Transgenic crops expressing insecticidal Cry proteins from Bacillus thuringiensis bacteria, known as Bt-crops, have become important tools for the management of insect crop pests (Carrière et al., 2003; Cattaneo et al., 2006; Hutchison et al., 2010; Shelton et al., 2002; Tabashnik et al., 2010). Planting of Bt-crops effectively suppresses the targeted insects, decreasing insecticide use and promoting biocontrol services (Bravo et al., 2011; Carrière et al., 2003; Cattaneo et al., 2006; Hutchison et al., 2010; Lu et al., 2010; Lu et al., 2012; Shelton et al., 2002; Tabashnik et al., 2002; Wu, 2010; Wu et al., 2008). We have previously shown that the commercialization of transgenic Bt-cotton in China brought significant changes in the ecology of insects utilizing the crop (Lu et al., 2010; Swiatkiewicz et al., 2014; Wu et al., 2008). However, the effect of Bt-crops on other organisms, such as microbes, which could be playing important roles in the life cycle of insect populations, remains largely unknown.

Recently, we showed in laboratory trials that infection with a densovirus, Helicoverpa armigera densovirus-1 (HaDV2, named as HaDNV-1 previously, GenBank accession number: NC_015718), was associated with significantly enhanced tolerance of cotton bollworm, H. armigera, to a baculovirus (H. armigera nucleopolyhedrovirus, HaNPV) (Xu et al., 2014), and there was some suggestion that the densovirus also increased tolerance to Cry1Ac toxin in a Bt-susceptible strain of H. armigera (Xu et al., 2014; Xu et al., 2017a; Xu et al., 2017b). HaDV2 was found to be widespread in wild populations of H. armigera adults (>67% prevalence between 2008 and 2012) (Xu et al., 2014). The densovirus was mainly distributed in the fat body of the insect and could be both horizontally and vertically transmitted. Moreover, HaDV2-positive individuals showed faster development and higher fecundity than non-infected individuals. There was no evidence for a negative effect of HaDV2 infection on H. armigera in relation to other fitness-related traits, suggesting a possible mutualistic interaction between the cotton bollworm and HaDV2 (Xu et al., 2014).

Here, we further explore the interaction between H. armigera, HaDV2, and Bt-cotton, to establish its relevance to field populations and to test the hypothesis that the widespread adoption of Bt-cotton in China has selected for cotton bollworm carrying the densovirus. Laboratory experiments show that HaDV2 infection in both Cry1Ac-resistant and Cry1Ac-susceptible strains of cotton bollworm enhances larval tolerance to Bt and overall fitness. Field experiments indicate that H. armigera populations infected with HaDV2 also have a higher tolerance to Bt-cotton relative to those not infected with HaDV2. Moreover, field monitoring over a 10-year period indicates that the frequency of HaDV2-infected cotton bollworm is significantly higher in regions planted with Bt-cotton than in those areas where Bt-cotton is not grown, and that in Bt-cotton-growing areas, the prevalence of HaDV2 infection increases with time since Bt-cotton adoption and with the proportion of cotton that is grown which is transgenic. Further, we found that increased Bt tolerance is associated with activated immune pathways to HaDV2 infection. These results indicate that increased HaDV2 infection in cotton bollworm is correlated with the wide-scale adoption of Bt-cotton in China. Our data are consistent with the notion that exposure to Bt-crops selects for beneficial interactions between the target pest and a microorganism that enhances their fitness in response to Bt exposure under field conditions.

Commercialization of transgenic Bt-crops has brought some significant benefits to farmers (Carrière et al., 2003; Cattaneo et al., 2006; Lu et al., 2012; Shelton et al., 2002; Wu et al., 2008). These Bt-plants successfully control target insect pests and have resulted in the reduced use of insecticides in the field (Bravo et al., 2011; Lu et al., 2012; Wu et al., 2008). Here, we show that HaDV2 infection enhances tolerance to Cry1Ac in both susceptible and resistant strains of H. armigera. We also show that there appears to have been a strong positive selection for HaDV2-infected H. armigera in populations exposed to Cry1Ac-cotton in the field, especially (but not exclusively) when this exposure has been for prolonged periods of time. Intensive monitoring in two provinces where Bt-cotton has been grown over a number of years showed a strong temporal increase in HaDV2 infection levels, from around 40% in 2007 to nearly 100% in 2016, with high levels of HaDV2 infection being associated with higher larval growth rates on Bt-cotton in the field. Indeed, at locations where Bt-cotton is not grown, H. armigera shows much lower rates of HaDV2 infection (12–44% vs. 81–90%), consistent with weaker selection for HaDV2-infected H. armigera in the absence of Bt-crops. Moreover, the prevalence of HaDV2 infection increased with the number of years since Bt-cotton was first introduced to a province and with the proportion of cotton grown that is transgenic, consistent with Bt-cotton being a key selection pressure. There were no significant relationships between HaDV2 prevalence and the proportional cover of any other main crops grown locally (cotton, rice, corn, wheat, beans, tubers, oil-producing crops, and vegetables) or with any of the environmental variables tested (rainfall, temperature, and altitude). Thus, our data suggest that the Cry1Ac-toxin selected for HaDV2-infected H. armigera following exposure to Bt-cotton and our RNA-Seq analysis suggests that the increased tolerance of HaDV2-infected insects is caused, in part at least, by the activation of a series of immune pathways and pathways that enhance development.

The emergence and rapid spread of a symbiont through a host population have been observed previously (Himler et al., 2011; Turelli and Hoffmann, 1991; Weeks et al., 2007). For example, the bacterial symbiont, Rickettsia sp. nr. bellii, swept through a population of invasive sweet potato whitefly, Bemisia tabaci, in just 6 years (Himler et al., 2011). Although we do not know when HaDV2 first infected H. armigera in China, in two areas where Bt-cotton is grown extensively, and where nearly 100% of all insects are currently infected with HaDV2, the prevalence of the densovirus was as low as 40% in 2007, when the earliest samples were collected (Figure 5). Moreover, extrapolation of the observed temporal trends (Figure 5A,B and Figure 7) would suggest that emergence of HaDV2 may have coincided with the introduction of Bt-cotton in China two decades ago. This apparently rapid spread is perhaps not surprising given the strong fitness benefits of carrying the densovirus (amounting to a ~40% increase in H. armigera R₀) (Figure 3). Consistent with this, based on these estimated increases in R₀, a simple population growth model (Himler et al., 2011) suggests that HaDV2 would go to near fixation in 20–30 generations in Bt-cotton-growing areas (Figure 3—figure supplement 1).

Rather than being a recent introduction to H. armigera in China, it is possible that the association between the HaDV2 and its host is more ancient, but that the increase in HaDV2 prevalence in recent years is because it has only recently evolved from a parasitic or commensal relationship into one that is more mutualistic (Weeks et al., 2007), perhaps under direct or indirect selection from Bt-cotton. Indeed, most of the densoviruses that have been studied thus far have tended to be at the parasitic end of the symbiotic spectrum and some of these have even been promoted as potential biological pesticides (El-Far et al., 2012). However, the observation that densoviruses tend to be parasitic in nature is likely biased by the fact that viruses with notable pathological effects on their hosts are more likely to be reported (Roossinck, 2011; Roossinck, 2015; Webster et al., 2015; Xu et al., 2020). With the advent of modern molecular methods, such as suppression subtractive hybridization and RNA-seq, it has become apparent that there are many ‘good viruses’ that have failed to be discovered due to their relatively benign, or even beneficial, effects on their hosts (Roossinck, 2011; Roossinck, 2015; Webster et al., 2015; Xu et al., 2020), including HaDV2 (Xu et al., 2014). Although there is an increasing number of studies suggesting that symbiotic microbes can impact an insect host’s ability to combat pathogens and parasites (Graham et al., 2012; Hedges et al., 2008; Oliver et al., 2003; Xu et al., 2020), as far as we are aware, this is the first field study to provide support for the notion that a symbiotic virus could protect a crop pest from Bt toxin.

Regardless of whether or not larvae are exposed to Cry1Ac, HaDV2 appears to enhance the fitness of both Bt-resistant and Bt-susceptible H. armigera (Xu et al., 2012; Figure 3). Theoretically, the infection rate should naturally increase in the H. armigera population both in Bt-cotton and non-Bt-cotton regions because of efficient transmission with horizontal and vertical modes and the mutualistic relationship between HaDV2 and its host, especially increasing its reproduction (Xu et al., 2014). We monitored HaDV2 infection rates at 38 locations across 16 provinces during the period 2014–2016. Indeed, our data showed that HaDV2 infection levels increased both in Bt-cotton and non-Bt-cotton areas. However, with the exception of samples from Changde (Hunan Province), the other 37 locations showed consistent trends that HaDV2 infection rates were significantly higher in Bt-cotton areas than in non-Bt-cotton areas. Previously, we also quantified the infection rate of HaDV2 in samples collected from Changde in 3 years (Xu et al., 2012). The final infection rate in samples from Changde in the 4 years was 45%, which is higher than the infection rate of samples from non-Bt-cotton planting regions (26%). Changde is located at the southernmost point of Bt-cotton-growing range, where the planted cotton included both non-Bt- and Bt-cotton and the fluctuation of HaDV2 infection rate in Changde might be due to both the lower pressure of Bt-cotton and the migration of H. armigera between Bt- and non-Bt-cotton-growing areas. Previously, we showed that there was evidence for a significant decline in HaDV2 prevalence from 2008 to 2012, especially in the migrating moths collected in Yantai (Beihuang Island), which is located in Bohai Sea between Bt- and non-Bt-cotton areas and where there were no resident populations of H. armigera (Feng et al., 2004; Feng et al., 2005; Feng et al., 2009; Xu et al., 2014). If we exclude the data from Yantai, however, there was no obvious temporal trend in HaDV2 prevalence between 2008 and 2012 (85%, 77%, 83%, 73%, and 75%, respectively). Other factors might also result in variation in HaDV2 infection rates. For example, there are four generations of H. armigera per year in northern China and the fourth generation overwinters as diapausing pupae, and if H. armigera grows too fast due to HaDV2 infection, it will overwinter at an inappropriate state which may lead to higher mortality of HaDV2-positive individuals (Mu et al., 1995; Zhang and Li, 2001).

The climate and crop structures of the locations where our samples were collected have been relatively constant over the last few decades and data analyses supported the notion that HaDV2 prevalence was not correlated with environmental variables or the areas of any other crops being grown. Using the PCR method, it is not possible to discount the possibility that HaDV2 was widespread in field populations of H. armigera as very low-titer covert infections, and that the higher incidence of virus in areas of Bt-cotton was due to the stress associated with larvae feeding on plants expressing Bt toxin. To test the hypothesis, using larvae with low dose of HaDV2 from single pair, we quantified the copy numbers of HaDV2 within the cotton bollworms feeding on artificial diets with or without Bt toxin. Interestingly, the results showed that feeding on the Bt toxin resulted in lower titers of HaDV2, which might be due to the Bt suppressing the growth of H. armigera larvae. These results suggest that the higher infection rate of HaDV2 might be due to lower mortality by higher Bt tolerance and the increased reproduction of the cotton bollworms with HaDV2 than those without. These findings support the notion that Bt-cotton has played an important role in increasing HaDV2 infection rates in field populations of H. armigera, and suggest the possibility that HaDV2 may threaten the future control of H. armigera by Bt.

We found some evidence to support this hypothesis from LC₅₀-bioassays using synthetic diets containing Cry1Ac protoxin, with the benefits of hosting HaDV2 being greatest for the most Bt-resistant strains (Figure 1), suggesting synergistic effects of Bt-resistance and HaDV2 infection. However, laboratory trials using non-Bt- and Bt-cotton plants suggested that the relative fitness benefits of harboring HaDV2 were independent of exposure to Bt-cotton and of Bt-resistance levels (at least in terms of larval growth rates) (Supplementary file 1f). This is at odds with the observation that HaDV2 infection levels in the field are higher when populations are exposed to Bt-cotton for prolonged periods, and may indicate that LC50-bioassays are a more reliable measure of relative fitness than larval growth on Bt-cotton plants in the laboratory. Alternatively, it is possible that there are added benefits to HaDV2 infection for H. armigera exposed to Bt-cotton in the field that our laboratory bioassays cannot fully capture, such as the enhanced capacity to resist predators and parasitoids, or reduced exposure to chemical pesticides. In this latter regard, there may be parallels here with the increase in outbreaks of mirid bugs (Heteroptera: Miridae) following the wide-scale adoption of Bt-cotton in China and the subsequent reduction in pesticide application rate on crops (Lu et al., 2010; Zhang et al., 2018).

The evolution of tolerance to Bt-toxins could endanger the utility of this GM technology (Gahan et al., 2001, Gahan et al., 2007; Gahan et al., 2010; Heckel, 2012; Tabashnik, 2015; Tabashnik et al., 2008; Tabashnik et al., 2013). However, as observed here, resistance to Cry toxins is often associated with significant fitness costs that are likely to delay the establishment of Bt-resistant populations under field conditions (Gassmann et al., 2009; Horikoshi et al., 2016; Liu et al., 2017; Raymond et al., 2005; Santos-Amaya et al., 2017). Interestingly, we show here that Bt-resistant strains with different resistance mechanisms, such as mutations affecting ABCC2 (strain LF60) or cadherin (strain 96CAD) (Liang et al., 2008; Xiao et al., 2014), incurred significantly reduced fitness costs when they were infected with HaDV2. The reduction of fitness costs by HaDV2 infection, especially increasing the reproduction of their hosts, could speed up the establishment of resistant populations. The Bt resistance induced by ABCC2 and cadherin is due to genomic heritable variation (Liang et al., 2008; Xiao et al., 2014), while the Bt tolerance induced by HaDV2 appears to be due to the regulation of immune and other pathways. ABCC2 and cadherin can directly mediate high levels of resistance to Bt toxin in H. armigera, but with significant fitness costs (e.g., lower reproduction) (Cao et al., 2014); however, HaDV2 infection could enhance host reproduction and tolerance to Cry1Ac in both susceptible and resistant strains of H. armigera, increasing larval survival rate. Susceptible strains infected with HaDV2 showed only 1.5 times greater tolerance to Cry1Ac toxin. In the case of the Cry1Ac-resistant strains, infection with HaDV2 again showed a significant increase in their resistance relative to the corresponding strains without HaDV2 infection, ranging between 30% and 130% enhanced resistance. Thus, a potential implication of these results is that the increased prevalence of HaDV2 infections under field conditions could impact the evolution of H. armigera populations resistant to Bt-cotton, which might decrease the control efficacy by Bt-cotton expressing Cry1Ac toxin and promote the development of novel strategies for H. armigera control.

The temporal increase in HaDV2 infection levels observed in Xiajin and Anci, two cotton-growing counties >300 km apart in north-east China, was associated with parallel temporal increases in relative growth rates (RADR) (Figure 5C,D). In a previous study of these two populations, the temporal increase in RADR between 2002 and 2014 was ascribed to evolved genetic resistance to Cry1Ac in H. armigera, despite the failure to identify the key genetic locus conferring resistance in these populations (An et al., 2015). The relatively strong correlation between the annual prevalence of HaDV2 in H. armigera and their mean annual RADR in each of these populations (Figure 5E,F) suggests that the putative increase in genetic resistance over this period may, at least in part, be due to the phenotypic expression of HaDV2 infection. The fact that the densovirus is mostly located in the insect’s fat body suggests that it may play a role in H. armigera development (Xu et al., 2014). Lepidopteran larvae tend to become more tolerant to pathogens and toxins as they age and grow, a phenomenon known as developmental resistance (Engelhard and Volkman, 1995). HaDV2-infected H. armigera not only accumulate more fat body than non-infected individuals, but they also grow faster and larger (Xu et al., 2012). Therefore, developmental resistance could provide a potential mechanism to explain the enhanced tolerance of densovirus-infected insects. HaDV2-infected larvae have more fat body than non-infected insects (Xu et al., 2014), and the fat body plays an important role in insect immunity as it is a major site for the production and secretion of antimicrobial peptides (Hoffmann, 2003; Lemaitre and Hoffmann, 2007), so immunological resistance is another potential mechanism by which HaDV2 may enhance resistance to both baculovirus and Cry1Ac.

To explore further the molecular interaction between the HaDV2 and its host, we performed an RNA-seq experiment using H. armigera larvae. Due to the observed effects of HaDV2 on its host, we focused on molecular pathways related to immunity and development (Jindra et al., 2013; Kingsolver and Hardy, 2012; Kingsolver et al., 2013; Lin and Smagghe, 2019; Shields, 2017). In H. armigera larvae at 24 and 48 hr, the Jak-STAT pathway was significantly enriched by upregulation in HaDV2-positive individuals. In fruit flies and mosquitoes, this pathway controls the expression of genes in response to infection with a range of viruses and bacteria, including Drosophila C virus, dengue virus, West Nile virus, Escherichia coli, and Micrococcus luteus (Barillas-Mury et al., 1999; Marques and Imler, 2016). The Jak-STAT pathway was not significantly enriched in larvae at 72 hr, however, pathways related to other antimicrobials were, for example, the lysosome and MAPK signaling pathways (Takano et al., 2019; Watts, 2012). Previously, we found that HaDV2-positive individuals developed faster than non-infected insects (Xu et al., 2014). Interestingly, the transcriptome data suggest that several pathways related to development are also significantly enriched, including the insect hormone synthesis, insulin, mTOR, and AMPK signaling pathways (Bland et al., 2010; Jindra et al., 2013; Lin and Smagghe, 2019; Saxton and Sabatini, 2017). We did not observe the differential expression of genes playing pivotal roles in Bt resistance of H. armigera, for example, cadherin, APN, and ALP (Chen et al., 2015; Gahan et al., 2001; Zhang et al., 2009), suggesting that HaDV2 may not enhance resistance to Bt using traditional molecular resistance pathways, though we did observe that the ABC transporter pathways, which has been reported to be associated with Bt-resistance (Bretschneider et al., 2016; Dermauw and Van Leeuwen, 2014), were significantly upregulated at 48 hr post challenge.

Generally, the mode of action of Bt toxins agrees that Bt protoxins are first converted to activated toxins by midgut proteases, then the toxins bind to the midgut receptors, for example, CAD, APN, and ALP, finally leading to insect death (Xiao and Wu, 2019). A change in any of these steps will lead to Bt resistance, such as mutations in genes for toxin activation, toxin-binding, and changes in insect immunity (Xiao et al., 2014; Zhang et al., 2009). To understand the responses of H. armigera to Bt toxins with or without HaDV2, we conducted RNA-seq after larvae had been exposed to Cry1Ac. In insects lacking HaDV2, Cry1Ac increased the activation of Bt protoxins by increasing the expression level of proteases, such as trypsin. In a defensive response to Cry1Ac, receptor genes of H. armigera, such as APN and ALP, were significantly downregulated to reduce the toxin-binding capacity. Carboxylesterase genes and most of ABC transporters genes were significantly upregulated to improve insect immunity, while other pathways related to antimicrobials, for example, MAPK signaling pathways, were significantly downregulated, reducing resistance to Bt toxin (Yang et al., 2020). In contrast, when H. armigera larvae were infected with HaDV2, these genes and pathways were generally not significantly enriched after Cry1Ac exposure: one trypsin gene was downregulated and some genes involved in drug metabolism were upregulated to increase the metabolism of xenobiotics, improving Bt tolerance. Through RNA-seq analysis, we did not find significant upregulation or downregulation of genes known to be related to typical Bt tolerance. Thus, it is difficult to perform further experiments, e.g. CRISPR. In spite of this, our data still support the notion that HaDV2 increased the Bt tolerance level of H. armigera via related immune mechanisms.

Whilst data from the field are inevitably correlational, when combined with the laboratory experiments, we feel that the most parsimonious explanation for the observations reported here is that HaDV2 directly or indirectly enhances tolerance of H. armigera to Bt in the field, probably via increasing larval growth rates and via priming of immune defenses. However, demonstrating causation conclusively in the field will prove difficult. One possibility would be to plant some Bt-cotton in areas that are currently Bt-free and to compare larval growth patterns and HaDV2 infection levels in neighboring Bt and non-Bt areas, mirroring the ‘natural’ field experiments we report here. As was found with the rapid spread of mutualistic Rickettsia in whiteflies (1–97% prevalence in just 6 years or around 80 field generations; Himler et al., 2011), we envisage that HaDV2 infection levels will eventually go to fixation (or close to it) in both Bt and non-Bt areas, due to the growth benefits associated harboring this mutualist, but that the time to get to this point will take longer in non-Bt areas, due to the lower fitness benefits. Likewise, we envisage that the spread of HaDV2 infection would slow down in Bt areas if Bt-cotton were to be replaced by conventional cotton or a GM variety that did not rely on Bt toxins. Another possibility would be to conduct laboratory evolution experiments using populations of H. armigera infected or not with HaDV2 growing on either Bt- or non-Bt-cotton over several generations. We envisage that HaDV2 infection levels would increase over time on both Bt- and non-Bt-cotton due to the fitness benefits of HaDV2 infection, but that the rate of spread would be faster on Bt-cotton. We also envisage that the fitness of H. armigera (R₀ and cumulative population size after several generations) would be determined by the interaction between HaDV2 infected-status and cotton plant Bt-status. A similar experiment to this was conducted by Himler et al., 2011 for laboratory cages of whitefly populations infected with Rickettsia, who found that over five generations, the prevalence of Rickettsia increased from 14% in the parental generation to 40–70% on three different host plant species. Repeating such experiments with H. armigera is feasible but logistically much more difficult due to their much larger size. In summary, here, we report the rapid increase in the prevalence of a mutualistic virus in a major crop pest and show that its spread is greatest for field populations exposed to Bt-cotton for prolonged periods. Our findings support a novel mechanism by which insects may cope with changes in engineered host plant defenses, namely via infection with a mutualistic virus that enhances their tolerance to the toxins expressed by Bt-cotton crops. Our study has significant implications for understanding the co-evolution of host-pathogen-symbiont interactions. Although we show that HaDV2 increases the tolerance of its host to Bt, it is not feasible to manipulate HaDV2 infection status in the field in order to enhance the capacity of Bt to manage H. armigera because of the lack of suitable antivirals (against HaDV2) and because of the efficient vertical and horizontal transmission of this virius in the field.

RNA-seq data have been deposited in NCBI, see Supplementary file 8. All data generated or analysed during this study are included in the manuscript and supplementary file.

1. 1. Xiao YT
   2. Li WJ
   3. Yang XM
   4. Xu PJ
   5. Jin MH
   6. Yuan H
   7. Zheng WG
   8. Soberón M
   9. Bravo A
   10. Wilson K
   11. Wu KM

   (2021) NCBI BioProject

   ID PRJNA638220. Rapid spread of a symbiotic virus in a major crop pest following wide-scale adoption of Bt-cotton in China.

   https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA638220
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   (2021) NCBI BioProject

   ID PRJNA638972. Rapid spread of a symbiotic virus in a major crop pest following wide-scale adoption of Bt-cotton in China.

   https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA638972

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Author details

1. Yutao Xiao

   1. The State Key Laboratory for Biology of Plant Disease and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China
   2. Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China

   Contribution

   Formal analysis, Validation, Methodology

   Contributed equally with

   Wenjing Li, Xianming Yang and Pengjun Xu

   Competing interests

   No competing interests declared

2. Wenjing Li

   1. The State Key Laboratory for Biology of Plant Disease and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China
   2. Institute of Plant Protection and Soil Fertility, Hubei Academy of Agricultural Sciences, Wuhan, China

   Contribution

   Data curation, Investigation

   Contributed equally with

   Yutao Xiao, Xianming Yang and Pengjun Xu

   Competing interests

   No competing interests declared

3. Xianming Yang

   The State Key Laboratory for Biology of Plant Disease and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China

   Contribution

   Resources, Formal analysis, Supervision

   Contributed equally with

   Yutao Xiao, Wenjing Li and Pengjun Xu

   Competing interests

   No competing interests declared

4. Pengjun Xu

   1. Tobacco Research Institute, Chinese Academy of Agricultural Sciences, Qingdao, China
   2. Lancaster Environment Centre, Lancaster University, Lancaster, United Kingdom

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Methodology, Writing - original draft, Writing - review and editing

   Contributed equally with

   Yutao Xiao, Wenjing Li and Xianming Yang

   Competing interests

   No competing interests declared

5. Minghui Jin

   Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China

   Contribution

   Software, Methodology

   Competing interests

   No competing interests declared

6. He Yuan

   Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China

   Contribution

   Software, Methodology, Writing - original draft

   Competing interests

   No competing interests declared

7. Weigang Zheng

   Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China

   Contribution

   Data curation, Software

   Competing interests

   No competing interests declared

8. Mario Soberón

   Instituto de Biotecnología, Universidad Nacional Autónoma de México, Morelos, United States

   Contribution

   Resources, Methodology, Writing - original draft

   Competing interests

   coauthor of a patent on modified Bt toxins, "Suppression of Resistance in Insects to Bacillus thuringiensis Cry Toxins, Using Toxins that do not Require the Cadherin Receptor" (patent numbers: CA2690188A1, CN101730712A, EP2184293A2, EP2184293A4, EP2184293B1, WO2008150150A2, WO2008150150A3).

9. Alejandra Bravo

   Instituto de Biotecnología, Universidad Nacional Autónoma de México, Morelos, United States

   Contribution

   Resources, Methodology, Writing - original draft

   Competing interests

   coauthor of a patent on modified Bt toxins, "Suppression of Resistance in Insects to Bacillus thuringiensis Cry Toxins, Using Toxins that do not Require the Cadherin Receptor" (patent numbers: CA2690188A1, CN101730712A, EP2184293A2, EP2184293A4, EP2184293B1, WO2008150150A2, WO2008150150A3).

10. Kenneth Wilson

    1. Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China
    2. Lancaster Environment Centre, Lancaster University, Lancaster, United Kingdom

    Contribution

    Data curation, Software, Funding acquisition, Methodology, Writing - original draft, Project administration, Writing - review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-5264-6522

11. Kongming Wu

    The State Key Laboratory for Biology of Plant Disease and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China

    Contribution

    Resources, Supervision, Funding acquisition, Validation, Methodology, Writing - original draft, Project administration, Writing - review and editing

    For correspondence

    wukongming@caas.cn

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-3555-4292

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