Sex of an insect is determined by the chromosome complement it inherits from its parents. The chromosome systems that underly genetic sex-determination are quite diverse among insect species (Bachtrog et al., 2014; Beukeboom and Perrin, 2014; Biedler and Tu, 2016). Flies and mosquitoes are among the many insects that evolved the XX/XY sex chromosome system, where the heterogametic (XY) individuals are males and the homogametic (XX) individuals are females. Lepidopterans such as the silkworm, Bombyx mori, evolved the ZZ/ZW sex chromosome system where ZZ males are the homogametic sex while heterogametic ZW individuals are females. Hemizygous sex chromosome systems are also found including XX/XO in several insect orders, where the males are hemizygous as they only have one X chromosome (XO); and ZZ/ZO in some lepidopteran and tricopteran species, where the females are hemizygous (ZO). Although species within an insect order tend to share the same type of sex chromosome system, variations can occur within an order or even a family. In the aforementioned systems, the sex of an offspring is determined by the genotype of the gamete of the heterogametic or hemigametic parent. In Hymenopteran and Thysanopteran insects, however, sex is instead determined by the haplodiploidy of the individual, where fertilized diploid eggs (2n) develop to females while unfertilized haploid eggs (n) develop as males (reviewed in Beukeboom and Perrin, 2014; Biedler and Tu, 2016).

In contrast to the apparent plasticity and diversity of the sex-determining chromosome systems, two highly conserved transcription factors doublesex (dsx) and fruitless (fru) control the development of sexual dimorphism in all insects studied thus far (Herpin and Schartl, 2015; Biedler and Tu, 2016; Hopkins and Kopp, 2021). Sex-specific isoforms of the DSX and FRU proteins, which result from sex-specific splicing of their primary RNA transcripts, program sexual differentiation (Figure 1). Therefore, sex determination is a process in which the primary sex-specific signals, which reflect the sex-specific chromosome composition of the early embryo, are transduced in a signal cascade to modulate sex-specific splicing of the RNA transcripts of dsx and fru. Figure 1 presents two simplified models using dsx as an example. In the vinegar fly Drosophila melanogaster, the double dosage of the X chromosome in the females (XX) initiates the transcription of the sex lethal (sxl) gene in the early embryo, leading to the production of the primary signal which is the SXL protein (Figure 1A). The presence of SXL leads to the production of a functional protein isoform of transformer (TRA), which in turn enables female-specific splicing of the primary RNA transcripts of dsx and fru. In the male (XY) embryo, the single X chromosome fails to initiate the production of the primary signal SXL, leading to the default male-specific splicing of dsx and fru transcripts and hence the production of male-specific DSX and FRU protein isoforms. In the Mediterranean fruit fly Ceratitis capitata, however, the default sex is female (Figure 1B). The primary signal, a male-determining factor (M factor) MoY (Meccariello et al., 2019), resides on the Y chromosome. The presence of the M factor in the early male (XY) embryos results in male-specific splicing of the tra pre-mRNA, leading to the production of a non-functional TRA protein and subsequently, male-specific splicing of dsx and fru. The lack of the Y chromosome in females (XX) enables the TRA protein complex to catalyze the female-specific splicing of dsx and fru. The TRA intermediate evolved much faster than DSX and FRU and TRA is not found in all insects (Biedler and Tu, 2016). Recent advances have brought significant molecular insights into the diverse mechanisms of sex determination in an increasing number of insects (e.g., Kiuchi et al., 2014; Hall et al., 2015, 2016; Criscione et al., 2016; Krzywinska et al., 2016, 2021; Sharma et al., 2017; Meccariello et al., 2019; Qi et al., 2019; Wexler et al., 2019; Aryan et al., 2020; Liu et al., 2020; Zou et al., 2020; Lutrat et al., 2021; Zhuo et al., 2021).

A relatively balanced male to female sex ratio is expected for most insects. However, selection may shift the optimal sex ratios and meiotic drive and microbial manipulation can result in sex ratio distortion (SRD). In the following sections, we will review both naturally occurring and engineered SRD in the context of developing biological control of insects to help improve One Health, sustain agriculture, and conserve endangered species.

We discuss insect SRDs from three main perspectives in the context of the Anthropocene. First, we consider whether or not climate change may impact the sex ratio of wild insect populations. It is not yet clear whether climate change will introduce instability to the otherwise relatively stable sex-determination pathways in some insects. It is also not clear how climate change may affect the naturally occurring SRDs including those mediated by endosymbiotic bacteria. However, sex-biased heat-tolerance has been shown in diverse insects which may lead to shifting sex ratios in response to climate change (Edmands, 2021). Temperature can also affect female fertilization and alter the sex ratio in Hymenoptera parasitic wasps (Moiroux et al., 2014). One study demonstrated that longer drought periods caused by a delay in the timing of summer rainfall in the Mediterranean region led to a female sex ratio bias in the acorn Weevil (Bonal et al., 2015). Endosymbiotic manipulation of sex ratio in Pezothrips kellyanus Thrips is influenced by abiotic factors such as temperature (Katlav et al., 2022). It has also been suggested that temperature may differentially impact male and female body size, mortality, protandry, and population-level sex ratios of wild bees (Slominski and Burkle, 2019).

Second, engineered SRDs have shown great promise in controlling insect pests of agricultural and medical importance as discussed in previous sections. These efforts are critical to help sustain agriculture and improve human health. However, a less discussed but perhaps equally important application of SRDs relates to conservation of wildlife or endangered species that are under the threat of insect-borne infectious diseases (National Academies of Sciences [NAS] et al., 2016). For example, only 20 of the 46 recorded forest bird species in Hawaii are still extant in the wild (Fortini et al., 2015). Many of these species are threatened by avian malaria, transmitted by the Culex quinquefasciatus mosquito. The presence of avian malaria constrains these birds to a narrow range of habitats that are unsuitable for the mosquito (Samuel et al., 2011). Climate change is expected to broaden the distribution of C. quinquefasciatus, thereby further shrink the habitat range for susceptible bird species (Benning et al., 2002; Ahumada et al., 2009; Samuel et al., 2011; Fortini et al., 2015). Integrating SRD-mediated mosquito population suppression strategies into the long-term conservation efforts would allow Hawaiian forest birds to reclaim lost habitat. New genomic resources¹ and newly established genome-editing methods (Feng et al., 2021; Purusothaman et al., 2021) for C. quinquefasciatus provide the foundation for SRD development.

Finally, the potential environmental impacts of the engineered SRD control strategies should be critically evaluated in the context of current methods. Current insect control methods rely heavily on insecticides and increasing resistance has significantly reduced their effectiveness. Some widely used insecticides such as neonicotinoids, which were previously thought to be safe and highly target-specific (reviewed in Jeschke and Nauen, 2008), have been shown to have potential health risks (Thompson et al., 2020), can impact non-target invertebrates and insectivorous birds (Hallmann et al., 2014; Pisa et al., 2015), and potentially contribute to the decline of honeybees (Rundlöf et al., 2015). Genetic control strategies are species-specific as they all require mating and thus a direct impact on non-target species is not anticipated. However, some of the SRD-mediated methods, especially the ones involving gene drives, are very powerful and could potentially eliminate a pest species from a large region, which may have ecological consequences. There are ongoing efforts to fine-tune, confine or neutralize the power of some of the gene drive systems (Vella et al., 2017; Kandul et al., 2019; Noble et al., 2019; Li et al., 2020, 2021; Taxiarchi et al., 2021). It is unlikely that any one control measure will be the “silver bullet.” Integration or selective implementation of a set of control measures most appropriate to the specific goals and the social and environmental context will likely be most effective. Therefore, continued development of a diverse range of genetic control methods for insect pests are important for promoting sustainable agriculture, improving One Health, and preserving wildlife.

AC and ZT wrote and revised the manuscript. Both authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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