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• W2953792953 abstract "Sexing Diptera represents a major obstacle to operationalizing vector-control methods based on the mass release of males, such as the sterile insect technique or the incompatible insect technique.The recent progress made in gene editing, as well as the growing understanding of sex-determination pathways in Diptera, offer new perspectives to develop sexing systems in target species that allow female elimination during mass rearing.The developmental stage at which the sexes are separated, or females are eliminated, is one of the key parameters for assessing the cost efficiency of a sexing technology.Challenges remain in the development of sex-separating systems that are used early in mass rearing, without major genetic defects or lack of competitiveness in produced males, as well as good social and regulatory acceptability of the methods used, considering their operational deployment in the field. In the pursuit of better pest- and vector-control strategies, attention returns to an old proven technology, the sterile insect technique (SIT) and related insect population-suppression methods. A major obstacle for any of these approaches that involves the release of sterile males is the separation of males from females during the mass rearing stage, in order to improve the cost-efficiency of these methods and to prevent the release of biting and disease-vectoring females. This review describes recent sex-sorting developments in dipteran flies with an emphasis on assessing the suitability of these methods for large-scale rearing of male vectors for mass release. In the pursuit of better pest- and vector-control strategies, attention returns to an old proven technology, the sterile insect technique (SIT) and related insect population-suppression methods. A major obstacle for any of these approaches that involves the release of sterile males is the separation of males from females during the mass rearing stage, in order to improve the cost-efficiency of these methods and to prevent the release of biting and disease-vectoring females. This review describes recent sex-sorting developments in dipteran flies with an emphasis on assessing the suitability of these methods for large-scale rearing of male vectors for mass release. Disease-vectoring Diptera are responsible for millions of parasitic and viral infections in humans and livestock annually [1.Kassebaum N.J. et al.Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015.Lancet. 2016; 388: 1603-1658Abstract Full Text Full Text PDF PubMed Scopus (1342) Google Scholar]. As a more environmentally friendly alternative to broad-spectrum chemical insecticides, many researchers have been inspired by Knipling’s proposal in 1955 [2.Knipling E.F. Possibilities of insect control or eradication through the use of sexually sterile males.J. Econ. Entomol. 1955; 48: 459-462Crossref Google Scholar] to develop methods of releasing sterile males to reduce pest insect populations. This so-called sterile insect technique (SIT) (see Glossary) has proven effective for a variety of insects, but its implementation is slowed down by the necessity of removing females before release in the case of mosquitoes. In addition to minimizing the health and economic risks posed by released females, models and trials have also shown that releasing only males was much more cost-efficient than releasing both sexes [2.Knipling E.F. Possibilities of insect control or eradication through the use of sexually sterile males.J. Econ. Entomol. 1955; 48: 459-462Crossref Google Scholar, 3.Rendón P. et al.Medfly (Diptera:Tephritidae) genetic sexing: large-scale field comparison of males-only and bisexual sterile fly releases in Guatemala.J. Econ. Entomol. 2004; 97: 1547-1553Crossref PubMed Scopus (198) Google Scholar]. These cost savings may arise from either reduced cost in mass-rearing the insects and/or in field performance, where released males will not be distracted by coreleased females. Other genetic control methods, including release of insects carrying a dominant lethal (RIDL) and the Wolbachia-based incompatible insect technique (IIT), also require consistent sexing methods. Models show that the release of only a small proportion of Wolbachia-infected females could lead to population replacement instead of eliminationi. In mosquitoes, whose females cause nuisance and transmit pathogens, very little female contamination can be tolerated in any genetic control strategy. In these applications, sex sorting, or ‘sexing’, refers to the separation of males from females, and more specifically the removal of females. Sexing can rely on mechanical separation of the sexes based on natural or engineered sexually dimorphic differences, or sexing can use more complex technologies to modify gene expression and conditionally masculinize or kill females during development. Overall, sex-separation strategies need to meet several criteria, summarized as ‘the 7 Ses’ by Papathanos and colleagues [4.Papathanos P.A. et al.Sex separation strategies: past experience and new approaches.Malar. J. 2009; 8S5Crossref PubMed Scopus (94) Google Scholar]: small, simple, switchable, stable, stringent, sexy, and sellable. Sexing developments have been reviewed numerous times [5.Alphey L. Genetic control of mosquitoes.Annu. Rev. Entomol. 2014; 59: 205-224Crossref PubMed Scopus (254) Google Scholar, 6.Gilles J.R.L. et al.Towards mosquito sterile insect technique programmes: Exploring genetic, molecular, mechanical and behavioural methods of sex separation in mosquitoes.Acta Trop. 2014; 132: S178-S187Crossref PubMed Scopus (72) Google Scholar, 7.Bernardini F. et al.Molecular tools and genetic markers for the generation of transgenic sexing strains in Anopheline mosquitoes.Parasit. Vectors. 2018; 11: 660Crossref PubMed Scopus (7) Google Scholar, 8.Häcker I. Schetelig M.F. Molecular tools to create new strains for mosquito sexing and vector control.Parasit. Vectors. 2018; 11: 645Crossref PubMed Scopus (4) Google Scholar], focusing mostly on particular species or genera, as well as on the engineering methods employed. Here, we aim to review all sexing methods developed recently in Diptera. We have chosen not to focus solely on vector species since there has been a number of interesting technical developments in other dipteran insects that could complement technologies for mosquitoes and other disease vectors. With an emphasis on an operational perspective of sexing methods, we explored advantages and disadvantages of each innovation in a mass-rearing context compared to what is currently being done. Our survey starts in 2003, as the most recent comprehensive review of all available insect sexing strains was published in 2002 [9.Robinson A.S. Mutations and their use in insect control.Mutat. Res. Mutat. Res. 2002; 511: 113-132Crossref PubMed Scopus (74) Google Scholar]. Most current-day genetic control programs target pest flies for which sex-sorting is not always an option. For instance, the Australian and Thai Bactrocera mass-rearing facilities produce tens of millions of fruit flies per week without removing females [10.Fanson B.G. et al.A review of 16 years of quality control parameters at a mass-rearing facility producing Queensland fruit fly, Bactrocera tryoni.Entomol. Exp. Appl. 2014; 151: 152-159Crossref Scopus (53) Google Scholar, 11.Orankanok W. et al.Area-wide integrated control of oriental fruit fly Bactrocera dorsalis and guava fruit fly Bactrocera correcta in Thailand.in: Vreysen M.J.B. Area-Wide Control of Insect Pests. Springer, 2007: 517-526Crossref Scopus (52) Google Scholar]. Similarly, the screwworm Cochliomyia hominivorax has been targeted for years by weekly releases of 15 million sterile flies at the Panama–Colombia border (reviewed in [12.Scott M.J. et al.Review of research advances in the screwworm eradication program over the past 25 years.Entomol. Exp. Appl. 2017; 164: 226-236Crossref Scopus (38) Google Scholar]), without mass sex-separation strategy. With this scale of production, a sexing method at the pupal stage is being considered [13.Concha C. et al.A transgenic male-only strain of the New World screwworm for an improved control program using the sterile insect technique.BMC Biol. 2016; 14: 72Crossref PubMed Scopus (47) Google Scholar], with predicted savings of over US$ 1 million per year. To the authors’ knowledge, the Mediterranean fruit fly Ceratitis capitata and the Mexican fruit fly Anastrepha ludens are amongst the only flies of agricultural importance for which sexing strains are used in mass-rearing plants around the world, improving greatly their release efficiencyii [14.Augustinos A.A. et al.Ceratitis capitata genetic sexing strains: laboratory evaluation of strains from mass-rearing facilities worldwide.Entomol. Exp. Appl. 2017; 164: 305-317Crossref Scopus (29) Google Scholar]. Where sex-sorting is mandatory, time-consuming approaches are often the only available option. Culicinae mosquitoes (including the genera Aedes and Culex) exhibit size sexual dimorphism as pupae. Consequently, Aedes mosquitoes have been, and are still, mechanically separated based on pupal size [15.Papathanos P.A. et al.A perspective on the need and current status of efficient sex separation methods for mosquito genetic control.Parasit. Vectors. 2018; 11: 654Crossref PubMed Scopus (27) Google Scholar]. In Italy, a SIT trial to control Ae. albopictus was initiated in 2005 [16.Bellini R. et al.Pilot field trials with Aedes albopictus irradiated sterile males in Italian urban areas.J. Med. Entomol. 2013; 50: 317-325Crossref PubMed Scopus (107) Google Scholar]. Over a 4-year period, 2 million males were sex-sorted with metal sieving plates before release. This method recovered only 26–29% of the males, and female contamination was still about 1.2%. In China, Fay-Morlan glass sorters, also based on size, enabled the release of more than 197 million Ae. albopictus males in 2016 and 2017 for a combined IIT/SIT trial in two river island settings, with greater male recovery, and female contamination about 0.3% [17.Zheng X. et al.Incompatible and sterile insect techniques combined eliminate mosquitoes..Nature. 2019; https://doi.org/10.1038/s41586-019-1407-9Crossref Scopus (236) Google Scholar]. Similar sexual dimorphism-based methods are being deployed for Dengue control on La Reunion Island in a trial against Ae. albopictusiii and in French Polynesia against Ae. aegypti and Ae. polynesiensisiv,v. In Anopheles mosquitoes, the current sex separation method is based on manual pupal identification, which allows sex-sorting of only 500 pupae per hour (reviewed in [15.Papathanos P.A. et al.A perspective on the need and current status of efficient sex separation methods for mosquito genetic control.Parasit. Vectors. 2018; 11: 654Crossref PubMed Scopus (27) Google Scholar]). The working time is therefore very high, and the number of mosquitoes necessary for a program is difficult to reach. In tsetse flies, both sexes feed exclusively on blood and can act as vectors of trypanosomes. Release of sterile trypanocide-treated males demands low-throughput manual separation of chilled adults or the use of pupal protogyny [18.Bouyer F. et al.Ex-ante benefit-cost analysis of the elimination of a Glossina palpalis gambiensis population in the Niayes of Senegal.PLoS Negl. Trop. Dis. 2014; 8e3112Crossref PubMed Scopus (31) Google Scholar, 19.Seck M.T. et al.Quality of sterile male tsetse after long distance transport as chilled, irradiated pupae.PLoS Negl. Trop. Dis. 2015; 9e0004229Crossref PubMed Scopus (32) Google Scholar]. During the elimination program of Glossina palpalis gambiensis in Senegal, 5 million males were produced using a protogyny-based sorting method [19.Seck M.T. et al.Quality of sterile male tsetse after long distance transport as chilled, irradiated pupae.PLoS Negl. Trop. Dis. 2015; 9e0004229Crossref PubMed Scopus (32) Google Scholar]. Sex-sorting at the pupal or adult stage requires rearing and feeding both male and female larvae, the latter being discarded to retain only males. Moreover, increasing densities of larvae would reduce fitness and slow down development [20.Agnew P. et al.A minimalist approach to the effects of density-dependent competition on insect life-history traits.Ecol. Entomol. 2002; 27: 396-402Crossref Scopus (104) Google Scholar]. Therefore, removal of females early in development is advantageous to avoid competition between males and females [21.Phuc H.K. et al.Late-acting dominant lethal genetic systems and mosquito control.BMC Biol. 2007; 5: 11Crossref PubMed Scopus (308) Google Scholar]. When rearing millions of flies, early sex-separation translates into major savings in time, labor, and money and also decreases the risks of female mosquitoes feeding on workers in the mass-rearing facility. For these reasons, we will review sex-sorting methods by distinguishing two categories: removal of females during the first larval stages and later in development. Disruption of the sex-determination pathway has been explored in many pest insects, with the goal of identifying genes that are essential for female development. The Drosophila melanogaster system has been used as a template for inquiry of other sex-determination cascades. However, even within closely related species, exploration of the primary signal and downstream factors has revealed major differences. Box 1 reviews our current understanding of primary sex-determination signals and downstream factors in Diptera. These genes can be manipulated to produce male-biased populations early in the insect’s development (Table 1). Although only a few of them have actually been applied to mass rearing conditions, we classified these innovations according to their outcome, as an indicator of their potential efficiency.Box 1The Sex Determination Pathways in DipteraSexual dimorphism in insects is controlled by diverse mechanisms to determine sex and differentiate sexual morphologies. Figure I illustrates what is known about dipteran sex-determination pathways.Sex-determination mechanisms in Diptera range from what is familiar to many: dosage compensation of X and Y chromosomes in Drosophila melanogaster [83.Lucchesi J.C. Kuroda M.I. Dosage compensation in Drosophila.Cold Spring Harb. Perspect. Biol. 2015; 7a019398Crossref PubMed Scopus (114) Google Scholar] to the homomorphic chromosomes of Aedes aegypti, in which transcription of the autosomal gene nix appears to be the maleness (M) factor initiating the determination of male mosquitoes [84.Hall A.B. et al.A male-determining factor in the mosquito Aedes aegypti.Science. 2015; 348: 1268-1270Crossref PubMed Scopus (171) Google Scholar]. Rapid evolution of these factors has produced a high degree of variation in the function of the genes involved, with marked differences described between closely related species [85.Sharma A. et al.Male sex in houseflies is determined by Mdmd, a paralog of the generic splice factor gene CWC22.Science. 2017; 356: 642-645Crossref PubMed Scopus (69) Google Scholar].What is common to all Diptera studied to date is the central regulator doublesex (dsx), a gene with female-specific exons and transcripts that have been targeted to induce female sterility or lethality [39.Whyard S. et al.Silencing the buzz: a new approach to population suppression of mosquitoes by feeding larvae double-stranded RNAs.Parasit. Vectors. 2015; 8: 96Crossref PubMed Scopus (94) Google Scholar, 86.Kyrou K. et al.A CRISPR–Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes.Nat. Biotechnol. 2018; 36: 1062-1066Crossref PubMed Scopus (350) Google Scholar, 87.Clough E. et al.Sex- and tissue-specific functions of Drosophila doublesex transcription factor target genes.Dev. Cell. 2014; 31: 761-773Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. Dsx is a transcription factor in the doublesex/mab-3 related gene family. Recently reviewed by Kopp [88.Kopp A. Dmrt genes in the development and evolution of sexual dimorphism.Trends Genet. 2012; 28: 175-184Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar], this gene family appears to be conserved in arthropods, but the diversity of roles that dsx plays in other lineages [89.Verhulst E.C. van de Zande L. Double nexus – doublesex is the connecting element in sex determination.Brief. Funct. Genomics. 2015; 14: 396-406Crossref PubMed Scopus (46) Google Scholar] suggests that it has been frequently coopted to new roles. Briefly, male or female dsx is expressed in tissues that require sexual identity. In Drosophila melanogaster, dsx is regulated by alternative splicing of transformer (tra), another conserved gene that has been successfully targeted for female lethality, which, in turn, is regulated by sex-lethal (sxl) [83.Lucchesi J.C. Kuroda M.I. Dosage compensation in Drosophila.Cold Spring Harb. Perspect. Biol. 2015; 7a019398Crossref PubMed Scopus (114) Google Scholar]. In the muscids studied to date, only tra is known to be an upstream regulator of dsx [85.Sharma A. et al.Male sex in houseflies is determined by Mdmd, a paralog of the generic splice factor gene CWC22.Science. 2017; 356: 642-645Crossref PubMed Scopus (69) Google Scholar]. In the mosquito species studied so far, only the male determining factors nix (Aedes aegypti) [90.Gomulski L.M. et al.The Nix locus on the male-specific homologue of chromosome 1 in Aedes albopictus is a strong candidate for a male-determining factor.Parasit. Vectors. 2018; 11: 647Crossref PubMed Scopus (12) Google Scholar], yob (An. gambiae) [40.Krzywinska E. et al.A maleness gene in the malaria mosquito Anopheles gambiae.Science. 2016; 353: 67-69Crossref PubMed Scopus (70) Google Scholar] and guy1 (An. stephensi) [91.Criscione F. et al.GUY1 confers complete female lethality and is a strong candidate for a male-determining factor in Anopheles stephensi.eLife. 2016; 5e19281Crossref PubMed Scopus (38) Google Scholar] are known or presumed regulators of dsx, but there may be other upstream factors regulating dsx. A role for tra-2 in mosquito sperm development has been shown, resulting in reduction of female offspring in the second generation after RNAi knockdown [38.Hoang K.P. et al.Mechanisms of sex determination and transmission ratio distortion in Aedes aegypti.Parasit. Vectors. 2016; 9: 49Crossref PubMed Scopus (16) Google Scholar]. Intriguingly, putative tra/tra2 orthologues appear to be highly conserved in mosquitoes [38.Hoang K.P. et al.Mechanisms of sex determination and transmission ratio distortion in Aedes aegypti.Parasit. Vectors. 2016; 9: 49Crossref PubMed Scopus (16) Google Scholar], but tra/tra2 has not been implicated as a regulator of dsx in any mosquito, although tra-2 is involved in ovarian development in Ae. albopictus [92.Li X. et al.Two of the three Transformer-2 genes are required for ovarian development in Aedes albopictus.Insect Biochem. Mol. Biol. 2019; 109: 92-105Crossref PubMed Scopus (9) Google Scholar]. The M-factor in tephritid flies has recently been described and shown to regulate tra’s auto-regulatory positive-feedback loop [93.Meccariello A. et al.Maleness-on-the-Y (MoY) orchestrates male sex determination in major agricultural fruit fly pests.bioRxiv. 2019; (Published online February 7, 2019. http://doi.org/10.1101/533646)Google Scholar]. Similarly, in two phlebotomine sandflies, tra has been recently identified and shown to also be self-regulating [94.Petrella V. et al.Genomics and transcriptomics to unravel sex determination pathway and its evolution in sand flies.bioRxiv. 2019; (Published online January 4, 2019. https://doi.org/10.1101/510586)Google Scholar]. There are likely to be many new opportunities to distort sex ratios by discovering players in the diverse pathways that have evolved in Diptera.Table 1Early Acting Methods for Sexing in Diptera since 2003OutcomeTechniqueaTechniques are detailed in Figure S1 in the supplemental information online.Sorting mechanismSpeciesRefsSex ratio distortionInterfering RNASilencing of transformer (tra) and transformer-2 (tra-2)Ceratitis capitata22.Saccone G. et al.New sexing strains for Mediterranean fruit fly Ceratitis capitata: transforming females into males.in: Vreysen M.J.B. Area-Wide Control of Insect Pests. Springer, 2007: 95-102Crossref Scopus (25) Google ScholarVisual separationTransposase-mediated plasmid integrationRFP or GFP marker + COPASAnopheles gambiae, Anopheles arabiensis28.Marois E. et al.High-throughput sorting of mosquito larvae for laboratory studies and for future vector control interventions.Malar. J. 2012; 11: 302Crossref PubMed Scopus (32) Google Scholar, 29.Bernardini F. et al.Site-specific genetic engineering of the Anopheles gambiae Y chromosome.Proc. Natl. Acad. Sci. U. S. A. 2014; 111: 7600-7605Crossref PubMed Scopus (49) Google Scholar, 30.Bernardini F. et al.Cross-species Y chromosome function between malaria vectors of the Anopheles gambiae species complex.Genetics. 2017; 207: 729-740PubMed Google ScholartTA system using tra intron and fluorescent markerLucilia cuprina31.Li F. et al.Transgenic sexing system for genetic control of the Australian sheep blow fly Lucilia cuprina.Insect Biochem. Mol. Biol. 2014; 51: 80-88Crossref PubMed Scopus (44) Google ScholarFemale lethalityTransposase-mediated plasmid integration (piggyBac)tTA driving expression of proapoptotic transgeneAnastrepha suspensa, C. capitata, L. cuprina32.Ogaugwu C.E. et al.Transgenic sexing system for Ceratitis capitata (Diptera: Tephritidae) based on female-specific embryonic lethality.Insect Biochem. Mol. Biol. 2013; 43: 1-8Crossref PubMed Scopus (69) Google Scholar, 33.Schetelig M.F. Handler A.M. A transgenic embryonic sexing system for Anastrepha suspensa (Diptera: Tephritidae).Insect Biochem. Mol. Biol. 2012; 42: 790-795Crossref PubMed Scopus (75) Google Scholar, 34.Yan Y. et al.Building early-larval sexing systems for genetic control of the Australian sheep blow fly Lucilia cuprina using two constitutive promoters.Sci. Rep. 2017; 7: 2538Crossref PubMed Scopus (17) Google ScholarInterfering RNASilencing of tra and/or tra-2Bactrocera dorsalis, Aedes aegypti37.Liu G. et al.RNAi-mediated knock-down of transformer and transformer 2 to generate male-only progeny in the oriental fruit fly, Bactrocera dorsalis (Hendel).PLoS One. 2015; 10e0128892PubMed Google Scholar, 38.Hoang K.P. et al.Mechanisms of sex determination and transmission ratio distortion in Aedes aegypti.Parasit. Vectors. 2016; 9: 49Crossref PubMed Scopus (16) Google ScholarSilencing of dsxAe. aegypti39.Whyard S. et al.Silencing the buzz: a new approach to population suppression of mosquitoes by feeding larvae double-stranded RNAs.Parasit. Vectors. 2015; 8: 96Crossref PubMed Scopus (94) Google ScholarmRNA injectionOverexpression of Yob by injecting mRNAAn. gambiae, Anopheles arabiensis40.Krzywinska E. et al.A maleness gene in the malaria mosquito Anopheles gambiae.Science. 2016; 353: 67-69Crossref PubMed Scopus (70) Google ScholarIntersex femalesTransposase-mediated plasmid integration (piggyBac)Plasmid injection causes overexpression of Yob under vasa2 promoterAn. gambiae41.Krzywinska E. Krzywinski J. Effects of stable ectopic expression of the primary sex determination gene Yob in the mosquito Anopheles gambiae.Parasit. Vectors. 2018; 11: 648Crossref PubMed Scopus (10) Google ScholarCRISPR-Cas9 knockdownDouble knockdown of tra-2A. suspensa42.Li J. Handler A.M. CRISPR/Cas9-mediated gene editing in an exogenous transgene and an endogenous sex determination gene in the Caribbean fruit fly, Anastrepha suspensa.Gene. 2019; 691: 160-166Crossref PubMed Scopus (8) Google Scholara Techniques are detailed in Figure S1 in the supplemental information online. Open table in a new tab Sexual dimorphism in insects is controlled by diverse mechanisms to determine sex and differentiate sexual morphologies. Figure I illustrates what is known about dipteran sex-determination pathways. Sex-determination mechanisms in Diptera range from what is familiar to many: dosage compensation of X and Y chromosomes in Drosophila melanogaster [83.Lucchesi J.C. Kuroda M.I. Dosage compensation in Drosophila.Cold Spring Harb. Perspect. Biol. 2015; 7a019398Crossref PubMed Scopus (114) Google Scholar] to the homomorphic chromosomes of Aedes aegypti, in which transcription of the autosomal gene nix appears to be the maleness (M) factor initiating the determination of male mosquitoes [84.Hall A.B. et al.A male-determining factor in the mosquito Aedes aegypti.Science. 2015; 348: 1268-1270Crossref PubMed Scopus (171) Google Scholar]. Rapid evolution of these factors has produced a high degree of variation in the function of the genes involved, with marked differences described between closely related species [85.Sharma A. et al.Male sex in houseflies is determined by Mdmd, a paralog of the generic splice factor gene CWC22.Science. 2017; 356: 642-645Crossref PubMed Scopus (69) Google Scholar]. What is common to all Diptera studied to date is the central regulator doublesex (dsx), a gene with female-specific exons and transcripts that have been targeted to induce female sterility or lethality [39.Whyard S. et al.Silencing the buzz: a new approach to population suppression of mosquitoes by feeding larvae double-stranded RNAs.Parasit. Vectors. 2015; 8: 96Crossref PubMed Scopus (94) Google Scholar, 86.Kyrou K. et al.A CRISPR–Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes.Nat. Biotechnol. 2018; 36: 1062-1066Crossref PubMed Scopus (350) Google Scholar, 87.Clough E. et al.Sex- and tissue-specific functions of Drosophila doublesex transcription factor target genes.Dev. Cell. 2014; 31: 761-773Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. Dsx is a transcription factor in the doublesex/mab-3 related gene family. Recently reviewed by Kopp [88.Kopp A. Dmrt genes in the development and evolution of sexual dimorphism.Trends Genet. 2012; 28: 175-184Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar], this gene family appears to be conserved in arthropods, but the diversity of roles that dsx plays in other lineages [89.Verhulst E.C. van de Zande L. Double nexus – doublesex is the connecting element in sex determination.Brief. Funct. Genomics. 2015; 14: 396-406Crossref PubMed Scopus (46) Google Scholar] suggests that it has been frequently coopted to new roles. Briefly, male or female dsx is expressed in tissues that require sexual identity. In Drosophila melanogaster, dsx is regulated by alternative splicing of transformer (tra), another conserved gene that has been successfully targeted for female lethality, which, in turn, is regulated by sex-lethal (sxl) [83.Lucchesi J.C. Kuroda M.I. Dosage compensation in Drosophila.Cold Spring Harb. Perspect. Biol. 2015; 7a019398Crossref PubMed Scopus (114) Google Scholar]. In the muscids studied to date, only tra is known to be an upstream regulator of dsx [85.Sharma A. et al.Male sex in houseflies is determined by Mdmd, a paralog of the generic splice factor gene CWC22.Science. 2017; 356: 642-645Crossref PubMed Scopus (69) Google Scholar]. In the mosquito species studied so far, only the male determining factors nix (Aedes aegypti) [90.Gomulski L.M. et al.The Nix locus on the male-specific homologue of chromosome 1 in Aedes albopictus is a strong candidate for a male-determining factor.Parasit. Vectors. 2018; 11: 647Crossref PubMed Scopus (12) Google Scholar], yob (An. gambiae) [40.Krzywinska E. et al.A maleness gene in the malaria mosquito Anopheles gambiae.Science. 2016; 353: 67-69Crossref PubMed Scopus (70) Google Scholar] and guy1 (An. stephensi) [91.Criscione F. et al.GUY1 confers complete female lethality and is a strong candidate for a male-determining factor in Anopheles stephensi.eLife. 2016; 5e19281Crossref PubMed Scopus (38) Google Scholar] are known or presumed regulators of dsx, but there may be other upstream factors regulating dsx. A role for tra-2 in mosquito sperm development has been shown, resulting in reduction of female offspring in the second generation after RNAi knockdown [38.Hoang K.P. et al.Mechanisms of sex determination and transmission ratio distortion in Aedes aegypti.Parasit. Vectors. 2016; 9: 49Crossref PubMed Scopus (16) Google Scholar]. Intriguingly, putative tra/tra2 orthologues appear to be highly conserved in mosquitoes [38.Hoang K.P. et al.Mechanisms of sex determination and transmission ratio distortion in Aedes aegypti.Parasit. Vectors. 2016; 9: 49Crossref PubMed Scopus (16) Google Scholar], but tra/tra2 has not been implicated as a regulator of dsx in any mosquito, although tra-2 is involved in ovarian development in Ae. albopictus [92.Li X. et al.Two of the three Transformer-2 genes are required for ovarian development in Aedes albopictus.Insect Biochem. Mol. Biol. 2019; 109: 92-105Crossref PubMed Scopus (9) Google Scholar]. The M-factor in tephritid flies has recently been described and shown to regulate tra’s auto-regulatory positive-feedback loop [93.Meccariello A. et al.Maleness-on-the-Y (MoY) orchestrates male sex determination in major agricultural fruit fly pests.bioRxiv. 2019; (Published online February 7, 2019. http://doi.org/10.1101/533646)Google Scholar]. Similarly, in two phlebotomine sandflies, tra has been recently identified and shown to also be self-regulating [94.Petrella V. et al.Genomics and transcriptomics to unravel sex determination pathway and its evolution in sand flies.bioRxiv. 2019; (Published online January 4, 2019. https://doi.org/10.1101/510586)Google Scholar]. There are likely to be many new opportunities to distort sex ratios by discovering players in th" @default.
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• W2953792953 date "2019-08-01" @default.
• W2953792953 modified "2023-09-30" @default.
• W2953792953 title "Sex Sorting for Pest Control: It’s Raining Men!" @default.
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• W2953792953 doi "https://doi.org/10.1016/j.pt.2019.06.001" @default.
• W2953792953 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31255488" @default.
• W2953792953 hasPublicationYear "2019" @default.

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