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Table 2 List of identified plausible pathways to potential harm from field release of dsxFCRISPRh transgenics in West Africa

From: Systematic identification of plausible pathways to potential harm via problem formulation for investigational releases of a population suppression gene drive to control the human malaria vector Anopheles gambiae in West Africa

Protection goal Plausible pathway to potential Harm Cause of potential harm Effect of potential harm Correlation of Exposure Levels with Transgene Efficacy Relevance to ERAs for other transgenic mosquito strains
Biodiversity 1 Potential toxicological effects of dsxFCRISPRh transgenics on NTOs could reduce ecosystem services. Transgenic contains toxin or allergen Direct: Reduced density of valued species or ecosystem services Positive with gene drive; negative with population suppression; dependent on presence of transgene All transgenic strains
2 Potentially broader tolerances for humidity, temperature, salinity, or desiccation in dsxFCRISPRh transgenics could reduce densities of valued species or ecosystem services. Increased fitness in transgenic; changes in competitive interactions Direct: Reduced density of valued species or ecosystem services Positive with gene drive; negative with population suppression; dependent on presence of transgene All transgenic strains
3 Potentially cumulative Cas9/gRNA off-target or retargeted nuclease activity in dsxFCRISPRh transgenics could cause broader tolerances for humidity, temperature, salinity, or egg desiccation to reduce densities of valued species or ecosystem services. Off-target or re-targeted mutations; increased fitness in transgenic; changes in competitive interactions Direct: Reduced density of valued species or ecosystem services Positive with gene drive; negative with population suppression; independent of presence of transgene All CRISPR-Cas9-based transgenic strains
4 Potential horizontal gene flow of the dsxFCRISPRh transgene that would contain construct backbone sequences could confer a growth advantage to bacteria that are pathogenic to a valued species, thus reducing densities of valued species or ecosystem services. Gene flow to NTOs Indirect: Reduced density of valued species or ecosystem services Positive with gene drive; negative with population suppression; dependent on presence of transgene All transgenic strains
5 Potential horizontal gene flow of the dsxFCRISPRh transgene to a NTO eukaryote could lead to its unintended population suppression, thus reducing densities of valued species or ecosystem services. Gene flow to NTOs Indirect: Reduced density of valued species or ecosystem services Positive with gene drive; negative with population suppression; dependent on presence of transgene All population suppression gene drive transgenic strains
6 Reduction in densities of valued species or ecosystem services could be caused by their increased consumption by a predator. Transgenic has altered physiology, anatomy, or behaviour; population suppression; changes in predator-prey interactions Indirect: Reduced density of valued species or ecosystem services Positive with gene drive; positive with population suppression; independent of presence of transgene in some circumstances All population suppression gene drive transgenic strains, but potentially applicable any other successful gene drive transgenic strains
7 Upon population suppression of Anopheles gambiae via gene drive, its niche could be occupied by competitor species that could cause suppression of a valued species to affect ecosystem services. Changes in competitive interactions Indirect: Reduced density of valued species or ecosystem services Positive with gene drive; positive with population suppression; independent of presence of transgene All population suppression gene drive transgenic strains, but potentially applicable any other successful vector control approaches
8 Potential reductions in densities of valued species or ecosystem servicers due to poor nutrient composition of aquatic habitats could be caused by potentially increased dsxFCRISPRh transgenic larval mortality. Fitness costs in transgenic Indirect: Reduced density of valued species or ecosystem services Positive with gene drive; negative with population suppression; dependent on presence of transgene Gene drive transgenic strains
Water quality 9 Potential adverse impact on quality of water, and its flora and fauna, from reduced nutrient composition of aquatic habitats could be caused by potential toxicity of dsxFCRISPRh transgenic products. Fitness costs in transgenic; transgenic contains toxin or allergen. Indirect: Toxic water quality for NTOs Positive with gene drive; negative with population suppression; dependent on presence of transgene All transgenic strains
10 Potential adverse impact on drinking water in aquatic habitats could be caused by potentially higher mortality of dsxFCRISPRh transgenic larvae. Fitness costs in transgenic Indirect: Reduced water quality for humans and livestock Positive with gene drive; negative with population suppression; dependent on presence of transgene All transgenic strains
Human health 11 Transgenic proteins could cause specific allergic or toxicological responses in humans from dsxFCRISPRh transgenic bites beyond responses to non-transgenic bites. Transgenic contains toxin or allergen Direct: Increased allergic or immune responses in humans; increased toxicity in humans Independent of efficacy of gene drive or population suppression as defined by allergic responses in individual humans; dependent on presence of transgene All transgenic strains
12 Potential incidental ingestion or inhalation of dsxFCRISPRh transgenic material could cause specific allergic responses in humans beyond responses to non-transgenic material. Transgenic contains toxin or allergen Direct: Increased allergic or immune responses in humans Independent of efficacy of gene drive or population suppression as defined by allergic responses in individual humans; dependent on presence of transgene All transgenic strains
13 Increased allergenicity in humans could occur from potentially altered levels of endogenous allergens in dsxFCRISPRh transgenics. Transgenic contains toxin or allergen Direct: Increased allergic or immune responses in humans Independent of efficacy of gene drive or population suppression as defined by allergic responses in individual humans; dependent on presence of transgene All transgenic strains
14 Potentially decreased mosquito defence response to pathogen in dsxFCRISPRh transgenics from altered levels of endogenous RNA, protein or microbiome could lead to increased human disease. Transgenic has altered physiology, anatomy, or behaviour; increased vector competence in transgenic Direct: Increased disease transmission in humans Positive with gene drive; negative with population suppression; dependent on presence of transgene Arises from specific anatomical alterations in homozygous dsxFCRISPRh transgenics but could be applicable to other transgenic strains
15 Potentially decreased human defence response to pathogen from altered levels of endogenous RNA or protein in the saliva dsxFCRISPRh transgenics could lead to increased disease in humans. Transgenic has altered physiology, anatomy, or behaviour Direct: Increased disease transmission in humans Positive with gene drive; negative with population suppression; dependent on presence of transgene Arises from specific anatomical alterations in homozygous dsxFCRISPRh transgenics but could be applicable to other transgenic strains
16 Potential immunopathological responses via biting exposure to gRNA expressed in saliva of dsxFCRISPRh transgenic could lead to increases in morbidity and mortality in humans. Transgenic has altered physiology, anatomy, or behaviour Direct: Increased allergic or immune responses in humans Independent of efficacy of gene drive or population suppression as defined by allergic responses in individual humans; dependent on presence of transgene All CRISPR-Cas9-based transgenic strains
17 Potential secondary toxicological effects in humans from consuming NTOs which would have fed on dsxFCRISPRh transgenics. Transgenic contains toxin or allergen Indirect: Increased toxicity in humans Positive with gene drive; negative with population suppression; dependent on presence of transgene All transgenic strains
18 Potentially increased fitness, including insecticide resistance, of dsxFCRISPRh transgenics could increase disease transmission in humans. Transgenic has altered physiology, anatomy, or behaviour; increased fitness in transgenic Direct: Increased disease transmission in humans Positive with gene drive; negative with population suppression; dependent on presence of transgene All transgenic strains
19 Potentially increased biting rate of dsxFCRISPRh transgenics could increase disease transmission in humans. Transgenic has altered physiology, anatomy, or behaviour; increased biting rates Direct: Increased disease transmission in humans Positive with gene drive; negative with population suppression; dependent on presence of transgene Arises from specific anatomical alterations in homozygous dsxFCRISPRh transgenics but could be applicable to other transgenic strains
20 Potentially increased vector competence in dsxFCRISPRh transgenics could increase disease transmission in humans. Transgenic has altered physiology, anatomy, or behaviour; increased vector competence in transgenic Direct: Increased disease transmission in humans Positive with gene drive; negative with population suppression; dependent on presence of transgene All transgenic strains
21 Potentially altered anatomy, or host-seeking behaviour, in dsxFCRISPRh transgenics could increase the transmission of human diseases, including lymphatic filariasis. Transgenic has altered physiology, anatomy, or behaviour; increased vector competence in transgenic; increased biting rates Direct: Increased disease transmission in humans Positive with gene drive; negative with population suppression; dependent on presence of transgene Arises from specific anatomical alterations in homozygous dsxFCRISPRh transgenics but could be applicable to other transgenic strains
22 Potentially altered anatomy in dsxFCRISPRh transgenics could lead them to vector human disease not previously-vectored by Anopheles gambiae. Transgenic has altered physiology, anatomy, or behaviour; increased vector competence in transgenic Direct: Novel disease transmission in humans Positive with gene drive; negative with population suppression; dependent on presence of transgene Arises from specific anatomical alterations in homozygous dsxFCRISPRh transgenics but could be applicable to other transgenic strains
23 Potentially altered physiology in dsxFCRISPRh transgenics could increase disease transmission in humans. Transgenic has altered physiology, anatomy, or behaviour; increased vector competence in transgenic Direct: Increased disease transmission in humans Positive with gene drive; negative with population suppression; dependent on presence of transgene Arises from specific anatomical alterations in homozygous dsxFCRISPRh transgenics but could be applicable to other transgenic strains
24 Potentially altered physiology in dsxFCRISPRh transgenic could lead them to vector human disease not previously-vectored by Anopheles gambiae. Transgenic has altered physiology, anatomy, or behaviour; increased vector competence in transgenic Direct: Novel disease transmission in humans Positive with gene drive; negative with population suppression; dependent on presence of transgene Arises from specific anatomical alterations in homozygous dsxFCRISPRh transgenics but could be applicable to other transgenic strains
25 Potentially cumulative Cas9/gRNA off-target or retargeted nuclease activity in dsxFCRISPRh transgenics could cause heritable increase in insecticide resistance, fitness or vector competence to increase human disease. Off-target or re-targeted mutations; transgenic has altered physiology, anatomy, or behaviour; increased vector competence in transgenic; increased fitness in transgenic Direct: Increased disease transmission in humans Positive with gene drive; negative with population suppression; independent of presence of transgene All CRISPR-Cas9-based transgenic strains
26 Potentially broader tolerances for humidity, temperature, salinity, or desiccation in dsxFCRISPRh transgenic could lead to increased disease transmission in humans. Transgenic has altered physiology, anatomy, or behaviour; increased transgenic fitness Direct: Increased disease transmission in humans Positive with gene drive; negative with population suppression; dependent on presence of transgene All transgenic strains
27 Increased or novel human disease transmission could be caused by replacement of Anopheles gambiae niche with another disease vector. Population suppression; changes in competitive interactions Indirect: Increased disease transmission in humans Positive with gene drive; positive with population suppression; independent of presence of transgene All population suppression gene drive transgenic strains, but potentially applicable to any other successful vector control approaches
28 Potential toxicological effects of dsxFCRISPRh transgenics on NTOs could increase disease transmission in humans. Transgenic contains toxin or allergen Indirect: increased disease transmission in humans Positive with gene drive; negative with population suppression; dependent on presence of transgene All transgenic strains
29 Potentially reduced density of a predator species caused by population suppression of Anopheles gambiae could lead to increases in density of another human disease vector species. Population suppression; changes in predator-prey interactions Indirect: increased disease transmission in humans Positive with gene drive; positive with population suppression; independent of presence of transgene All population suppression gene drive transgenic strains, but potentially applicable to any other successful vector control approaches
30 Potential increases in disease levels beyond those pre-gene drive intervention following a resurgence in pathogen transmission after initial population suppression would have reduced human immunity to pathogen. Population suppression; changes in herd immunity Indirect: Increased disease transmission in humans Positive with gene drive; positive with population suppression; independent of presence of transgene All population suppression gene drive transgenic strains, but potentially applicable to any other successful vector control approaches
Animal health 31 Potential toxicity in livestock from dsxFCRISPRh transgenic proteins in saliva. Transgenic contains toxin or allergen Direct: Increased toxicity in livestock Positive with gene drive; negative with population suppression; dependent on presence of transgene All transgenic strains
32 Potentially decreased mosquito defence response to pathogen in dsxFCRISPRh transgenics from altered levels of endogenous RNA, protein or microbiome could lead to increased disease in livestock. Transgenic has altered physiology, anatomy, or behaviour; increased vector competence in transgenic Direct: Increased disease transmission in livestock Positive with gene drive; negative with population suppression; dependent on presence of transgene Arises from specific anatomical alterations in homozygous dsxFCRISPRh transgenics but could be applicable to other transgenic strains
33 Potentially decreased livestock defence response to pathogen from altered levels of endogenous RNA or protein in saliva of dsxFCRISPRh transgenics could lead to increased disease in livestock. Transgenic has altered physiology, anatomy, or behaviour Direct: Increased disease transmission in livestock Positive with gene drive; negative with population suppression; dependent on presence of transgene Arises from specific anatomical alterations in homozygous dsxFCRISPRh transgenics but could be applicable to other transgenic strains
34 Potentially increased fitness, including insecticide resistance, of dsxFCRISPRh transgenic could increase disease transmission in livestock. Transgenic has altered physiology, anatomy, or behaviour; increased fitness in transgenic Direct: Increased disease transmission in livestock Positive with gene drive; negative with population suppression; dependent on presence of transgene All transgenic strains
35 Potentially increased biting rate of dsxFCRISPRh transgenic could increase disease transmission in livestock. Transgenic has altered physiology, anatomy, or behaviour; increased biting rates Direct: Increased disease transmission in livestock Positive with gene drive; negative with population suppression; dependent on presence of transgene Arises from specific anatomical alterations in homozygous dsxFCRISPRh transgenics but could be applicable to other transgenic strains
36 Potentially increased vector competence of dsxFCRISPRh transgenic could increase disease transmission in livestock. Transgenic has altered physiology, anatomy, or behaviour; increased vector competence in transgenic Direct: Increased disease transmission in livestock Positive with gene drive;
negative with population suppression;
dependent on presence of transgene
All transgenic strains
37 Potentially altered anatomy, or host-seeking behaviour, in dsxFCRISPRh transgenic could increase disease transmission in livestock. Transgenic has altered physiology, anatomy, or behaviour; increased vector competence in transgenic; increased biting rates Direct: Increased disease transmission in livestock Positive with gene drive; negative with population suppression; dependent on presence of transgene Arises from specific anatomical alterations in homozygous dsxFCRISPRh transgenics but could be applicable to other transgenic strains
38 Potentially altered anatomy in dsxFCRISPRh transgenic could lead it to vector livestock animal disease not previously-vectored by Anopheles gambiae. Transgenic has altered physiology, anatomy, or behaviour; increased vector competence in transgenic; increased biting rates Direct: Novel disease transmission in livestock Positive with gene drive; negative with population suppression; dependent on presence of transgene Arises from specific anatomical alterations in homozygous dsxFCRISPRh transgenics but could be applicable to other transgenic strains
39 Potentially altered physiology in dsxFCRISPRh transgenic could increase disease transmission in livestock. Transgenic has altered physiology, anatomy, or behaviour; increased vector competence in transgenic Direct: Increased disease transmission in livestock Positive with gene drive; negative with population suppression; dependent on presence of transgene Arises from specific anatomical alterations in homozygous dsxFCRISPRh transgenics but could be applicable to other transgenic strains
40 Potentially altered physiology in dsxFCRISPRh transgenic could lead it to vector animal disease not previously-vectored by Anopheles gambiae. Transgenic has altered physiology, anatomy, or behaviour; increased vector competence in transgenic Direct: Novel disease transmission in livestock Positive with gene drive; negative with population suppression; dependent on presence of transgene Arises from specific anatomical alterations in homozygous dsxFCRISPRh transgenics but could be applicable to other transgenic strains
41 Potentially cumulative Cas9/gRNA off-target or retargeted nuclease activity in dsxFCRISPRh transgenic could cause increase in insecticide resistance, fitness or vector competence to increase disease transmission in livestock. Off-target or re-targeted mutations; transgenic has altered physiology, anatomy, or behaviour; increased fitness in transgenic; increased vector competence in transgenic Direct: Increased disease transmission in livestock Positive with gene drive; negative with population suppression; independent of presence of transgene All CRISPR-Cas9-based transgenic strains
42 Potentially broader tolerances for humidity, temperature, salinity, or desiccation in dsxFCRISPRh transgenics could lead to increased disease transmission in livestock. Transgenic has altered physiology, anatomy, or behaviour; increased fitness in transgenic Direct: Increased disease transmission in livestock Positive with gene drive; negative with population suppression; dependent on presence of transgene All transgenic strains
43 Increased or novel disease transmission in livestock animals could be caused by replacement of Anopheles gambiae niche with another disease vector. Population suppression: changes in competitive interactions Indirect: Increased disease transmission in livestock Positive with gene drive; positive with population suppression; independent of presence of transgene All population suppression gene drive transgenic strains, but potentially applicable to any other successful vector control approaches
44 Potential toxicological effects of dsxFCRISPRh transgenics on NTOs could increase disease transmission in livestock. Transgenic contains toxin or allergen Indirect: Increased disease transmission in livestock Positive with gene drive; negative with population suppression; dependent on presence of transgene All transgenic strains
45 Reduced density of a predator species that could be caused by population suppression of Anopheles gambiae could lead to increases in density of another animal disease vector species. Population suppression: changes in predator-prey interactions Indirect: Increased disease transmission in livestock Positive with gene drive; positive with population suppression; independent of presence of transgene All population suppression gene drive transgenic strains, but potentially applicable to any other successful vector control approaches
46 Potential increases in livestock disease beyond pre-gene drive intervention levels following resurgence in pathogen transmission after initial population suppression would have reduced livestock immunity to pathogen. Population suppression: changes in herd immunity Indirect: Increased disease transmission in livestock Positive with gene drive; positive with population suppression; independent of presence of transgene All population suppression gene drive transgenic strains, but potentially applicable to any other successful vector control approaches
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