Annex 1
Examples of plants falling under excluded categories,
based upon scientific publications or regulatory files accessible in public databases
These examples are taken from the literature or from regulatory files. We tried to find, from available public information, the origin of the model alleles. Thus, for each example, and when available, the first reference discloses the edited plant and the other references describe the probable origin of the model alleles. Except for the plants already marketed in North America, these examples do not prejudge the fate of these edited plants and their commercial opportunities.
Methodology and criteria used:
- The example must describe an edited plant that has been achieved;
- For the examples of Categories 1 and 2, a model allele is identified in a plant that is sexually compatible (Category 1) or non-sexually compatible (Category 2);
- For the examples of Category 3, information is provided on the approaches used to obtain the edited gene, including results in transgenic plants (RNAi experiments for example);
- For category 4, information is provided on the inserted gene;
- For the edited plants we tried to use the original publication; for the model alleles we sought to find them in the publications cited by the inventors of the edited plant.
Category 1:
- An edited, salt-tolerant rice plant, following inactivation of the OsRR22 gene (known allele). Zhang et al., 2019; Takagi et al., 2015.
- A potato plant edited by inactivating the StGBSSI gene (known allele), leading to the accumulation of amylopectin (waxy starch) in the tuber. Based on the availability of potato mutants rich in amylopectin and on knowledge of the synthesis of amylopectin in cassava, corn and wheat. Veillet et al., 2019; Hovenkamp-Hermelink et al., 1987.
- A rice plant in which the promoter of three genes coding for sucrose transporters, SWEET11, SWEET13 and SWEET14 has been edited (modification of nucleotides) to no longer be sensitive to the transcription factor produced by Xanthomonas oryzae pv. Oryzae. There are rice mutants for these genes; several have been associated in this edited plant. Oliva et al., 2019; Zaka et al., 2018.
- A pink-fruited tomato plant following inactivation of the SlMYB12 gene (known allele). Deng et al., 2018; Fernandez-Moreno et al., 2016.
- A maize plant tolerant to Setosphaeria turcica (Helminthosporium turcicum) following the replacement, by edition, of the sensitive allele of the NLB 18 gene coding for a membrane kinase and responsible for the interaction with the fungus by the resistant allele identified in a corn tolerant to this fungus (known allele). Schmidt 2018; Hurni et al., 2015; Li & Wilson 2006.
- A maize plant accumulating only amylopectin in the seed following inactivation of the waxy (Wx1) gene coding for the Granule Bound Starch Synthase (GBSS) (known allele). Based upon the waxy maize mutant which has been marketed for many years. Schmidt 2016.
- A soybean plant with a high oleic acid content following inactivation of two fatty acid desaturase genes (FAD2-1A and FA D2-1B) (known alleles). Haun et al., 2014; Pham et al., 2010.
- A rapeseed plant edited to be tolerant to imidazolinone and sulfonylurea herbicide families by modifying a single nucleotide of the BnAHAS1 gene in Genome C and a single nucleotide of the BnAHAS3 gene in Genome A of Brassica Napus. https://www.inspection.gc.ca/plant-health/plants-with-novel-traits/approved-under-review/decision-documents/dd-2013-100/eng/1427383332253/1427383674669; https://www.canada.ca/en/health-canada/services/food-nutrition/genetically-modified-foods-other-novel-foods/approved-products/novel-food-information-cibus-canola-event-5715-imidazolinone-sulfonylurea-herbicide-tolerant.html. Many mutants of this enzyme are known to exist in rapeseed, conferring tolerance to sulfonylureas. Magha et al., 1993.
Category 2:
- A tomato plant whose gene SlJAZ2, orthologue of the AtJAZ2 gene of Arabidopsis, has been edited (modification of the nucleotide sequence) to reproduce the dominant mutant version of Arabidopsis (absence of the C-terminal - jas motif) to obtain the resistance to bacterial spot disease (Pseudomonas syringae pv. tomato (Pto) DC3000). This modified receptor, SlJAZ2Δjas, no longer fixes the coronatine synthesized by the bacteria and as a resultthe stomata do not open. Ortigosa et al., 2019; Gimenez-Ibanez et al., 2017.
- An edited grape cultivar in which (i) the Mlo gene has been suppressed to obtain powdery mildew resistance and (ii) the VvDMR6 gene has been suppressed based upon knowledge of the suppression of the analogous gene in Arabidopsis thaliana resulting in downy mildew resistance. Giacomelli et al., 2019; van Damme et al., 2008.
- A cassava plant resistant to potyvirus [Cassava brown streak disease (CBSD)] obtained by editing (modification of the nucleotide sequence) of the gene coding for the translation initiation factor elF4E. Many isoforms of this factor giving potyvirus resistance are known in many plants: chilli, tomato, pea, Arabidopsis mutants. Gomez et al., 2019; Bastet et al. 2019.
- An edited wheat plant in which the three genes corresponding to the Mildew resistance Locus (Mlo) called TaMlo‐A1, TaMlo‐B1 and TaMlo‐D1, located on chromosomes 5AL, 4BL and 4DL, are simultaneously inactivated to reproduce a phenotype resistant to powdery mildew, based upon the knowledge of Mlo alleles naturally present in barley. Wang et al., 2014; Büschges et al., 1997.
Category 3:
- An apple cultivar where the MdDIPM4 gene (a kinase receptor) is inactivated by editing to obtain resistance to scab (Erwinia amylovora). By analogy with Arabidopsis mutants and studies of receptor interaction with the bacterium effector (DspA / E) a sequence of MdDIPM4 was deleted in the apple gene. Pompili et al., 2019; Degrave et al., 2013; Borejsza-Wysocka et al., 2004.
- A petunia plant with prolonged flowering by inactivation of the Ph ACO1 gene which codes for a 1-aminocyclopropane-1-carboxylate oxidase involved in the production of ethylene (reduced quantity in the edited plant). By analogy with the results obtained by expressing antisense in petunia. Xu et al., 2019; Huang et al., 2007.
- A durum wheat plant that has been edited to inactivate up to 35 of the 45 α-gliadin genes (known alleles) on three chromosomes, causing a reduction in the production of α-gliadins and a drop in immunoreactivity by 85%. Sanchez Leon et al., 2018.
- A tomato plant of which the promoter of the SlCLV3 allele (new allele) has been edited in order to increase fruit size. Rodriguez-Leal et al., 2017.
- In several citrus species, the promoter of the CsLOB1 gene (LATERAL ORGAN BOUNDARIES 1) has been edited by deletion of the sequence EBEPthA4 (which fixes the effector produced by the bacteria) conferring resistance to citrus canker [Xanthomonas citri subsp. citri (Xcc)]. Based on knowledge of the interactions between the promoter and the effector of the bacteria and on similar works on rice. Jia et al, 2016a (grapefruit tree); Jia et al., 2016b (lemon tree); Peng et al., 2017 (orange tree). In order for these edited plants to benefit from the exclusion provided by this Category 3, the recombinant DNA used for the editing will need to be removed (null segregants).
Category 4:
We did not find any plants that met the criteria for this category. There are many examples of plants containing one or more cisgenes (see two examples below), but none are the result of insertion at a site and homologous recombination. The cisgenes introduced into the plants described below were obtained by transgenesis. With genome editing, a cisgene may be inserted in a chosen site by double homologous recombination, without any residual vector sequence.
- A potato plant in which several mildew resistant genes identified exclusively in wild potato species have been inserted using Agrobacterium tumefaciens, selected on the criteria that (i) all R genes are expressed and (ii) conformity to the varietal type is maintained. Haverkort et al., 2016.
- An apple cultivar made resistant to scab by inserting the cisgene FB_MR5 from the wild variety Malus × robusta 5 (Mr5) in chromosome 16. Kost et al., 2015.
Examples of edited plants having alleles in different categories:
As indicated earlier in this Explanatory Note, the same edited plant may contain alleles which correspond to different categories. Two examples are presented below.
- A tomato plant that has been edited by inactivating (1) the SIER gene (which regulates tomato stem length), (2) the SP5G gene (linked to rapid flowering) and (3) the SP gene (linked to precocious growth termination), all three genes having known mutant alleles, to make it compact and early yielding, suitable for urban agriculture. This plant contains edited genes corresponding to Category 1 for the alleles of the SlER and SP genes and to Category 3 for the allele of the SP5G gene. Kwon et al. 2019; Xu et al., 2015; Soyk et al., 2017, and Menda et al., 2004.
- An edited cassava plant accumulating amylopectin (waxy starch) instead of amylose following inactivation of the PTST1 gene encoding the Protein Targeting to STarch and the GBSS1 gene encoding the Granule Bound Starch Synthase. Based on the availability of cassava mutants rich in amylopectin and knowledge of the synthesis of amylopectin in potatoes, corn and wheat. This plant contains two edited genes, the allele of the GBSS1 gene corresponds to Category 1 and the allele of the PTST1 gene to Category 3. Bull et al., 2018; Morante et al., 2016
References cited in the above examples:
Bastet et al. 2019. Mimicking natural polymorphism in eIF4E by CRISPR-Cas9 base editing is associated with resistance to potyviruses.
Plant Biotechnology Journal 17: 1736–1750- doi: 10.1111/pbi.13096
Borejsza-Wysocka et al., 2004. Silencing of apple proteins that interact with DspE, a pathogenicity effector from Erwinia amylovora, as a strategy to
increase resistance to fire blight. Acta Horticulturae 663: 469–474 - doi:10.17660/ActaHortic.2004.663.81
Bull et al., 2018. Accelerated ex situ breeding of GBSS- and PTST1-edited cassava for modified starch.
Science Advances 4:eaat6086 - doi.org/10.1126/sciad v.aat60 86
Büschges, R. et al., 1997. The barley Mlo gene: A novel control element of plant pathogen resistance.
Cell 88: 695–705.
Degrave et al., 2013. The bacterial effector DspA/E is toxic in Arabidopsis thaliana and is required for multiplication and survival of fire blight pathogen.
Molecular Plant Pathology 14: 506–517 - DOI: 10.1111/mpp.12022.
Deng et al., 2018. Efficient generation of pink-fruited tomatoes using CRISPR/Cas9 system.
Journal of Genetics and Genomics 45: 51-54 - doi.org/10.1016/j.jgg.2017.10.002.
Fernandez-Moreno et al. 2016. Characterization of a new pink-fruited tomato mutant results in the identification of a null allele of the SlMYB12.
Plant Physiology 171: 1821-1826.
Giacomelli et al., 2019. Generation of mildew-resistant grapevine clones via genome editing,
ISHS Acta Horticulturae 1248: XII International Conference on Grapevine Breeding and Genetics - DOI: 10.17660/ActaHortic.2019.1248.28.
Ibanez et al., 2017. JAZ2 controls stomata dynamics during bacterial invasion.
New Phytologist 213: 1378–1392 - doi: 10.1111/nph.14354.
Gomez et al., 2019. Simultaneous CRISPR/Cas9-mediated editing of cassava eIF4E isoforms nCBP-1 and nCBP-2 reduces cassava
brown streak disease symptom severity and incidence. Plant Biotechnology Journal 17: 421–434 - doi: 10.1111/pbi.1298.
Haun et al., 2014. Improved soybean oil quality by targeted mutagenesis of the fatty acid desaturase 2 gene family.
Plant Biotechnology Journal 12: 934–940 - doi: 10.1111/pbi.12201.
Haverkort et al., 2016. Durable Late Blight Resistance in Potato Through Dynamic Varieties Obtained by Cisgenesis: Scientific and
Societal Advances in the DuRPh Project. Potato Research - DOI 10.1007/s11540-015-9312-6.
Hovenkamp-Hermelink et al., 1987. Isolation of an amylose-free starch mutant of the potato (Solanum tuberosum L.).
Theoretical Applied Genetics 75: 217–221 - https ://doi.org/10.1007/bf002 49167.
Huang et al., 2007. Delayed flower senescence of Petunia hybrida plants transformed with antisense broccoli ACC synthase and
ACC oxidase genes. Postharvest Biol. Technol. 46: 47–53.
Hurni et al., 2015. The maize disease resistance gene Htn1 against northern corn leaf blight encodes a wall associated receptor-like
kinase. Proceedings of the National Academy of Sciences 112: 8780-8785 - doi/10.1073/pnas.1502522112.
Jia et al., 2016a. Modification of the PthA4 effector binding elements in Type I CsLOB1 promoter using Cas9/sgRNA to produce
transgenic Duncan grapefruit alleviating XccDpthA4:dCsLOB1.3 infection. Plant Biotechnol. J. 14, 1291–1301.
Jia et al., 2016b. Genome editing of the disease susceptibility gene CsLOB1 in citrus confers resistance to citrus canker.
Plant Biotechnol. J., doi.org/10.1111/pbi.12677.
Kwon et al., 2019. Rapid customization of Solanaceae fruits crops for urban agriculture.
Nature Biotechnology - doi.org/10.1038/s41587-019-0361-2.
Kost et al., 2015. Development of the first cisgenic apple with Increased Resistance to Fire Blight.
PLoS ONE, 10, e0143980 - DOI:10.1371/journal.pone.0143980.
Li & Wilson, 2006. Composition and methods for enhancing resistance to northern leaf blight in maize.
World Intellectual Property Organization, Application No. PCT/US2011/041822.
Magha et al., 1993. Characterization of a spontaneous rapeseed mutant tolerant to sulfonylurea and imidazolinone herbicides.
Plant Breeding 111: 131-141.
Menda et al., 2004. In silico screening of a saturated mutation library of tomato.
Plant Journal 38: 861–872.
Morante et al., 2016. Discovery of new spontaneous sources of amylose-free cassava starch and analysis of their structure and
techno-functional properties. Food Colloids 56: 303-395 - doi.org/10.1016/j.foodhyd.2015.12.025.
Oliva et al., 2019. Broad-spectrum resistance to bacterial blight in rice using genome editing.
Nature Biotechnology 37: 1344-1350.
Ortigosa et al., 2019. Design of a bacterial speck resistant tomato by CRISPR/Cas9-mediated editing of SlJAZ2.
Plant Biotechnology Journal 17: 665–673 - doi: 10.1111/pbi.13006.
Peng et al., 2017. Engineering canker-resistant plants through CRISPR/Cas9-targeted editing of the susceptibility gene CsLOB1
promoter in citrus, Plant Biotechnology Journal 15: 1509–1519 - doi: 10.1111/pbi.12733.
Pham et al., 2010. Mutant alleles of FAD2-1A and FAD-1B combine to produce soybeans with the high oleic acid seed oil trait.
BMC Plant Biology 10: 195-206 - biomedcentral.com/1471-2229/10/195.
Pompili et al., 2019. Reduced fire blight susceptibility in apple cultivars using a high-efficiency CRISPR/Cas9-FLP/FRT-based gene
editing system. Plant Biotechnology Journal - doi: 10.1111/pbi.13253.
Rodriguez-Leal et al., 2017. Engineering Quantitative Trait Variation for Crop Improvement by Genome Editing,
Cell 171, 470–480, http://dx.doi.org/10.1016/j.cell.2017.08.030.
Sanchez Leon et al., 2018. Low-gluten, non-transgenic wheat engineered with CRISPR-Cas9.
Plant Biotechnology Journal 16: 902–910 - doi: 10.1111/pbi.12837.
Schmidt 2016. Corn with high content of amylopectin developed by CRISPR/Cas technology. 15-352-01_air_inquiry_cbidel Pioneer.
https://www.aphis.usda.gov/aphis/ourfocus/biotechnology/am-i-regulated/regulated_article_letters_of_inquiry/regulated_article_letters_of_inquiry.
Schmidt 2018. Corn with Improved Resistance to Northern Leaf Blight developed by CRISPR-Cas technology. 17-076-
018_air_inquiry_a1_cbidel revised Pioneer, https://www.aphis.usda.gov/aphis/ourfocus/biotechnology/am-i-regulated/regulated_article_letters_of_inquiry/regulated_article_letters_of_inquiry.
Soyk et al., 2017. Variation in the flowering gene SELF PRUNING 5G promotes day-neutrality and early yield in tomato.
Nature Genetics 49: 162–168.
Takagi et al., 2015. MutMap accelerates breeding of a salt-tolerant rice cultivar.
Nature Biotechnology 33: 445–449.
van Damme et al., 2008. Arabidopsis DMR6 encodes a putative 2OG-Fe(II) oxygenase that is defense-associated but required for
susceptibility to downy mildew. The Plant Journal 54:785-793 -. doi: 10.1111/j.1365-313X.2008.03427.x.
Veillet et al., 2019. The Solanum tuberosum GBSSI gene: a target for assessing gene and base editing in tetraploid potato,
Plant Cell Reports 38:1065–1080, https://doi.org/10.1007/s00299-019-02426-w
Wang et al., 2014. Simultaneous editing of three homoeoalleles in hexaploid bread wheat confers heritable resistance to powdery
mildew. Nature Biotechnology 32: 947-952 - doi:10.1038/nbt.2969.
Xu et al., 2020. CRISPR/Cas9-mediated editing of 1-aminocyclopropane-1-carboxylate oxidase1 enhances Petunia flower longevity.
Plant Biotechnology Journal 18: 287-297 - doi: 10.1111/pbi.13197.
Xu et al., 2015. A cascade of arabinosyltransferases controls shoot meristem size in tomato.
Nature Genet. 47, 784–792.
Zaka et al., 2018. Natural variations in the promoter of OsSWEET13 and OsSWEET14 expand the range of resistance against
Xanthomonas oryzae pv. PLoS ONE 13(9): e0203711 - doi.org/10.1371/journal.pone.0203711.
Zhang et al., 2019. Enhanced rice salinity tolerance via CRISPR/Cas9-targeted mutagenesis of the OsRR22 gene.
Mol Breeding 39: 47-56 - doi.org/10.1007/s11032-019-0954-y.
A few published reviews - For additional information on the production of plants by genome editing:
Chen et al., 2019. CRISPR/Cas genome editing and precision plant breeding in Agriculture.
Annual Review of Plant Biology 70: 28.1-28.31 – doi.org/10.1146/annurev-arplant-050718-100049.
Jaganathan et al., 2018. CRISPR for crop improvement. An update review.
Frontiers in Plant Science - doi:10.3389/fpls.2018.00985
Metje et al., 2020. Genome edited plants in the field.
Current Opinion in Biotechnology 61: 1-6 - doi.org/10.1016/j.copbio.2019.08.007.
Modrzejewski et al., 2019. Environmental Evidence - What is available evidence for the range of application of genome-editing as a
new tool? Environmental Evidence 8- https://doi.org/10.1186/s13750-019-0171-5.
Sharma et al., 2019. Recent advances in developing disease resistance in plants,
F1000Research, 8(F1000 Faculty Rev):1934 Last updated: 19 NOV 2019, doi.org/10.12688/f1000research.20179.1.
Soda et al., 2018. CRISPR-Cas9 based plant genome editing: significance, opportunities and recent advances.
Plant Physiology and Biochemistry 131: 2-11 – dx.doi.org/10.1016/j.plaphy.2017.10.024.
Zhang et al., 2018. Applications and potential of genome editing in crop improvement.
Genome Biology 19: 210-XXX – doi.org/10.1186/s13059-018-1586-y.