based gene drive: an evaluation in Drosophila melanogaster Genetics 188, 33– 44 DOI: 10.1534/genetics.111.127506
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        Chan, Y.-S., Takeuchi, R., Jarjour, J., Huen, D. S., Stoddard, B. L., and Russell, S. (2013) The design and in vivo evaluation of engineered I-OnuI-based enzymes for HEG gene drive PLoS One 8, e74254 DOI: 10.1371/journal.pone.0074254
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        The design and in vivo evaluation of engineered I-Onui-based enzymes for HEG gene drive
        Chan, Yuk-Sang; Takeuchi, Ryo; Jarjour, Jordan; Huen, David S.; Stoddard, Barry L.; Russell, Steven
        PLoS One (2013), 8 (9), e74254CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
        The homing endonuclease gene (HEG) drive system, a promising genetic approach for controlling arthropod populations, utilizes engineered nucleases to spread deleterious mutations that inactivate individual genes throughout a target population. Previous work with a naturally occurring LAGLIDADG homing endonuclease (I-SceI) demonstrated its feasibility in both Drosophila and Anopheles. Here we report on the next stage of this strategy: the redesign of HEGs with customized specificity in order to drive HEG-induced 'homing' in vivo via break-induced homologous recombination. Variants targeting a sequence within the Anopheles AGAP004734 gene were created from the recently characterized I-OnuI endonuclease and tested for cleavage activity and frequency of homing using a model Drosophila HEG drive system. We obsd. cleavage and homing at an integrated reporter for all endonuclease variants tested, demonstrating for the first time that engineered HEGs can cleave their target site in insect germline cells, promoting targeted mutagenesis and homing. However, in comparison to our previously reported work with I-SceI, the engineered I-OnuI variants mediated homing with a reduced frequency, suggesting that site-specific cleavage activity is insufficient by itself to ensure efficient homing. Taken together, our expts. take a further step towards the development of a viable HEG-based population control strategy for insects.
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      47. 47
        Windbichler, N., Menichelli, M., Papathanos, P. A., Thyme, S. B., Li, H., Ulge, U. Y., Hovde, B. T., Baker, D., Monnat, R. J., Jr., Burt, A., and Crisanti, A. (2011) A synthetic homing endonuclease-based gene drive system in the human malaria mosquito Nature 473, 212– 215 DOI: 10.1038/nature09937
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        47
        A synthetic homing endonuclease-based gene drive system in the human malaria mosquito
        Windbichler, Nikolai; Menichelli, Miriam; Papathanos, Philippos Aris; Thyme, Summer B.; Li, Hui; Ulge, Umut Y.; Hovde, Blake T.; Baker, David; Monnat, Raymond J.; Burt, Austin; Crisanti, Andrea
        Nature (London, United Kingdom) (2011), 473 (7346), 212-215CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
        Genetic methods of manipulating or eradicating disease vector populations have long been discussed as an attractive alternative to existing control measures because of their potential advantages in terms of effectiveness and species specificity. The development of genetically engineered malaria-resistant mosquitoes has shown, as a proof of principle, the possibility of targeting the mosquito's ability to serve as a disease vector. The translation of these achievements into control measures requires an effective technol. to spread a genetic modification from lab. mosquitoes to field populations. The authors have suggested previously that homing endonuclease genes (HEGs), a class of simple selfish genetic elements, could be exploited for this purpose. Here they demonstrate that a synthetic genetic element, consisting of mosquito regulatory regions and the homing endonuclease gene I-SceI, can substantially increase its transmission to the progeny in transgenic mosquitoes of the human malaria vector Anopheles gambiae. The authors show that the I-SceI element is able to invade receptive mosquito cage populations rapidly, validating math. models for the transmission dynamics of HEGs. Mol. analyses confirm that expression of I-SceI in the male germline induces high rates of site-specific chromosomal cleavage and gene conversion, which results in the gain of the I-SceI gene, and underlies the obsd. genetic drive. These findings demonstrate a new mechanism by which genetic control measures can be implemented. The results also show in principle how sequence-specific genetic drive elements like HEGs could be used to take the step from the genetic engineering of individuals to the genetic engineering of populations.
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      48. 48
        Simoni, A., Siniscalchi, C., Chan, Y.-S., Huen, D. S., Russell, S., Windbichler, N., and Crisanti, A. (2014) Development of synthetic selfish elements based on modular nucleases in Drosophila melanogaster Nucleic Acids Res. 42, 7461– 7472 DOI: 10.1093/nar/gku387
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        Gantz, V. M. and Bier, E. (2015) The mutagenic chain reaction: a method for converting heterozygous to homozygous mutations Science 348, 442– 444 DOI: 10.1126/science.aaa5945
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        49
        The mutagenic chain reaction: A method for converting heterozygous to homozygous mutations
        Gantz, Valentino M.; Bier, Ethan
        Science (Washington, DC, United States) (2015), 348 (6233), 442-444CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
        An organism with a single recessive loss-of-function allele will typically have a wild-type phenotype, whereas individuals homozygous for two copies of the allele will display a mutant phenotype. We have developed a method called the mutagenic chain reaction (MCR), which is based on the CRISPR/Cas9 genome-editing system for generating autocatalytic mutations, to produce homozygous loss-of-function mutations. In Drosophila, we found that MCR mutations efficiently spread from their chromosome of origin to the homologous chromosome, thereby converting heterozygous mutations to homozygosity in the vast majority of somatic and germline cells. MCR technol. should have broad applications in diverse organisms.
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      50. 50
        Gantz, V. M., Jasinskiene, N., Tatarenkova, O., Fazekas, A., Macias, V. M., Bier, E., and James, A. A. (2015) Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi Proc. Natl. Acad. Sci. U. S. A. 112, E6736– E6743 DOI: 10.1073/pnas.1521077112
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        50
        Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi
        Gantz, Valentino M.; Jasinskiene, Nijole; Tatarenkova, Olga; Fazekas, Aniko; Macias, Vanessa M.; Bier, Ethan; James, Anthony A.
        Proceedings of the National Academy of Sciences of the United States of America (2015), 112 (49), E6736-E6743CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
        Genetic engineering technologies can be used both to create transgenic mosquitoes carrying antipathogen effector genes targeting human malaria parasites and to generate gene-drive systems capable of introgressing the genes throughout wild vector populations. We developed a highly effective autonomous Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-assocd. protein 9 (Cas9)-mediated gene-drive system in the Asian malaria vector Anopheles stephensi, adapted from the mutagenic chain reaction (MCR). This specific system results in progeny of males and females derived from transgenic males exhibiting a high frequency of germ-line gene conversion consistent with homol.-directed repair (HDR). This system copies an ∼17-kb construct from its site of insertion to its homologous chromosome in a faithful, site-specific manner. Dual anti-Plasmodium falciparum effector genes, a marker gene, and the autonomous gene-drive components are introgressed into ∼99.5% of the progeny following outcrosses of transgenic lines to wild-type mosquitoes. The effector genes remain transcriptionally inducible upon blood feeding. In contrast to the efficient conversion in individuals expressing Cas9 only in the germ line, males and females derived from transgenic females, which are expected to have drive component mols. in the egg, produce progeny with a high frequency of mutations in the targeted genome sequence, resulting in near-Mendelian inheritance ratios of the transgene. Such mutant alleles result presumably from nonhomologous end-joining (NHEJ) events before the segregation of somatic and germ-line lineages early in development. These data support the design of this system to be active strictly within the germ line. Strains based on this technol. could sustain control and elimination as part of the malaria eradication agenda.
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      51. 51
        Hammond, A., Galizi, R., Kyrou, K., Simoni, A., Siniscalchi, C., Katsanos, D., Gribble, M., Baker, D., Marois, E., Russell, S., Burt, A., Windbichler, N., Crisanti, A., and Nolan, T. (2016) A CRISPR-Cas9 gene drive system-targeting female reproduction in the malaria mosquito vector Anopheles gambiae Nat. Biotechnol. 34, 78– 83 DOI: 10.1038/nbt.3439
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        Eckhoff, P. A., Wenger, E. A., Godfray, H. C. J., and Burt, A. (2017) Impact of mosquito gene drive on malaria elimination in a computational model with explicit spatial and temporal dynamics Proc. Natl. Acad. Sci. U. S. A. 114, E255– E264 DOI: 10.1073/pnas.1611064114
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        Godfray, H. C. J., North, A., and Burt, A. (2017) How driving endonuclease genes can be used to combat pests and disease vectors BMC Biol. 15, 81 DOI: 10.1186/s12915-017-0420-4
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        53
        How driving endonuclease genes can be used to combat pests and disease vectors
        Godfray H Charles J; North Ace; Burt Austin
        BMC biology (2017), 15 (1), 81 ISSN:.
        Driving endonuclease genes (DEGs) spread through a population by a non-Mendelian mechanism. In a heterozygote, the protein encoded by a DEG causes a double-strand break in the homologous chromosome opposite to where its gene is inserted and when the break is repaired using the homologue as a template the DEG heterozygote is converted to a homozygote. Some DEGs occur naturally while several classes of endonucleases can be engineered to spread in this way, with CRISPR-Cas9 based systems being particularly flexible. There is great interest in using driving endonuclease genes to impose a genetic load on insects that vector diseases or are economic pests to reduce their population density, or to introduce a beneficial gene such as one that might interrupt disease transmission. This paper reviews both the population genetics and population dynamics of DEGs. It summarises the theory that guides the design of DEG constructs intended to perform different functions. It also reviews the studies that have explored the likelihood of resistance to DEG phenotypes arising, and how this risk may be reduced. The review is intended for a general audience and mathematical details are kept to a minimum.
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        Beaghton, A., Beaghton, P. J., and Burt, A. (2017) Vector control with driving Y chromosomes: modelling the evolution of resistance Malar. J. 16, 286 DOI: 10.1186/s12936-017-1932-7
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        54
        Vector control with driving Y chromosomes: modelling the evolution of resistance
        Beaghton Andrea; Beaghton Pantelis John; Burt Austin
        Malaria journal (2017), 16 (1), 286 ISSN:.
        BACKGROUND: The introduction of new malaria control interventions has often led to the evolution of resistance, both of the parasite to new drugs and of the mosquito vector to new insecticides, compromising the efficacy of the interventions. Recent progress in molecular and population biology raises the possibility of new genetic-based interventions, and the potential for resistance to evolve against these should be considered. Here, population modelling is used to determine the main factors affecting the likelihood that resistance will evolve against a synthetic, nuclease-based driving Y chromosome that produces a male-biased sex ratio. METHODS: A combination of deterministic differential equation models and stochastic analyses involving branching processes and Gillespie simulations is utilized to assess the probability that resistance evolves against a driving Y that otherwise is strong enough to eliminate the target population. The model considers resistance due to changes at the target site such that they are no longer cleaved by the nuclease, and due to trans-acting autosomal suppressor alleles. RESULTS: The probability that resistance evolves increases with the mutation rate and the intrinsic rate of increase of the population, and decreases with the strength of drive and any pleiotropic fitness costs of the resistant allele. In seasonally varying environments, the time of release can also affect the probability of resistance evolving. Trans-acting suppressor alleles are more likely to suffer stochastic loss at low frequencies than target site resistant alleles. CONCLUSIONS: As with any other intervention, there is a risk that resistance will evolve to new genetic approaches to vector control, and steps should be taken to minimize this probability. Two design features that should help in this regard are to reduce the rate at which resistant mutations arise, and to target sequences such that if they do arise, they impose a significant fitness cost on the mosquito.
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      55. 55
        Beaghton, A., Hammond, A., Nolan, T., Crisanti, A., Godfray, H. C. J., and Burt, A. (2017) Requirements for driving antipathogen effector genes into populations of disease vectors by homing Genetics 205, 1587– 1596 DOI: 10.1534/genetics.116.197632
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        Champer, J., Reeves, R., Oh, S. Y., Liu, C., Liu, J. X., Clark, A. G., and Messer, P. W. (2017) Novel CRISPR/Cas9 gene drive constructs reveal insights into mechanisms of resistance allele formation and drive efficiency in genetically diverse populations PLoS Genet. 13, e1006796 DOI: 10.1371/journal.pgen.1006796
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        56
        Novel CRISPR/Cas9 gene drive constructs reveal insights into mechanisms of resistance allele formation and drive efficiency in genetically diverse populations
        Champer, Jackson; Reeves, Riona; Oh, Suh Yeon; Liu, Chen; Liu, Jingxian; Clark, Andrew G.; Messer, Philipp W.
        PLoS Genetics (2017), 13 (7), e1006796/1-e1006796/18CODEN: PGLEB5; ISSN:1553-7404. (Public Library of Science)
        A functioning gene drive system could fundamentally change our strategies for the control of vector-borne diseases by facilitating rapid dissemination of transgenes that prevent pathogen transmission or reduce vector capacity. CRISPR/Cas9 gene drive promises such a mechanism, which works by converting cells that are heterozygous for the drive construct into homozygotes, thereby enabling super-Mendelian inheritance. Although CRISPR gene drive activity has already been demonstrated, a key obstacle for current systems is their propensity to generate resistance alleles, which cannot be converted to drive alleles. In this study, we developed two CRISPR gene drive constructs based on the nanos and vasa promoters that allowed us to illuminate the different mechanisms by which resistance alleles are formed in the model organism Drosophila melanogaster. We obsd. resistance allele formation at high rates both prior to fertilization in the germline and post-fertilization in the embryo due to maternally deposited Cas9. Assessment of drive activity in genetically diverse backgrounds further revealed substantial differences in conversion efficiency and resistance rates. Our results demonstrate that the evolution of resistance will likely impose a severe limitation to the effectiveness of current CRISPR gene drive approaches, esp. when applied to diverse natural populations.
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      57. 57
        Hammond, A. M., Kyrou, K., Bruttini, M., North, A., Galizi, R., Karlsson, X., Kranjc, N., Carpi, F. M., D’Aurizio, R., Crisanti, A., and Nolan, T. (2017) The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito PLoS Genet. 13, e1007039 DOI: 10.1371/journal.pgen.1007039
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        57
        The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito
        Hammond, Andrew M.; Kyrou, Kyros; Bruttini, Marco; North, Ace; Galizi, Roberto; Karlsson, Xenia; Kranjc, Nace; Carpi, Francesco M.; D'Aurizio, Romina; Crisanti, Andrea; Nolan, Tony
        PLoS Genetics (2017), 13 (10), e1007039/1-e1007039/16CODEN: PGLEB5; ISSN:1553-7404. (Public Library of Science)
        Gene drives have enormous potential for the control of insect populations of medical and agricultural relevance. By preferentially biasing their own inheritance, gene drives can rapidly introduce genetic traits even if these confer a neg. fitness effect on the population. We have recently developed gene drives based on CRISPR nuclease constructs that are designed to disrupt key genes essential for female fertility in the malaria mosquito. The construct copies itself and the assocd. genetic disruption from one homologous chromosome to another during gamete formation, a process called homing that ensures the majority of offspring inherit the drive. Such drives have the potential to cause long-lasting, sustainable population suppression, though they are also expected to impose a large selection pressure for resistance in the mosquito. One of these population suppression gene drives showed rapid invasion of a caged population over 4 generations, establishing proof of principle for this technol. In order to assess the potential for the emergence of resistance to the gene drive in this population we allowed it to run for 25 generations and monitored the frequency of the gene drive over time. Following the initial increase of the gene drive we obsd. a gradual decrease in its frequency that was accompanied by the spread of small, nuclease-induced mutations at the target gene that are resistant to further cleavage and restore its functionality. Such mutations showed rates of increase consistent with pos. selection in the face of the gene drive. Our findings represent the first documented example of selection for resistance to a synthetic gene drive and lead to important design recommendations and considerations in order to mitigate for resistance in future gene drive applications.
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      58. 58
        WHO Vector-borne diseases. http://www.who.int/mediacentre/factsheets/fs387/en/ (accessed Nov 26, 2017) .
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